Perceived stress and allostatic load: Results from the <i>All of Us</i> Research Program

by Faith Morley, Lauren Mount, Anjile An, Erica Phillips, Rulla M. Tamimi, Kevin H. Kensler

The rising prevalence of individuals reporting extreme stress has major public health implications as it increases vulnerability to accelerated premature biological aging, thus increasing risk of chronic disease. To examine the impact of stress on premature biological aging, we assessed the association between exposure to increased stress, quantified by the Perceived Stress Scale, and odds of high allostatic load (AL). To illuminate previously unexplored socio-contextual factors, we controlled for self-reported individual and neighborhood social determinants of health that included discrimination, loneliness, food insecurity, neighborhood disorder, and neighborhood social cohesion. We utilized a cross-sectional design to examine the association between perceived stress and AL among 7,415 participants ages 18–65 in the All of Us Research Program, who enrolled from 2017–2022. We used logistic regression to evaluate the association between stress and high AL, controlling for sociodemographic factors and self-reported social determinants of health. Participants who were younger, receiving Medicaid, or Hispanic had increased prevalence of high stress. High stress was associated with elevated odds of high AL in age and sex-adjusted models (OR=2.18, 95%CI = 1.78, 2.66, high stress vs. low), an association which remained significant after adjusting for social determinants of health (OR=1.29, 95%CI = 1.01, 1.65). Using restricted cubic splines, high stress was significantly associated with increased odds of high AL, even after controlling for upstream individual and neighborhood-level determinants of health. While individuals living below the medium poverty-to-income ratio demonstrated little appreciable association between high stress and increased odds of high allostatic load, those living above the median poverty-to-income ratio reporting increased stress appeared to have increased odds of high allostatic load. Through addressing the upstream factors causing undue burdens of stress, which particularly affect marginalized communities and younger generations, we can begin to address premature biological aging and the comorbid conditions it accompanies.

Shaping the future of medical education: A cross-sectional study on ChatGPT attitude and usage among medical students in Sudan

by Weam Mohamed Meargni Ahmed, Malaz M. Abdalmotalib, Mohamed H. Elbadawi, Galia Tajelsir Fadulelmula Mohammed, Waad Mohamed Ibrahim Mohamed, Fatima Salih Babiker Mohammed, Hajar Saad Salih, Hiba Omer Yousif Mohamed

Background

Artificial intelligence (AI) is revolutionizing education globally, yet its adoption in medical education remains inadequately understood. ChatGPT, a generative AI tool, offers promising yet doubtful potential for enhancing academic and clinical training.

Methods

This study employed an analytical cross-sectional design, involving 1,443 Sudanese medical students who participated through an online, structured questionnaire. The questionnaire was designed to assess ChatGPT awareness, usage, and associated factors. Statistical analysis was performed using SPSS software to identify key determinants influencing ChatGPT awareness and usage among the participants.

Objective

This study investigates the levels of awareness, attitude, and usage of ChatGPT among Sudanese medical students, identifying key socio-demographic, economic, and institutional factors influencing its adoption.

Results

Among the participants, 65.8% were aware of ChatGPT, yet only 41.9% reported using it. Gender differences were statistically significant, with males demonstrating higher usage rates (p 300,000 SDGs) showed significantly greater usage (p  Conclusions

The findings underscore the urgent need for targeted interventions, including curriculum reform to integrate AI literacy, enhanced digital infrastructure, and gender-equity initiatives. Addressing these systemic gaps will scale up AI adoption in medical education. This study provides actionable insights for educators and policymakers, emphasizing the urgency of bridging socio-economic and institutional inequities to foster equitable access to AI tools in medical training.

The histone deacetylase inhibitor CT-101 flips the switch to fetal hemoglobin expression in sickle cell disease mice

by Mayuko Takezaki, Biaoru Li, Hongyan Xu, Nikhil Patel, Rudolf Lucas, Ryan E. Cerbone, Sivanagireddy Koti, Clifford L. Hendrick, Louis H. Junker, Betty S. Pace

The most common hemoglobin disorder worldwide is sickle cell disease (SCD) caused by a point mutation in the adult β-globin gene. As a result, hemoglobin S production occurs leading to clinical symptoms including vaso-occlusive pain, organ damage, and a shortened lifespan. Hydroxyurea is the only FDA-approved fetal hemoglobin (HbF) inducer in the United States that ameliorates the clinical severity of SCD. Due to challenges with hydroxyurea, our study aimed to address the unmet need for the development of non-chemotherapeutic HbF inducers. We investigated the ability of CT-101, a Class 1 histone deacetylase inhibitor, to flip the γ-globin to β-globin switch in a humanized SCD mouse model. Pharmacokinetic parameters were assessed in CD-1 and Townes SCD mice after a single intraperitoneal drug dose. Similar drug uptake and half-life were observed in both animals. Subsequent studies in β-YAC mice expressing human γ-globin and β-globin genes established the optimal dose of CT-101 that induces HbF without peripheral blood toxicity. Subsequent confirmatory studies were conducted in the SCD mouse treated with intraperitoneal CT-101, demonstrating increases in F-cells, HbF, and γ-globin gene mRNA levels. Hydroxyurea combined with CT-101 significantly decreased spleen size and hemorrhagic infarcts and improved splenic extramedullary hematopoiesis. Our novel agent, CT-101, flipped the switch by activating γ-globin gene transcription and HbF protein synthesis in the preclinical SCD mouse model without significant toxicity in the peripheral blood. These findings support the development of an oral CT-101 formulation for clinical testing in SCD.

Burnout syndrome and healthy lifestyle among Egyptian physicians: A cross-sectional study

by Nehal Mohamed Eisa, Mohamed A. M. El-Tabakh, Nourhan M. Kamal, Sara M. Gharbia, Mahmoud M. Samir, Wajid Syed, Mahmood Basil A. Al-Rawi, Ahmed Essam Abou Warda, Abdelrahman S. H. Refaee

Introduction

The phenomenon of burnout and the lifestyle of physicians significantly influence the delivery of healthcare. Over time, burnout intensifies, negatively impacting professional performance, which in turn leads to decreased quality of treatment, patient satisfaction, and productivity. Additionally, it increases the occurrence of medical mistakes and turnover among physicians. In addition to the direct influence of lifestyle on those components.

Aim of the study

The purpose of this study is to assess burnout syndrome among Egyptian physicians, as well as to investigate factors that contribute to burnout, especially demographic characteristics, lifestyle patterns, and health habits.

Methods

A cross-sectional study examined burnout prevalence and determinants among 502 Egyptian physicians in different governorates. An electronic questionnaire was used to collect data for the study. Questionnaire covered socio-demographics, The abbreviated Maslach Burnout Inventory (aMBI), and The Health Lifestyle and Personal Control Questionnaire (HLPCQ).

Results

Younger physicians under 30 showed higher burnout on emotional exhaustion and depersonalization scales, with significant findings (P = 0.047), (P Conclusion

These findings highlight the intricate relationship between burnout and lifestyle among physicians. A healthy lifestyle, including diet, routines, social support, and physical activity was linked to reduced burnout, while dietary harm avoidance was negatively correlated. This suggests opportunities to enhance the well-being of medical professionals through lifestyle interventions.

Impact of diabetes mellitus on 30-day mortality among acute stroke patients in northern Tanzania

by Eugénie M. Kamabu, Justin L. Paluku, William P. Howlett, Abid M. Sadiq, Eliada B. Nziku, Doreen T. Eliah, Ibrahim Ali Ibrahim Muhina, Fuad H. Said, Tumaini E. Mirai, Elifuraha W. Mkwizu, Furaha S. Lyamuya, Elichilia R. Shao, Kajiru G. Kilonzo, Venance P. Maro, Sarah J. Urasa, Nyasatu G. Chamba

Background

Among acute stroke patients (ASPs), diabetes mellitus (DM) is associated with a higher risk of death, functional dependency, and recurrence. This study aimed to determine the impact of DM on the 30-day mortality among admitted ASPs in northern Tanzania.

Materials and methods

This was a hospital-based prospective cohort study performed among ASPs with and without DM who were admitted to Kilimanjaro Christian Medical Centre from November 2022 to May2023. ASPs were followed for 30 days after the onset of an acute stroke to identify the primary outcome, which was all-cause mortality. Descriptive statistics, logistic regression, and survival analysis were conducted,

Results

Out of 213 ASP, 82 (38.5%) had DM. The overall crude mortality rate was 46.9%. ASPs with DM had a higher mortality rate of 53.7% compared with those without DM (42.7%). A higher proportion of acute stroke patients with DM (84.1%) had a poor outcome (mRS 3-6) (p = 0.038). DM was statistically non-significant for 30-day mortality (aHR 1.56; 95% CI: 0.73–3.32; p = 0.252). However, fever (p = 0.005), severe admission Glasgow coma scale (p = 0.005), severe stroke (p = 0.008), elevated serum creatinine (p = 0.008), and an abnormal respiratory pattern (p = 0.042), were predictors of 30-day mortality,

Conclusion

This study demonstrated a high mortality in ASPs. Although DM did not have a significant impact on 30-day mortality, other factors, such as altered mental state, stroke severity, fever, elevated creatinine, and abnormal respiration, need to be accounted for that may have a significant impact on the mortality in ASPs. These findings highlight the significant burden of DM in stroke patients and underscore the importance of early diagnosis and treatment of ASPs, in the hopes of improving clinical practice and guidelines and reducing morbidity and mortality in Tanzania.

Negative impact of chemotherapy on kinetic growth rate of the future liver remnant if applied following PVE or ALPPS

by Klara Welcker, Martin A. Schneider, Tim Reese, Andrea Ehrenfeld, Hauke Weilert, Axel Stang, Peter Wohlmuth, Mia-Maria Warnke, Carolin Reiner, Thomas von Hahn, Karl J. Oldhafer, Andreas H. Mahnken, Roland Brüning

Purpose

Modern liver surgery has improved the percentage of potentially resectable malignant tumors. However, if the future liver remnant is small, patients remain at risk of developing postoperative liver failure. Thus, the future liver remnant must be increased, while at the same time, the primary tumor may have to be controlled by chemotherapy. To address this conflict, we retrospectively analyzed the changes in hypertrophy before and after Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) or Portal Vein Embolization (PVE), with or without parallel systemic chemotherapy.

Materials and Methods

We retrospectively analysed 172 patients (54 female and 118 male), treated with ALPPS in 90 patients (median age 61 years [Q1, Q3: 52,71]) and with PVE in 82 patients (median age 66 years [Q1, Q3: 56,73]). The median control interval was 4.9 [Q1, Q3: 4.0, 6.0] weeks after the PVE, and 2.6 [Q1, Q3: 1.6, 5.8] weeks after ALPPS step 1.

Results

The overall kinetic growth rate (median) for the entire group was 0.02 (2%) per week. When systemic chemotherapy was administered prior to intervention, the kinetic growth rate of these treated patients (vs. untreated) exhibited a median of 0.020 [Q1, Q3: 0.011, 0.067] compared to 0.024 [Q1, Q3: 0.013, 0.041] (p = 0.949). When chemotherapy was administered after the PVE/ ALPPS treatment, the kinetic growth rate declined from a median of 0.025 [Q1, Q3: 0.013, 0.053] to 0.011 [Q1, Q3: 0.007, 0.021] (p = 0.005). Subgroup analysis showed statistically significant effects only in the PVE group (median ALPPS -45% (p = 0.157), PVE -47% (p = 0.005)).

Conclusion

This retrospective analysis indicated that systemic chemotherapy given after PVE/ the first step of the ALPPS procedure, i.e., the growth phase, has a negative effect on the kinetic growth rate.

Mis-splicing drives loss of function of p53^E224D point mutation

by Ian C. Lock, Nathan H. Leisenring, Warren Floyd, Eric S. Xu, Lixia Luo, Yan Ma, Erin C. Mansell, Diana M. Cardona, Chang-Lung Lee, David G. Kirsch

Background

The tumor suppressor p53 (Trp53), also known as p53, is the most commonly mutated gene in cancer. Canonical p53 DNA damage response pathways are well characterized and classically thought to underlie the tumor suppressive effect of p53. Challenging this dogma, mouse models have revealed that p53-driven apoptosis and cell cycle arrest are dispensable for tumor suppression. Here, we investigated the inverse context of a p53 mutation predicted to drive the expression of canonical targets but is detected in human cancer.

Methods

We established a novel mouse model with a single base pair mutation (GAG>GAT, p53^E221D) in the DNA-Binding domain that has wild-type function in screening assays, but is paradoxically found in human cancer in Li-Fraumeni syndrome. Using mouse p53^E221D and the analogous human p53^E224D mutants, we evaluated expression, transcriptional activation, and tumor suppression in vitro and in vivo.

Results

Expression of human p53^E224D from cDNA translated to a fully functional p53 protein. However, p53^E221D/E221D RNA transcribed from the endogenous locus is mis-spliced resulting in nonsense-mediated decay. Moreover, fibroblasts derived from p53^E221D/E221D mice do not express a detectable protein product. Mice homozygous for p53^E221D exhibited increased tumor penetrance and decreased life expectancy compared to p53^WT/WT animals.

Conclusions

Mouse p53^E221D and human p53^E224D mutations lead to splice variation and a biologically relevant p53 loss of function in vitro and in vivo.

Antibiotic prescription patterns and associated symptoms in children living with HIV at Arthur Davison Children’s Hospital in Ndola, Zambia

by Jonathan Gwasupika, Davidson H. Hamer, Victor Daka, Ephraim Chikwanda, David Mwakazanga, Ruth L. Mfune, Choolwe Jacobs

Background

Children with human immunodeficiency virus (HIV) infection are disproportionately susceptible to bacterial infections. There are a wide range of antibacterial agents available to manage HIV positive children with bacterial infections. However, administration of antibiotics in most children is empirical which could lead to antimicrobial resistance.

Objectives

This study aimed to determine commonly prescribed antibiotics and associated symptoms in children at Arthur Davison children’s hospital antiretroviral therapy clinic in Ndola, Zambia.

Methods

This was a cross-sectional study that analysed the antibiotic prescribing patterns from routinely collected secondary data at Arthur Davison children’s hospital. Children diagnosed with HIV before the age of 5, actively attending antiretroviral therapy clinic identified by SmartCare software and who had taken antiretroviral therapy for at least 6 months were eligible. Data were collected from files of children who met the eligibility criteria. STATA software version 16 SE (STATA Corp., College Station, Texas, USA) was used for analysis. A p-value less than 0.05 was considered statistically significant at a confidence interval of 95%.

Results

From a total of 132 children included in the study, 37.9% presented with symptoms with the most common symptoms being cough (70.0%) and diarrhoea (30.0%). A larger proportion of children (62.1%) were on arbacavir/lamivudine/dolutogravr combination of antiretroviral therapy while 8.2% were on the tenoforvir alafenamide/lamivudine/dolutobravir regimen. Children who were on abacavir/lamivudine/dolutegravir regimen presented with more symptoms (48.8%) compared to those on tenofovir alafenamide/lamivudine/dolutegravir (21.0%) and tenofovir disoproxil fumarate/lamivudine/dolutegravir (18.2%) (p = 0.006). Approximately 60.0% of children presenting with symptoms were prescribed antibiotics. Co-trimoxazole was the most commonly (38.0%) prescribed, while erythromycin (2.0%) and Cephalexin (2.0%) were the least.

Conclusions

Respiratory and gastrointestinal symptoms were the most common presentations suggestive of a suspected infection requiring antibiotic prescription in HIV-positive children on ART. Despite co-trimoxazole being the prophylactic drug among HIV-positive children, it was the most common antibiotic among children presenting with symptoms suggestive of an infection. This calls for the prudent use of co-trimoxazole to avoid its resistance.

Mesothelial cell responses to acute appendicitis or small bowel obstruction reactive ascites: Insights into immunoregulation of abdominal adhesion

by Melissa A. Hausburg, Kaysie L. Banton, Christopher D. Cassidy, Robert M. Madayag, Carlos H. Palacio, Jason S. Williams, Raphael Bar-Or, Rebecca J. Ryznar, David Bar-Or

Previous abdominal surgery (PAS) increases risk of small bowel obstruction (SBO) due to adhesions, and appendectomy (appy) is an independent risk factor for abdominal adhesion-related complications. Peritoneal inflammation, e.g., acute appendicitis (AA), causes formation of reactive ascitic fluid (rA) that activates peritoneum surface mesothelial cells (MCs) to form adhesions. Pathologic adhesions may arise if restoration of MC-regulated fibrinolysis and secretion of glycocalyx (GCX) are disrupted. Proteins affecting these processes may originate from peritoneal rA. This is a prospective observational IRB-approved study at three Level 1 trauma centers where rA is collected prior to surgical intervention for non-perforated AA or adhesiolysis for SBO. Samples from 48 appy and 15 SBO patients were used to treat human MCs and subjected to quantification of 85 inflammatory mediators. Results were compared between patients with surgically naïve abdomens (naïve) and patients with >1 PAS. Select rA caused MCs to form clusters of fibroblastic cells, extracellular matrix fibers (FIB), and secretion of GCX. PAS and naïve patient rA fluids were clustered into “fiber-GCX” (FIB-GCX) groups: highFIB-highGCX, highFIB-lowGCX, noFIB-highGCX, noFIB-lowGCX, and noFIB-noGCX. Between groups, 26 analytes were differentially abundant including innate immune response, wound healing, and mucosal defense proteins. Factors that contributed to the differences between groups were rA-induced highFIB and history of PAS. Overall, PAS patient rA showed a muted immune response compared to rA from naïve patients. Our data suggest that abdominal surgery may negatively impact future immune responses in the abdomen. Further, quantifying immunomodulators in peritoneal rA may lead to the development a personalized approach to post-surgical adhesion treatment and prevention.

Assessing the impact of the COVID-19 pandemic on uptake and experiences of gestational diabetes mellitus screening in Ontario: A parallel convergent mixed-methods study

by Dima Hadid, Rebecca H. Correia, Sarah D. McDonald, Elizabeth K. Darling, David Kirkwood, Aaron Jones, Andrea Carruthers, Cassandra Kuyvenhoven, Michelle Howard, Devon Greyson, Sujane Kandasamy, Meredith Vanstone

Objective

Gestational diabetes mellitus (GDM) is a common medical complication of pregnancy that leads to adverse outcomes for both infants and pregnant people. Early detection and treatment can mitigate these negative outcomes. The COVID-19 pandemic strained healthcare and laboratory services, including GDM screening programs. Adapted GDM screening guidelines were introduced in many jurisdictions. This study examined changes in uptake, modality, and experiences of GDM screening in Ontario, Canada during the COVID-19 pandemic.

Methods

This convergent mixed-method study involved a population-based retrospective cohort analysis of Ontario-based health administrative data to describe and compare gestational diabetes screening rates among 85,228 individuals with live, in-hospital births between January 1-March 31 before (2019) and during the COVID-19 pandemic (2021 and 2022). Descriptive analyses were conducted for GDM screening pathways aligning with usual and pandemic-adapted screening guidance. Qualitative descriptive interviews were conducted about experiences and decision-making of GDM screening with 43 Ontario residents who gave birth between May 2020 and December 2021. Data were integrated during the design and interpretation phases.

Results

There were small but significant increases in GDM screening during the pandemic; likelihood of screening completion using any modality increased in 2021 and 2022 compared to 2019. Testing modality shifted; the alternate screening strategies introduced during COVID-19 were adopted by clinicians. Interview participants perceived GDM screening to be important and obligatory but accompanied by a degree of stress about potential COVID-19 exposure.

Conclusion

Despite health system challenges experienced in Ontario during the COVID-19 pandemic, GDM screening rates increased in the study population, demonstrating the success of adapted GDM screening guidelines. Decisions about screening modalities were driven by clinician expertise, and interview participants were satisfied to provide informed consent to these recommendations.

Non-pharmaceutical interventions for people living with HIV with cognitive impairment: A scoping review

by Lucinda Stuart, Kate Alford, Jamie H. Vera

Background

Cognitive impairment (CI) in HIV is often of multifactorial causation, and remains a prominent issue in the age of effective combination antiretroviral therapy (cART), affecting approximately 14% of people living with HIV. Despite the 2018 BHIVA directive stating the importance of commencing rehabilitation strategies in people living with HIV with CI, no types of cognitive rehabilitations or other non-pharmaceutical interventions are specifically recommended. This scoping review aimed to describe the types of and evidence relating to the non-pharmaceutical interventions which have been examined in people living with HIV with CI.

Methods

Studies were identified from five electronic databases. Criteria for study inclusion were studies describing a non-pharmaceutical intervention published after 1st January 2000 in English, in a population of adults living with HIV with CI detected at baseline, without significant psychiatric or substance-misuse co-morbidity.

Results

Fourteen studies met the criteria for inclusion, with the Frascati criteria most commonly used to define CI within participant populations. The median intervention length was 12 weeks (IQR = 6.5). Nine studies investigated interventions with some component of computerised cognitive training (CCT); other interventions included diet, exercise and goal management training. Studies most commonly examined neurocognitive outcomes, but also considered other outcomes including quality of life, depressive symptomatology, intervention acceptability and cART adherence. Eight studies observed improvement in cognition with CCT, with effects often maintained for several weeks post-intervention, however, results were not always statistically significant. Self-reported cognitive improvement and intervention acceptability was high amongst participants completing CCT.

Conclusions

There was heterogeneity across studies not only in intervention type, but in diagnostic tools used, the chosen outcome measures and cognitive batteries, making comparison difficult. Findings, however, indicate that CCT interventions may produce benefits in cognition and are acceptable to patients. Further research is required in larger samples, alongside identifying specific intervention components that improve outcomes.

Multi-session adaptation to audiovisual and sensorimotor biofeedback is heterogeneous among adolescents with cerebral palsy

by Alyssa M. Spomer, Benjamin C. Conner, Michael H. Schwartz, Zachary F. Lerner, Katherine M. Steele

Background

There is growing interest in the use of biofeedback-augmented gait training in cerebral palsy (CP). Audiovisual, sensorimotor, and immersive biofeedback paradigms are commonly used to elicit short-term gait improvements; however, outcomes remain variable. Because biofeedback training requires that individuals have the capacity to both adapt their gait in response to feedback and retain improvements across sessions, changes in either capacity may affect outcomes. Yet, neither has been explored extensively in CP.

Methods

In this study, we evaluated the extent to which adolescents with CP (7M/1F; 14 years (12.5,15.26)) could adapt gait and retain improvements across four, 20-minute sessions using combined audiovisual and sensorimotor biofeedback. Both systems were designed to target plantarflexor activity. Audiovisual biofeedback displayed real-time soleus activity and sensorimotor biofeedback was provided using a bilateral resistive ankle exoskeleton. We quantified the time-course of change in muscle activity within and across sessions and overground walking function before and after the four sessions.

Results

All individuals were able to significantly increase soleus activity from baseline using multimodal biofeedback (p 0.11).

Conclusions

This work suggests that individuals with CP have the capacity to adapt their gait using biofeedback, but responses are highly variable. Characterizing the factors driving adaptation to biofeedback may be a promising avenue to understand the heterogeneity of existing biofeedback training outcomes and inform future system optimization for integration into clinical care.