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Wednesday, March 20, 2024

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Tuesday, March 19, 2024

• Role of Key Enzymes That Drive Cancer Mutations Discovered

Monday, March 18, 2024

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Two key brain systems are central to psychosis, Stanford Medicine-led study finds

When the brain has trouble filtering incoming information and predicting what’s likely to happen, psychosis can result, Stanford Medicine-led research shows.

April 11, 2024 - By Erin Digitale

People with psychosis have trouble filtering relevant information (mesh funnel) and predicting rewarding events (broken crystal ball), creating a complex inner world. Emily Moskal

Inside the brains of people with psychosis, two key systems are malfunctioning: a “filter” that directs attention toward important external events and internal thoughts, and a “predictor” composed of pathways that anticipate rewards.

Dysfunction of these systems makes it difficult to know what’s real, manifesting as hallucinations and delusions. 

The findings come from a Stanford Medicine-led study , published April 11 in  Molecular Psychiatry , that used brain scan data from children, teens and young adults with psychosis. The results confirm an existing theory of how breaks with reality occur.

“This work provides a good model for understanding the development and progression of schizophrenia, which is a challenging problem,” said lead author  Kaustubh Supekar , PhD, clinical associate professor of psychiatry and behavioral sciences.

The findings, observed in individuals with a rare genetic disease called 22q11.2 deletion syndrome who experience psychosis as well as in those with psychosis of unknown origin, advance scientists’ understanding of the underlying brain mechanisms and theoretical frameworks related to psychosis.

During psychosis, patients experience hallucinations, such as hearing voices, and hold delusional beliefs, such as thinking that people who are not real exist. Psychosis can occur on its own and isa hallmark of certain serious mental illnesses, including bipolar disorder and schizophrenia. Schizophrenia is also characterized by social withdrawal, disorganized thinking and speech, and a reduction in energy and motivation.

It is challenging to study how schizophrenia begins in the brain. The condition usually emerges in teens or young adults, most of whom soon begin taking antipsychotic medications to ease their symptoms. When researchers analyze brain scans from people with established schizophrenia, they cannot distinguish the effects of the disease from the effects of the medications. They also do not know how schizophrenia changes the brain as the disease progresses. 

To get an early view of the disease process, the Stanford Medicine team studied young people aged 6 to 39 with 22q11.2 deletion syndrome, a genetic condition with a 30% risk for psychosis, schizophrenia or both. 

Kaustubh Supekar

Brain function in 22q11.2 patients who have psychosis is similar to that in people with psychosis of unknown origin, they found. And these brain patterns matched what the researchers had previously theorized was generating psychosis symptoms.

“The brain patterns we identified support our theoretical models of how cognitive control systems malfunction in psychosis,” said senior study author  Vinod Menon , PhD, the Rachael L. and Walter F. Nichols, MD, Professor; a professor of psychiatry and behavioral sciences; and director of the  Stanford Cognitive and Systems Neuroscience Laboratory .

Thoughts that are not linked to reality can capture the brain’s cognitive control networks, he said. “This process derails the normal functioning of cognitive control, allowing intrusive thoughts to dominate, culminating in symptoms we recognize as psychosis.”

Cerebral sorting  

Normally, the brain’s cognitive filtering system — aka the salience network — works behind the scenes to selectively direct our attention to important internal thoughts and external events. With its help, we can dismiss irrational thoughts and unimportant events and focus on what’s real and meaningful to us, such as paying attention to traffic so we avoid a collision.

The ventral striatum, a small brain region, and associated brain pathways driven by dopamine, play an important role in predicting what will be rewarding or important. 

For the study, the researchers assembled as much functional MRI brain-scan data as possible from young people with 22q11.2 deletion syndrome, totaling 101 individuals scanned at three different universities. (The study also included brain scans from several comparison groups without 22q11.2 deletion syndrome: 120 people with early idiopathic psychosis, 101 people with autism, 123 with attention deficit/hyperactivity disorder and 411 healthy controls.) 

The genetic condition, characterized by deletion of part of the 22nd chromosome, affects 1 in every 2,000 to 4,000 people. In addition to the 30% risk of schizophrenia or psychosis, people with the syndrome can also have autism or attention deficit hyperactivity disorder, which is why these conditions were included in the comparison groups.

The researchers used a type of machine learning algorithm called a spatiotemporal deep neural network to characterize patterns of brain function in all patients with 22q11.2 deletion syndrome compared with healthy subjects. With a cohort of patients whose brains were scanned at the University of California, Los Angeles, they developed an algorithmic model that distinguished brain scans from people with 22q11.2 deletion syndrome versus those without it. The model predicted the syndrome with greater than 94% accuracy. They validated the model in additional groups of people with or without the genetic syndrome who had received brain scans at UC Davis and Pontificia Universidad Católica de Chile, showing that in these independent groups, the model sorted brain scans with 84% to 90% accuracy.

The researchers then used the model to investigate which brain features play the biggest role in psychosis. Prior studies of psychosis had not given consistent results, likely because their sample sizes were too small. 

Vinod Menon

Comparing brain scans from 22q11.2 deletion syndrome patients who had and did not have psychosis, the researchers showed that the brain areas contributing most to psychosis are the anterior insula (a key part of the salience network or “filter”) and the ventral striatum (the “reward predictor”); this was true for different cohorts of patients.

In comparing the brain features of people with 22q11.2 deletion syndrome and psychosis against people with psychosis of unknown origin, the model found significant overlap, indicating that these brain features are characteristic of psychosis in general.

A second mathematical model, trained to distinguish all subjects with 22q11.2 deletion syndrome and psychosis from those who have the genetic syndrome but without psychosis, selected brain scans from people with idiopathic psychosis with 77.5% accuracy, again supporting the idea that the brain’s filtering and predicting centers are key to psychosis.

Furthermore, this model was specific to psychosis: It could not classify people with idiopathic autism or ADHD.

“It was quite exciting to trace our steps back to our initial question — ‘What are the dysfunctional brain systems in schizophrenia?’ — and to discover similar patterns in this context,” Menon said. “At the neural level, the characteristics differentiating individuals with psychosis in 22q11.2 deletion syndrome are mirroring the pathways we’ve pinpointed in schizophrenia. This parallel reinforces our understanding of psychosis as a condition with identifiable and consistent brain signatures.” However, these brain signatures were not seen in people with the genetic syndrome but no psychosis, holding clues to future directions for research, he added.

Applications for treatment or prevention

In addition to supporting the scientists’ theory about how psychosis occurs, the findings have implications for understanding the condition — and possibly preventing it.

“One of my goals is to prevent or delay development of schizophrenia,” Supekar said. The fact that the new findings are consistent with the team’s prior research on which brain centers contribute most to schizophrenia in adults suggests there may be a way to prevent it, he said. “In schizophrenia, by the time of diagnosis, a lot of damage has already occurred in the brain, and it can be very difficult to change the course of the disease.”

“What we saw is that, early on, functional interactions among brain regions within the same brain systems are abnormal,” he added. “The abnormalities do not start when you are in your 20s; they are evident even when you are 7 or 8.”

Our discoveries underscore the importance of approaching people with psychosis with compassion.

The researchers plan to use existing treatments, such as transcranial magnetic stimulation or focused ultrasound, targeted at these brain centers in young people at risk of psychosis, such as those with 22q11.2 deletion syndrome or with two parents who have schizophrenia, to see if they prevent or delay the onset of the condition or lessen symptoms once they appear. 

The results also suggest that using functional MRI to monitor brain activity at the key centers could help scientists investigate how existing antipsychotic medications are working. 

Although it’s still puzzling why someone becomes untethered from reality — given how risky it seems for one’s well-being — the “how” is now understandable, Supekar said. “From a mechanistic point of view, it makes sense,” he said.

“Our discoveries underscore the importance of approaching people with psychosis with compassion,” Menon said, adding that his team hopes their work not only advances scientific understanding but also inspires a cultural shift toward empathy and support for those experiencing psychosis. 

“I recently had the privilege of engaging with individuals from our department’s early psychosis treatment group,” he said. “Their message was a clear and powerful: ‘We share more similarities than differences. Like anyone, we experience our own highs and lows.’ Their words were a heartfelt appeal for greater empathy and understanding toward those living with this condition. It was a call to view psychosis through a lens of empathy and solidarity.”

Researchers contributed to the study from UCLA, Clinica Alemana Universidad del Desarrollo, Pontificia Universidad Católica de Chile, the University of Oxford and UC Davis.

The study was funded by the Stanford Maternal and Child Health Research Institute’s Uytengsu-Hamilton 22q11 Neuropsychiatry Research Program, FONDEYCT (the National Fund for Scientific and Technological Development of the government of Chile), ANID-Chile (the Chilean National Agency for Research and Development) and the U.S. National Institutes of Health (grants AG072114, MH121069, MH085953 and MH101779).

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

Artificial intelligence

Exploring ways AI is applied to health care

MARK H. EBELL, MD, MS, AND ROLAND GRAD, MD, MSc

June 8, 2020 Editor's Note: The hypertension study (reference 5) is under investigation by the editor of the journal in which it was published due to inconsistencies in the data noted by others. Caution is warranted regarding applying these findings to clinical care.

Am Fam Physician. 2020;101(10):608-617

Author disclosure: Dr. Ebell is cofounder and editor-in-chief of Essential Evidence Plus. See Editor's Note . Dr. Grad has no relevant financial affiliations.

In 2019, regular surveillance of 110 English-language research journals identified 254 studies that met the criteria to become POEMs (patient-oriented evidence that matters). Physician members of the Canadian Medical Association rated these POEMs for their relevance to patients in their practices. This article summarizes the clinical questions and bottom-line answers from the top 20 POEMs of 2019. Taking blood pressure medications at night results in a large mortality reduction over six years compared with morning dosing. Automated devices are the best way to measure blood pressure. Nonfasting lipid profiles are preferred over fasting lipid profiles, and nonfasting and fasting lipid profiles are equally effective at predicting risk. The benefit of statins for primary prevention in people 75 years and older is uncertain at best. Aspirin has no net benefit for primary prevention of cardiovascular disease and has no effect on cancer outcomes. An Italian study found fecal immunochemical testing over five biennial screening cycles has a similar colorectal cancer yield as screening colonoscopy, whereas a meta-analysis found that taking aspirin, an anticoagulant, or a nonsteroidal anti-inflammatory drug has no impact on the positive predictive value of fecal immunochemical testing. Regarding infections, a meta-analysis showed that patients presenting with symptoms of acute respiratory tract infection are unlikely to have pneumonia if vital signs and the lung examination findings are normal. For streptococcal pharyngitis (strep throat), penicillin V at a dosage of 800 mg four times a day for five days is at least as effective as a dosage of 1,000 mg three times a day for 10 days. A primary care study in the United Kingdom reinforced that clinicians should counsel parents of children with lower respiratory tract symptoms to be patient, because these infections can take three weeks or more to fully resolve. Among direct oral anticoagulants, apixaban has the lowest bleeding risk, and cotreating with a proton pump inhibitor significantly reduces bleeding risk. Single ibuprofen doses from 400 to 800 mg significantly reduce acute pain to a similar degree. The two-dose recombinant zoster vaccine is much more effective than the single-dose live, attenuated vaccine but with a greater risk of injection site pain. Exercise helps reduce the risk of falls in older adults. Practice guidelines from 2019 on antithrombotics for atrial fibrillation, the management of type 2 diabetes mellitus, and screening for breast cancer were judged to be especially relevant.

Every year for the past 21 years, a team of experts in evidence-based medicine have systematically reviewed more than 110 English-language research journals to identify the original research most likely to change and improve primary care practice. The team includes experts in family medicine, pharmacology, hospital medicine, and women's health. 1 , 2

The goal of this process is to identify POEMs (patient-oriented evidence that matters). A POEM must report at least one patient-oriented outcome, such as improvement in symptoms, morbidity, or mortality. It should also be free of important methodologic bias, making the results valid and trustworthy. Finally, if applied in practice, the results would change what some family physicians do in patient care by prompting them to adopt a beneficial new practice or discontinue one that is ineffective or harmful. This should improve patient outcomes. Of more than 20,000 research studies published in 2019 in the journals reviewed by the POEMs team, 254 met criteria for validity, relevance, and practice change.

The Canadian Medical Association (CMA) purchases a subscription to POEMs for its members, many of whom receive the daily POEM by email. When members read a POEM, they can rate it with a validated questionnaire called the Information Assessment Method. POEM ratings address the domains of clinical relevance, cognitive impact, use in practice, and expected health benefits if that POEM were to be applied in patient care. 3 , 4 In 2019, each of the 254 POEMs were rated by an average of 1,530 physicians.

In this article, we present the 20 POEMs rated highest for clinical relevance by CMA members in 2019. This installment of our annual series ( https://www.aafp.org/afp/toppoems ) summarizes the clinical question and bottom-line answer for each research study identified as a top 20 POEM, organized by topic and followed by a brief discussion. We also present the three most relevant practice guidelines identified by CMA members. The full text of the POEMs in this article are available at https://www.aafp.org/journals/afp/content/top-poems/2019.html .

Hypertension

Hypertension is among the most common conditions managed by primary care physicians and is the topic of the two POEMs rated most relevant to readers in 2019 ( Table 1 ) . 5 , 6 Researchers randomized 19,168 adults with hypertension to take their antihypertensive medications at bedtime or first thing in the morning. 5 Patients were prescribed an antihypertensive from an approved list of the most common therapies. Patients taking their medications at bedtime had a lower likelihood of the composite outcome of myocardial infarction (MI), coronary revascularization, heart failure, stroke, or cardiovascular death (hazard ratio = 0.55; 95% CI, 0.50 to 0.61; number needed to treat to prevent one event over 6.3 years = 20). All-cause mortality was reduced to a similar extent. This is a large effect for a six-year study, and a practice-changer for many patients and physicians. Best of all, it costs nothing to make this change. See Editor's Note

How we measure blood pressure continues to be a subject of research. The next POEM was a meta-analysis of 31 studies, which included a total of 9,279 patients and compared automated in-office blood pressure readings with in-office manual measurements or ambulatory automated recordings during waking hours (the reference standard). 6 Automated in-office measurements were performed without anyone present to activate the machine and used three to five readings separated by one- to two-minutes. Ambulatory automated measurements were 13.4/5.9 mm Hg lower than the manual in-office measurements and were similar to the in-office automated measurements. To avoid starting or intensifying antihypertensive medication unnecessarily, it is critical to measure blood pressure using an automated device. Patients should also bring in their home device so that it can be calibrated with the office device.

Behavioral Medicine

Behavioral medicine POEMs are summarized in Table 2 . 7 – 9 The first POEM in this group was a well-executed network meta-analysis of medical therapy for generalized anxiety disorder. 7 A network meta-analysis includes studies comparing drugs with each other and with placebo, allowing for direct and indirect comparisons. The meta-analysis included 89 studies involving 25,000 patients and 22 different drugs; none of the studies were longer than 26 weeks. After excluding drugs that were poorly tolerated such as quetiapine (Seroquel), paroxetine (Paxil), and benzodiazepines, the most effective commercially available drugs overall were, in order of effectiveness, bupropion (Wellbutrin), duloxetine (Cymbalta), mirtazapine (Remeron), hydroxyzine, sertraline (Zoloft), pregabalin (Lyrica), venlafaxine, escitalopram (Lexapro), fluoxetine (Prozac), buspirone (Buspar), and citalopram (Celexa). Drugs that did not significantly decrease anxiety scores included imipramine, maprotiline, opipramol (not available in the United States), tiagabine (Gabitril), vilazodone (Viibryd), and vortioxetine (Trintellix). The drugs with the best combination of effectiveness and tolerability were duloxetine, pregabalin, venlafaxine, and escitalopram.

The next POEM included videotaped encounters between 252 patients and 15 English primary care physicians. 8 Patients were asked about the main reason for their visit beforehand, and this reason was almost always addressed during the visit. However, of the 139 patients who identified at least one symptom in the previsit interview, 43 failed to disclose a total of 67 symptoms during the visit, most often stress, worries or sadness; tiredness or sleep problems; problems passing urine; headache; and intimate or other personal problems. Although physicians cannot ask every patient about all of their problems during a visit, it is important to know that patients may not fully disclose symptoms. Physicians should make patients feel as safe as possible while looking for cues to undisclosed symptoms, and routinely asking, “Is there anything else I can help you with?”

The last POEM in the behavioral medicine group was an individual patient data meta-analysis of how early treatment response impacts later outcomes in patients with depression. 9 The researchers combined the individual patient data from 30 randomized trials, with 2,184 patients receiving placebo and 6,058 receiving active therapy. After six weeks of treatment, about 50% of patients in the active treatment group responded to treatment, with 32% achieving remission of symptoms. Response was defined as at least a 50% reduction in the Hamilton Rating Scale for Depression score, and remission was defined as a score of 7 points or less. By 12 weeks, the response rate was 68% in the active treatment group, with 49% achieving remission. Patients with improvement at two weeks were more likely to respond by six weeks, whereas among patients without early improvement, 33% responded by six weeks and 43% by 12 weeks. The absence of an early response does not preclude later response; therefore, physicians should not be too quick to change antidepressant medications.

Cardiovascular

Cardiovascular medicine POEMs are summarized in Table 3 . 10 – 14 The first two POEMs in this group address statin use. Many physicians and laboratory staff continue to insist that patients be fasting for lipid profile testing. The first POEM compared fasting and nonfasting lipid profiles in the same patients four weeks apart. 10 There was little difference between fasting and nonfasting measurements of low-density and high-density lipoprotein cholesterol levels and only a small increase in triglyceride levels (25 mg per dL [0.28 mmol per L]) with nonfasting measurements. Most importantly, the association between lipid levels and subsequent cardiovascular events was identical for fasting and nonfasting lipid measurements. Guidelines support nonfasting lipid measurements. 15 , 16 It is time to simplify our patients' lives and educate local laboratory staff, who often turn away patients who disclose that they are not fasting.

In the next POEM, data were pooled from 28 randomized trials of statins with more than 186,000 total patients. 11 This report focused on the 14,000 patients who were 75 years or older; the median follow-up was five years. There was only a small reduction in the composite outcome of MI and cardiovascular death among all patients (2.6% with statins vs. 3.0% with placebo; number needed to treat = 250 per year); the benefit was significant only in patients with preexisting cardiovascular disease. Statins had no effect on revascularization, stroke, cancer incidence, or cancer mortality.

This was a big year for aspirin studies. The next three POEMs, from two separate trials, examine the benefits and harms of aspirin therapy for primary prevention in contemporary populations. Prior studies that found a net benefit of aspirin for the primary prevention of cardiovascular disease and cancer (mostly colorectal) all recruited patients before 2002. In more recent years, fewer patients smoke or have uncontrolled hypertension, more are taking a statin, and we have widespread colorectal cancer screening. In this context, does aspirin still have a role?

Two aspirin POEMs were from the ASPREE (Aspirin in Reducing Events in the Elderly) trial, which included 19,114 adults 70 years and older in the United States and Australia (65 and older if black or Hispanic). Patients without known cardiovascular disease were randomized to aspirin, 100 mg, or placebo and were followed for a median of 4.7 years. The first POEM found no significant reduction in the likelihood of cardiovascular disease with aspirin, including fatal cardiovascular disease, fatal or nonfatal MI, and fatal or nonfatal ischemic stroke. However, they found a significant increase in major hemorrhages with aspirin. 12 The second POEM from the ASPREE trial found no difference between groups for disability-free survival, defined as a composite of death, dementia, or persistent physical disability. 13 A separate report from the ASPREE investigators (not one of the top 20 POEMs) found an increase in all-cause mortality with aspirin, primarily due to a significant increase in cancer-specific mortality (3.1% vs. 2.3%).

The third aspirin POEM was from the ASCEND (A Study of Cardiovascular Events in Diabetes) trial and included 15,480 adults 40 years and older with diabetes mellitus but no known cardiovascular disease. The patients were randomized to aspirin, 100 mg, or placebo and were followed for a median of 7.4 years. 14 There was a reduction in the composite of nonfatal MI, nonfatal stroke, or cardiovascular death with aspirin, but a corresponding increase in major hemorrhage with no effect on cardiovascular or all-cause mortality.

What do we tell our patients? A recent meta-analysis compared trials of aspirin therapy that recruited patients from 1978 to 2002 with four large trials that recruited patients since 2005. 17 The newer studies showed fewer cardiovascular benefits and no reduction in cancer incidence or mortality with aspirin as primary prevention. Based on a meta-analysis of the four most recent studies with a total of 61,604 patients, for every 1,200 patients taking aspirin instead of placebo for five years, there would be four fewer major cardiovascular events and three fewer ischemic strokes but eight more major hemorrhages, including three more intracranial hemorrhages. This study agrees with recent European guidelines that no longer recommend aspirin for primary prevention. 18 The 2016 U.S. Preventive Services Task Force (USPSTF) and 2019 American College of Cardiology guidelines recommend consideration of aspirin for primary prevention only in selected patients at high cardiovascular risk and low bleeding risk. 19 , 20 The USPSTF recommendation is currently being updated. 21

Cancer Screening

The three POEMs on cancer screening ( Table 4 ) address colorectal cancer. 22 – 24 Fecal immunochemical testing (FIT) is the recommended method for colorectal cancer screening in most countries that have screening programs and is the subject of the first two POEMs in this group. The first POEM is an Italian study that reported the diagnostic yield of five rounds of biennial FIT in persons 50 to 69 years of age submitting a single specimen. 22 The highest rates of detection occurred in the first round, as prevalent cancers were detected, and declined and then stabilized in later rounds. Over the 10-year study, about 25% of men and 18% of women had a positive test result requiring a follow-up colonoscopy. The cumulative rate was 6% for advanced adenoma and 0.85% for colorectal cancer, which are similar to findings in studies of colonoscopy in Italy and the United States. 25 , 26 These results mean we can have confidence in FIT as a screening test while we wait for the results of ongoing randomized trials of FIT vs. colonoscopy-based screening.

The second POEM about FIT was a meta-analysis evaluating the impact of aspirin, nonsteroidal anti-inflammatory drugs, and anticoagulants on the positive predictive value of the test. 23 It could theoretically go in either direction, increasing false positives by making noncancerous lesions more likely to bleed or increasing true positives by making cancers and adenomas more likely to bleed. The researchers found that the use of any of these medications had almost no effect on the positive predictive value, which was approximately 6% for colorectal cancer and 40% for advanced neoplasia. FIT requires only a single specimen and no dietary preparation, and now we know that patients undergoing FIT can continue to take medications that increase bleeding risk.

Finally, a study used a Swedish cancer registry with 173,796 patients to determine the impact of family history on the risk of colorectal cancer. 24 The relative risk of colorectal cancer using no affected relatives as the reference was 1.2 for a single second-degree relative with a history of colorectal cancer, 1.6 for a single first-degree relative or two second-degree relatives, 2.3 for one first-degree relative and one second-degree relative, 2.5 for two first-degree relatives, and 5.4 for one first-degree and two second-degree relatives. However, a previous study found that this family history–related risk is attenuated once patients reach 55 years of age. 27

POEMs on managing infections are summarized in Table 5 . 28 – 30 The first POEM is a meta-analysis of studies that recruited outpatients with acute respiratory tract infections who received chest radiography. 28 The goal was to identify the best sign, symptom, or combination that allows clinicians to rule out community-acquired pneumonia (CAP). The researchers found that for patients with the combination of normal vital signs and normal lung examination findings, the likelihood of CAP is low at 0.4%. This could help reduce unnecessary chest radiography if applied consistently.

The second POEM in this group was selected as one of the top three research studies out of more than 400 presented at the 2019 North American Primary Care Research Group meeting. 29 This Swedish study included 422 adults and children presenting to a primary care physician with moderately severe streptococcal pharyngitis (strep throat). Patients were randomized to penicillin V at a dosage of 800 mg four times a day for five days or 1,000 mg three times a day for 10 days. Those receiving the higher dose over a shorter course of treatment had similar cure rates as those receiving longer-duration therapy, with quicker symptom resolution and no increase in recurrence. Many other studies have found similar results with antibiotics for a range of infections.

An accurate prognosis can potentially help patients avoid unnecessary antibiotic use and return visits. The third POEM in this group recruited 485 healthy children in the United Kingdom, and parents were instructed to contact the researchers every time the child had a respiratory tract infection. 30 One-half of the children had at least one infection, with a median duration of nine days; 90% recovered by day 23. Lower respiratory tract infections were associated with a longer duration of symptoms and ear infections were associated with a shorter duration. This reinforces that clinicians should counsel parents of children with lower respiratory tract symptoms to be patient.

Miscellaneous

Four additional POEMs are summarized in Table 6 . 31 – 34 The first is a cohort study of more than 1.6 million Medicare beneficiaries who started an anticoagulant between 2011 and 2015. 31 Bleeding rates were compared, adjusting for available covariates using propensity score matching (i.e., matching patients who were similar other than choice of anticoagulant). The adjusted incidence of hospitalization for upper gastrointestinal tract bleeding was significantly higher in those who received rivaroxaban (Xarelto) compared with those who received dabigatran (Pradaxa), warfarin (Coumadin), or apixaban (Eliquis); 144 per 10,000 person-years vs. 120, 113, and 73, respectively). For all agents combined, adding a proton pump inhibitor significantly reduced bleeding risk (76 out of 10,000 per year vs. 115 out of 10,000 per year; number needed to treat = 256), although rivaroxaban still had the highest bleeding rate.

The next POEM identified 225 adults presenting to the emergency department with acute pain (mostly musculoskeletal); the average pain score was 6 to 7 out of 10. 32 They were then randomized to a single dose of 400-mg, 600-mg, or 800-mg ibuprofen. An hour after taking the medication, there was no difference between groups, which all had pain scores between 4.4 and 4.5.

The third POEM in this group is a meta-analysis of studies comparing two doses of the recombinant zoster vaccine (Shingrix) with one dose of the live, attenuated vaccine (Zostavax) for the prevention of shingles. 33 Shingrix was more effective but caused more systemic adverse events, although mild, and more injection site pain.

Finally, a systematic review identified 46 studies of the impact of exercise on fall risk in patients 59 years or older. 34 Most of the programs used moderate-intensity exercise, with about one hour of exercise three times per week. The researchers found that exercise significantly decreased the overall risk of falls and resulting injuries but did not affect the risk of multiple falls, hospitalization, or mortality. Fractures were less likely in the exercise group but not significantly.

Practice Guidelines

POEMs sometimes summarize high-impact practice guidelines from important organizations. Key messages from the three highest-rated guidelines are summarized in Table 7 . 35 – 37

The American College of Chest Physicians recommends initiating direct oral anticoagulant therapy in patients with newly diagnosed atrial fibrillation, avoiding aspirin or aspirin plus clopidogrel (Plavix) to prevent thromboembolism, using risk scores for stroke and bleeding, and avoiding cotreatment with aspirin and an anticoagulant if possible. 35

The American Diabetes Association/European Association for the Study of Diabetes guideline for type 2 diabetes mellitus continues to recommend educating patients about diabetes self-management and providing support as the cornerstone of therapy, and metformin as the preferred initial therapy. 36 If a second agent is needed, there are many options, although glucagon-like peptide 1 receptor antagonists or sodium-glucose cotransporter 2 inhibitors are recommended for patients with established heart disease; sodium-glucose cotransporter 2 inhibitors are preferred for patients with heart failure or chronic kidney disease.

The American College of Physicians recommendations for breast cancer screening generally parallel those of the USPSTF, which are supported by the American Academy of Family Physicians. Recommendations include shared decision-making in women 40 to 49 years of age, biennial mammography from 50 to 74 years of age or until the woman's life expectancy is less than 10 years, and eliminating the clinical breast examination as a screening test for women who undergo regular mammography. 37 – 39

The full text of the POEMs discussed in this article is available at https://www.aafp.org/journals/afp/content/top-poems/2019.html .

A list of top POEMs from previous years is available at https://www.aafp.org/afp/toppoems .

Editor's Note: This article was cowritten by Dr. Mark Ebell, who is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell, Inc. Because of Dr. Ebell's dual roles and ties to Essential Evidence Plus, the concept for this article was independently reviewed and approved by a group of AFP 's medical editors. In addition, the article underwent peer review and editing by three of AFP 's medical editors. Dr. Ebell was not involved in the editorial decision-making process.—Sumi Sexton, MD, Editor-in-Chief.

The authors thank Wiley-Blackwell, Inc., for giving permission to excerpt the POEMs; Drs. Allen Shaughnessy, Henry Barry, David Slawson, Nita Kulkarni, and Linda Speer for their work in selecting and writing the original POEMs; the academic family medicine fellows and faculty of the University of Missouri–Columbia for their work as peer reviewers; Pierre Pluye, PhD, for his work in codeveloping the Information Assessment Method; and Maria Vlasak for her assistance with copyediting the POEMs for the past 26 years.

Shaughnessy AF, Slawson DC, Bennett JH. Becoming an information master: a guidebook to the medical information jungle. J Fam Pract. 1994;39(5):489-499.

Ebell MH, Barry HC, Slawson DC, et al. Finding POEMs in the medical literature. J Fam Pract. 1999;48(5):350-355.

Grad RM, Pluye P, Mercer J, et al. Impact of research-based synopses delivered as daily e-mail: a prospective observational study. J Am Med Inform Assoc. 2008;15(2):240-245.

Pluye P, Grad RM, Johnson-Lafleur J, et al. Evaluation of email alerts in practice: Part 2. Validation of the information assessment method. J Eval Clin Pract. 2010;16(6):1236-1243.

• Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial [published online October 22, 2019]. Eur Heart J . 2019. Accessed March 10, 2020. https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehz754/5602478

Roerecke M, Kaczorowski J, Myers MG. Comparing automated office blood pressure readings with other methods of blood pressure measurement for identifying patients with possible hypertension. A systematic review and meta-analysis. JAMA Intern Med. 2019;179(3):351-362.

Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder [published correction appears in Lancet . 2019;393(10182):1698]. Lancet. 2019;393(10173):768-777.

Paskins Z, Sanders T, Croft PR, et al. Non-disclosure of symptoms in primary care: an observational study. Fam Pract. 2018;35(6):706-711.

de Vries YA, Roest AM, Bos EH, et al. Predicting antidepressant response by monitoring early improvement of individual symptoms of depression: individual patient data meta-analysis. Br J Psychiatry. 2019;214(1):4-10.

Mora S, Chang CL, Moorthy MV, et al. Association of nonfasting vs fasting lipid levels with risk of major coronary events in the Anglo-Scandinavian Cardiac Outcomes Trial–lipid lowering arm. JAMA Intern Med. 2019;179(7):898-905.

Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407-415.

McNeil JJ, Wolfe R, Woods RL, et al.; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509-1518.

McNeil JJ, Woods RL, Nelson MR, et al.; ASPREE Investigator Group. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379(16):1499-1508.

Bowman L, Mafham M, Wallendszus K, et al.; ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529-1539.

Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile—a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016;37(25):1944-1958.

Grundy SM, Stone NJ. 2018 cholesterol clinical practice guidelines: Synopsis of the 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline. Ann Intern Med. 2019;170(11):779-783.

Moriarty F, Ebell MH. A comparison of contemporary versus older studies of aspirin for primary prevention [published online November 21, 2019]. Fam Pract . 2019. Accessed March 10, 2020. https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmz080/5637484

Piepoli MF, Hoes AW, Agewall S, et al.; The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2016;37(29):2315-2381.

Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in J Am Coll Cardiol . 2019;74(10):1429–1430]. J Am Coll Cardiol. 2019;74(10):e177-e232.

Bibbins-Domingo K. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164(12):836-845.

U.S. Preventive Services Task Force. Aspirin use to prevent cardiovascular disease and colorectal cancer: preventive medication. April 2016. Accessed February 14, 2010. https://bit.ly/343LnT6

Zorzi M, Hassan C, Capodaglio G, et al. Long-term performance of colorectal cancer screening programmes based on the faecal immunochemical test. Gut. 2018;67(12):2124-2130.

Nieuwenburg SAV, Vuik FER, Kruip MJHA, et al. Effect of anticoagulants and NSAIDs on accuracy of faecal immunochemical tests (FITs) in colorectal cancer screening: a systematic review and meta-analysis. Gut. 2019;68(5):866-872.

Tian Y, Kharazmi E, Sundquist K, et al. Familial colorectal cancer risk in half siblings and siblings: nationwide cohort study. BMJ. 2019;364:l803.

Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.

Segnan N, Senore C, Andreoni B, et al. Comparing attendance and detection rate of colonoscopy with sigmoidoscopy and FIT for colorectal cancer screening. Gastroenterology. 2007;132(7):2304-2312.

Schoen RE, Razzak A, Yu KJ, et al. Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer. Gastroenterology. 2015;149(6):1438-1445.e1.

Marchello CS, Ebell MH, Dale AP, et al. Signs and symptoms that rule out community-acquired pneumonia in outpatient adults: a systematic review and meta-analysis. J Am Board Fam Med. 2019;32(2):234-247.

Skoog Ståhlgren G, Tyrstrup M, Edlund C, et al. Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study. BMJ. 2019;367:l5337.

Hay AD, Anderson E, Ingle S, et al. Respiratory tract infections in children in the community: prospective online inception cohort study. Ann Fam Med. 2019;17(1):14-22.

Ray WA, Chung CP, Murray KT, et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA. 2018;320(21):2221-2230.

Motov S, Masoudi A, Drapkin J, et al. Comparison of oral ibuprofen at three single-dose regimens for treating acute pain in the emergency department: a randomized controlled trial. Ann Emerg Med. 2019;74(4):530-537.

Tricco AC, Zarin W, Cardoso R, et al. Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50 and older: systematic review and network meta-analysis. BMJ. 2018;363:k4029.

de Souto Barreto P, Rolland Y, Vellas B, et al. Association of long-term exercise training with risk of falls, fractures, hospitalizations, and mortality in older adults. A systematic review and meta-analysis. JAMA Intern Med. 2019;179(3):394-405.

Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest. 2018;154(5):1121-1201.

Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.

Qaseem A, Lin JS, Mustafa RA, et al. Screening for breast cancer in average-risk women: a guidance statement from the American College of Physicians. Ann Intern Med. 2019;170(8):547-560.

U.S. Preventive Services Task Force. Breast cancer: screening. January 2016. Accessed February 14, 2020. https://bit.ly/2ykUZwU

American Academy of Family Physicians. Clinical preventive service recommendation. Breast cancer. Accessed February 14, 2020. https://www.aafp.org/patient-care/clinical-recommendations/all/breast-cancer.html

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April 15, 2024

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Canada likely to miss WHO's hepatitis C elimination target, research shows

by University of Waterloo

Canada will not reach the original World Health Organization's (WHO) target of eliminating the hepatitis C virus (HCV) by 2030 and lags in comparison to other developed countries, a new study led by researchers at the University of Waterloo has found.

HCV is an infection that poses a major public health threat that affects an estimated 250,000 Canadians—despite having a highly effective medication.

When gone unscreened, HCV is a highly debilitating infection that causes liver failure and could lead to death. Due to its asymptomatic nature, it is also known as a silent killer to those infected with the virus. The infection typically spreads through contact with an infected person's blood, most commonly through needle sharing.

"There is no model in Canada to track the elimination process," said Dr. William W.L. Wong, associate professor at Waterloo's School of Pharmacy, which offers the most innovative pharmacy curriculum in North America by integrating biomedical and pharmacy science with clinical, behavioral and social sciences to emphasize patient-focused care.

Wong, the study's lead author and newly appointed 2024 Applied Public Health Chair, added, "We are not likely to reach the WHO goal of eliminating HCV by 2030 if screening and treatment are the only focus for policymakers. We need to screen for the disease earlier and encourage harm-reduction strategies be put in place. If patients do not change high-risk behaviors, such as sharing needles, HCV re-infection can be high even after they were cured the first time."

Wong used a novel mathematical modeling system to help determine how Canada's progress would fare to eradicate HCV. Based on Wong's model, reaching the WHO goals by 2030 will be impossible if the current status quo treatment and screening policies don't change.

"Picture a game, such as The Sims, where you build a dynamic population," Wong said. "Similar to the game, we simulated Ontario's population, including those with HCV. We looked at how the disease is transmitted and how it moves around the population with different risk activities triggered."

The researchers suggest that policymakers should consider harm-reduction strategies such as implementing clean needle distributions, reducing the sharing of drug use equipment and other high-risk exposures.

The researchers will be integrating future work with other sexually transmitted and blood-borne infections, including hepatitis B virus, human papillomavirus and HIV.

The study, " Feasibility of hepatitis C elimination by screening and treatment alone in high-income countries ," was recently published in the journal Hepatology .

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