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The Catholic Health Association amoxil best buy on Friday joined the growing chorus of prominent healthcare associations and health systems supporting or implementing employee buy antibiotics vaccination mandates. CHA said it "strongly supports" member health systems as they take necessary steps toward amoxil best buy ensuring as many healthcare workers get vaccinated as possible. The organization's announcement comes after dozens of providers and several associations have backed treatment mandates for healthcare workers. "The alarming rise in buy antibiotics cases over the past several amoxil best buy weeks due to the delta variant and treatment hesitancy is a stark reminder of the serious health threat the amoxil poses, particularly for the elderly and individuals with underlying medical conditions," Sister Mary Haddad, CHA's CEO, said in a statement. "The escalation in buy antibiotics cases also threatens our ability to be in communion with one another.

Attending family amoxil best buy gatherings, visiting friends and worshiping together safely are all critically important to our individual and collective well-being."States with the highest buy antibiotics spikes in recent weeks are also those with the lowest vaccination rates, data from Johns Hopkins University's antibiotics Tracking Center show. The American Hospital Association on Wednesday announced it supports hospitals and health systems that are requiring buy antibiotics treatments for their employees. The AHA amoxil best buy represents almost 5,000 hospitals and health systems. The Association of American Medical Colleges last week urged its member medical schools and teaching hospitals to require their workers get vaccinated. Individual healthcare providers have announced their own mandates, too, including Atrium Health, based in Charlotte, N.C., Trinity Health in Livonia, Mich., amoxil best buy and Boston's Mass General Brigham.

The CHA's Haddad continued that the high level of treatment amoxil best buy hesitancy creates the potential need to reinstate restrictions to stem the spread of the amoxil. "By accepting the treatment, Catholic healthcare professionals working in hospitals, clinics, long-term care facilities and in the community give witness to Christ's call to love one another," she said. CHA's membership includes more than 600 hospitals and 1,600 long-term care and other healthcare facilities.Updated data from CMS amoxil best buy shows only 59% of staff at U.S. Nursing homes and other long-term care facilities are fully or partially vaccinated, even seven months after the first treatments became available to medical providers.Rachel Norton has been a critical care nurse for 14 years. She's worked as a staff nurse at a amoxil best buy hospital, as a flight nurse and, currently on an as-needed basis for a system in Denver.

And every so often, she takes on travel nursing assignments, sometimes spending a month at a new hospital when there's a need. Norton's flexible nursing career is one that's become more amoxil best buy common in the past year as staff nurses have taken lucrative travel nursing contracts, reduced their hours or left the workforce altogether from burnout or for early retirement. And nurses aren't alone. Across the amoxil best buy healthcare industry, healthcare providers are clamoring for workers. Jobs numbers for the sector fell again in June, in a rollercoaster of peaks and dips over more than a amoxil best buy year that has yet to fully recover from the massive losses early in the buy antibiotics amoxil.

And, while hospitals and other providers have seen some recovery, nursing homes have been on a nearly steady downward trend since 2020. "Everybody is looking for caregivers," said Namrata Yocom-Jan, president of Seniors Helping Seniors, an in-home care franchise that is trying to fill more than 1,000 caregiver jobs across the amoxil best buy country. "I think the caregiver shortage has been front and center in home care for the better part of five years now. It certainly also has been exacerbated by buy antibiotics." amoxil best buy Nationwide, providers like Seniors Helping Seniors are offering hiring incentives and, in some cases, retention or referral bonuses to attract and retain staff and address a workforce shortage the American Health Care Association and National Center for Assisted Living is calling "a legitimate crisis."Incentivizing workersAt Seniors Helping Seniors, which has more than 100 franchise partners in 30 states, franchisees are offering workers a sign-on bonus of $100 to $500, with a percentage of that bonus being donated directly to the Alzheimer's Association. The idea is attract workers but also bring in people who want to help charity, said Seniors Helping Seniors COO Daniel Jan."There are other companies providing bonuses but there are no companies that provide a greater good component to the recruiting bonus.

I think what that's going to allow us to do is recruit a different amoxil best buy kind of individual," Daniel Jan said. For Seniors Helping Seniors caregivers, the hourly rate averages $12-13, which is an increase of about $1.50 over the past year. Raising salaries usually means raising rates amoxil best buy to clients though, so it's a balance to maintain margins, Daniel Jan said."Because caregivers are so vital to our seniors, we want to make sure they're compensated well. But we also have to make sure we're making a margin as well," he said. Nebraska Medicine is offering undisclosed amoxil best buy bonuses to roles it calls "critical talent." These are positions the system has trouble recruiting for and where it has shortages, such as emergency department nurses, medical assistants and certified nursing assistants, said Frank Venuto, chief human capital officer at Nebraska Health.

"To compete, we had to offer hiring bonuses," Venuto said amoxil best buy. While bonuses are nothing new to attract for high-demand roles, the number of bonuses and the price tag on those incentives is higher, Venuto said. "The reality is we need to appropriately staff our patient care units and other areas within the organization," Venuto amoxil best buy said. "It does eat at our margins. We know that, and we plan for it amoxil best buy.

That's why we're driving for cost efficiencies in other areas so we can afford the labor costs."The system constantly works to build its pipeline of new talent, Venuto said. Nebraska Health offers scholarship opportunities for those in minority communities and will directly help pay off a student's debt amoxil best buy if they work for the system. DCH Health System in West Alabama is offering $15,000 signing bonuses to nurses in med surge and the emergency department, as well some hiring bonuses to nurses in critical care and women's services, who commit to working full-time at one of the system's two largest facilities for a year. The program started in the spring amoxil best buy and already has encouraged students who won't graduate until 2022 to sign on. DCH Health has offered bonuses before but never as high, said Lori Royer amoxil best buy Sommers, human resources director of compensation, employment and workforce development for DCH Health."This is the largest amount we've done for a one-year period," Royer Summers said.

"I think what happened during buy antibiotics is a lot of nurses left to travel. We're hoping amoxil best buy bonuses help."The system, too, is offering $6,000 bonuses to employees who refer full-time registered nurses. Norton, who also works with Vivian Health, a job marketplace for healthcare workers, said some hospitals in her area are offering as high as $25,000 signing bonuses to potential employees, while others are providing new hires with medical benefits on their first day on the job. "I think the sign-on bonuses are a really great way to attract staff, especially if there are staff in the area," Norton said amoxil best buy. "I would like to see hospitals offer at least a portion of it to the highly experienced nurses with no strings attached."Bonuses that come with time commitments can sometimes be seen as a red flag to nurses who worry they will be trapped in a workplace with a staffing shortage, Norton said.

"Are you going to get there and be super short amoxil best buy staffed?. Those are he types of things that make you want to leave a place," Norton said. For many nurses, workplace culture can matter more amoxil best buy than a one-time bonus, she said. "That's a struggle nationwide for hospitals, especially as we come out of the amoxil. Nurses have left amoxil best buy the bedside because they're burnt out.

It's almost like no amount of money could amoxil best buy entice them back to the workplace," Norton said. An added benefitDavid Coppins, co-founder and CEO of IntelyCare, a workforce management solution for post-acute facilities, said employers can't rely on one-time bonuses to retain workers. "Instead, they should listen to employees and amoxil best buy provide them with meaningful benefits while paying them what they deserve," Coppins said. "Making this kind of investment can go a long way to ensure that workers feel protected and appreciated."Nurses have told IntelyCare they want increased health and malpractice insurance, retirement plans, wellness services, childcare discounts,and help with necessities like groceries, Coppins said. Some companies, like home healthcare startup Papa, are trying to offer amoxil best buy other benefits to get workers to join their ranks.

Papa introduced a hybrid office at its Miami headquarters, provides paid parental leave, offers a 401K match and gives workers a monthly lunch stipend and a Spotify account. The company is looking to add another 400 employees to its workforce by the end of the year amoxil best buy. "We think beyond hourly rates. We really think about earnings," said Papa CEO and founder Andrew Parker.Healthcare providers are finding new ways to adequately staff facilities in response to escalating costs for travel nurses and rising buy antibiotics cases.The high demand for nurses has created a competitive market for temporary staffing, leading some healthcare companies to leverage internal resources and change up existing staff structures to meet patients' needs.The resurgence of the antibiotics amoxil driven by the Delta variant, especially in states with low vaccination rates, is burdening providers whose staffing shortages have worsened just as amoxil best buy demand spikes. States including Arizona, Arkansas, Missouri and Texas are enduring significant increases in daily cases, hospitalizations and deaths, triggering an urgent need for healthcare professionals.Those practitioners can command higher wages as a result.

Nurse pay rose five-fold during the most competitive period in that labor market during the amoxil, said Betty Jo Rocchio, senior vice president and chief nursing officer at Mercy Northwest Hospital in Rogers, Arkansas.Hospitals can control amoxil best buy the cost of temporary staffing by monitoring local and regional buy antibiotics statistics and hospital-specific workforce trends, said Blaine Douglas, managing principal at Vizient. "It is amoxil best buy also important to have a partner in place to speed up the process for adding staff when the need arises, with flexibility around requirements that do not compromise patient safety," he said.Mercy Hospital takes a regional approach to staffing, floating its nurses between communities to address needs when they arise and to provide expertise in specific areas, Rocchio said. Mercy aligns the hours of highest patient with the hours its nurses are on site, she said.The hospital supplements its workforce through agency partners that bring in nurses with critical specialties, such those with experience in emergency medicine and intensive care and those who have treated buy antibiotics patients, Rocchio said. A large contingent of recent nursing school graduates also provided a staffing boost, she said.While many healthcare providers thought the cost and difficulty hiring clinical staff would diminish as the amoxil projects, they now anticipate the situation will not change until well into next year, amoxil best buy said Beth Feldpush, senior vice president of policy and advocacy at America's Essential Hospitals. The trade group for safety-net hospitals continues to push President Joe Biden's administration to distribute leftover relief funds to help providers afford adequate staffing, she said.Hospitals must be flexible and agile to function effectively during public health emergencies when it comes to mobilizing, reassigning, and recruiting workers, said Tener Goodwin Veenema, a contributing scholar at the Johns Hopkins Center for Health Security.New approaches to hiring and staffing can also save hospitals money, Veenema said.

The amoxil has shown retaining the existing workforce with better salary and benefits amoxil best buy is more cost-effective than relying on traveling nurses, she said."If the amoxil taught employers anything, it would be to value their workers," David Coppins, co-founder and CEO of IntelyCare, a Quincy, Massachusetts-based healthcare staffing company, said in a news release.IntelyCare converted all of its workers from contractors to employees and offered them fringe benefits to better compensate them for their heavy workloads and the emotional strain of treating buy antibiotics patients, Coppins said. The result has been higher retention and more hiring, he said."At IntelyCare, we've heard from nurses firsthand that they want increased health and malpractice insurance, retirement plans, wellness services, childcare discounts, and help with necessities like groceries," Coppins said. "Making this kind of investment can go a long way to ensure that workers feel protected and appreciated."Although these strategies can be effective, the more permanent solution to rising labor costs is ending the amoxil, Zeenema amoxil best buy said. "I hope that we see vaccination rates increasing in order to protect our national healthcare workforce and to protect nurses as one of our most valuable assets," she said.Software companies that assist healthcare providers with managing health data have raised $3.7 billion in investment funding so far this year, up from $2 billion in the same period last year, according to a second-quarter report from market research firm Mercom Capital Group.In 2021's second quarter, such health information management companies amassed $1.7 billion in funding from investors, down from $2.1 billion in the first quarter but up 136.5% from $709 raised during the same period last year, according to the report. Health information management companies are just a portion of a broader digital health subsector that comprises tools for healthcare providers and practices.Most investor funding goes toward amoxil best buy digital health companies that focus on consumers."There's a lot of attention, both from VCs and from media, on patient-facing technologies," said Jeff Becker, a principal analyst at CB Insights, a firm that analyzes data on venture capital and startups.

"There's certainly very cool things amoxil best buy happening in that space. But there's also innovation at the bedside."In the second quarter, companies focused on providers and practices raised $2.4 billion, accounting for 31.2% of the quarter's total $7.7 billion in funding.That total marks a new quarterly funding record for the full digital health sector. Analytics companies amoxil best buy raised $565 million during the quarter, one-third of all funding raised by health information management companies and nearly one-quarter of investments that went to provider- and practice-focused companies. Benefits ($513 million), practice management tools ($480 million) and clinical decision-support ($434 million) companies also raised significant funds.Practice management tools experienced sizable growth—raising $753 million in the first half of 2021 compared to $233 million during the same period last year.Other top growth categories included clinical decision-support and analytics, according to Mercom's report.Many health systems are turning to digital tools to address persistent challenges like clinical documentation, which has been linked with provider burnout, said Nathan Ray, a director in consultancy West Monroe's healthcare and life sciences practice. Internal and family medicine clinicians, in particular, spend substantial time working amoxil best buy in the electronic health record system, according to a recent study.For these uses, innovative digital technology is working "behind-the-scenes" as part of a doctor's workflow, according to Ray.

More providers are turning to software tools that help capture data from a patient visit and document it into the patient's record, as well as to draw out insights that can be used to identify at-risk patients and suggest next steps. Providers are also looking at involves workforce management, such as software tools that credential and schedule clinical staff, for "back-office digital innovation," he said.Alayacare, a company that sells practice management software for home healthcare providers, raised roughly $183 million in a Series D funding round.There were 20 mergers amoxil best buy or acquisitions of practice management tools during the first half of the year. Telehealth was the only digital health category with more M&A transactions at 25.In total, 136 M&A transactions took place during the first half of the year, 73 of which took place in 2021's second quarter. Provider- and practice-focused companies "dominated" M&A activity for the quarter, comprising 43 of the 73 amoxil best buy transactions, according to Mercom's report. Thirty of those transactions involved health information management companies.Health information management companies were involved in 59 M&A transactions in the first half of 2021, compared to 34 in the first half of 2020.Microsoft Corp.'s $19.7 billion purchase of Nuance Communications—a company that sells artificial-intelligence clinical documentation tools—represents the priciest acquisition so far this year, followed by Optum's $13 billion purchase of Change Healthcare—a company that sells revenue cycle management tools—which is being reviewed by the Justice Department..

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IntroductionThalassaemia is an inherited anaemia that exerts an enormous disease burden amoxil drug worldwide.1 Along with sickle cell disease, it is one of the two most common single gene disorders. Indeed, ‘the alpha and beta thalassaemias are the most common inherited single-gene disorders in the world…’2A newly published study by Olivieri, Sabouhanian and Gallie3 analyses and assesses the comparative efficacy and safety profile of two drugs. Deferiprone (Ferriprox amoxil drug. Apotex) and deferasirox (Exfade. Novartis).

Both of these ‘iron-chelating’ drugs remove (‘chelate’) iron deposited, as a result of transfusions, in the tissues of patients with thalassaemia.The present-day first-line chelator, deferasirox, was licensed by the US FDA in 2005. The evidence for its safety and effectiveness was judged to be substantial and, accordingly, the FDA licensed it as a first-line agent. The prime advantage of deferasirox, in comparison to deferoxamine, an older drug that was formerly the gold standard of iron-chelating therapy for thalassaemia, is that deferasirox is orally active (that is, taken in pill form), while deferoxamine is more burdensome for patients because it has to be taken parenterally (that is, via injection). Deferiprone, like deferasirox, is taken orally but has not been licensed anywhere as first-line treatment. The FDA withheld market approval for deferiprone because there were/are no controlled trials demonstrating direct treatment benefit.

Although the FDA did eventually approve deferiprone, in 2011, it gave approval only as a last-resort treatment for those patients in whom other chelators had been tried unsuccessfully.1The data presented by Olivieri et al in their PLOS ONE paper indicate that the drugs differ significantly with respect to their effectiveness and safety. This commentary explores some of the ethical issues raised by the PLOS data.Historical contextIn order to understand properly the significance of the PLOS ONE Study some historical context will be helpful. What follows is a brief sketch of that context.2In 1993 Dr Nancy Olivieri, a specialist in blood diseases at Toronto’s Hospital for Sick Children (HSC or ‘Sick Kids’) and Professor of Pediatrics and Medicine at the University of Toronto (U of T), signed a contract with Apotex, a generic drug company, to continue studies of deferiprone, the early promise of which she had already reported in the literature. Olivieri’s thalassaemia research was initially supported by the Medical Research Council of Canada, but now she sought additional funding to extend her clinical trials. Apotex contributed this additional funding, thereby obtaining worldwide patents on the still-experimental drug.Despite early promise, by 1996 Olivieri’s research began to indicate that deferiprone might be inadequately effective in many patients, posing risks of potentially serious harm.

Olivieri communicated to Apotex her intention to inform patients of this unexpected risk and she proposed also to amend the study’s consent forms. She wished to continue amended studies of the drug, and to publish her findings.Apotex responded to Olivieri that they disagreed with her interpretation of the data and the company’s CEO threatened her with ‘all legal remedies’ should she inform patients or publish her findings. In issuing these threats, Apotex relied on a confidentiality clause in a legal contract Olivieri had signed with Apotex in 1993. This contract prohibited disclosure ‘to any third party’ without the express permission of Apotex.3Despite the objections raised by Apotex, Olivieri saw it as her professional duty to disclose her findings. The Research Ethics Board (REB) of Sick Kids Hospital reached the same conclusion.

In compliance with instructions from the Hospital’s REB, Olivieri duly informed both her patients and the regulatory authorities.When Olivieri later identified a second risk—that liver damage progressed during deferiprone exposure—Apotex issued additional legal warnings. Olivieri nevertheless proceeded to inform her patients of this additional risk and published her findings.Since patient safety, research integrity and academic freedom were all at stake in this dispute, Olivieri appealed for assistance, repeatedly, to senior officials at both the U of T and Sick Kids Hospital. Neither the University nor the Hospital provided the support she requested. In the words of the Report of the Committee of Inquiry on the Case Involving Dr Nancy Olivieri, the HSC, the U of T, and Apotex Inc4:The HSC and the U of T did not provide effective support either for Dr Olivieri and her rights, or for the principles of research and clinical ethics, and of academic freedom, during the first two and a half years of this controversy.Instead, both the University and the Hospital ‘took actions that were harmful to Dr. Olivieri’s interests and professional reputation and disrupted her work’.4 The harmful actions included firing Olivieri from her position as Director of the Hemoglobinopathy Program at Sick Kids Hospital and referring her for discipline to the College of Physicians and Surgeons of Ontario (CPSO).Only later did it emerge that, during this period of conflict, the U of T was negotiating with Apotex for a major donation towards building the University’s proposed new molecular medicine building.

Some speculated that the University’s failure to support Olivieri may not have been unconnected from its desire to appease a wealthy corporate donor. This speculation was reinforced when it was discovered that the then President of the University, Robert Prichard, had secretly lobbied the government of Canada for changes in drug patent law, changes that would favour Apotex.4Apotex proceeded to sue Olivieri for defaming both the company and their drug. She sued the company for defaming her.The Canadian Association of University Teachers (CAUT) and the U of T Faculty Association (UTFA), to whom Olivieri appealed for assistance after being rebuffed by the U of T and HSC, viewed the underlying issue as one of academic freedom. Both CAUT and UTFA provided support, including legal advice, to Olivieri.Thus began what is widely acknowledged to be the greatest scandal in Canadian academic history. Commissions of inquiry, books and articles (both scholarly and popular) proliferated, not to mention newspaper and television stories.

John le Carré’s novel The Constant Gardener and the Hollywood movie based on the book both appeared to draw heavily on the Olivieri-Apotex scandal. An inquiry into the dispute commissioned by Sick Kids Hospital (the Naimark Inquiry)5 absolved Apotex of wrongdoing but suggested that Olivieri was seriously at fault.5 She was charged with research misconduct and failures of patient care and was referred first to the Hospital’s Medical Advisory Council and subsequently to the disciplinary committee of the CPSO. Unsurprisingly, these widely publicised referrals were prejudicial to Olivieri’s reputation.The CAUT then commissioned an independent inquiry.6 The 540-page CAUT report on the Olivieri/Apotex affair4 gave a markedly different account of the scandal from that offered by the hospital-commissioned Naimark Report. A few excerpts from the CAUT report will convey its central findings:Apotex issued more legal warnings to deter Dr. Olivieri from communicating this second unexpected risk of L1 (deferiprone) to anyone.

However, she was legally and ethically obligated to communicate the risk to those taking or prescribing the drug as there were potential safety implications for patients, and she fulfilled these obligations despite the legal warnings.Apotex acted against the public interest in issuing legal warnings to Dr. Olivieri to deter her from communicating about risks of L1.Apotex’s legal warnings violated Dr. Olivieri’s academic freedom.7Shortly after the CAUT report absolved Olivieri of misconduct, the CPSO published the findings of its inquiry. The CPSO report exonerated Olivieri of all misconduct charges. Indeed, their report concluded that her conduct had been ‘commendable’.6 This favourable verdict did not, however, bring an end to litigation.In 2004, 8 years after the first legal threats had been issued, Apotex signed a mediated settlement with Olivieri.

Nevertheless, litigation continued for another 10 years. Those unfamiliar with the workings of the law may wonder how it is possible for litigation to continue for such a long period after a mediated settlement. Litigation continued because Apotex alleged that Olivieri had violated their agreement. Olivieri insisted that she was in compliance with the terms of the settlement. Court decisions were appealed by both parties.

A final settlement was not reached between Olivieri and Apotex until 2014.8 Shades of Jarndyce v. Jarndyce in Charles Dicken’s novel Bleak House.The HSC settled its dispute with Olivieri in 2006 and, although her research programme at the Hospital continued, she ceased to provide clinical care to HSC patients. From 1997 to 2009, Olivieri served as Director of the University Health Network (UHN) Hemoglobinopathy Program. She continued, as she had since 1997, to assist in the clinical care of UHN patients with thalassaemia and to enrol them in her research studies. In March 2009, however, Olivieri was dismissed by UHN from her position as Director.

No reason was given for her dismissal (Personal communication. Olivieri, 2019).The PLOS ONE Study data3 show that, after Olivieri’s dismissal from her position as Director, the UHN thalassaemia Clinic began almost immediately to switch patients to (unlicensed) deferiprone. Olivieri has described how her UHN research work, from this time forward, was marginalised (https://inthepatientsinterest.org/wp-content/uploads/2019/12/2018-12-20-GallieOlivieri-to-SmithHodges.pdf).Meanwhile, Freedom of Information (FOI) requests filed by Olivieri after her dismissal revealed that Apotex was supplying unrestricted educational grants to UHN’s thalassaemia programme as well as providing research support. The FOI requests filed by Olivieri also revealed that Apotex was strategising with the programme’s new director about how best to obtain licensing for deferiprone from the regulator (Health Canada).9 With this dramatic background as historical context, we commence our discussion of the ethical implications of the PLOS ONE paper.Findings of the PLOS ONE paperIn their 2019 PLOS ONE study Olivieri et al conclude, based on a retrospective review of patient data at Toronto’s UHN, that deferiprone is inadequately effective and associated with serious toxicity. Their review also confirms that, by contrast, deferasirox is effective and associated with relatively few adverse effects.3Olivieri et al report that ‘[b]etween 2009 and 2015, a third of patients transfused and managed in Canada’s largest transfusion programme were switched from first-line, licensed drugs to regimens of unlicensed deferiprone’.3 This finding raises the ethically troubling question.

How and why were so many locally transfused patients at UHN treated over such a long time period with an unlicensed drug of unproven safety and efficacy?. This ethical concern is followed immediately by another related concern. Why did the UHN thalassaemia programme continue to treat large numbers of its patients with deferiprone—despite ongoing evidence of inadequate effectiveness and serious (and often irreversible) adverse effects?. 3To recapitulate. The PLOS ONE paper demonstrates that a substantial proportion of UHN patients with thalassaemia was switched, between the years 2009 and 2015, from first-line licensed therapies (deferasirox or deferoxamine) to deferiprone.

During this entire period, deferiprone was unlicensed in Canada. To this day in every jurisdiction in which deferiprone has been licensed it has been licensed only as ‘last resort’ therapy. The ethical concern is to explain and to explore possible justifications for how and why so many patients at one particular thalassaemia treatment centre were prescribed a drug whose safety and efficacy were unproven in face of availability of licensed effective drugs. The urgency of the concern derives partly from the paper’s finding that those patients who were switched to deferiprone displayed evidence of increases in body iron and experienced the harms associated with body iron increase.3 This finding raises a second troubling ethical question. Why were patients not switched back to a first-line licensed therapy after they began to experience serious adverse effects from treatment with unlicensed deferiprone?.

How and why?. In a sustained effort to discover answers to these questions, Olivieri and Gallie have been in communication since 2015, by email and in personal meetings, with senior officials at UHN. Olivieri and Gallie report, however, that no definitive answers have yet been provided to any of their questions. FOI requests were filed but they, too, failed to produce definitive answers. (Olivieri and Gallie to Smith &.

Porter, 2019, https://inthepatientsinterest.org/wp-content/uploads/2019/12/2019-04-23-OlivieriGallie-to-SmithPorter.pdf).10 I, too, wrote to the CEO/President of UHN and to the Chief of Medical Staff, in an attempt to discover answers to a number of the ethical questions posed in this commentary. The hospital, however, has not responded to any of my questions.11Olivieri and Gallie have recently posted documentation of their correspondence with senior UHN administrators (https://inthepatientsinterest.org/). In September 2019 the UHN administration responded to the PLOS ONE paper by revealing that it had conducted a ‘Review of chelation practice in the red blood cell disorders program at UHN’. However, as Olivieri and Gallie document on the web, the hospital’s ‘Review’ does not address any of the safety concerns flagged in the PLOS ONE paper (https://inthepatientsinterest.org/wp-content/uploads/2019/12/Letter-to-Smith-and-Hodges-2-12-19.pdf). Nor does the ‘Review’ address any of the ethical concerns raised here.Despite UHN’s apparent reluctance to provide the information requested, here’s what we know or can reasonably infer.

Deferiprone was unlicensed in Canada during the relevant period, that is, from 2009 to 2015. €˜Unlicensed’ is different from ‘off-label’, the latter referring to a drug that has been licensed but is being provided for an indication other than that for which it is approved. Prescription of any unlicensed drug to Canadian patients can be accomplished only in one of two mutually exclusive ways. Either through Health Canada’s ‘Special Access Program (SAP)’ or via an REB approved clinical trial. It has to be one or the other since, as Health Canada’s Guidance Document7 makes clear, patients cannot be simultaneously treated through SAP and in a research trial.12 Under the SAP, the treating physician must confirm to Health Canada that ‘conventional therapies have failed, or are unsuitable or unavailable’.

Although some of the UHN patients’ records indicate that deferiprone was released under the SAP, Olivieri et al report that they ‘could identify no explanation for a proposed switch to deferiprone that was supported by evidence of failure of licensed therapy prescribed as recommended’3. Indeed, the authors write that many patients appear to have been switched to deferiprone despite optimal responses, or improvements during treatment with first-line therapies. Here’s the relevant paragraph from their PLOS ONE article:Deferiprone was prescribed to 41 study patients between 2009 and 2015. We could identify in the electronic medical records no explanation for a proposed switch to deferiprone that was supported by evidence of failure of licensed therapy prescribed as recommended. There was no indication that any patient switched to deferiprone over these 6 years had ‘failed’ therapy with either deferoxamine or deferasirox.

Many patients were recorded as tolerant of at least one and (in most), both licensed first-line chelating agents. Some had sustained minor adverse events during deferasirox that had resolved by the time deferiprone was prescribed.3In other words, according to the data found in UHN patient records, there is no evidence that the patients with thalassaemia who were switched to deferiprone met Health Canada’s eligibility criteria under SAP. Since deferiprone is licensed only as a ‘last resort’ therapy, its employment to treat patients who can tolerate either of the first-line therapies might improperly expose those patients to risks of serious medical harms, up to and including death.On the other hand, one should also consider the alternate possibility that, over the 6-year period studied by Olivieri et al, deferiprone was prescribed as part of a clinical trial. In favour of this hypothesis, one notes that the UHN physician primarily responsible for the widespread prescribing of deferiprone during the relevant time period claimed, in 2011, that deferiprone was provided to patients under a study approved by the REB of the UHN.8 UHN physicians also made this identical claim in a publicly available letter to the US FDA.9 Moreover, in response to an FOI application filed by Olivieri, UHN claimed that deferiprone was provided at UHN during a clinical trial (the data of which are protected from scrutiny under FOI laws), and not under SAP (the data of which are not protected from scrutiny under FOI). However, Olivieri et al have been unable to find any record of registration for such a trial, as required by Canadian Clinical Trial guidelines.13 Requests to the UHN administration for confirmation that a clinical trial existed remain unanswered.14 My own efforts to find some registration record for this putative clinical trial of deferiprone have been equally unsuccessful.15Two core ethical principles.

Harm-minimisation and informed consentIf the deferiprone used to treat UHN patients with thalassaemia was obtained from Apotex as part of a randomised clinical trial, responsibility for approving the trial would fall to the UHN’s REB. In Canada, both researchers and REBs are governed by the Tri-Council Policy Statement (TCPS) ‘Ethical Conduct for Research Involving Humans’.10 The 1998 version of this policy statement (TCPS1) and the subsequent 2010 version (TCPS2), both applicable to research trials during this period, stipulate that clinical trials must be designed so that harm to research subjects will be minimised.16 For example, TCPS1 specifies, in section 1.5, that ‘Research subjects must not be subjected to unnecessary risks of harm’. TCPS2, under the rubric ‘Core Principles’, requires similarly that clinical trials must ‘ensure that participants are not exposed to unnecessary risks’.Data presented by Olivieri et al in their PLOS ONE Study indicate that UHN patients exposed to unlicensed deferiprone, either as monotherapy or in combination with low dose of a first-line chelator (‘combination therapy’), experienced significant harms as a result of poor iron control, but very few if any compensating benefits.We provide new evidence of inadequate reduction in hepatic iron, a 17% incidence of new diabetes and new liver dysfunction in 65% of patients, many who were challenged and rechallenged with deferiprone despite elevated liver enzymes developed during previous exposure. We identified no evidence of ‘cardio-protective’ effect during deferiprone therapy.3In light of PLOS ONE Study data indicating serious adverse events (SAEs) for patients switched to deferiprone from first-line drugs one is led to question why the study protocol did not, in anticipation of such a contingency, provide for a resumption of licensed therapy for patients doing poorly on the unlicensed drug. Moreover, the investigators were obliged to report adverse events to the hospital’s REB.

Were the adverse events so reported?. And if they were then why did the UHN REB not seek to protect patient safety by insisting that licensed therapy be resumed for deferiprone-harmed patients?. In an effort to establish whether the deferiprone ‘clinical trial’ satisfied the TCPS harm-minimisation principle, I made inquiries about how the adverse findings described by the PLOS ONE paper were reported to the hospital’s REB and also how they were reported to the regulatory authorities, that is, Health Canada and the US FDA. But my queries, like those made previously by Olivieri and Gallie, have not succeeded in eliciting this ethically relevant information.17 Neither UHN nor its thalassaemia clinic responded to my letters of inquiry. It is known, however, from a publicly available 2011 document, that physicians in the UHN thalassaemia clinic strongly supported the market approval of deferiprone by the FDA.18 This support is difficult to reconcile with the toxicities recorded in UHN patient records.

So, a final verdict on the issue of whether the UHN deferiprone ‘clinical trial design’ violated the TCPS harm-minimisation principle cannot be reached until those involved in conducting and monitoring clinical trials at UHN make available the relevant information. An independent public inquiry may be necessary to achieve the necessary degree of accountability.Reference has been made, above, to the TCPS core ethical requirement of harm-minimisation, applicable in Canada both to researchers and to REBs. It is important to note, however, that TCPS2, like its predecessor, TCPS1 (and, indeed, like virtually every postwar code of research ethics) also stipulates as a second ‘core principle’ that ‘Researchers shall provide to prospective participants, or authorised third parties, full disclosure of all information necessary for making an informed decision’.19 Moreover, as the then-current TCPS guidelines make clear, ‘consent is an ongoing process’. So, assurance should be given to prospective participants that they ‘will be given in a timely manner throughout the course of the research project, information that is relevant to their decision to continue or withdraw from participation’.20 (My emphasis). Finally, TCPS2 imposes on researchers the additional ethical requirement that they disclose to research subjects ‘information concerning the possibility of commercialisation of research findings, and the presence of any real, potential or perceived conflicts of interest on the part of the researchers, their institutions or the research sponsors’.21 There is also an expectation that conflicts of interest will be disclosed to the REB.

Whether there was adequate disclosure of Apotex funding either to research subjects or to the UHN REB is still unknown.Thus, in order to assess the ethical adequacy of the putative UHN thalassaemia clinical trial one must inquire whether UHN patients/subjects were given adequate risk information when they were first enrolled, subsequently, when they were switched from treatment with deferasirox or deferoxamine to treatment with deferiprone and then, finally, when they experienced SAEs. That is, in order to know whether the putative deferiprone clinical trial conformed to established principles of research ethics, one would need to know whether patients/research subjects understood that they were being switched from licensed first-line drugs of proven efficacy to an unlicensed and unproven third-line drug. One would also need to know whether the deferiprone ‘research subjects’ were informed about conflicts of interest arising from Apotex donations (A) to the UHN. (B) To the hospital’s thalassaemia programme,22 as well as the hoped-for commercialisation of deferiprone via Health Canada and FDA licensing.If there was a failure to obtain ongoing informed consent and/or a failure to disclose conflicts of interest (to patients and to the REB) then this would constitute a violation of research ethics. Unfortunately, my attempts to elicit the clinical trial’s consent to research information from the UHN and its thalassaemia clinic met with as little success as earlier attempts made by the PLOS ONE authors.23REB review.

Safety monitoringAlthough every clinical trial requires safety monitoring, those trials which involve non-negligible risk of significant harm to patients/subjects require especially rigorous safety monitoring.24 Because the exposure of deferiprone to UHN patients posed risks of organ dysfunction and death, the need for safety monitoring was exigent. As the TCPS1 and TCPS2 both make clear, those who conduct research have an obligation to monitor and protect the safety of their research subjects.Moreover, it is now widely recognised that individuals closely involved with the design and conduct of a trial may not be able to be fully objective in reviewing interim data for any emerging concerns.25 Hence the importance of REBs, part of whose role is to provide safety monitoring initially and, for ongoing trials, over the entire period of the trial. In order to assess the adequacy of the safety monitoring for the UHN ‘deferiprone trial’ one would need to know whether the hospital’s REB was provided with regular and accurate reports of SAEs and what actions this REB took in response to those reports.It has become common practice in North America ‘that for any controlled trial of any size that will compare rates of mortality or major morbidity’, a data safety monitoring board (DSMB) will be established.26,11 12 A DSMB is constituted by a panel of independent (and otherwise unbiased) individuals with expertise pertinent to reviewing trial data on a regular ongoing basis. Its role is to advise the sponsors regarding the safety of trial subjects and to recommend early termination where indicated, for example, on grounds of patient safety.27Since there are no specifically Canadian requirements with respect to the establishment of DSMBs, Canadian REBs tend to follow FDA guidelines. Those guidelines recommend that a DSMB should be established when the study end point is such that a highly favourable or unfavourable result at an interim analysis might ethically require termination of the study.

Advance information suggesting the possibility of serious toxicity with the study treatment is another a priori reason for safety concern that would justify the establishment of a DSMB.12For reasons given above, the UHN deferiprone trial appears to have been a prime candidate for the establishment of a DSMB. But it is not known whether the study’s research protocol, purportedly submitted for approval to the hospital’s REB, included a DSMB. Nor is it known whether a DSMB was established and reported regularly to the trial’s sponsors. Data on the toxicity of deferiprone, provided by Olivieri et al from their retrospective study of UHN patient records, suggest that had a DSMB existed for this putative clinical trial the trial might, on grounds of patient safety, have been a candidate for premature cancellation. Lacunae in our knowledge of the safety monitoring provisions of the deferiprone ‘clinical trial’ make it difficult to reach any firm conclusion as to whether the ‘trial’ met prevailing safety monitoring requirements.The apparent unwillingness of the UHN to answer questions relating to safety monitoring might mean that an inquiry is needed to fill in our knowledge gaps and thereby make ethical evaluation possible.

For the findings of such an inquiry to be minimally credible it should be carried out by individuals who possess the requisite scientific/medical expertise and who are independent of the hospital and its thalassaemia clinic and who are demonstrably impartial. An inquiry carried out, for example, by someone whose research has been funded by Apotex and/or by an expert with close professional and personal ties to one or more of the physicians in the UHN thalassaemia clinic would not satisfy the hospital’s duty of accountability for patient safety.Ethical concernsA RecapitulationThe serious complications experienced by deferiprone-exposed UHN patients, as described by Olivieri et al in their PLOS ONE article, raise a number of ethically important questions. How could an unlicensed drug of unproven efficacy and safety—a drug that has been questioned by regulatory agencies such that it is licensed only as a “last resort” therapy—have been administered to so many patients over a period of so many years when two licensed drugs, both proven adequately safe and effective and licensed as first-line therapies, were available?. How did UHN physicians gain access to deferiprone from Health Canada when there is little evidence in UHN patient records that the deferiprone-exposed patients satisfied Health Canada’s criteria for Special Access?. Why was a putative UHN REB-approved research study involving deferiprone not registered as a clinical trial?.

Did the trial design include a DSMB, to protect patient safety and, if not, why not?. Were SAEs reported to the UHN REB and to regulators, as required?. Were deferiprone-treated UHN patients with thalassaemia adequately informed of the unlicensed status, unproven efficacy and reported toxicities of deferiprone?. Were deferiprone-exposed patients informed of harms they themselves had sustained during deferiprone from this exposure?. 28 Did the evidence of systematic treatment failure, as outlined in the PLOS ONE paper, raise red flags for thalassaemia clinic physicians and for the REB of UHN?.

And if serious problems were flagged what actions were taken to protect patient safety?. Institutional conflict of interestThe literature on biomedical conflicts of interest tends to focus on the ways in which financial support of individual researchers by the pharmaceutical industry can adversely affect both research integrity and patient safety.13–16 But similar ethical problems arise at the macro level when institutions, such as hospitals and clinics, depend on drug company funding to support patient care and clinical research.13 15 Notable scandals associated with institutional conflicts of interest include the David Healy/Eli Lilly scandal at Toronto’s Centre for Addictions and Mental Health (CAMH),13 the Aubrey Blumsohn/Proctor and Gamble scandal at Sheffield University (UK)17 and the Carl Elliott/Janssen Pharmaceuticals scandal at the University of Minnesota.17 The underlying pattern in each of these scandals involves (A) a biomedical researcher who is concerned about patient safety coming into conflict with (B) a pharmaceutical company which funds both the researcher’s hospital and university and (C) a failure by the institutions involved vigorously to defend patient safety and research integrity when doing so might offend a wealthy sponsor.It should not be assumed that corporate influence on university medical centres is necessarily exerted by means of threats or other direct forms of intervention. The mere presence of corporate funding can be sufficient to produce a corporate-friendly result. This point is illustrated by a recent STAT article, a propos the financial support which Purdue Pharma provided to Massachusetts General Hospital. The very title of the article encapsulates the ethical problem of institutional conflict of interest.

€˜Purdue Pharma cemented ties with universities and hospitals to expand opioid sales, documents contend’.18 Nor should it be supposed that the problem of institutional conflict of interest arises exclusively in the context of biomedical research. A recent Guardian article on the Mobil Oil Corporation describes how ‘Oil giant Mobil sought to make tax-exempt donations to leading universities … to promote the company’s interests and undermine environmental regulation, according to internal documents from the early 1990s obtained by the Guardian’.19As mentioned above, deferiprone, whose safety and efficacy are the central concern of Olivieri et al’s PLOS ONE paper, is manufactured by Apotex. When we seek to understand why deferiprone was so frequently prescribed to UHN patients, from 2009 to 2016, despite its being unlicensed and despite evidence of poor patient outcomes,3 it may be relevant to note that Apotex provided substantial funding to the UHN thalassaemia clinic.29 Moreover, a publicly displayed UHN banner lists ‘Apotex Inc – Barry and Honey Sherman’ as having donated between $1 million and $5 million to the hospital itself.30As every biomedical researcher understands, correlation is not causation. Nevertheless, the correlation between industry funding of hospitals, on the one hand, and industry-friendly decisions made by researchers and administrators at those hospitals, on the other, is worth pondering. Physicians and researchers who speak or write critically of drugs manufactured by wealthy donor companies may find that their careers are jeopardised.

Nancy Olivieri’s dismissal from two Apotex-funded teaching hospitals illustrates this phenomenon as does the termination of psychiatrist David Healy from Toronto’s CAMH.13 Healy’s appointment as Head of the CAMH Mood Disorders Clinic was rescinded almost immediately after he gave a public lecture at the hospital—a lecture in which he called for further research into the potentially adverse effects of Eli Lilly’s antidepressant drug, Prozac. Healy was particularly concerned about SSRI-induced suicidal ideation. After his lecture the hospital decided that he was not ‘a good fit’ with their programme and terminated his appointment. Shortly thereafter the hospital opened its Eli Lilly wing.13UHN, like every other research and teaching hospital in Canada, receives most of its funding, directly or indirectly, from governments.20 ,31 Nevertheless, UHN, again like other hospitals, faces ongoing pressure to find additional sources of revenue to support both patient care and clinical research.32 The pharmaceutical industry is a prime source of much-needed ‘top-up’ financial support for Canadian hospital research and clinical care.21 Hospital administrators, researchers and clinicians are thereby placed, willy nilly, in a conflict-of-interest situation. Because of funding exigencies, hospitals and other healthcare institutions, like individual physicians and researchers, have a strong vested interest in pleasing corporate sponsors and encouraging their ongoing support.

Moreover, institutional administrators, not unlike individual researchers and clinicians, typically experience a need to express their gratitude to donors by returning kindness for kindness and benefit for benefit. Thus, both the need for ongoing corporate sponsorship and the need to reciprocate for past corporate generosity create for hospital administrators (as well as for researchers and clinicians who work within hospitals) a conflict-of-interest situation in which their decision making may be skewed, consciously or unconsciously, in favour of the benefactors’ products.13 15 16 21Here’s an example of the manner in which an institutional conflict-of-interest situation can potentially bias the judgement of hospital administrators. Hospitals are required to exercise their disinterested judgement in the appointment of medical and scientific staff and in the ethical monitoring of research. This moral obligation follows directly from their fundamental commitment to promote and defend patient safety and research integrity. To illustrate.

UHN’s website, under the heading Purpose, Values and Principles, declares that ‘[o]ur Primary Value and above all else. The needs of patients come first’.22 It would be difficult to find any hospital whose Mission Statement did not proclaim a similar commitment to the primacy of patient well-being. In a similar vein, the UHN website, under the heading Information for Patients, subheaded Our Mission, declares. €˜We believe that health equity is achieved when each person is. Enabled to choose the best care and treatment based on the most current knowledge available’.From this fundamental commitment, it follows that healthcare institutions are obliged rigorously to monitor the quality of care provided to their patients and research subjects.

As an important element of protecting patient safety, hospitals are required to appoint the most qualified and competent candidates to clinical and research positions. But, as noted above, conflicts of interest are a risk factor for bias, conscious or unconscious, in personnel decisions.22 So, when a research hospital depends on corporate donations there is a risk that physicians and researchers may be appointed to key positions because they are known to be sympathetic to the donors’ product(s) rather than because they are the best qualified and the most competent. Contrariwise, physicians and researchers believed to be unsympathetic to the donors’ products are at risk of losing their jobs or of not being hired in the first place. The cases of Olivieri, Healy and Blumsohn illustrate this point.13 17As explained above, we know from the extensive literature on conflict of interest that when research and clinical care are funded by industry there is a marked tendency for both to favour the sponsors’/donors’ products.13 15 16 18 Significantly, the UHN itself explicitly recognises the danger to patient safety posed by systemic biases. Its Mission Statement commits the hospital to ensuring that every patient is ‘[m]ade aware of existing systemic biases to support the best possible health decisions’.22 Unfortunately, it is not possible at present to ascertain whether UHN conformed to this ethical commitment in the case of its deferiprone research/treatment clinic.

In order to make such an ethical determination we would need to know the mechanism by which the UHN thalassaemia clinic gained access to deferiprone and whether the clinic provided information about systemic bias to patients with thalassaemia and to the hospital’s REB.ConclusionsHospitals worldwide proclaim that their primary commitment is to meet the needs of their patients. Institutional codes of ethics and mission statements insist that patient needs come first. Indeed, meeting ‘patient needs’ is agreed to be the fundamental value to which all other hospital goals should be subordinated. Toronto’s UHN declares unequivocally that it shares this value. €˜[t]he needs of patients come first’.22Although patients have many and various needs, the need for safety must be counted as the sine qua non.

If the need for safety is not met then other needs become irrelevant.The findings of Olivieri et al in their PLOS ONE paper raise many troubling questions about the safety of patients in UHN’s thalassaemia clinic. One would expect that when top UHN officials became aware of the PLOS ONE data they would immediately have recognised the ethical red flags. Hospitals are ethically obliged both to investigate thoroughly possible safety failures and to rectify any problems identified.Over a period of several years, both before and after the publication of their research findings, Drs Olivieri and Gallie communicated regularly with UHN officials (https://inthepatientsinterest.org/). Multiple safety concerns were brought to the hospital’s attention. Numerous questions were asked by the PLOS ONE authors and specific concerns were raised.

To date, the hospital has not definitively addressed these issues. I posed a series of ethically salient questions to these same hospital officials (see online supplementary appendix A). My queries were ignored. There was no response from UHN.Supplemental materialIf a healthcare institution such as UHN claims that patient safety is its top priority then when safety issues are raised, it necessarily incurs an obligation of accountability. It would, for example, scarcely be adequate for a hospital, such as UHN, unilaterally to investigate alleged failures, declare that there has been no violation of patient care standards, and then to stonewall all further inquiries, whether those inquiries originate from its own medical staff, as was the case with Olivieri and Gallie, or from outside scholars, as was the case with me.When an unlicensed drug is prescribed to hospital patients, over a period of years, as happened in the UHN thalassaemia programme, it is surely the hospital’s obligation to answer questions about how and why this extraordinary practice occurred.

When hospital records reveal that patients switched from licensed to unlicensed medication, have experienced serious harms, up to and including death, it is surely the hospital’s obligation to answer in a conscientious and complete manner all the ethically troubling questions that have been identified. This obligation of accountability is owed both to patients and to staff. Thus far, UHN has not been willing to accept the implications of its own mission statement (https://www.uhn.ca/corporate/AboutUHN/Quality_Patient_Safety).The PLOS ONE Study by Olivieri Sabouhanian and Gallie spurs us to inquire whether the benefits which accrue to society from corporate sponsorship of healthcare institutions may, on balance, be outweighed by the associated harms. Admittedly, for governments committed to constraining public expenditures, the transfer of substantial healthcare costs to private corporations represents a benefit for public finances. But, as we have seen, when one considers this financial benefit, one ought also to take into account the spectrum of negative consequences potentially generated by institutional conflicts of interest.

The price for our continued acceptance of corporate funding of scientific research and clinical care may be the erosion of public trust. Arguably, it would be preferable if our research hospital were to aim instead for the complete elimination of systemic biases.Data availability statementAll data relevant to the study are included in the article or uploaded as supplementary informationEthics statementsPatient consent for publicationNot required.AcknowledgmentsThe author thanks the editors of JME and two JME reviewers for their criticisms of and suggestions for change to an earlier version of this paper..

IntroductionThalassaemia is an inherited anaemia that exerts an enormous disease burden amoxil best buy worldwide.1 Along with sickle cell disease, it is one of the two most http://www.em-sarah-banzet-oberhausbergen.site.ac-strasbourg.fr/continuite/salle-4/ common single gene disorders. Indeed, ‘the alpha and beta thalassaemias are the most common inherited single-gene disorders in the world…’2A newly published study by Olivieri, Sabouhanian and Gallie3 analyses and assesses the comparative efficacy and safety profile of two drugs. Deferiprone (Ferriprox amoxil best buy. Apotex) and deferasirox (Exfade. Novartis).

Both of these ‘iron-chelating’ drugs remove (‘chelate’) iron deposited, as a result of transfusions, in the tissues of patients with thalassaemia.The present-day first-line chelator, deferasirox, was licensed by the US FDA in 2005. The evidence for its safety and effectiveness was judged to be substantial and, accordingly, the FDA licensed it as a first-line agent. The prime advantage of deferasirox, in comparison to deferoxamine, an older drug that was formerly the gold standard of iron-chelating therapy for thalassaemia, is that deferasirox is orally active (that is, taken in pill form), while deferoxamine is more burdensome for patients because it has to be taken parenterally (that is, via injection). Deferiprone, like deferasirox, is taken orally but has not been licensed anywhere as first-line treatment. The FDA withheld market approval for deferiprone because there were/are no controlled trials demonstrating direct treatment benefit.

Although the FDA did eventually approve deferiprone, in 2011, it gave approval only as a last-resort treatment for those patients in whom other chelators had been tried unsuccessfully.1The data presented by Olivieri et al in their PLOS ONE paper indicate that the drugs differ significantly with respect to their effectiveness and safety. This commentary explores some of the ethical issues raised by the PLOS data.Historical contextIn order to understand properly the significance of the PLOS ONE Study some historical context will be helpful. What follows is a brief sketch of that context.2In 1993 Dr Nancy Olivieri, a specialist in blood diseases at Toronto’s Hospital for Sick Children (HSC or ‘Sick Kids’) and Professor of Pediatrics and Medicine at the University of Toronto (U of T), signed a contract with Apotex, a generic drug company, to continue studies of deferiprone, the early promise of which she had already reported in the literature. Olivieri’s thalassaemia research was initially supported by the Medical Research Council of Canada, but now she sought additional funding to extend her clinical trials. Apotex contributed this additional funding, thereby obtaining worldwide patents on the still-experimental drug.Despite early promise, by 1996 Olivieri’s research began to indicate that deferiprone might be inadequately effective in many patients, posing risks of potentially serious harm.

Olivieri communicated to Apotex her intention to inform patients of this unexpected risk and she proposed also to amend the study’s consent forms. She wished to continue amended studies of the drug, and to publish her findings.Apotex responded to Olivieri that they disagreed with her interpretation of the data and the company’s CEO threatened her with ‘all legal remedies’ should she inform patients or publish her findings. In issuing these threats, Apotex relied on a confidentiality clause in a legal contract Olivieri had signed with Apotex in 1993. This contract prohibited disclosure ‘to any third party’ without the express permission of Apotex.3Despite the objections raised by Apotex, Olivieri saw it as her professional duty to disclose her findings. The Research Ethics Board (REB) of Sick Kids Hospital reached the same conclusion.

In compliance with instructions from the Hospital’s REB, Olivieri duly informed both her patients and the regulatory authorities.When Olivieri later identified a second risk—that liver damage progressed during deferiprone exposure—Apotex issued additional legal warnings. Olivieri nevertheless proceeded to inform her patients of this additional risk and published her findings.Since patient safety, research integrity and academic freedom were all at stake in this dispute, Olivieri appealed for assistance, repeatedly, to senior officials at both the U of T and Sick Kids Hospital. Neither the University nor the Hospital provided the support she requested. In the words of the Report of the Committee of Inquiry on the Case Involving Dr Nancy Olivieri, the HSC, the U of T, and Apotex Inc4:The HSC and the U of T did not provide effective support either for Dr Olivieri and her rights, or for the principles of research and clinical ethics, and of academic freedom, during the first two and a half years of this controversy.Instead, both the University and the Hospital ‘took actions that were harmful to Dr. Olivieri’s interests and professional reputation and disrupted her work’.4 The harmful actions included firing Olivieri from her position as Director of the Hemoglobinopathy Program at Sick Kids Hospital and referring her for discipline to the College of Physicians and Surgeons of Ontario (CPSO).Only later did it emerge that, during this period of conflict, the U of T was negotiating with Apotex for a major donation towards building the University’s proposed new molecular medicine building.

Some speculated that the University’s failure to support Olivieri may not have been unconnected from its desire to appease a wealthy corporate donor. This speculation was reinforced when it was discovered that the then President of the University, Robert Prichard, had secretly lobbied the government of Canada for changes in drug patent law, changes that would favour Apotex.4Apotex proceeded to sue Olivieri for defaming both the company and their drug. She sued the company for defaming her.The Canadian Association of University Teachers (CAUT) and the U of T Faculty Association (UTFA), to whom Olivieri appealed for assistance after being rebuffed by the U of T and HSC, viewed the underlying issue as one of academic freedom. Both CAUT and UTFA provided support, including legal advice, to Olivieri.Thus began what is widely acknowledged to be the greatest scandal in Canadian academic history. Commissions of inquiry, books and articles (both scholarly and popular) proliferated, not to mention newspaper and television stories.

John le Carré’s novel The Constant Gardener and the Hollywood movie based on the book both appeared to draw heavily on the Olivieri-Apotex scandal. An inquiry into the dispute commissioned by Sick Kids Hospital (the Naimark Inquiry)5 absolved Apotex of wrongdoing but suggested that Olivieri was seriously at fault.5 She was charged with research misconduct and failures of patient care and was referred first to the Hospital’s Medical Advisory Council and subsequently to the disciplinary committee of the CPSO. Unsurprisingly, these widely publicised referrals were prejudicial to Olivieri’s reputation.The CAUT then commissioned an independent inquiry.6 The 540-page CAUT report on the Olivieri/Apotex affair4 gave a markedly different account of the scandal from that offered by the hospital-commissioned Naimark Report. A few excerpts from the CAUT report will convey its central findings:Apotex issued more legal warnings to deter Dr. Olivieri from communicating this second unexpected risk of L1 (deferiprone) to anyone.

However, she was legally and ethically obligated to communicate the risk to those taking or prescribing the drug as there were potential safety implications for patients, and she fulfilled these obligations despite the legal warnings.Apotex acted against the public interest in issuing legal warnings to Dr. Olivieri to deter her from communicating about risks of L1.Apotex’s legal warnings violated Dr. Olivieri’s academic freedom.7Shortly after the CAUT report absolved Olivieri of misconduct, the CPSO published the findings of its inquiry. The CPSO report exonerated Olivieri of all misconduct charges. Indeed, their report concluded that her conduct had been ‘commendable’.6 This favourable verdict did not, however, bring an end to litigation.In 2004, 8 years after the first legal threats had been issued, Apotex signed a mediated settlement with Olivieri.

Nevertheless, litigation continued for another 10 years. Those unfamiliar with the workings of the law may wonder how it is possible for litigation to continue for such a long period after a mediated settlement. Litigation continued because Apotex alleged that Olivieri had violated their agreement. Olivieri insisted that she was in compliance with the terms of the settlement. Court decisions were appealed by both parties.

A final settlement was not reached between Olivieri and Apotex until 2014.8 Shades of Jarndyce v. Jarndyce in Charles Dicken’s novel Bleak House.The HSC settled its dispute with Olivieri in 2006 and, although her research programme at the Hospital continued, she ceased to provide clinical care to HSC patients. From 1997 to 2009, Olivieri served as Director of the University Health Network (UHN) Hemoglobinopathy Program. She continued, as she had since 1997, to assist in the clinical care of UHN patients with thalassaemia and to enrol them in her research studies. In March 2009, however, Olivieri was dismissed by UHN from her position as Director.

No reason was given for her dismissal (Personal communication. Olivieri, 2019).The PLOS ONE Study data3 show that, after Olivieri’s dismissal from her position as Director, the UHN thalassaemia Clinic began almost immediately to switch patients to (unlicensed) deferiprone. Olivieri has described how her UHN research work, from this time forward, was marginalised (https://inthepatientsinterest.org/wp-content/uploads/2019/12/2018-12-20-GallieOlivieri-to-SmithHodges.pdf).Meanwhile, Freedom of Information (FOI) requests filed by Olivieri after her dismissal revealed that Apotex was supplying unrestricted educational grants to UHN’s thalassaemia programme as well as providing research support. The FOI requests filed by Olivieri also revealed that Apotex was strategising with the programme’s new director about how best to obtain licensing for deferiprone from the regulator (Health Canada).9 With this dramatic background as historical context, we commence our discussion of the ethical implications of the PLOS ONE paper.Findings of the PLOS ONE paperIn their 2019 PLOS ONE study Olivieri et al conclude, based on a retrospective review of patient data at Toronto’s UHN, that deferiprone is inadequately effective and associated with serious toxicity. Their review also confirms that, by contrast, deferasirox is effective and associated with relatively few adverse effects.3Olivieri et al report that ‘[b]etween 2009 and 2015, a third of patients transfused and managed in Canada’s largest transfusion programme were switched from first-line, licensed drugs to regimens of unlicensed deferiprone’.3 This finding raises the ethically troubling question.

How and why were so many locally transfused patients at UHN treated over such a long time period with an unlicensed drug of unproven safety and efficacy?. This ethical concern is followed immediately by another related concern. Why did the UHN thalassaemia programme continue to treat large numbers of its patients with deferiprone—despite ongoing evidence of inadequate effectiveness and serious (and often irreversible) adverse effects?. 3To recapitulate. The PLOS ONE paper demonstrates that a substantial proportion of UHN patients with thalassaemia was switched, between the years 2009 and 2015, from first-line licensed therapies (deferasirox or deferoxamine) to deferiprone.

During this entire period, deferiprone was unlicensed in Canada. To this day in every jurisdiction in which deferiprone has been licensed it has been licensed only as ‘last resort’ therapy. The ethical concern is to explain and to explore possible justifications for how and why so many patients at one particular thalassaemia treatment centre were prescribed a drug whose safety and efficacy were unproven in face of availability of licensed effective drugs. The urgency of the concern derives partly from the paper’s finding that those patients who were switched to deferiprone displayed evidence of increases in body iron and experienced the harms associated with body iron increase.3 This finding raises a second troubling ethical question. Why were patients not switched back to a first-line licensed therapy after they began to experience serious adverse effects from treatment with unlicensed deferiprone?.

How and why?. In a sustained effort to discover answers to these questions, Olivieri and Gallie have been in communication since 2015, by email and in personal meetings, with senior officials at UHN. Olivieri and Gallie report, however, that no definitive answers have yet been provided to any of their questions. FOI requests were filed but they, too, failed to produce definitive answers. (Olivieri and Gallie to Smith &.

Porter, 2019, https://inthepatientsinterest.org/wp-content/uploads/2019/12/2019-04-23-OlivieriGallie-to-SmithPorter.pdf).10 I, too, wrote to the CEO/President of UHN and to the Chief of Medical Staff, in an attempt to discover answers to a number of the ethical questions posed in this commentary. The hospital, however, has not responded to any of my questions.11Olivieri and Gallie have recently posted documentation of their correspondence with senior UHN administrators (https://inthepatientsinterest.org/). In September 2019 the UHN administration responded to the PLOS ONE paper by revealing that it had conducted a ‘Review of chelation practice in the red blood cell disorders program at UHN’. However, as Olivieri and Gallie document on the web, the hospital’s ‘Review’ does not address any of the safety concerns flagged in the PLOS ONE paper (https://inthepatientsinterest.org/wp-content/uploads/2019/12/Letter-to-Smith-and-Hodges-2-12-19.pdf). Nor does the ‘Review’ address any of the ethical concerns raised here.Despite UHN’s apparent reluctance to provide the information requested, here’s what we know or can reasonably infer.

Deferiprone was unlicensed in Canada during the relevant period, that is, from 2009 to 2015. €˜Unlicensed’ is different from ‘off-label’, the latter referring to a drug that has been licensed but is being provided for an indication other than that for which it is approved. Prescription of any unlicensed drug to Canadian patients can be accomplished only in one of two mutually exclusive ways. Either through Health Canada’s ‘Special Access Program (SAP)’ or via an REB approved clinical trial. It has to be one or the other since, as Health Canada’s Guidance Document7 makes clear, patients cannot be simultaneously treated through SAP and in a research trial.12 Under the SAP, the treating physician must confirm to Health Canada that ‘conventional therapies have failed, or are unsuitable or unavailable’.

Although some of the UHN patients’ records indicate that deferiprone was released under the SAP, Olivieri et al report that they ‘could identify no explanation for a proposed switch to deferiprone that was supported by evidence of failure of licensed therapy prescribed as recommended’3. Indeed, the authors write that many patients appear to have been switched to deferiprone despite optimal responses, or improvements during treatment with first-line therapies. Here’s the relevant paragraph from their PLOS ONE article:Deferiprone was prescribed to 41 study patients between 2009 and 2015. We could identify in the electronic medical records no explanation for a proposed switch to deferiprone that was supported by evidence of failure of licensed therapy prescribed as recommended. There was no indication that any patient switched to deferiprone over these 6 years had ‘failed’ therapy with either deferoxamine or deferasirox.

Many patients were recorded as tolerant of at least one and (in most), both licensed first-line chelating agents. Some had sustained minor adverse events during deferasirox that had resolved by the time deferiprone was prescribed.3In other words, according to the data found in UHN patient records, there is no evidence that the patients with thalassaemia who were switched to deferiprone met Health Canada’s eligibility criteria under SAP. Since deferiprone is licensed only as a ‘last resort’ therapy, its employment to treat patients who can tolerate either of the first-line therapies might improperly expose those patients to risks of serious medical harms, up to and including death.On the other hand, one should also consider the alternate possibility that, over the 6-year period studied by Olivieri et al, deferiprone was prescribed as part of a clinical trial. In favour of this hypothesis, one notes that the UHN physician primarily responsible for the widespread prescribing of deferiprone during the relevant time period claimed, in 2011, that deferiprone was provided to patients under a study approved by the REB of the UHN.8 UHN physicians also made this identical claim in a publicly available letter to the US FDA.9 Moreover, in response to an FOI application filed by Olivieri, UHN claimed that deferiprone was provided at UHN during a clinical trial (the data of which are protected from scrutiny under FOI laws), and not under SAP (the data of which are not protected from scrutiny under FOI). However, Olivieri et al have been unable to find any record of registration for such a trial, as required by Canadian Clinical Trial guidelines.13 Requests to the UHN administration for confirmation that a clinical trial existed remain unanswered.14 My own efforts to find some registration record for this putative clinical trial of deferiprone have been equally unsuccessful.15Two core ethical principles.

Harm-minimisation and informed consentIf the deferiprone used to treat UHN patients with thalassaemia was obtained from Apotex as part of a randomised clinical trial, responsibility for approving the trial would fall to the UHN’s REB. In Canada, both researchers and REBs are governed by the Tri-Council Policy Statement (TCPS) ‘Ethical Conduct for Research Involving Humans’.10 The 1998 version of this policy statement (TCPS1) and the subsequent 2010 version (TCPS2), both applicable to research trials during this period, stipulate online doctor amoxil that clinical trials must be designed so that harm to research subjects will be minimised.16 For example, TCPS1 specifies, in section 1.5, that ‘Research subjects must not be subjected to unnecessary risks of harm’. TCPS2, under the rubric ‘Core Principles’, requires similarly that clinical trials must ‘ensure that participants are not exposed to unnecessary risks’.Data presented by Olivieri et al in their PLOS ONE Study indicate that UHN patients exposed to unlicensed deferiprone, either as monotherapy or in combination with low dose of a first-line chelator (‘combination therapy’), experienced significant harms as a result of poor iron control, but very few if any compensating benefits.We provide new evidence of inadequate reduction in hepatic iron, a 17% incidence of new diabetes and new liver dysfunction in 65% of patients, many who were challenged and rechallenged with deferiprone despite elevated liver enzymes developed during previous exposure. We identified no evidence of ‘cardio-protective’ effect during deferiprone therapy.3In light of PLOS ONE Study data indicating serious adverse events (SAEs) for patients switched to deferiprone from first-line drugs one is led to question why the study protocol did not, in anticipation of such a contingency, provide for a resumption of licensed therapy for patients doing poorly on the unlicensed drug. Moreover, the investigators were obliged to report adverse events to the hospital’s REB.

Were the adverse events so reported?. And if they were then why did the UHN REB not seek to protect patient safety by insisting that licensed therapy be resumed for deferiprone-harmed patients?. In an effort to establish whether the deferiprone ‘clinical trial’ satisfied the TCPS harm-minimisation principle, I made inquiries about how the adverse findings described by the PLOS ONE paper were reported to the hospital’s REB and also how they were reported to the regulatory authorities, that is, Health Canada and the US FDA. But my queries, like those made previously by Olivieri and Gallie, have not succeeded in eliciting this ethically relevant information.17 Neither UHN nor its thalassaemia clinic responded to my letters of inquiry. It is known, however, from a publicly available 2011 document, that physicians in the UHN thalassaemia clinic strongly supported the market approval of deferiprone by the FDA.18 This support is difficult to reconcile with the toxicities recorded in UHN patient records.

So, a final verdict on the issue of whether the UHN deferiprone ‘clinical trial design’ violated the TCPS harm-minimisation principle cannot be reached until those involved in conducting and monitoring clinical trials at UHN make available the relevant information. An independent public inquiry may be necessary to achieve the necessary degree of accountability.Reference has been made, above, to the TCPS core ethical requirement of harm-minimisation, applicable in Canada both to researchers and to REBs. It is important to note, however, that TCPS2, like its predecessor, TCPS1 (and, indeed, like virtually every postwar code of research ethics) also stipulates as a second ‘core principle’ that ‘Researchers shall provide to prospective participants, or authorised third parties, full disclosure of all information necessary for making an informed decision’.19 Moreover, as the then-current TCPS guidelines make clear, ‘consent is an ongoing process’. So, assurance should be given to prospective participants that they ‘will be given in a timely manner throughout the course of the research project, information that is relevant to their decision to continue or withdraw from participation’.20 (My emphasis). Finally, TCPS2 imposes on researchers the additional ethical requirement that they disclose to research subjects ‘information concerning the possibility of commercialisation of research findings, and the presence of any real, potential or perceived conflicts of interest on the part of the researchers, their institutions or the research sponsors’.21 There is also an expectation that conflicts of interest will be disclosed to the REB.

Whether there was adequate disclosure of Apotex funding either to research subjects or to the UHN REB is still unknown.Thus, in order to assess the ethical adequacy of the putative UHN thalassaemia clinical trial one must inquire whether UHN patients/subjects were given adequate risk information when they were first enrolled, subsequently, when they were switched from treatment with deferasirox or deferoxamine to treatment with deferiprone and then, finally, when they experienced SAEs. That is, in order to know whether the putative deferiprone clinical trial conformed to established principles of research ethics, one would need to know whether patients/research subjects understood that they were being switched from licensed first-line drugs of proven efficacy to an unlicensed and unproven third-line drug. One would also need to know whether the deferiprone ‘research subjects’ were informed about conflicts of interest arising from Apotex donations (A) to the UHN. (B) To the hospital’s thalassaemia programme,22 as well as the hoped-for commercialisation of deferiprone via Health Canada and FDA licensing.If there was a failure to obtain ongoing informed consent and/or a failure to disclose conflicts of interest (to patients and to the REB) then this would constitute a violation of research ethics. Unfortunately, my attempts to elicit the clinical trial’s consent to research information from the UHN and its thalassaemia clinic met with as little success as earlier attempts made by the PLOS ONE authors.23REB review.

Safety monitoringAlthough every clinical trial requires safety monitoring, those trials which involve non-negligible risk of significant harm to patients/subjects require especially rigorous safety monitoring.24 Because the exposure of deferiprone to UHN patients posed risks of organ dysfunction and death, the need for safety monitoring was exigent. As the TCPS1 and TCPS2 both make clear, those who conduct research have an obligation to monitor and protect the safety of their research subjects.Moreover, it is now widely recognised that individuals closely involved with the design and conduct of a trial may not be able to be fully objective in reviewing interim data for any emerging concerns.25 Hence the importance of REBs, part of whose role is to provide safety monitoring initially and, for ongoing trials, over the entire period of the trial. In order to assess the adequacy of the safety monitoring for the UHN ‘deferiprone trial’ one would need to know whether the hospital’s REB was provided with regular and accurate reports of SAEs and what actions this REB took in response to those reports.It has become common practice in North America ‘that for any controlled trial of any size that will compare rates of mortality or major morbidity’, a data safety monitoring board (DSMB) will be established.26,11 12 A DSMB is constituted by a panel of independent (and otherwise unbiased) individuals with expertise pertinent to reviewing trial data on a regular ongoing basis. Its role is to advise the sponsors regarding the safety of trial subjects and to recommend early termination where indicated, for example, on grounds of patient safety.27Since there are no specifically Canadian requirements with respect to the establishment of DSMBs, Canadian REBs tend to follow FDA guidelines. Those guidelines recommend that a DSMB should be established when the study end point is such that a highly favourable or unfavourable result at an interim analysis might ethically require termination of the study.

Advance information suggesting the possibility of serious toxicity with the study treatment is another a priori reason for safety concern that would justify the establishment of a DSMB.12For reasons given above, the UHN deferiprone trial appears to have been a prime candidate for the establishment of a DSMB. But it is not known whether the study’s research protocol, purportedly submitted for approval to the hospital’s REB, included a DSMB. Nor is it known whether a DSMB was established and reported regularly to the trial’s sponsors. Data on the toxicity of deferiprone, provided by Olivieri et al from their retrospective study of UHN patient records, suggest that had a DSMB existed for this putative clinical trial the trial might, on grounds of patient safety, have been a candidate for premature cancellation. Lacunae in our knowledge of the safety monitoring provisions of the deferiprone ‘clinical trial’ make it difficult to reach any firm conclusion as to whether the ‘trial’ met prevailing safety monitoring requirements.The apparent unwillingness of the UHN to answer questions relating to safety monitoring might mean that an inquiry is needed to fill in our knowledge gaps and thereby make ethical evaluation possible.

For the findings of such an inquiry to be minimally credible it should be carried out by individuals who possess the requisite scientific/medical expertise and who are independent of the hospital and its thalassaemia clinic and who are demonstrably impartial. An inquiry carried out, for example, by someone whose research has been funded by Apotex and/or by an expert with close professional and personal ties to one or more of the physicians in the UHN thalassaemia clinic would not satisfy the hospital’s duty of accountability for patient safety.Ethical concernsA RecapitulationThe serious complications experienced by deferiprone-exposed UHN patients, as described by Olivieri et al in their PLOS ONE article, raise a number of ethically important questions. How could an unlicensed drug of unproven efficacy and safety—a drug that has been questioned by regulatory agencies such that it is licensed only as a “last resort” therapy—have been administered to so many patients over a period of so many years when two licensed drugs, both proven adequately safe and effective and licensed as first-line therapies, were available?. How did UHN physicians gain access to deferiprone from Health Canada when there is little evidence in UHN patient records that the deferiprone-exposed patients satisfied Health Canada’s criteria for Special Access?. Why was a putative UHN REB-approved research study involving deferiprone not registered as a clinical trial?.

Did the trial design include a DSMB, to protect patient safety and, if not, why not?. Were SAEs reported to the UHN REB and to regulators, as required?. Were deferiprone-treated UHN patients with thalassaemia adequately informed of the unlicensed status, unproven efficacy and reported toxicities of deferiprone?. Were deferiprone-exposed patients informed of harms they themselves had sustained during deferiprone from this exposure?. 28 Did the evidence of systematic treatment failure, as outlined in the PLOS ONE paper, raise red flags for thalassaemia clinic physicians and for the REB of UHN?.

And if serious problems were flagged what actions were taken to protect patient safety?. Institutional conflict of interestThe literature on biomedical conflicts of interest tends to focus on the ways in which financial support of individual researchers by the pharmaceutical industry can adversely affect both research integrity and patient safety.13–16 But similar ethical problems arise at the macro level when institutions, such as hospitals and clinics, depend on drug company funding to support patient care and clinical research.13 15 Notable scandals associated with institutional conflicts of interest include the David Healy/Eli Lilly scandal at Toronto’s Centre for Addictions and Mental Health (CAMH),13 the Aubrey Blumsohn/Proctor and Gamble scandal at Sheffield University (UK)17 and the Carl Elliott/Janssen Pharmaceuticals scandal at the University of Minnesota.17 The underlying pattern in each of these scandals involves (A) a biomedical researcher who is concerned about patient safety coming into conflict with (B) a pharmaceutical company which funds both the researcher’s hospital and university and (C) a failure by the institutions involved vigorously to defend patient safety and research integrity when doing so might offend a wealthy sponsor.It should not be assumed that corporate influence on university medical centres is necessarily exerted by means of threats or other direct forms of intervention. The mere presence of corporate funding can be sufficient to produce a corporate-friendly result. This point is illustrated by a recent STAT article, a propos the financial support which Purdue Pharma provided to Massachusetts General Hospital. The very title of the article encapsulates the ethical problem of institutional conflict of interest.

€˜Purdue Pharma cemented ties with universities and hospitals to expand opioid sales, documents contend’.18 Nor should it be supposed that the problem of institutional conflict of interest arises exclusively in the context of biomedical research. A recent Guardian article on the Mobil Oil Corporation describes how ‘Oil giant Mobil sought to make tax-exempt donations to leading universities … to promote the company’s interests and undermine environmental regulation, according to internal documents from the early 1990s obtained by the Guardian’.19As mentioned above, deferiprone, whose safety and efficacy are the central concern of Olivieri et al’s PLOS ONE paper, is manufactured by Apotex. When we seek to understand why deferiprone was so frequently prescribed to UHN patients, from 2009 to 2016, despite its being unlicensed and despite evidence of poor patient outcomes,3 it may be relevant to note that Apotex provided substantial funding to the UHN thalassaemia clinic.29 Moreover, a publicly displayed UHN banner lists ‘Apotex Inc – Barry and Honey Sherman’ as having donated between $1 million and $5 million to the hospital itself.30As every biomedical researcher understands, correlation is not causation. Nevertheless, the correlation between industry funding of hospitals, on the one hand, and industry-friendly decisions made by researchers and administrators at those hospitals, on the other, is worth pondering. Physicians and researchers who speak or write critically of drugs manufactured by wealthy donor companies may find that their careers are jeopardised.

Nancy Olivieri’s dismissal from two Apotex-funded teaching hospitals illustrates this phenomenon as does the termination of psychiatrist David Healy from Toronto’s CAMH.13 Healy’s appointment as Head of the CAMH Mood Disorders Clinic was rescinded almost immediately after he gave a public lecture at the hospital—a lecture in which he called for further research into the potentially adverse effects of Eli Lilly’s antidepressant drug, Prozac. Healy was particularly concerned about SSRI-induced suicidal ideation. After his lecture the hospital decided that he was not ‘a good fit’ with their programme and terminated his appointment. Shortly thereafter the hospital opened its Eli Lilly wing.13UHN, like every other research and teaching hospital in Canada, receives most of its funding, directly or indirectly, from governments.20 ,31 Nevertheless, UHN, again like other hospitals, faces ongoing pressure to find additional sources of revenue to support both patient care and clinical research.32 The pharmaceutical industry is a prime source of much-needed ‘top-up’ financial support for Canadian hospital research and clinical care.21 Hospital administrators, researchers and clinicians are thereby placed, willy nilly, in a conflict-of-interest situation. Because of funding exigencies, hospitals and other healthcare institutions, like individual physicians and researchers, have a strong vested interest in pleasing corporate sponsors and encouraging their ongoing support.

Moreover, institutional administrators, not unlike individual researchers and clinicians, typically experience a need to express their gratitude to donors by returning kindness for kindness and benefit for benefit. Thus, both the need for ongoing corporate sponsorship and the need to reciprocate for past corporate generosity create for hospital administrators (as well as for researchers and clinicians who work within hospitals) a conflict-of-interest situation in which their decision making may be skewed, consciously or unconsciously, in favour of the benefactors’ products.13 15 16 21Here’s an example of the manner in which an institutional conflict-of-interest situation can potentially bias the judgement of hospital administrators. Hospitals are required to exercise their disinterested judgement in the appointment of medical and scientific staff and in the ethical monitoring of research. This moral obligation follows directly from their fundamental commitment to promote and defend patient safety and research integrity. To illustrate.

UHN’s website, under the heading Purpose, Values and Principles, declares that ‘[o]ur Primary Value and above all else. The needs of patients come first’.22 It would be difficult to find any hospital whose Mission Statement did not proclaim a similar commitment to the primacy of patient well-being. In a similar vein, the UHN website, under the heading Information for Patients, subheaded Our Mission, declares. €˜We believe that health equity is achieved when each person is. Enabled to choose the best care and treatment based on the most current knowledge available’.From this fundamental commitment, it follows that healthcare institutions are obliged rigorously to monitor the quality of care provided to their patients and research subjects.

As an important element of protecting patient safety, hospitals are required to appoint the most qualified and competent candidates to clinical and research positions. But, as noted above, conflicts of interest are a risk factor for bias, conscious or unconscious, in personnel decisions.22 So, when a research hospital depends on corporate donations there is a risk that physicians and researchers may be appointed to key positions because they are known to be sympathetic to the donors’ product(s) rather than because they are the best qualified and the most competent. Contrariwise, physicians and researchers believed to be unsympathetic to the donors’ products are at risk of losing their jobs or of not being hired in the first place. The cases of Olivieri, Healy and Blumsohn illustrate this point.13 17As explained above, we know from the extensive literature on conflict of interest that when research and clinical care are funded by industry there is a marked tendency for both to favour the sponsors’/donors’ products.13 15 16 18 Significantly, the UHN itself explicitly recognises the danger to patient safety posed by systemic biases. Its Mission Statement commits the hospital to ensuring that every patient is ‘[m]ade aware of existing systemic biases to support the best possible health decisions’.22 Unfortunately, it is not possible at present to ascertain whether UHN conformed to this ethical commitment in the case of its deferiprone research/treatment clinic.

In order to make such an ethical determination we would need to know the mechanism by which the UHN thalassaemia clinic gained access to deferiprone and whether the clinic provided information about systemic bias to patients with thalassaemia and to the hospital’s REB.ConclusionsHospitals worldwide proclaim that their primary commitment is to meet the needs of their patients. Institutional codes of ethics and mission statements insist that patient needs come first. Indeed, meeting ‘patient needs’ is agreed to be the fundamental value to which all other hospital goals should be subordinated. Toronto’s UHN declares unequivocally that it shares this value. €˜[t]he needs of patients come first’.22Although patients have many and various needs, the need for safety must be counted as the sine qua non.

If the need for safety is not met then other needs become irrelevant.The findings of Olivieri et al in their PLOS ONE paper raise many troubling questions about the safety of patients in UHN’s thalassaemia clinic. One would expect that when top UHN officials became aware of the PLOS ONE data they would immediately have recognised the ethical red flags. Hospitals are ethically obliged both to investigate thoroughly possible safety failures and to rectify any problems identified.Over a period of several years, both before and after the publication of their research findings, Drs Olivieri and Gallie communicated regularly with UHN officials (https://inthepatientsinterest.org/). Multiple safety concerns were brought to the hospital’s attention. Numerous questions were asked by the PLOS ONE authors and specific concerns were raised.

To date, the hospital has not definitively addressed these issues. I posed a series of ethically salient questions to these same hospital officials (see online supplementary appendix A). My queries were ignored. There was no response from UHN.Supplemental materialIf a healthcare institution such as UHN claims that patient safety is its top priority then when safety issues are raised, it necessarily incurs an obligation of accountability. It would, for example, scarcely be adequate for a hospital, such as UHN, unilaterally to investigate alleged failures, declare that there has been no violation of patient care standards, and then to stonewall all further inquiries, whether those inquiries originate from its own medical staff, as was the case with Olivieri and Gallie, or from outside scholars, as was the case with me.When an unlicensed drug is prescribed to hospital patients, over a period of years, as happened in the UHN thalassaemia programme, it is surely the hospital’s obligation to answer questions about how and why this extraordinary practice occurred.

When hospital records reveal that patients switched from licensed to unlicensed medication, have experienced serious harms, up to and including death, it is surely the hospital’s obligation to answer in a conscientious and complete manner all the ethically troubling questions that have been identified. This obligation of accountability is owed both to patients and to staff. Thus far, UHN has not been willing to accept the implications of its own mission statement (https://www.uhn.ca/corporate/AboutUHN/Quality_Patient_Safety).The PLOS ONE Study by Olivieri Sabouhanian and Gallie spurs us to inquire whether the benefits which accrue to society from corporate sponsorship of healthcare institutions may, on balance, be outweighed by the associated harms. Admittedly, for governments committed to constraining public expenditures, the transfer of substantial healthcare costs to private corporations represents a benefit for public finances. But, as we have seen, when one considers this financial benefit, one ought also to take into account the spectrum of negative consequences potentially generated by institutional conflicts of interest.

The price for our continued acceptance of corporate funding of scientific research and clinical care may be the erosion of public trust. Arguably, it would be preferable if our research hospital were to aim instead for the complete elimination of systemic biases.Data availability statementAll data relevant to the study are included in the article or uploaded as supplementary informationEthics statementsPatient consent for publicationNot required.AcknowledgmentsThe author thanks the editors of JME and two JME reviewers for their criticisms of and suggestions for change to an earlier version of this paper..

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NSW recorded 1,029 new locally amoxicillin amoxil price usa acquired cases of buy antibiotics in the 24 hours to 8pm last http://pgecapital.com/amoxil-online-canadian-pharmacy night. Of these locally acquired cases, 185 are linked to a known case or cluster – 160 are household contacts and 25 are close contacts – and the source of for 844 cases is under investigation.Ninety-one were in isolation throughout their infectious period and amoxicillin amoxil price usa 33 were in isolation for part of their infectious period. Sixty-one cases were infectious in the community, and the isolation status of 844 cases remains under investigation.Five new cases were acquired overseas in the 24 hours to 8pm last night and 18 previously reported cases have been excluded following further investigation. The total number of cases in amoxicillin amoxil price usa NSW since the beginning of the amoxil is 21,282.

Sadly, NSW Health is reporting the recent deaths of three people who had buy antibiotics.Three men who were being cared for in the community in western Sydney died at their homes – a man in his 30s, a man in his 60s, and a man in his 80s.NSW Health extends its deepest sympathies to their loved ones.This brings the number of buy antibiotics-related deaths to 79 since 16 June 2021, and the number of lives lost to 135 since the beginning of the amoxil.There have been 15,684 locally acquired cases reported since 16 June 2021, when the first case in this outbreak was reported. There are currently 698 buy antibiotics cases admitted to hospital, with 116 people in intensive care, 43 of whom require ventilation.There were 151,272 buy antibiotics tests reported to 8pm amoxicillin amoxil price usa last night, compared with the previous day’s total of 149,252. Confirmed cases (including interstate residents in NSW health care facilities) 21,282 Deaths (in NSW from confirmed cases) 135 Total tests carried out 12,553,257 Total vaccinations administered in NSW 6,280,700 NSW Health administered 51,232 buy antibiotics treatments in the 24 hours to 8pm last night, including 11,754 at the vaccination centre at Sydney Olympic Park.The total number of treatments administered in NSW is now 6,280,700, with 2,304,017 doses administered by NSW Health to 8pm last night and 3,976,683 administered by the GP network and other providers to 11:59pm on Tuesday 24 August 2021.Of the 1,029 locally acquired cases reported to 8pm last night, 403 are from Western Sydney Local Health District (LHD), 309 are from South Western Sydney LHD, 112 are from Sydney LHD, 71 are from Nepean Blue Mountains LHD, 35 are from Western NSW LHD, 57 are from South Eastern Sydney LHD, 17 are from Northern Sydney LHD, six are from Far West LHD, two are from Illawarra Shoalhaven LHD, two are from Central Coast LHD, no new cases for Hunter New England LHD and 15 cases are yet to be assigned to an LHD.Across the Western NSW Local Health District there have been 35 new cases of buy antibiotics reported to 8pm last night. People in the affected areas throughout Western NSW need to be extremely vigilant and get tested at the first sign of symptoms.Due to ongoing concerns about community transmission, stay-at-home orders in place for amoxicillin amoxil price usa regional NSW will be extended by two weeks, until at least 11:59pm on 10 September, in line with existing orders for the Greater Sydney area.Everyone must stay at home unless they have a reasonable excuse to leave.

They also cannot have visitors in their home from outside their household, including family and friends. NSW Health's ongoing sewage surveillance program has recently detected fragments of the amoxil that causes buy antibiotics at the sewage treatment plants in Tamworth, Merimbula, Cooma and Brewarrina.The Tamworth sewage treatment plant serves approximately 45,000 people and the Merimbula sewage amoxicillin amoxil price usa treatment plant serves 15,000 people. The Cooma sewage treatment plant serves amoxicillin amoxil price usa approximately 8,000 people and the Brewarrina sewage treatment plant serves 1,100 people. These detections are a concern as there are no known cases in these areas.

Everyone in this area is urged to monitor for the onset of symptoms, and if they appear, to immediately be tested and isolate until a negative result is received.If you are directed to get tested for buy antibiotics‑19 or self-isolate at any time, you must follow the rules whether or not the venue or exposure setting is listed on the NSW amoxicillin amoxil price usa Health website.It remains vital that anyone who has any symptoms or is a close or casual contact of a person with buy antibiotics, isolates and is tested immediately. When testing clinics are busy, please ensure you stay in line, identify yourself to staff and tell them that you have symptoms or are a contact of a case.Please check the NSW Government website regularly, and follow the relevant health advice if you have attended a venue of concern or travelled on a public transport route at the same time as a confirmed case of buy antibiotics. This list is being updated regularly as case investigations proceed.There are more than 460 buy antibiotics testing locations across NSW, many of which amoxicillin amoxil price usa are open seven days a week. To find your nearest clinic visit.

buy antibiotics clinics amoxicillin amoxil price usa or contact your GP. Likely source of confirmed buy antibiotics cases in NSWOverseas 5 19 3,409 Interstate 0 0 94 Locally acquired – linked to known case or cluster 185 1,726 9,373 Locally acquired – no links to known case or cluster0 23 527 Locally acquired – investigation ongoing 844 3,972 7,879 Under initial investigation0 0 0 Note. Case counts reported for a particular day may vary over time due to amoxicillin amoxil price usa ongoing investigations and case review. *notified from 8pm 24 August 2021 to 8pm 25 August 2021 **from 8pm 19 August 2021 to 8pm 25 August 2021 buy antibiotics vaccination amoxicillin amoxil price usa updateNSW Health – first doses39,168 1,467,775 NSW Health – second doses 12,064 836,242 *notified from 8pm 24 August 2021 to 8pm 25 August 2021NSW recorded 919 new locally acquired cases of buy antibiotics in the 24 hours to 8pm last night.

Of these locally acquired cases, 178 are linked to a known case or cluster – 153 are household contacts and 25 are close contacts – and the source of for 741 cases is under investigation.One hundred and six cases were in isolation throughout their infectious period and 18 were in isolation for part of their infectious period. Thirty-seven cases amoxicillin amoxil price usa were infectious in the community, and the isolation status of 758 cases remains under investigation.Two new cases were acquired overseas in the 24 hours to 8pm last night and nine previously reported cases have been excluded following further investigation. The total number of cases in NSW since the beginning of the amoxil is 20,266. Sadly, NSW Health has been notified of the deaths amoxicillin amoxil price usa of two people who had buy antibiotics.

As announced yesterday, a woman in her 30s from Sydney’s west died at home. Her death amoxicillin amoxil price usa is being investigated by the coroner. A man in his 80s from Sydney’s north died at Hornsby Ku-ring-gai Hospital, having acquired his at the Greenwood Aged Care in Normanhurst. His is the third death linked to amoxicillin amoxil price usa an outbreak at this aged care facility.NSW Health extends its deepest sympathies to their loved ones.

This brings the number of buy antibiotics-related deaths to 76 since 16 June 2021, and the number of lives lost to 132 since the beginning of the amoxil.There have been 14,673 locally acquired cases reported since 16 June 2021, when the first case in this outbreak was reported. There are currently 645 buy antibiotics cases admitted to hospital, with 113 people in intensive care, 40 of whom require ventilation.There amoxicillin amoxil price usa were 149,252 buy antibiotics tests reported to 8pm last night, compared with the previous day’s total of 138,472. Confirmed cases (including interstate residents in NSW health care facilities) 20,266 Deaths (in NSW from confirmed cases) 132 Total tests carried out 12,401,985 Total vaccinations administered in NSW 6,143,824 NSW Health administered 45,073 buy antibiotics treatments in the 24 hours amoxicillin amoxil price usa to 8pm last night, including 10,964 at the vaccination centre at Sydney Olympic Park. The total number of treatments administered in NSW is now 6,143,824, with 2,252,785 doses administered by NSW Health to 8pm last night and 3,891,039 administered by the GP network and other providers to 11:59pm on Monday, 23rd August 2021.Of the 919 locally acquired cases reported to 8pm last night, 387 are from Western Sydney Local Health District (LHD), 247 are from South Western Sydney LHD, 82 are from Sydney LHD, 71 are from Nepean Blue Mountains LHD, 49 are from Western NSW LHD, 39 are from South Eastern Sydney LHD, 12 are from Northern Sydney LHD, seven are from Far West LHD, eight are from Illawarra Shoalhaven LHD, four are from Hunter New England LHD, one is from Central Coast LHD, and 12 cases are yet to be assigned to an LHD.Across the Western NSW Local Health District there have been 49 new cases of buy antibiotics reported to 8pm last night.

People in the affected areas throughout Western NSW need to be extremely vigilant and get tested at the first sign of symptoms.NSW Health's ongoing sewage surveillance program has recently detected fragments of the amoxil that causes buy antibiotics at the sewage treatment plants in Bateau Bay, Toukley and amoxicillin amoxil price usa Merimbula, which serve around 39,000, 29,000 and 15,500 people respectively.Everyone in these areas is urged to monitor for the onset of symptoms, and if they appear, to immediately be tested and isolate until a negative result is received.If you are directed to get tested for buy antibiotics‑19 or self-isolate at any time, you must follow the rules whether or not the venue or exposure setting is listed on the NSW Health website.It remains vital that anyone who has any symptoms or is a close or casual contact of a person with buy antibiotics, isolates and is tested immediately. When testing clinics are busy, please ensure you stay in line, identify yourself to staff and tell them that you have symptoms or are a contact of a case.Please check the NSW Government website regularly, and follow the relevant health advice if you have attended a venue of concern or travelled on a public transport route at the same time as a confirmed case of buy antibiotics. This list is being updated regularly as case investigations proceed.There are more than 460 buy antibiotics testing locations across NSW, many of which are amoxicillin amoxil price usa open seven days a week. To find your nearest clinic visit.

buy antibiotics clinics or amoxicillin amoxil price usa contact your GP. Likely source of confirmed buy antibiotics cases in NSWOverseas 2 17 3,404 Interstate 0 2 94 Locally acquired – linked to known case or cluster 178 1,662 9,017 Locally acquired – no links to known case or cluster0 21 521 Locally acquired – investigation ongoing 741 3,657 7,230 Under initial investigation0 0 0 Note. Case counts reported for a particular day may amoxicillin amoxil price usa vary over time due to ongoing investigations and case review. *notified from 8pm 23 August 2021 to 8pm 24 August 2021 **from 8pm 18 August 2021 to 8pm 24 August 2021 buy antibiotics vaccination updateNSW Health – first doses33,576 1,428,607 NSW Health – second doses 11,497 824,178 *notified from 8pm 23 August 2021 to 8pm 24 August 2021 Video of today's press conference will be uploaded to buy antibiotics (antibiotics) - press conferences and video updates..

NSW recorded 1,029 new locally acquired cases http://pgecapital.com/amoxil-online-canadian-pharmacy of buy antibiotics in the 24 hours amoxil best buy to 8pm last night. Of these locally acquired cases, 185 are linked to a known case or cluster – 160 are household contacts and 25 are close amoxil best buy contacts – and the source of for 844 cases is under investigation.Ninety-one were in isolation throughout their infectious period and 33 were in isolation for part of their infectious period. Sixty-one cases were infectious in the community, and the isolation status of 844 cases remains under investigation.Five new cases were acquired overseas in the 24 hours to 8pm last night and 18 previously reported cases have been excluded following further investigation. The total number of cases in NSW since the beginning of the amoxil is 21,282 amoxil best buy.

Sadly, NSW Health is reporting the recent deaths of three people who had buy antibiotics.Three men who were being cared for in the community in western Sydney died at their homes – a man in his 30s, a man in his 60s, and a man in his 80s.NSW Health extends its deepest sympathies to their loved ones.This brings the number of buy antibiotics-related deaths to 79 since 16 June 2021, and the number of lives lost to 135 since the beginning of the amoxil.There have been 15,684 locally acquired cases reported since 16 June 2021, when the first case in this outbreak was reported. There are currently 698 buy antibiotics cases admitted to hospital, with 116 people in intensive care, 43 of whom require ventilation.There were 151,272 buy antibiotics tests reported to 8pm last night, compared with amoxil best buy the previous day’s total of 149,252. Confirmed cases (including interstate residents in NSW health care facilities) 21,282 Deaths (in NSW from confirmed cases) 135 Total tests carried out 12,553,257 Total vaccinations administered in NSW 6,280,700 NSW Health administered 51,232 buy antibiotics treatments in the 24 hours to 8pm last night, including 11,754 at the vaccination centre at Sydney Olympic Park.The total number of treatments administered in NSW is now 6,280,700, with 2,304,017 doses administered by NSW Health to 8pm last night and 3,976,683 administered by the GP network and other providers to 11:59pm on Tuesday 24 August 2021.Of the 1,029 locally acquired cases reported to 8pm last night, 403 are from Western Sydney Local Health District (LHD), 309 are from South Western Sydney LHD, 112 are from Sydney LHD, 71 are from Nepean Blue Mountains LHD, 35 are from Western NSW LHD, 57 are from South Eastern Sydney LHD, 17 are from Northern Sydney LHD, six are from Far West LHD, two are from Illawarra Shoalhaven LHD, two are from Central Coast LHD, no new cases for Hunter New England LHD and 15 cases are yet to be assigned to an LHD.Across the Western NSW Local Health District there have been 35 new cases of buy antibiotics reported to 8pm last night. People in the affected areas throughout Western NSW need to be extremely vigilant amoxil best buy and get tested at the first sign of symptoms.Due to ongoing concerns about community transmission, stay-at-home orders in place for regional NSW will be extended by two weeks, until at least 11:59pm on 10 September, in line with existing orders for the Greater Sydney area.Everyone must stay at home unless they have a reasonable excuse to leave.

They also cannot have visitors in their home from outside their household, including family and friends. NSW Health's ongoing sewage surveillance program has recently detected fragments of the amoxil that causes amoxil best buy buy antibiotics at the sewage treatment plants in Tamworth, Merimbula, Cooma and Brewarrina.The Tamworth sewage treatment plant serves approximately 45,000 people and the Merimbula sewage treatment plant serves 15,000 people. The Cooma sewage treatment plant serves approximately 8,000 amoxil best buy people and the Brewarrina sewage treatment plant serves 1,100 people. These detections are a concern as there are no known cases in these areas.

Everyone in this area is urged to monitor for the amoxil best buy onset of symptoms, and if they appear, to immediately be tested and isolate until a negative result is received.If you are directed to get tested for buy antibiotics‑19 or self-isolate at any time, you must follow the rules whether or not the venue or exposure setting is listed on the NSW Health website.It remains vital that anyone who has any symptoms or is a close or casual contact of a person with buy antibiotics, isolates and is tested immediately. When testing clinics are busy, please ensure you stay in line, identify yourself to staff and tell them that you have symptoms or are a contact of a case.Please check the NSW Government website regularly, and follow the relevant health advice if you have attended a venue of concern or travelled on a public transport route at the same time as a confirmed case of buy antibiotics. This list is being updated regularly as case investigations proceed.There are more than 460 buy antibiotics testing locations across NSW, many of which amoxil best buy are open seven days a week. To find your nearest clinic visit.

buy antibiotics clinics or contact your GP amoxil best buy. Likely source of confirmed buy antibiotics cases in NSWOverseas 5 19 3,409 Interstate 0 0 94 Locally acquired – linked to known case or cluster 185 1,726 9,373 Locally acquired – no links to known case or cluster0 23 527 Locally acquired – investigation ongoing 844 3,972 7,879 Under initial investigation0 0 0 Note. Case counts reported for a particular day may vary over time due to ongoing investigations and amoxil best buy case review. *notified from 8pm 24 August 2021 to 8pm 25 August 2021 **from 8pm 19 August 2021 to 8pm 25 August 2021 buy antibiotics vaccination updateNSW Health – first doses39,168 1,467,775 NSW Health – second doses 12,064 836,242 *notified from amoxil best buy 8pm 24 August 2021 to 8pm 25 August 2021NSW recorded 919 new locally acquired cases of buy antibiotics in the 24 hours to 8pm last night.

Of these locally acquired cases, 178 are linked to a known case or cluster – 153 are household contacts and 25 are close contacts – and the source of for 741 cases is under investigation.One hundred and six cases were in isolation throughout their infectious period and 18 were in isolation for part of their infectious period. Thirty-seven cases were infectious in the community, and the isolation amoxil best buy status of 758 cases remains under investigation.Two new cases were acquired overseas in the 24 hours to 8pm last night and nine previously reported cases have been excluded following further investigation. The total number of cases in NSW since the beginning of the amoxil is 20,266. Sadly, NSW Health has amoxil best buy been notified of the deaths of two people who had buy antibiotics.

As announced yesterday, a woman in her 30s from Sydney’s west died at home. Her death is being amoxil best buy investigated by the coroner. A man in his 80s from Sydney’s north died at Hornsby Ku-ring-gai Hospital, having acquired his at the Greenwood Aged Care in Normanhurst. His is the third death linked to an outbreak at this aged care facility.NSW Health amoxil best buy extends its deepest sympathies to their loved ones.

This brings the number of buy antibiotics-related deaths to 76 since 16 June 2021, and the number of lives lost to 132 since the beginning of the amoxil.There have been 14,673 locally acquired cases reported since 16 June 2021, when the first case in this outbreak was reported. There are amoxil best buy currently 645 buy antibiotics cases admitted to hospital, with 113 people in intensive care, 40 of whom require ventilation.There were 149,252 buy antibiotics tests reported to 8pm last night, compared with the previous day’s total of 138,472. Confirmed cases (including interstate residents in NSW health care facilities) 20,266 Deaths (in NSW from confirmed cases) 132 Total tests carried out 12,401,985 Total vaccinations administered in NSW 6,143,824 NSW Health administered 45,073 buy antibiotics treatments in the 24 hours to 8pm last night, including 10,964 at the vaccination centre at Sydney amoxil best buy Olympic Park. The total number of treatments administered in NSW is now 6,143,824, with 2,252,785 doses administered by NSW Health to 8pm last night and 3,891,039 administered by the GP network and other providers to 11:59pm on Monday, 23rd August 2021.Of the 919 locally acquired cases reported to 8pm last night, 387 are from Western Sydney Local Health District (LHD), 247 are from South Western Sydney LHD, 82 are from Sydney LHD, 71 are from Nepean Blue Mountains LHD, 49 are from Western NSW LHD, 39 are from South Eastern Sydney LHD, 12 are from Northern Sydney LHD, seven are from Far West LHD, eight are from Illawarra Shoalhaven LHD, four are from Hunter New England LHD, one is from Central Coast LHD, and 12 cases are yet to be assigned to an LHD.Across the Western NSW Local Health District there have been 49 new cases of buy antibiotics reported to 8pm last night.

People in the affected areas throughout Western NSW need to be extremely vigilant and get tested amoxil best buy at the first sign of symptoms.NSW Health's ongoing sewage surveillance program has recently detected fragments of the amoxil that causes buy antibiotics at the sewage treatment plants in Bateau Bay, Toukley and Merimbula, which serve around 39,000, 29,000 and 15,500 people respectively.Everyone in these areas is urged to monitor for the onset of symptoms, and if they appear, to immediately be tested and isolate until a negative result is received.If you are directed to get tested for buy antibiotics‑19 or self-isolate at any time, you must follow the rules whether or not the venue or exposure setting is listed on the NSW Health website.It remains vital that anyone who has any symptoms or is a close or casual contact of a person with buy antibiotics, isolates and is tested immediately. When testing clinics are busy, please ensure you stay in line, identify yourself to staff and tell them that you have symptoms or are a contact of a case.Please check the NSW Government website regularly, and follow the relevant health advice if you have attended a venue of concern or travelled on a public transport route at the same time as a confirmed case of buy antibiotics. This list is being updated regularly as case investigations proceed.There are more than 460 buy antibiotics testing locations across NSW, many of which are amoxil best buy open seven days a week. To find your nearest clinic visit.

buy antibiotics clinics or contact amoxil best buy your GP. Likely source of confirmed buy antibiotics cases in NSWOverseas 2 17 3,404 Interstate 0 2 94 Locally acquired – linked to known case or cluster 178 1,662 9,017 Locally acquired – no links to known case or cluster0 21 521 Locally acquired – investigation ongoing 741 3,657 7,230 Under initial investigation0 0 0 Note. Case counts reported for a particular day may vary over time due to ongoing investigations and case amoxil best buy review. *notified from 8pm 23 August 2021 to 8pm 24 August 2021 **from 8pm 18 August 2021 to 8pm 24 August 2021 buy antibiotics vaccination updateNSW Health – first doses33,576 1,428,607 NSW Health – second doses 11,497 824,178 *notified from 8pm 23 August 2021 to 8pm 24 August 2021 Video of today's press conference will be uploaded to buy antibiotics (antibiotics) - press conferences and video updates..

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A study published today by researchers at the National Institutes of Health revealed that about half of individuals who said they don’t want to receive secondary genomic findings changed their mind generic amoxil online for sale after their healthcare provider gave them more detailed information. The paper, published in Genomics in Medicine, examines people's attitudes about receiving secondary genomic findings related to treatable or preventable diseases. The study generic amoxil online for sale was led by scientists at the National Human Genome Research Institute (NHGRI) and the National Institute of Environmental Health Sciences (NIEHS), both part of NIH. Your browser does not support the video tag.

Animation of patient filling out an informed consent form generic amoxil online for sale and checking the "YES" checkboxes for both Expected Outcome and Secondary Findings. Credit. Ernesto del Aguila III, NHGRI. With the broader adoption of genome sequencing in clinical care, researchers and the bioethics generic amoxil online for sale community are considering options for how to navigate the discovery of secondary genomic findings.

Secondary findings that come out of genome sequencing reflect information that is separate from the primary reason for an individual's medical care or participation in a study. For example, the genomic data of a patient who undergoes genome sequencing to address an autoimmune problem might reveal genomic variants that are associated generic amoxil online for sale with a heightened risk for breast cancer. Based on the American College of Medical Genetics and Genomics recommendations in 2021, individuals who have their genomes sequenced for a clinical reason should also be screened for genomic variants in 73 genes, including BRCA1 and BRCA2, both of which are linked to an increased risk of breast and ovarian cancer. All 59 genes are associated with treatable or potentially severe generic amoxil online for sale diseases.

Proponents of a person’s right to not know their secondary genomic findings have argued that, to maintain autonomy, individuals should have the opportunity to decide whether to be provided information about genomic variants in these additional genes. "Because these genomic findings can have life-saving implications, we wanted to ask the question. Are people really understanding what they are saying no to? generic amoxil online for sale. If they get more context, or a second opportunity to decide, do they change their mind?.

" said Benjamin Berkman, J.D., M.P.H., deputy director of the NHGRI Bioethics Core and senior generic amoxil online for sale author on the study. The research group worked with participants from the Environmental Polymorphisms Registry, an NIEHS study examining how genetic and environmental factors influence human health. Out of 8,843 participants, generic amoxil online for sale 8,678 elected to receive secondary genomic findings, while 165 opted out. Researchers assessed those 165 individuals to determine how strongly and consistently they maintained their "right not to know" decision.

The researchers wanted to determine whether providing additional information to people about their genomic variants influenced their decision and to better understand why some people still refused their secondary genomic findings after they received the additional information. Following the generic amoxil online for sale intervention, the researchers found that the 165 people sorted into two groups. "reversible refusers" who switched their decision to accept to know their secondary genomic findings and "persistent refusers" who still refused. Because these genomic findings can have life-saving implications, we wanted generic amoxil online for sale to ask the question.

Are people really understanding what they are saying no to?. If they get more context, or a second opportunity generic amoxil online for sale to decide, do they change their mind?. "It is worth noting that nearly three-quarters of reversible refusers thought they had originally agreed to receive secondary genomic findings," said Will Schupmann, a doctoral candidate at UCLA and first author on the study. "This means that we should be skeptical about whether checkbox choices are accurately capturing people’s preferences.” Based on the results, the researchers question whether healthcare providers should ask people who have their genome sequenced if they want to receive clinically important secondary genomic findings.

Investigators argue that enough data supports a default practice of returning secondary genomic findings without first asking participants generic amoxil online for sale if they would like to receive them. But research studies should create a system that also allows people who do not want to know their secondary genomic findings to opt out. The researchers suggest generic amoxil online for sale that if healthcare providers actively seek their patients’ preferences to know or not know about their secondary genomic findings, the providers should give the individuals multiple opportunities to make and revise their choice. "The right not to know has been a contentious topic in the genomics research community, but we believe that our real-world data can help move the field towards a new policy consensus," said Berkman.

Researchers at the NIH Department of Bioethics, NIEHS, Harvard University and Social generic amoxil online for sale &. Scientific Systems collaborated on the study.NIH research could lead to new treatment strategies for stomach cancer Glucocorticoids and androgens promote a healthy stomach pit by inhibiting inflammation, left, while their absence promotes inflammation and SPEM seen in a diseased pit, right. SPEM glands are also much larger than healthy stomach glands. (Photo courtesy of Jonathan Busada, Ph.D./NIEHS) Scientists at the National Institutes of Health determined that stomach inflammation is regulated differently generic amoxil online for sale in male and female mice after finding that androgens, or male sex hormones, play a critical role in preventing inflammation in the stomach.

The finding suggests that physicians could consider treating male patients with stomach inflammation differently than female patients with the same condition. The study was published in Gastroenterology.Researchers at NIH’s National Institute of Environmental Health Sciences (NIEHS) made the discovery after removing generic amoxil online for sale adrenal glands from mice of both sexes. Adrenal glands produce glucocorticoids, hormones that have several functions, one of them being suppressing inflammation. With no glucocorticoids, the female mice soon generic amoxil online for sale developed stomach inflammation.

The males did not. However, after removing androgens from the males, they exhibited the same stomach inflammation seen in the females."The fact that androgens are regulating inflammation is a novel idea," said co-corresponding author John Cidlowski, Ph.D., deputy chief of the NIEHS Laboratory of Signal Transduction and head of the Molecular Endocrinology Group. "Along with glucocorticoids, androgens offer a new way to control immune function in humans."While this study provides insight into how inflammation generic amoxil online for sale is being regulated in males, Cidlowski said additional research is underway to understand the process in females. The scientist handling this phase of research is co-corresponding author Jonathan Busada, Ph.D., assistant professor at West Virginia University School of Medicine in Morgantown.

When Busada started the project several years ago, he was a postdoctoral fellow working in Cidlowski’s group.Whether inflammation is inside the stomach or elsewhere in the body, Busada said rates of chronic inflammatory and autoimmune generic amoxil online for sale diseases vary depending on sex. He said eight out of 10 individuals with autoimmune disease are women, and his long-term goal is to figure out how glucocorticoids and androgens affect stomach cancer, which is induced by chronic inflammation.The current research focused on stomach glands called pits, which are embedded in the lining of the stomach.Busada said the study showed that glucocorticoids and androgens act like brake pedals on the immune system and are essential for regulating stomach inflammation. In his analogy, glucocorticoids are the primary brakes and androgens are the emergency brakes."Females only have one layer of protection, so if you generic amoxil online for sale remove glucocorticoids, they develop stomach inflammation and a pre-cancerous condition in the stomach called spasmolytic polypeptide-expressing metaplasia (SPEM)," Busada said. "Males have redundancy built in, so if something cuts the glucocorticoid brake line, it is okay, because the androgens can pick up the slack."The research also offered a possible mechanism — or biological process — behind this phenomenon.

In healthy stomach glands, the presence of glucocorticoids and androgens inhibit special immune cells called type 2 innate lymphoid cells (ILC2s). But in diseased stomach glands, the hormones are missing generic amoxil online for sale. As a result, ILC2s may act like a fire alarm, directing other immune cells called macrophages to promote inflammation and damage gastric glands leading to SPEM and ultimately cancer."ILC2s are the only immune cells that contain androgen receptors and could be a potential therapeutic target," Cidlowski said.This press release describes a basic research finding. Basic research increases our understanding of human behavior and generic amoxil online for sale biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease.

Science is an unpredictable and incremental process — each research advance builds on past discoveries, often in unexpected ways. Most clinical generic amoxil online for sale advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit Basic Research – Digital Media Kit.Grant Numbers:ZIAES090057Fi2GM123974P20GM103434P20GM121322U54GM104942P30GM103488 Reference. Busada JT, Peterson KN, Khadka S, Xu, X, Oakley RH, Cook DN, Cidlowski JA.

2021. Glucocorticoids and androgens protect from gastric metaplasia by suppressing group 2 innate lymphoid cell activation. Gastroenterology. Doi.

10.1053/j.gastro.2021.04.075 [Online 7 May 2021]..

A study published today by researchers at the National Institutes of Health revealed http://controlmyproject.com/?p=1 that about half of individuals who said they don’t want to receive secondary genomic findings changed their mind amoxil best buy after their healthcare provider gave them more detailed information. The paper, published in Genomics in Medicine, examines people's attitudes about receiving secondary genomic findings related to treatable or preventable diseases. The study was amoxil best buy led by scientists at the National Human Genome Research Institute (NHGRI) and the National Institute of Environmental Health Sciences (NIEHS), both part of NIH. Your browser does not support the video tag. Animation of patient filling out amoxil best buy an informed consent form and checking the "YES" checkboxes for both Expected Outcome and Secondary Findings.

Credit. Ernesto del Aguila III, NHGRI. With the broader adoption of genome sequencing amoxil best buy in clinical care, researchers and the bioethics community are considering options for how to navigate the discovery of secondary genomic findings. Secondary findings that come out of genome sequencing reflect information that is separate from the primary reason for an individual's medical care or participation in a study. For example, the genomic data of a patient who undergoes genome sequencing to address an autoimmune problem might reveal genomic variants that are associated amoxil best buy with a heightened risk for breast cancer.

Based on the American College of Medical Genetics and Genomics recommendations in 2021, individuals who have their genomes sequenced for a clinical reason should also be screened for genomic variants in 73 genes, including BRCA1 and BRCA2, both of which are linked to an increased risk of breast and ovarian cancer. All 59 genes are associated with treatable amoxil best buy or potentially severe diseases. Proponents of a person’s right to not know their secondary genomic findings have argued that, to maintain autonomy, individuals should have the opportunity to decide whether to be provided information about genomic variants in these additional genes. "Because these genomic findings can have life-saving implications, we wanted to ask the question. Are people amoxil best buy really understanding what they are saying no to?.

If they get more context, or a second opportunity to decide, do they change their mind?. " said Benjamin Berkman, J.D., M.P.H., deputy director of the NHGRI Bioethics Core and senior author on the study amoxil best buy. The research group worked with participants from the Environmental Polymorphisms Registry, an NIEHS study examining how genetic and environmental factors influence human health. Out of 8,843 participants, 8,678 elected to receive secondary genomic findings, amoxil best buy while 165 opted out. Researchers assessed those 165 individuals to determine how strongly and consistently they maintained their "right not to know" decision.

The researchers wanted to determine whether providing additional information to people about their genomic variants influenced their decision and to better understand why some people still refused their secondary genomic findings after they received the additional information. Following the intervention, amoxil best buy the researchers found that the 165 people sorted into two groups. "reversible refusers" who switched their decision to accept to know their secondary genomic findings and "persistent refusers" who still refused. Because these genomic findings can have life-saving implications, amoxil best buy we wanted to ask the question. Are people really understanding what they are saying no to?.

If they get more context, or amoxil best buy a second opportunity to decide, do they change their mind?. "It is worth noting that nearly three-quarters of reversible refusers thought they had originally agreed to receive secondary genomic findings," said Will Schupmann, a doctoral candidate at UCLA and first author on the study. "This means that we should be skeptical about whether checkbox choices are accurately capturing people’s preferences.” Based on the results, the researchers question whether healthcare providers should ask people who have their genome sequenced if they want to receive clinically important secondary genomic findings. Investigators argue that enough data supports a default practice of returning secondary genomic findings amoxil best buy without first asking participants if they would like to receive them. But research studies should create a system that also allows people who do not want to know their secondary genomic findings to opt out.

The researchers suggest that if healthcare providers actively seek their patients’ amoxil best buy preferences to buy amoxil without a prescription know or not know about their secondary genomic findings, the providers should give the individuals multiple opportunities to make and revise their choice. "The right not to know has been a contentious topic in the genomics research community, but we believe that our real-world data can help move the field towards a new policy consensus," said Berkman. Researchers at the NIH Department of amoxil best buy Bioethics, NIEHS, Harvard University and Social &. Scientific Systems collaborated on the study.NIH research could lead to new treatment strategies for stomach cancer Glucocorticoids and androgens promote a healthy stomach pit by inhibiting inflammation, left, while their absence promotes inflammation and SPEM seen in a diseased pit, right. SPEM glands are also much larger than healthy stomach glands.

(Photo courtesy of Jonathan Busada, Ph.D./NIEHS) Scientists at the National Institutes of Health determined that stomach inflammation is regulated differently in male and female mice after finding that androgens, or male sex hormones, play a critical amoxil best buy role in preventing inflammation in the stomach. The finding suggests that physicians could consider treating male patients with stomach inflammation differently than female patients with the same condition. The study was published in Gastroenterology.Researchers at NIH’s National Institute of Environmental Health Sciences (NIEHS) made the amoxil best buy discovery after removing adrenal glands from mice of both sexes. Adrenal glands produce glucocorticoids, hormones that have several functions, one of them being suppressing inflammation. With no glucocorticoids, the female mice soon developed stomach amoxil best buy inflammation.

The males did not. However, after removing androgens from the males, they exhibited the same stomach inflammation seen in the females."The fact that androgens are regulating inflammation is a novel idea," said co-corresponding author John Cidlowski, Ph.D., deputy chief of the NIEHS Laboratory of Signal Transduction and head of the Molecular Endocrinology Group. "Along with glucocorticoids, amoxil best buy androgens offer a new way to control immune function in humans."While this study provides insight into how inflammation is being regulated in males, Cidlowski said additional research is underway to understand the process in females. The scientist handling this phase of research is co-corresponding author Jonathan Busada, Ph.D., assistant professor at West Virginia University School of Medicine in Morgantown. When Busada started the project several years ago, he was a postdoctoral fellow working in Cidlowski’s group.Whether inflammation is inside the stomach or elsewhere in amoxil best buy the body, Busada said rates of chronic inflammatory and autoimmune diseases vary depending on sex.

He said eight out of 10 individuals with autoimmune disease are women, and his long-term goal is to figure out how glucocorticoids and androgens affect stomach cancer, which is induced by chronic inflammation.The current research focused on stomach glands called pits, which are embedded in the lining of the stomach.Busada said the study showed that glucocorticoids and androgens act like brake pedals on the immune system and are essential for regulating stomach inflammation. In his analogy, glucocorticoids are the primary brakes and androgens are the emergency brakes."Females only have one layer of protection, so if you remove amoxil best buy glucocorticoids, they develop stomach inflammation and a pre-cancerous condition in the stomach called spasmolytic polypeptide-expressing metaplasia (SPEM)," Busada said. "Males have redundancy built in, so if something cuts the glucocorticoid brake line, it is okay, because the androgens can pick up the slack."The research also offered a possible mechanism — or biological process — behind this phenomenon. In healthy stomach glands, the presence of glucocorticoids and androgens inhibit special immune cells called type 2 innate lymphoid cells (ILC2s). But in amoxil best buy diseased stomach glands, the hormones are missing.

As a result, ILC2s may act like a fire alarm, directing other immune cells called macrophages to promote inflammation and damage gastric glands leading to SPEM and ultimately cancer."ILC2s are the only immune cells that contain androgen receptors and could be a potential therapeutic target," Cidlowski said.This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better amoxil best buy ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process — each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not amoxil best buy be possible without the knowledge of fundamental basic research. To learn more about basic research, visit Basic Research – Digital Media Kit.Grant Numbers:ZIAES090057Fi2GM123974P20GM103434P20GM121322U54GM104942P30GM103488 Reference.

Busada JT, Peterson KN, Khadka S, Xu, X, Oakley RH, Cook DN, Cidlowski JA. 2021. Glucocorticoids and androgens protect from gastric metaplasia by suppressing group 2 innate lymphoid cell activation. Gastroenterology. Doi.

10.1053/j.gastro.2021.04.075 [Online 7 May 2021]..