A 3-part series on the manifestations of physician burnout, how COVID-19 changed its scope and revealed systemic fractures, and finally, the path towards resolution and reformation. 

Crisis Point: The Physician Burnout Crisis

. Prior to joining MJH Life Sciences in 2019, he worked as a digital reporter covering nanotechnology, life sciences, material science and more with 

. He graduated with a degree in journalism from Temple University in 2008 and began his career as a local reporter for a chain of weekly newspapers based on the Jersey shore. When not working, he enjoys going to the beach and enjoying the shore in the summer and watching North Carolina Tar Heel basketball in the winter.

Folic acid prescriptions result in a significant drop in 

 and overall suicidal events, according to new research.

A team, led by Robert D. Gibbons, PhD, University of Chicago, confirmed a previous signal for a decreased risk of suicide attempts after prescription fills for folic acid.

Overall, suicides have increased by more than 30% in the US between 2000-2018.

“An inexpensive, safe, widely available treatment for preventing suicidal behavior could reverse this trend,” the authors wrote.

In the national pharmacoepidemiologic study, the investigators examined data from 866,586 patients treated with folic acid with a within-person exposure only cohort design to identify the dynamic association between folic acid prescription fills over a 24-month time period and suicide attempts and intentional self-harm.

Of the more than 850,000 patients with data included in the analysis, 81.30% (n = 704,514) were female and 10.42% (n = 90,296) were aged 60 years or older.

The team used a pharmacoepidemiologic database of US medical claims to identify patients with private health insurance who filled a folic acid prescription between 2012-2017. They then repeated the analysis with a control supplement of cyanocobalamin.

The investigators sought main outcomes of suicide attempts or intentional self-harm resulting in an outpatient visit or inpatient admission as identified by codes from the 

International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification

The analysis shows 261 suicidal events during months covered by a folic acid prescription (5,512,597 person-months. The rate of suicidal events was 4.73 events per 100,000 person-months. This was lower than the 895 suicidal events during months without folic acid (8,432,340 person-months) for a rate of 10.61 suicidal events per 100,000 person-months.

After adjusting for age and sex, the investigators found diagnoses related to suicidal behavior, folic acid deficiency, folate-reducing medications, history of folate-reducing medications, and history of suicidal events yielded a hazard ratio for folic acid for suicide events of 0.56 (95% CI, 0.48-0.65).

There were similar results for modal dosage of 1 mg of folic acid per day (HR, 0.57; 95% CI, 0.48-0.69) and women of childbearing age (HR, 0.60; 95% CI, 0.50-0.73).

However, a further duration-response analysis of 1-mg dosage produced a 5% decrease in suicidal events per month of additional treatment (HR, 0.95; 95% CI, 0.93-0.97) and the same analysis for cyanocobalamin showed no association with suicide attempts (HR, 1.01; 95% CI, 0.80-1.27).

“This large-scale pharmacoepidemiologic study of folic acid found a beneficial association in terms of lower rates of suicide attempts,” the authors wrote. “The results warrant the conduct of a randomized clinical trial with suicidal ideation and behavior as outcomes of interest. If confirmed, folic acid may be a safe, inexpensive, and widely available treatment for suicidal ideation and behavior.”

Association Between Folic Acid Prescription Fills and Suicide Attempts and Intentional Self-harm Among Privately Insured US Adults

Articles

A duration-response analysis of 1-mg dosage produced a 5% decrease in suicidal events per month of additional treatment.

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Folic Acid Decreases Rate of Suicidal Attempts

Tim Smith joined the MJH Life Sciences team as an assistant editor for HCPLive in August 2022. He graduated from UC Berkeley with a degree in political science, working in multimedia journalism as a staff writer prior to joining MJH. In his spare time, he enjoys reading, watching TV, listening to podcasts, and rock climbing. You can contact him at 

A recent study found that 8-weeks of apremilast and phototherapy as a combined treatment may be sufficient with 

, but it may require a longer regimen length.

Patients with moderate to severe psoriasis vulgaris are frequently 

 with apremilast—an oral phosphodiesterase-4 inhibitor—and phototherapy. However, their combined use’s safety and efficacy were not viewed to be properly studied prior to this research.

This study into their combined use was led by Akimichi Morita of the Nagoya City University Graduate School of Medical Sciences Department of Geriatric and Environmental Dermatology.

“Phototherapy has many advantages in the treatment of psoriasis, but continued use is inconvenient because the effects of the therapy appear only after a long time, and patients are required to frequently visit the clinic for irradiation,” Morita and colleagues wrote. “In this study, the combination of apremilast and phototherapy demonstrated sufficient therapeutic effects in psoriasis despite the reduced frequency of visits to the clinic, which may have considerable implications in clinical practice.”

The investigators’ research compared the safety and efficacy of only phototherapy (monotherapy) with that of the combination of apremilast and phototherapy (combination).

The investigators used a multicenter, randomized active-controlled study that was open-label and parallel-group, through 4 institutions in Japan between November of 2018 and February of 2020. Inclusion criteria for patients consisted of being 20 to 80 years old, having a moderate to severe psoriasis vulgaris diagnosis, and having an inadequate topical treatment response.

The researchers’ primary endpoint for the study—from baseline to 8 weeks of treatment—was a Psoriasis Area and Severity Index (PASI) score improvement rate. There were 7 secondary endpoints for their research, including:

The PASI score and improvement rate from baseline to 4 and 8 weeks after treatment;

Number and percentage of patients achieving PASI scores with ≥90%, ≥75%, and ≥50% improvements, or PASI90, PASI75, and PASI50

PASI score changes from baseline to each evaluation time point

BSA changes from baseline to each evaluation time point;

sPGA scores at baseline and at each time point;

Percentage of study participants having an sPGA score of 0 (disappeared) or 1 (almost disappeared)

Changes in EuroQol 5-dimensions 5-level (EQ-5D-5L), Dermatology Life Quality Index (DLQI), and visual analog scale (VAS) scores regarding itchiness from baseline to each evaluation time point

The investigators had the patients receive apremilast as 10, then 20, then 30, then 40, then 50 mg of apremilast on the first 5 days of the study, with 60 mg each day beginning on the sixth day. For phototherapy, NB-UVB treatment was administered 2 times per week.

In total, there were 42 participants recruited for the study, with 29 in the combination arm and 13 in the monotherapy arm. The results of the study found that the combination group reported significantly lower PASI scores by 4 and 8 weeks. The combination group also reported more patients achieving a PASI score improvement of ≥75% by 8 weeks.

By week 8, they did not observe a statistically significant difference between both groups. The investigators found that both the combination and the monotherapy group had a significant decrease in BSA. The combination group data leaned toward a greater BSA reduction. Adverse events (AEs) were also reported more often in the combination arm than the monotherapy arm of the study.

“Our findings indicate that phototherapy as monotherapy was insufficient in patients with high baseline BSA, and concomitant administration of apremilast improved the outcomes,” they wrote. “However, an 8-week treatment regimen may be insufficient for inducing subjective improvement.”

Efficacy and safety of apremilast and phototherapy versus phototherapy only in psoriasis vulgaris

A combination therapy approach may be useful for psoriasis treatment, though an 8-week regimen may not be long enough.

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Study Suggests Combination of Phototherapy, Apremilast Effective for Psoriasis Vulgaris

 Matt, for some of the complications that we’ve alluded to in this discussion, in terms of patients with sickle cell disease who have inherently unhealthy red blood cells for a number of reasons, how does this affect the patient’s quality of life?

 In sickle cell disease, when you think about the major symptoms and consequences, we think about frequent pain that disables you in a way that you’re unable to do your activities of daily living: to go to school or work. That can wreak havoc on your quality of life in terms of the things you want to be, your dreams, and your aspirations. That can have a huge effect on day-to-day quality of life, moods, etc. There’s a huge impact on that. Unpredictability of those events interferes with one’s hopes, dreams, and aspirations.

More chronically, this is a hemolytic anemia. Patients often have a low-baseline hemoglobin, with exertional fatigue, which an inability to do what they need to do or want to do. Some may need to limit themselves from what they see their peers doing. All of that has a way of singling you out as a child. As an adult, you may be completely able 95% of the time but 100% disabled 5% of the time. Unfortunately, that doesn’t meet most definitions of disability. [When we think of disability, we think of a] transected spinal cord, which is very static. [Sickle cell disease] is much more dynamic. It doesn’t meet many definitions of disability and, therefore, sometimes doesn’t get the support it needs. All these things can accumulate into the quality of life.

But these aren’t unique to sickle cell disease. Other diseases, such as the thalassemia, require chronic transfusion. [That means] missing work or school 1 or 2 days a month and the need for chelation for iron therapy. They are things also seen in sickle cell disease. If you’re not able to take 1 of the oral chelators, then you need to do daily subcutaneous infusion. All these things interfere with what 1 would consider a normal life or a normal trajectory of goals and aspirations. That can have a deleterious effect on quality of life and happiness overall. I’m sure you have eloquent descriptions.

 I agree with you 100%, Matt. When we talk about the agents, we have to treat patients and those that may be emerging and able to be prescribed in the future, our patients are telling us and families—with respect to children with sickle cell disease—that they want to feel better. They want outcomes that measure quality of life: fatigue, sleep, mood, the ability to maintain their educational, professional, and relationship goals. These are important markers of overall health, not just red blood cell health. But maybe there’s a relationship there. I agree with you 100%. Nirmish and Elna, is there anything else you might want to add regarding quality of life and sickle cell disease?

 When I enter a patient’s room, the first thing I do is not talk about pain. I talk about everything else going on in that patient’s life: what’s happening in school, what’s happening at work, how their boyfriend or girlfriend is doing, are they traveling. I try to focus on everything else going on in that patient’s life to get [a sense of that patient’s] quality of life. Are they having issues with school? Are they missing days that are technically not related to pain crisis but having fatigue issues that are leading to difficulties that we need to address? The focus on quality of life needs to happen because it influences every aspect of their life.

The numbers for PTSD, anxiety, depression, and mental health are so high in this population that it’s shocking. The rates of thinking about or attempting suicide are 1 in 11 to 1 in 13. It’s striking that we’re focused mostly on pain discussions, sometimes with medicine. But as a sickle cell community, we’ve started to pivot and rightfully focus on the quality of life for patients. I’m glad we’re trying focus on that.

 I agree. As pediatricians, we’re guilty as charged. We focus more on missed school days, pain, and whether you come to the hospital. We’ve created a culture in we always start the conversation with, “Give me a number. What’s your pain number?” But we forget that assessing the functional ability and quality of the, regardless of the individual is in front of you, is more important as we move on to functionalities analysis. As pediatricians, we don’t approach or address the fatigue question as a lot of adult providers do. When you treat adults, 1 of the top 5 things patients bring up is the degree of fatigue. We indirectly analyze a child’s degree of function of quality: “Are you able to play? Do you go outside and hoop with your friends?” How limited are their daily activities or desires hampered? You have to think about it when a child would just get up and go. It’s very important. We should shift and get more of that into end points [of our studies], not just number of the OCDs [obsessive-compulsive disorders] and using validated functional analyses. Any improvement of quality of life is very important, and we’re beginning to do that.

 Elna, your point about fatigue is interesting. If you ask a patient if they’re tired, they’re normalized to that. They’re used to feeling tired. It’s always trying to bring up something relative to it. “Can you keep up with your friends when you’re playing basketball? Do you stop earlier than your friends?” When you ask it that way, they’re like, “I have to take more breaks.” Otherwise, they’re like, “I’m fine, Dr Shah. I can get around. I can do whatever I need to do.” They always normalize it. Not until we improve on that do they look back and say, “You know what? Looking back, I have much more energy.” Thus, fatigue is a good point to bring up.

Videos

Matthew M. Heeney, MD, leads a discussion on the impact of unhealthy RBCs and blood disorders on a patient’s quality of life.

Clinical

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Impact of RBC Disorders on Patient QoL

 That’s the perfect segue into a question I want to ask Matt. How does an increase in the levels of 2,3-DPG [diphosphoglycerate] impact red blood cell function?

 An increase in 2,3-DPG shifts the sigmoid-shaped oxygen dissociation curve to the right. That increases the p50 measure we use in the lab, which is the partial pressure of oxygen at which 50% of the hemoglobin is saturated at that time. By increasing 2,3-DPG, you decrease hemoglobin affinity for oxygen. Imagine if you went for a run. You’d increase acid in the muscle, and you’d increase temperature in the muscle. You could also increase 2,3-DPG to allow more oxygen delivery to that muscle. It’s working and needs more oxygen and more energy delivery. That’s 1 way the body can alter how it responds physiologically to certain situations.

Pharmacologically, the other way to manipulate this curve would be to try and find a way to decrease 2,3-DPG. That’s why there’s a great deal of interest in pyruvate kinase activators—allosteric activators that increase the activity of 1 of the final steps of the glycolytic pathway—to increase flux through that pathway and to produce more ATP [adenosine triphosphate] energy, which may make the cell healthier but also decreases some of the shunt product of 2,3-DPG. By doing that, by using up or not allowing that 2,3-DPG to accumulate, you can increase oxygen affinity and therefore have potentially beneficial effects in some red blood cell disease states. It’s an interesting molecule, and it’s 1 way we’ve developed over time to modulate the oxygen delivery to our tissues when they’re needed. We can potentially manipulate that pharmacologically.

 It’s super exciting to talk about pharmacological manipulation of these important biochemical pathways. I want to pivot a little. I’m going to go back to you, Elna. Talk about some of the genetic and epigenetic factors that play a role in the health and wellness of red blood cells. Where is there going to be some pathology that leads to an unhealthy red blood cell with respect to genetics and epigenetics?

 That’s another 60-min discussion. In sickle cell [disease] and red blood cells, we’ve looked for end points and biomarkers over the past 2 to 3 decades to give us an indication of how severe an individual patient’s sickle cell disease might be. A few have been validated and are known. The first of them is fetal hemoglobin. With fetal hemoglobin of patients, if you retain after the switching from fetal to adult hemoglobin, it’s supposed to completely disappear by 6 months of age. Patients with hemoglobinopathies retain some of that fetal hemoglobin, and that depends on a lot of genetic inheritance patterns. Some people retain more, and some lose almost all of it—and have just 3%, 5%, 7%—and some retain slightly higher fetal hemoglobin. Fetal hemoglobin induces, and that’s how we figured out that inducing hemoglobin as a pharmacological modality—as a disease-modifying agent—is very valuable. We have 20 years for us to validate the proof of principle.

The other thing that’s genetically modulated is the concomitant inheritance of the alpha thalassemia trait. We’re talking about beta-hemoglobin disorders. If you have an inheritance of the alpha thalassemia trait and a little more microcytosis, it modulates the disease and intends to have slightly higher hemoglobin and slightly modulated pathophysiological events in an end-organ dysfunction. [There are] other things, such as epigenetics. In patients who have concomitant iron deficiency, it may make the red blood cell a little more stiff. Iron overload, on the other hand, is when patients have loaded from transfusion that we give.

The one that hasn’t been validated over time and … is the slightly higher white blood cell count. The Genome Center [at The University of Texas at Dallas] proved that that may not be as strong of an epigenetic or genetic biomarker as we thought. All red blood cell and white blood cell microantigens, like Duffy [antigens], also correlate with a slightly low white blood cell count. Those indirect things may modulate the severity of sickle cell disease. But by and large, very few have been validated as potential biomarkers of disease severity or how healthy the sickle cell behaves.

 Thank you, Elna. Nirmish or Matt, would you like to talk more about some other epigenetic factors that are becoming more well-known?

 I’ll start by emphasizing that even if you have hemoglobin SS or sickle cell disease SS, there’s a lot of variation. There are patients who have SS and have high hemoglobins…. We have patients with SS who historically have lots of problems. There are subphenotypes, and part of that is genetic. I don’t think we have a complete understanding. Some are well described, as Elna said, as having fetal hemoglobin or alpha-globin abnormalities. But there’s a lot that’s not understood. There’s an effort to do whole-genome sequencing. Look at these smaller mutations to try to find the subphenotypes. That’s critical because when you find these subphenotypes, it would be nice to be able to find—this is almost the holy grail—subphenotypes of patients who have, for example, type SS but would be most responsive to this type of therapy vs another type. Right now, we’re throwing everything at patients, and I’m so thankful that we have options. But we don’t have that subphenotyping yet. The genetics is part of the puzzle. I’m glad it’s being brought up because that’s where we need to go.

Matthew M. Heeney, MD, and Elna Saah, MD, highlight the role of 2,3-disphosphoglycerate as well as epigenetic and genetic factors in RBC form and function. 

Impact of Biochemical, Epigenetic, and Genetic Factors in RBC Health 

New European-based updated guidelines call for the use of posterior partial fundoplication as the surgical option for patients with 

Surgery is an option for patients with GERD who wish to avoid medication, as well as for patients with persistent symptoms despite medication. The most established antireflux operation is laparoscopic Nissen, which is also associated with dysphagia in approximately 13% of patients beyond 1 year following surgery. While partial fundoplications are an alternative, there are concerns about their long-term effectiveness for reflux control.

With several options available for surgical management of adult patients with GERD, previous guidelines and systematic reviews have focused on the effects of total fundoplication compared to the pooled effects of different techniques of partial fundoplication.

An international, multidisciplinary panel of surgeons, gastroenterologists, and a patient representative, led by Sheraz Markar, MSc, PhD, Nuffield Department of Surgery, University of Oxford, developed evidence-informed, trustworthy, pertinent recommendations for the use of total, posterior partial, and anterior partial fundoplications for the management of adult patients with GERD.

The new recommendations call for posterior partial fundoplication over total posterior or anterior 90° fundoplication in adult patients with GERD and anterior >90° fundoplication as an alternative.

“We suggest posterior partial fundoplication over total posterior or anterior 90° fundoplication in adult patients with gastroesophageal reflux disease,” the authors wrote. “Anterior >90° fundoplication is suggested as an alternative, although relevant comparative evidence is limited (weak recommendation).”

While total fundoplication is the most frequently performed antireflux surgery in Europe, the authors suggest offering posterior partial fundoplication in their services to reduce the risk of short-term complications and long-term dysphagia, as well as lowering the risk of major complications and reoperations.

The reccomendations also might have an impact on future studies.

“Researchers in the field of antireflux surgery are advised to collect and report a minimum of critical and important outcomes, including major and minor complications, ideally graded using the Clavien-Dindo classification; heartburn; regurgitation; dysphagia; gas-bloat; ability to belch; reoperation; use of antacids; and, importantly, quality of life,” the authors wrote.

The updated reccomendations are based on 43 reports from the original review, with 8 additional reports. The final updated recommendations included 49 reports of 31 randomized trials.

In the updated systematic review, network meta-analysis, and evidence appraisal, the investigators used the GRADE approach and the Confidence in Network Meta-Analysis methodologies.

The team reached a unanimous consensus using an evidence-to-decision framework to select among multiple interventions and a Delphi process to formulate the recommendations.

“This rapid guideline was developed in line with highest methodological standards and provides evidence-informed recommendations on the surgical management of GERD,” the authors wrote. “It provides user-friendly decision aids to inform healthcare professionals' and patients' decision making. 

There is a planned update to these guidelines expected in 2028.

UEG and EAES rapid guideline: Update systematic review, network meta-analysis, CINeMA and GRADE assessment, and evidence-informed European recommendations on surgical management of GERD

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, IBS and IBD, Crohn's disease, and more.

Gastroesophageal Reflux Disease (GERD)

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Updated GERD Guidelines Recommend Posterior Partial Fundoplication

Podcasts

Martha Gulati, MD, joins The Heart Team to share her professional experiences and recommendations in treating female-specific cardiovascular disease.

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Fighting the Historic Disparities of Women's Heart Disease with Martha Gulati, MD

Overall, 30.60% of pediatric patients who presented to the emergency department with mild head trauma were diagnosed with ADHD, compared to 8.96% of the control group.

ADHD

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Prevalence of ADHD Higher in Pediatric Patients With Mild Head Trauma

Drs Abraham and Feuerstadt share recent data with emerging live biotherapeutic products, SER-109, CP101, and VE303, for treatment of recurrent C difficile infection (rCDI).

C Difficile Infection

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SER-109, CP101, VE303 for Treatment of Recurrent C. difficile Infection (rCDI)

Drs Feuerstadt, Abraham, and Chopra discuss clinical trial data for RBX2660, a live biotherapeutic product, in treatment of recurrent C difficile infection (rCDI), as well as data with RBX2660 that were presented at DDW 2022.

RBX2660 for Treatment of Recurrent C. difficile Infection (rCDI)

Martha Gulati, MD, joins episode 2 to discuss the burden of gender disparity in cardiovascular research, screening and care.

Heart Team: Making Ground on Women's Cardiovascular Health

A discussion with Dr. Lal on the successful trials and recent approval of dupilumab as a treatment for skin inflammation.

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Karan Lal, DO: Eczema Awareness Month and FDA Approval of Dupilumab

Data indicates a greater number of physicians is a better predictor of melanoma diagnoses than UV radiation rates.

High Melanoma Incidence Associated with Diagnostic Scrutiny Rather Than UV Exposure

Connor Iapoce is an associate editor for 

 and joined the MJH Life Sciences team in April 2021. He graduated from The College of New Jersey with a degree in Journalism and Professional Writing. He enjoys listening to records, going to concerts, and playing with his cat Squish. You can reach him at 

The SpyGlass IOL platform showcased a 45% drop in mean intraocular pressure at 3 months in first-in-human glaucoma trial. 

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Robert Cionni, MD: Innovations in Drug Delivery for Glaucoma Treatment

"Especially when untreated and in late stages of progression, ILD is well known to impact health related quality of life," according to Dr. Briana DiSilvio. "Chronic dyspnea, cough, and reduced exercise capacity can become disabling."

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Why Interstitial Lung Disease Diagnosis is Often Delayed

Safety data of the bioerodible sustained delivery intravitreal anti-VEGF treatment indicate no ocular or systemic serious adverse events with mild adverse events. 

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Latest News

Folic Acid Decreases Rate of Suicidal Attempts

Study Suggests Combination of Phototherapy, Apremilast Effective for Psoriasis Vulgaris

Impact of RBC Disorders on Patient QoL

Impact of Biochemical, Epigenetic, and Genetic Factors in RBC Health

Updated GERD Guidelines Recommend Posterior Partial Fundoplication