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Details of loan program coming and Trump’s use of malaria drug; In The News for May 20



In The News is a roundup of stories from The Canadian Press designed to kickstart your day. Here is what’s on the radar of our editors for the morning of May 20 …

COVID-19 in Canada …

The federal government is beefing up efforts to persuade businesses to rehire workers now that Canada’s economy is starting to emerge from the COVID-19 lockdown.


It is expected today to unveil more details of its promised loan program for large corporations and commercial rent relief for small- and mid-sized businesses.

That includes more information on how businesses can apply for the programs and what conditions will apply.

Today’s focus follows last week’s extension of the 75 per cent wage subsidy for three months, to the end of August, and Tuesday’s announcement that the government is expanding the eligibility criteria for its small business loan program.

The latter program provides interest-free loans of $40,000 for eligible small businesses to cover costs like rent and utilities, with the possibility of forgiving one-quarter of the amount if it is paid off by the end of 2022.

Tuesday’s fix extended the program to companies that don’t have traditional payrolls, such as family-run businesses that pay themselves in dividends and companies that employ only contractors.

“This is about getting people back to work and giving businesses the confidence to reopen, rehire and even grow because the way our economy will recover and the way our country will remain resilient and successful is by getting Canadians back to work,” Prime Minister Justin Trudeau said Tuesday.

In other Canadian news …

Statistics Canada is expected to report that the consumer price index decreased in April, the first full month the economy was gripped by the COVID-19 pandemic.

Economists on average had expected a reading of negative 0.28 per cent for April, according to financial markets data firm Refinitiv.

That’s a further decline from March when the annual pace of inflation in Canada was 0.9 per cent, marking the biggest one-month decrease in more than a decade.

It was down from 2.2 per cent in February as the price of oil collapsed and the economy then ground to a halt when governments ordered the closure of non-essential businesses in mid-March to slow the spread of COVID-19.

The Consumer Price Index measures price changes for a fixed basket of goods and services that are divided into eight major components.

These are food, shelter, household operations, furnishings and equipment, clothing and footwear, transportation, health and personal care, recreation, education and alcoholic beverages, tobacco products and recreational cannabis.

Also this …

As provinces take their cautious first steps to allow people back into local businesses, a new poll suggests most Canadians don’t think province-wide measures are the best way to reopen the economy.

The latest poll on the COVID-19 pandemic by Leger and the Association for Canadian Studies suggests only 35 per cent of people thought restrictions should be loosened for entire provinces.

In contrast, 47 per cent thought those decisions should apply to specific regions within each province. Just 18 per cent said reopening measures should apply to all of Canada at once.

Still, just over half of those polled said they trust provinces to make the call about what businesses should reopen and when, whereas about one-third said that should be up to Ottawa and 14 per cent said local governments should decide.

That is essentially what happened in Quebec, where the provincial government delayed the planned reopening of schools, daycares and businesses in the Greater Montreal area for one week because of the particularly high COVID-19 infection rate in the area and a shortage of health-care workers.

The proportion of people who said they would like decisions to be made region by region were highest in that province at 73 per cent, followed by Alberta at 52 per cent.

COVID-19 in the U.S. …

President Donald Trump emphatically defended himself against criticism from medical experts that his announced use of a malaria drug against the coronavirus could spark wide misuse by Americans of the unproven treatment with potentially fatal side effects.

Trump’s revelation a day earlier that he was taking hydroxychloroquine caught many in his administration by surprise and set off an urgent effort by officials to justify his action. But their attempt to address the concerns of health professionals was undercut by the president himself.

He asserted without evidence that a study of veterans raising alarm about the drug was “false” and an “enemy statement,” even as his own government warned that the drug should be administered for COVID-19 only in a hospital or research setting.

“If you look at the one survey, the only bad survey, they were giving it to people that were in very bad shape,” Trump said. That was an apparent reference to a study of hundreds of patients treated by the Department of Veterans Affairs in which more of those in a group who were administered hydroxychloroquine died than among those who weren’t.

“They were very old. Almost dead,” Trump said. “It was a Trump enemy statement.” During a Cabinet meeting, he elicited a defense of his practice from other officials, including VA Secretary Robert Wilkie who noted that the study in question was not conducted by his agency.

But the drug has not been shown to combat the virus in a multitude of other studies as well. Two large observational studies, each involving around 1,400 patients in New York, recently found no COVID benefit from hydroxychloroquine. Two new ones published last week in the medical journal BMJ reached the same conclusion.

No large, rigorous studies have found the drug safe or effective for preventing or treating COVID-19.

COVID-19 around the world …

President Donald Trump’s declaration that he was taking a malaria drug of dubious effectiveness to help fend off the coronavirus will likely be welcomed in India.

Trump’s previous endorsement of hydroxychloroquine catalyzed a tremendous shift in the South Asian country, spurring the world’s largest producer of the drug to make much more of it, prescribe it for front-line health workers treating the virus and deploy it as a diplomatic tool, despite mounting evidence against using the drug for COVID-19.

Trump said Monday that he was taking hydroxychloroquine as a measure of protection against the virus. The U.S. Food and Drug Administration, however, has cautioned against using it outside of hospitals because of the risk of serious heart problems.

Suhhil Gupta, a pharmacist in New Delhi, said Tuesday that Trump’s announcement shouldn’t carry any weight in India.

“He’s not a pharmacist. His statements are not relevant to the field,” Gupta said.

Still, India’s policy on the decades-old drug, used to prevent malaria and treat lupus and rheumatoid arthritis, drastically changed after Trump tweeted in March that the drug, used together with an antibiotic, could be “game changers” in the fight against the pandemic. India’s health ministry quickly approved it as a prophylactic for health care workers and others at high risk of infection, and as a treatment for critically ill patients.

In non-COVID-19 entertainment news …

Alanis Morissette is among the special guests set to appear in next week’s finale of the new incarnation of “Fraggle Rock” on Apple TV Plus.

The Ottawa-born singer-songwriter will appear along with several other stars in the sixth instalment of “Fraggle Rock: Rock On!” next Tuesday.

She’ll sing the classic “Fraggle Rock” theme song, along with Common, Jason Mraz, Neil Patrick Harris, Tiffany Haddish, and Ziggy Marley.

The original 1980s version of the children’s puppet series from the Jim Henson Company was filmed in Toronto.

The new U.S.-shot series features mini episodes that have appeared every Tuesday for free on the streaming service since last month.

COVID-19 in sports …

Alberta’s Jason Kenney is the latest premier to make a pitch for his province to host National Hockey League games should the league resume play.

The league suspended its season in February and is now eyeing a format to complete it with an improvised playoff scenario. One possibility is a tournament of 24 teams spread over two hub cities.

Kenney says he is working with the Edmonton Oilers on a proposal to be a host city and expects to be discussing the issue later this week with NHL commissioner Gary Bettman.

He says Edmonton would be a prime location, given it has low COVID numbers and a new downtown rink with a hotel attached to provide an isolation safe zone for players.

“I think we’ve got a tremendous pitch to make,” Kenney says.

This report by The Canadian Press was first published May 20, 2020

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Guidance for diagnosing and managing migraine – News-Medical.Net



Migraine is a major cause of disability, affecting about 12% of people. A 2-part series published in CMAJ (Canadian Medical Association Journal) on diagnosing and managing the condition with both acute and preventive therapy provides guidance for clinicians.

“The goal of treatment of migraine attacks is to provide rapid relief from pain and other migraine-related symptoms, to restore patient function and to prevent recurrence,” writes Dr. Tommy Chan, Department of Clinical Neurological Sciences, Western University, London, Ontario, with coauthors.

“A stratified approach to treatment that empowers patients to choose from different options, depending on attack symptoms and severity, and encourages them to combine medications from different classes (e.g., nonsteroidal anti-inflammatory drugs and triptans) for severe or prolonged attacks, is preferred.”


Part 2 of the review, which will be published February 6, focuses on preventive treatment to reduce the frequency and severity of migraine attacks.

Journal reference:

Tzankova, V., et al. (2023) Diagnosis and acute management of migraine. Canadian Medical Association Journal.

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COVID-19 outbreak declared over at Petrolia’s hospital



A COVID-19 outbreak at Petrolia’s hospital has been declared over, Bluewater Health officials said Monday.

Diligent infection prevention and control measures were key in helping control the outbreak, declared Jan. 17, Bluewater Health officials said in a news release.

Hospital officials said the decision to declare the outbreak over was done in consultation with Lambton public health.

Bluewater Health Monday reported seven COVID-positive patients in Sarnia and Petrolia hospitals.


Bluewater Health’s policy allows a maximum of two visitors at the bedside at a time, officials said, noting visitors must wear masks and cannot have food or drink within patient rooms.


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Diagnosis and acute management of migraine




See related review article at (to be published February 6, 2023) and a first-person account of the difficulty of finding migraine treatment at


  • Migraine is a leading cause of disability across all age groups.

  • Routine imaging is not recommended in patients with migraine who have no red flags, atypical symptoms or abnormal findings on neurologic examination.

  • A stratified approach for acute migraine treatment empowers patients to choose from different treatment options depending on attack symptoms and severity and encourages patients to combine medications from different classes.

  • Effective acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs and triptans.

  • Ubrogepant and rimegepant are new, effective migraine treatments, suitable for patients with cardiovascular disease in whom triptans are contraindicated.

Migraine affects about 12% of adults, with a prevalence of 18% in women and 6% in men.13 Globally, in 2019, migraine was the second leading cause of disability among men and women across all age groups, and the leading cause of disability in women aged 15–49 years (expressed as years lived with disability). 4 In the United States, more than 70% of all migraine-related visits are to primary care providers,5 who play a central role in diagnosing and managing migraine. Recently, several new classes of migraine-specific medications have been shown to be effective and the evidence for the effectiveness of non-pharmacologic interventions is growing. In this article, we discuss the diagnosis and acute management of migraine, based on original research evidence, reviews and clinical practice guidelines (Box 1). We discuss prevention of migraine in a second article.6


Box 1: Evidence used in this review

We conducted a targeted search of Google Scholar and PubMed to identify original research, review articles and clinical practice guidelines published through November of 2021, using search terms that included, but were not limited to, “migraine acute treatment,” “migraine preventive treatment,” “migraine CGRP monoclonal antibodies,” “migraine 5-HT1F,” “migraine behavioural treatments” and “migraine neuromodulation.” We also consulted the most recent guidelines from the Canadian Headache Society and the American Headache Society, and the International Classification of Headache Disorders, 3rd edition.

What is the current understanding of migraine pathophysiology?

Migraine is characterized by neuronal hyperexcitability. Many genetic variants have been associated with increased susceptibility for migraine, suggesting a strong genetic basis.7 Migraine attacks can be broken down into 5 phases: prodrome, aura, headache, postdrome and interictal. However, not every migraine attack progresses through all phases (e.g., only one-third of people with migraine will experience aura) and the phases do not necessarily occur in succession (e.g., aura and headache can occur simultaneously).8,9

The pathophysiology of the headache phase is widely accepted to result from activation of the trigeminovascular pathway, which consists of peripheral trigeminal afferent nerves that innervate the dura and large cerebral arteries. When these neurons are stimulated, they release vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and transmit nociceptive signals to the trigeminal nucleus caudalis. Nociceptive signals from the trigeminal nucleus caudalis and the dorsal horn of the upper cervical roots (C1–C2) converge at the trigeminal cervical complex before being relayed to central structures involved in pain processing (brain stem, thalamus, hypothalamus, basal ganglia and cortex).8,9 Levels of CGRP increase during a migraine attack and decrease with treatment and between attacks, and CGRP infusion can trigger a migraine attack.10 Calcitonin gene-related peptide facilitates migraines through various mechanisms, including arterial vasodilation, inflammation in the dura, facilitation of neuronal signalling and modulation of nociceptive signal transmission at the trigeminal cervical complex.10 The hypothesis that migraine can be aborted or prevented by blocking the action of CGRP has been central to the development of drugs that target the CGRP ligand or receptor.11

What are the diagnostic criteria for migraine?

In the third edition of the International Classification of Headache Disorders (ICHD-3), migraine is subclassified into 6 categories: migraine without aura, migraine with aura, chronic migraine, complications of migraine, probable migraine and episodic syndromes that may be associated with migraine.12

Changes from ICHD-2 include modification of migraine with aura so that aura symptoms must meet 3 of 6 aura characteristics (at least 1 aura symptom spreads gradually over 5 min or more, 2 or more aura symptoms occur in succession, each individual aura symptom lasts 5–60 min, at least 1 aura symptom is unilateral, at least 1 aura symptom is positive, the aura is accompanied — or followed within 60 min — by headache), to better distinguish migraine aura from symptoms of transient ischemic attack.13 The diagnosis previously known as basilar artery migraine has been renamed “migraine with brain stem aura,” to reflect the low likelihood that the basilar artery is involved.12 Chronic migraine has been reclassified as a subtype of migraine rather than a complication of migraine, highlighting that it is a distinct entity with unique treatments. Although the diagnostic criteria for chronic migraine still require that headache be present on 15 or more days per month for more than 3 consecutive months, migraine-type headache need be present on only 8 of the headache days each month, in recognition that patients can often experience a mixture of headache phenotypes, including tension-type.12

The Visual Aura Rating Scale (VARS) has been validated for use in distinguishing migraine with visual aura from nonspecific visual symptoms and it has a 91% sensitivity and 96% specificity for diagnosis of visual aura when the score is ≥ 5. The 5 characteristics of the visual symptoms that make up the the scale are duration 6–60 minutes (3 points), develops gradually over 5 minutes or more (2 points), scotoma present (2 points), zigzag line present (2 points) and unilateral (1 point).14

The ID Migraine Screener, a tool that has been validated in primary care, screens for 3 key migraine-associated features: photophobia, functional impairment and nausea (with the mnemonic “PIN the diagnosis”). The screen is positive for migraine if the patient has 2 or more of the features, and a study of 563 patients presenting for routine primary care appointments and reporting headaches in the past 3 months found the sensitivity to be 0.81 (95% confidence interval [CI] 0.77–0.85), specificity to be 0.75 (95% CI 0.64–0.84) and the positive predictive value to be 0.93 (95% CI 0.54–0.82).15

When should imaging be ordered in patients with migraine?

For patients with stable headaches who meet criteria for migraine and have a normal neurologic examination, guidelines from the American College of Radiology and the American Headache Society strongly recommend against routine neuroimaging.16,17 A meta-analysis found that in such patients, the prevalence of important intracranial abnormalities on neuroimaging ranged from 0% to 3.1%, with a combined prevalence of 0.18% (upper 95% CI 0.59%).18 This is comparable to the prevalence of abnormalities detected on neuroimaging among the general population (neoplastic abnormalities 0.7% [95% CI 0.47%–0.98%], nonneoplastic abnormalities 2% [95% CI 1.10%–3.15%]).19 The detection of incidental findings can trigger undue patient anxiety and unnecessary investigations and procedures.16,17

Neuroimaging should be ordered in patients with an abnormal neurologic examination or red flags on history. Headache red flags consist of patient characteristics, features of the headache, and clinical symptoms or signs that should be assessed in every patient presenting with headache. The mnemonic SNOOP4 is a widely used, simple, yet comprehensive way to remember the headache red flags (Table 1).20,21 Neuroimaging should also be ordered in patients with unilateral headache that always occurs on the same side (side-locked), a feature of trigeminal autonomic cephalalgias, which can be mimicked by underlying central nervous system pathologies such as pituitary tumours, intracranial dissections or aneurysms, and infections; aura symptoms that are unusual, prolonged or persistent, a feature that could indicate an underlying lesion or seizure; and post-traumatic headache, because of the increased risk for intracranial hemorrhage or vascular injuries.17

Table 1:

Headache red flags — modified SNOOP420,21

Magnetic resonance imaging (MRI) is preferred over computed tomography (CT) as it provides better visualization of the brain parenchyma and is more sensitive in detecting subtle lesions.22 The use of contrast can further help with visualizing the brain parenchyma and meninges and should be considered when intracranial mass, infection or inflammation are suspected.16 However, CT is preferred when hemorrhages or fractures are suspected and should be performed first when there is concern for an acute abnormality and when MRI is not readily available.22 When headache is accompanied by optic disc edema, CT or MRI with venogram is suggested to rule out cerebral venous sinus thrombosis as a cause of high intracranial pressure.16 In some patients, additional investigations such as lumbar puncture, electroencephalogram and blood work may be indicated, but this is beyond the scope of this review. A comprehensive review of neuroimaging and workup of secondary causes of headache was recently published.23

What is the approach to acute treatment of a migraine attack?

The goal of treatment of migraine attacks is to provide rapid relief from pain and other migraine-related symptoms, to restore patient function and to prevent recurrence. Ideally, treatment should be self-administered, effective, well tolerated and affordable, and require minimal redosing.24 A stratified approach to treatment that empowers patients to choose from different options, depending on attack symptoms and severity, and encourages them to combine medications from different classes (e.g., nonsteroidal anti-inflammatory drugs and triptans) for severe or prolonged attacks, is preferred.25,26 Migraine attacks associated with mild disability can be treated with simple analgesics, with an additional dose of the same or a different agent in the next 2–24 hours, if needed. The Traffic Light of Headache is a tool that can help patients make acute treatment decisions using a stratified treatment plan, according to their level of functional impairment.27 All patients should be educated and screened for medication overuse, which can lead to medication-overuse headache and is a risk factor for transformation of episodic to chronic migraine.25,26

Classic pharmacologic acute treatments for migraine

Guidelines from the Canadian Headache Society and American Headache Society both indicate that acetaminophen, acetylsalicylic acid, diclofenac, ibuprofen, naproxen sodium and triptans have the highest level of evidence for treatment of migraine attacks (Table 2).26,28 Dihydroergotamine, which has been available for decades, can be useful as a first-line agent in some patients (patients with severe attacks or who do not respond well to triptans, or both). However, the Canadian Headache Society recommends against routine use of dihydroergotamine, given potential drug interactions and a high risk of vascular adverse effects, such as bradycardia and prolonged vasoconstriction (coronary, peripheral and central).26 Dihydroergotamine is contraindicated in patients who are pregnant or have a history of peripheral vascular disease, coronary artery disease, uncontrolled hypertension, stroke, sepsis, and renal or hepatic dysfunction.24 The Canadian Headache Society also strongly recommends against the routine use of combination analgesics containing codeine or tramadol, opioids, and butalbital-containing medications, owing to the high risk of sedation, dependence and the development of medication overuse headache.22,26

Table 2:

Traditional medications for acute migraine treatment26

New pharmacologic acute treatment of migraine

Two classes of orally administered small-molecule drugs have recently been approved by the US Food and Drug Administration for the treatment of migraine attacks with and without aura: ditans (lasmiditan) and gepants (ubrogepant and rimegepant) (Table 3). They can be used in patients with cardiovascular disease in whom triptans are contraindicated.2931 The gepants are currently being considered by Health Canada, but at the present time, lasmiditan will not be marketed in Canada.

Table 3:

New pharmacologic therapies for acute treatment of migraine, with or without aura

The safety and efficacy of each class of drug has been evaluated in phase 3, randomized, placebo-controlled trials, which assessed acute treatment response during a single migraine attack.29,30,3235 Study design and inclusion and exclusion criteria were similar across the trials. The co-primary outcomes were freedom from pain at 2 hours and resolution of the most bothersome migraine symptom at 2 hours. Inclusion criteria were a minimum 1-year history of migraine or migraine with aura, onset before age 50 years and 2–8 moderate-to-severe migraine headaches per month. Patients were excluded if they had 15 or more headache days per month, a history of medication overuse or a change in their baseline preventive treatment within the previous 3 months. Although patients with cardiovascular risk factors (e.g., obesity, diabetes, dyslipidemia, smoking) were included in all trials, patients with clinically important cardiovascular disease were excluded from all studies except 1 trial that evaluated lasmiditan.30 This is the most notable limitation of these studies, given that the greatest potential advantage of the ditans and gepants is their suitability for use in patients with clinically important cardiovascular disease in whom triptans are contraindicated.

Trial participants had a mean age between 40 and 42 years, 84.0%–88.0% were women and 75.0%–82.5% were white. All 3 drugs met the co-primary outcomes (freedom from pain at 2 h and resolution of the most bothersome migraine symptom at 2 h) compared with placebo, and treatment-related adverse effects were mild and transient (Table 3).29,30,3235 The most common adverse effects with the gepants were nausea, dizziness, dry mouth and dyspepsia.32,34 Open-label extension trials have not identified any long-term safety or tolerability concerns for up to 1 year.36,37 Dizziness and sedation were the most common adverse effects seen with lasmiditan, resulting in a label warning patients not to drive within 8 hours of its use (Table 3). Ongoing collection of real-world data is needed to monitor for emergence of additional potential adverse effects with use beyond 1 year.

No head-to-head studies have compared ditans or gepants with triptans. However, a recent systematic review and meta-analysis quantified the effect of lasmiditan, rimegepant and ubrogepant compared with triptans in treatment of migraine attacks.38 In terms of efficacy, triptans (except naratriptan 2.5 mg and almotriptan 6.25 mg) were more strongly associated with freedom from pain at 2 hours than lasmiditan (50 mg, 100 mg), rimegepant 75 mg and ubrogepant (50 mg, 100 mg). Patients treated with rizatriptan, sumatriptan and zolmitriptan had more adverse events than patients treated with rimegepant and ubrogepant.38 Patients treated with lasmiditan had more adverse events than most other treatments (triptans and gepants) at all doses, owing to a high incidence of dizziness and sedation. In summary, most triptans are more efficacious than the new drugs, but with similar or poorer tolerability than gepants. Lasmiditan appears to be associated with the most adverse events.

According to current evidence, triptans should remain the mainstay of acute treatment of migraines, while ditans and gepants can be alternatives for patients who cannot tolerate or do not respond well to triptans, as well as patients with cardiovascular disease in whom triptans are contraindicated. As of May 2021, rimegepant was also approved in the US for prevention for episodic migraine, making it the first oral medication with indications for both acute and preventive treatment, the latter being the subject of a subsequent article.6,33,35,39

What are the device- and procedure-related treatment options for migraine?

Neuromodulation devices and peripheral nerve blocks have a role in the management of a small number of patients with migraine. Evidence to support these is discussed in Appendix 1 (available at Neuromodulation devices, of which 2 are available in Canada, can be used alone or together with pharmacotherapy for the acute treatment of migraine. They are noninvasive and have minimal adverse effects. Peripheral nerve blockade with local anesthetic injection can be performed at various nerve branches of the trigeminocervical system and it is covered by most provincial public health plans in Canada.


Migraine is a leading cause of disability. Treatment of migraine attacks should aim to provide rapid relief from headache pain and related symptoms, restore patient functioning and prevent recurrence. Older medications remain effective, although newer medications may be preferred for certain groups of patients. In Box 2, we provide a practical clinical approach to management of the patient with migraine. Nonpharmacologic and pharmacologic approaches to the prevention of migraine will be discussed in a separate article.6

Box 2: A clinical approach to managing migraine

  • Identify that the primary headache type is migraine.

  • Order brain imaging to exclude secondary causes of headache if red flags or abnormalities on physical examination are present.

  • Categorize the disorder (episodic v. chronic migraine).

  • Identify comorbidities and exacerbating factors.

  • Assess disability and attack characteristics.

  • Review previous treatments, unmet needs and patient’s treatment goals.

  • Formulate a treatment plan.

    • Take a stratified approach to acute migraine treatment.

    • Individualized drugs: choose the medication best suited for the patient; with oral prevention drugs, start low and go slow.

    • Consider comorbidities and coverage for migraine prevention (e.g., consider an antidepressant if patient has comorbid psychological symptoms, avoid divalproex acid in people of childbearing age, be aware that calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) and onabotulinumtoxinA require a trial of at least 2 oral preventatives before they can be covered by public or private funding and that CGRP mAbs are approved for both episodic and chronic migraine, while onabotulinumtoxinA is approved only for chronic migraine).


  • Competing interests: Werner Becker reports receiving consulting fees from AbbView, Novartis, Lundbeck, Eli Lilly, Teva and McKesson, and honoraria for lectures, presentations, manuscript writing and educational events from AbbVie, Novartis, Weber and Weber, Lundbeck and Teva. Dr. Becker serves as a volunteer member on the board of Migraine Canada and on the board of the Pain Society of Alberta. In the past, he has served on the boards of the Canadian Headache Society and the American Headache Society. Tommy Lik Hang Chan reports receiving unrestricted education grants from AbbVie, Teva and Novartis; honoraria from AbbVie, Eli Lilly, Miravo and Novartis; and travel stipends for attending conferences and meetings from AbbVie. Dr. Chan is on the advisory board for AbbVie, Eli Lilly, Teva, Lundbeck, Miravo and Novartis. No other competing interests were declared.

  • This article was solicited and has been peer reviewed.

  • Contributors: All of the authors contributed to the conception and design of the work, drafted the manuscript, revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See:



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