bluuebunny/crossref_metadata_2025 huggingface dataset:
Divergent Neuroimmune Signatures in the Cerebrospinal Fluid Predict Differential Gender-Specific Survival Among Patients With HIV-Associated Cryptococcal Meningitis
Authors: Okurut Samuel , Boulware David R , Okafor Elizabeth , Rhein Joshua , Kajumbula Henry , Bagaya Bernard , Bwanga Freddie , Olobo Joseph O , Manabe Yukari C , Meya David B , Janoff Edward N ,   ASTRO trial team
Published: August 2023

Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, exceptionally among women with the increased threat of death on current optimal use of antifungal drugs.Cryptococcusdissemination into the central nervous system (CNS) prompts a neuroimmune reaction to activate pathogen concomitant factors. However, no consistent diagnostic or prognostic immune-mediated signature is reported to underpin the risk of death or mechanism to improve treatment or survival. We theorized that the distinct neuroimmune cytokine or chemokine signatures in the cerebrospinal fluid (CSF), distinguish survivors from people who died on antifungal treatment, who may benefit from tailored therapy. We considered the baseline clinical disease features, cryptococcal microbiologic factors, and CSF neuroimmune modulated signatures among 419 consenting adults by gender (biological sex assigned at birth) (168 females and 251 males) by 18 weeks of survival on antifungal management. Survival at 18 weeks was inferior among females than males (47% vs. 59%; hazard ratio HR=1.4, 95% CI: 1.0 to 1.9, and p=0.023). Unsupervised principal component analysis (PCA) demonstrated the divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, females displayed lower levels of PD-L1, IL-1RA, and IL-15 than males (all p≤0.028). Female survivors compared with those who died, expressed significant fold elevations in levels of CSF (CCL11 - myeloid and CXCL10 - lymphoid chemokine (in both p=0.001), and CSF Th1, Th2, and Th17 cytokines. In contrast, male survivors expressed distinctly lower levels of CSF IL-15 and IL-8 compared with those who died. Survivors of either gender demonstrated a significant increase in the levels of immune regulatory element, IL-10. In the finale, we classified divergent neuroimmune key signatures in CSF by gender, survival, and intragender-specific survival among people with HIV-associated cryptococcal meningitis. These intragender-specific survival associated-neuroimmune signatures, suggests the discrete role of gender immune regulating mechanisms as the possible targets for interventions to advance therapy to improve survival among people with HIV-associated cryptococcal meningitis.
Twenty-four hour activity-count behavior patterns associated with depressive symptoms: A big data-machine learning approach
Authors: Nawrin Saida Salima , Inada Hitoshi , Momma Haruki , Nagatomi Ryoichi
Published: August 2023

Depression is a global burden with profound personal and economic consequences. Previous studies have reported that the amount of physical activity is associated with depression. However, the relationship between the temporal patterns of physical activity and depressive symptoms is poorly understood. We hypothesize that the temporal patterns of daily physical activity could better explain the association of physical activity with depressive symptoms. To address the hypothesis, we investigated the association between depressive symptoms and daily dominant activity behaviors based on 24-hour temporal patterns of physical activity. We found that evening dominant behavior was positively associated with depressive symptoms compared to morning dominant behavior as the control group. Our results might contribute to monitoring and identifying individuals with latent depressive symptoms, emphasizing the importance of nuanced activity patterns and their probability of assessing depressive symptoms effectively.
High Extracellular-to-Intracellular Water Ratio in Limb Muscles is Associated with Low Muscle Strength in Patients with Heart Failure
Authors: Nakamura Kensuke , Kinugasa Yoshiharu , Sota Takeshi , Hirai Masayuki , Kato Masahiko , Yamamoto Kazuhiro
Published: August 2023

Background

A high extracellular water (ECW) to intracellular water (ICW) ratio of skeletal muscle as assessed by bioelectrical impedance analysis is reportedly associated with loss of muscle strength. However, the validity of this index for heart failure (HF), which is likely associated with changes in the water distribution, is unclear.

Methods

This study involved 190 patients with HF. The total ECW and ICW of both upper and lower extremities were measured, and a high ECW/ICW ratio was defined as an ECW/ICW ratio higher than the median (≥0.636 for men, ≥0.652 for women). Low muscle strength was defined as reduced handgrip strength according to the criteria established by the Asian Working Group for Sarcopenia.

Results

Patients with a high ECW/ICW ratio were older, had a higher left ventricular ejection fraction and B-type natriuretic peptide level, and had a lower body mass index, hemoglobin level, albumin level, estimated glomerular filtration rate, handgrip strength, and 6-minute walk distance than patients with a low ECW/ICW ratio (p < 0.05). An increasing ECW and/or decreasing ICW was associated with a higher ECW/ICW ratio (p < 0.05). In the multivariate logistic regression analysis, a high ECW/ICW ratio and low skeletal muscle mass were independently associated with low muscle strength (p < 0.05).

Conclusion

A high ECW/ICW ratio in limb muscles (i.e., an increasing ECW and/or decreasing ICW) is independently associated with muscle weakness regardless of skeletal muscle mass in patients with HF.

What Is New?

◆

A high extracellular water (ECW) to intracellular water (ICW) ratio of skeletal muscle as assessed by bioelectrical impedance analysis was independently associated with low muscle strength regardless of skeletal muscle mass in patients with heart failure (HF).

◆

Both an increasing ECW and decreasing ICW were independently associated with low muscle strength in patients with HF.

What Are the Clinical Implications?

◆

The ECW/ICW ratio in limb muscles is a new index that can be used to assess muscle function apart from muscle mass in patients with HF.
Evaluation of optical genome mapping in clinical genetic testing of facioscapulohumeral muscular dystrophy
Authors: Kovanda Anja , Lovrečić Luca , Rudolf Gorazd , Bozovic Ivana Babic , Jaklič Helena , Leonardis Lea , Peterlin Borut
Published: August 2023

Background

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular dystrophy, caused by the contraction of the D4Z4 repeats on the permissive 4qA haplotype on chromosome 4, resulting in the faulty expression of theDUX4gene. Traditional diagnostics is based on Southern blot, a time- and effort-intensive method that can be affected by single nucleotide (SNV), and copy number variants (CNV), as well as by the similarity of the D4Z4 repeats located on chromosome 10. We aimed to evaluate optical genome mapping (OGM) as an alternative molecular diagnostic method for the detection of FSHD.

Methods

We first performed optical genome mapping with EnFocus™ FSHD analysis using DLE-1 labeling and the Saphyr instrument, for our patients with inconclusive diagnostic Southern blot results, negative FSHD2 results, and clinically evident FSHD. Secondly, we performed OGM in parallel with the classical Southern blot analysis for our prospectively collected new FSHD cases. Finally, we used panel exome sequencing to confirm FSHD2.

Results

By using OGM we could resolve two cases with diagnostically inconclusive Southern blot results as having shortened D4Z4 repeats on the permissive 4qA allele, consistent with their clinical presentation. Results of the prospectively collected patients tested in parallel using Southern blot and OGM showed full concordance, showing OGM to be a useful alternative to the classical Southern blot method for detecting FSHD1. For a patient showing clinical FSHD but no shortened D4Z4 repeat on the 4qA allele using OGM or Southern blot, a likely pathogenic variant inSMCHD1was detected using exome sequencing, confirming FSHD2. OGM and panel exome sequencing can be used consecutively to detect FSHD2.
Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic
Authors: Hussein Yara , Weisblum-Neuman Hila , Ben-Zeev Bruria , Stern Shani
Published: August 2023

Objective

Epilepsy is a chronic neurological disorder related to various etiologies and the prevalence of active epilepsy is estimated to be between 4-10 per 1000 individuals having a significant role of genetic mutations. Next-Generation Sequencing (NGS) panels are utilized for genetic testing, still, a substantial proportion of the results remain uncertain and are not considered directly causative of epilepsy. This study aimed to reevaluate pediatric patients diagnosed with epilepsy who underwent genetic investigation using NGS panels, focusing on inconclusive variant findings or multiple Variants of Uncertain Significance (VUSs).

Methods

A subgroup of pediatric patients aged 0-25 years, diagnosed with epilepsy, who underwent genetic investigation with an NGS epilepsy panel at the Child Neurology Unit, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, between 2018-2022 through Invitae, was reevaluated. Patients with inconclusive variant findings or multiple VUSs in their test results were included. Genetic data were analyzed, focusing on identifying potentially pathogenic variants and frequent genetic combinations.

Results

Two unrelated potentially pathogenic variants were identified in the SCN9A and QARS1 genes. A frequent genetic combination, RANBP2&RYR3, was also observed among other combinations. The RANBP2 gene consistently co-occurred with RYR3 variants in uncertain results, suggesting potential pathogenicity. Analysis of unaffected parents’ data revealed certain combinations inherited from different parents, suggesting specific gene combinations as potential risk factors for the disease.

Significance

This study highlights the importance of reevaluating genetic data from pediatric epilepsy patients with inconclusive variant findings or multiple VUSs. Identification of potentially pathogenic variants and frequent genetic combinations, such as RANBP2&RYR3, could aid in understanding the genetic basis of epilepsy and identifying potential hotspots.

Plain Language Summary

We have performed a retrospective analysis on a subpopulation of pediatric patients diagnosed with epilepsy, we have found that specific genetic variants were repeatable indicating their potential pathogenicity to the disease.

Key points

60% of pediatric patients undergoing genetic testing receive an uncertain result emphasizing the complexity of genetic interpretation in epilepsy diagnostics.

Pathogenic variants in genes like SCN1A were common, underlining the importance of targeted gene sequencing.

Variants in genes like SCN9A and QARS1, currently classified as VUSs, showed consistent presence in epilepsy patients, indicating potential pathogenicity.

Specific genetic combinations, such as RANBP2&RYR3, were frequently observed among uncertain results, suggesting potential pathogenicity.
The social determinants associated with the advanced stage diagnosis of breast cancer in Egypt
Authors: Fekry Madonna A. , Kassem Loay , Yang Justin C. , Azim Hamdy A.
Published: August 2023

Background

Majority of Egyptian breast cancer (BC) patients present at advanced stages. We examined the sociodemographic and clinical factors associated with late presentation of BC.

Methods

This is a retrospective cohort study of patients who presented with BC between 2011 and 2020. Logistic regression was performed to examine the association between sociodemographic factors and advanced BC.

Results

This cohort included 1,953 patients with median age of 52 years. 1,098 (56.2%) patients were diagnosed at early stages, while 855 (43.8%) patients were diagnosed at advanced stages. Univariate logistic regression analyses revealed that several sociodemographic and clinical factors were associated with advanced BC, including having negative family history of BC (OR= 0.1.27; 95% CI:1.05 – 1.54), having no job (OR= 1.28; 95% CI: 1.06 – 1.53), being married (OR=1.27; 95% CI:1.02 – 1.57), rural residence (OR=1.27; 95% CI:1.02 – 1.57), having more than three children (OR=1.42; 95% CI:1.15 – 1.75), higher KI-67% score (OR=1.01; 95% CI:1.00 - 1.01), having HER2-Enriched or TNBC subtypes (OR= 1.44; 95% CI:1.16 – 1.79), and having tumor grate II/III (OR=4.12; 95% CI:1.58 – 10.77 & OR= 1.44; 95% CI:1.16 – 1.79, respectively). In the multivariate logistic regression model, only KI-67% (aOR=1.01; 95% CI:1.00 - 1.02), having no job (aOR=1.44; 95% CI:1.10 – 1.90), and rural residence (aOR=1.88; 95% CI:1.03 – 3.42) were significantly associated with advanced BC.

Conclusion

This study concluded that having no job and rural residence are highly associated with advanced BC. Raising the public awareness is the best strategy to encourage early detection of BC.
Development and validation of the pharmacological statin-associated muscle symptoms risk stratification (PSAMS-RS) score using real-world electronic health record data
Authors: Sun Boguang , Yew Pui Ying , Chi Chih-Lin , Song Meijia , Loth Matt , Liang Yue , Zhang Rui , Straka Robert J.
Published: August 2023

Introduction

Statin-associated muscle symptoms (SAMS) contribute to the nonadherence to statin therapy. In a previous study, we successfully developed a pharmacological SAMS (PSAMS) phenotyping algorithm that distinguishes objective versus nocebo SAMS using structured and unstructured electronic health records (EHRs) data. Our aim in this paper was to develop a pharmacological SAMS risk stratification (PSAMS-RS) score using these same EHR data.

Method

Using our PSAMS phenotyping algorithm, SAMS cases and controls were identified using University of Minnesota (UMN) Fairview EHR data. The statin user cohort was temporally divided into derivation (1/1/2010 to 12/31/2018) and validation (1/1/2019 to 12/31/2020) cohorts. First, from a feature set of 38 variables, a Least Absolute Shrinkage and Selection Operator (LASSO) regression model was fitted to identify important features for PSAMS cases and their coefficients. A PSAMS-RS score was calculated by multiplying these coefficients by 100 and then adding together for individual integer scores. The clinical utility of PSAMS-RS in stratifying PSAMS risk was assessed by comparing the hazard ratio (HR) between 4th vs 1st score quartile.

Results

PSAMS cases were identified in 1.9% (310/16128) of the derivation and 1.5% (64/4182) of the validation cohort. After fitting LASSO regression, 16 out of 38 clinical features were determined to be significant predictors for PSAMS risk. These factors are male gender, chronic pulmonary disease, neurological disease, tobacco use, renal disease, alcohol use, ACE inhibitors, polypharmacy, cerebrovascular disease, hypothyroidism, lymphoma, peripheral vascular disease, coronary artery disease and concurrent uses of fibrates, beta blockers or ezetimibe. After adjusting for statin intensity, patients in the PSAMS score 4th quartile had an over seven-fold (derivation) (HR, 7.1; 95% CI, 4.03-12.45) and six-fold (validation) (HR, 6.1; 95% CI, 2.15-17.45) higher hazard of developing PSAMS versus those in 1st score quartile.

Conclusion

The PSAMS-RS score can be a simple tool to stratify patients’ risk of developing PSAMS after statin initiation which can facilitate clinician-guided preemptive measures that may prevent potential PSAMS-related statin non-adherence.
Dynamic modes of Notch transcription hubs conferring memory and stochastic activation revealed by live imaging the co-activator Mastermind
Authors: deHaro-Arbona F Javier , Roussos Charalambos , Baloul Sarah , Townson Jonathan , Gomez-Lamarca Maria J. , Bray Sarah
Published: August 2023

Developmental programming involves the accurate conversion of signaling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the coactivator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, that correlates with Polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.
Performance of a large language model (ChatGPT-3.5) for Pooled Cohort Equation estimation of atherosclerotic cardiovascular disease risk
Authors: Marafino Ben J. , Liu Vincent X.
Published: August 2023

Despite demonstrated facility for arithmetic and other quantitative tasks, the performance of ChatGPT and other large language models for clinical risk calculation have yet to be assessed. Using synthetic patient data, this preliminary study aimed to assess the calibration, reproducibility, and potential for sociodemographic bias of ChatGPT-derived Pooled Cohort Equation (PCE) scores of atherosclerotic cardiovascular disease risk as compared to true scores. We found that ChatGPT-derived PCE scores, despite being moderately associated with the true PCE scores, displayed poor calibration with respect to true PCE scores, and exhibited instability between repeated rounds of prompting, suggesting lack of reproducibility. Moreover, ChatGPT-derived PCE scores also appeared inappropriately sensitive to contextual indicators of the sociodemographic status of the synthetic patients in this study. Further work is needed to confirm these results, and to assess performance on a wider variety of prompts as well as in other settings beyond cardiovascular disease prevention where accurate risk calculation is also vital to appropriate clinical decision-making.

Abstract Figure

Figure. Underestimation of true PCE risk estimates (x-axis) by ChatGPT (y-axis) on synthetic patient data.
Individual level analysis of digital proximity tracing for COVID-19 in Belgium highlights major bottlenecks
Authors: Geenen Caspar , Raymenants Joren , Gorissen Sarah , Thibaut Jonathan , McVernon Jodie , Lorent Natalie , André Emmanuel
Published: August 2023

To complement labour-intensive conventional contact tracing, digital proximity tracing was implemented widely during the COVID-19 pandemic. However, the privacy-centred design of the dominant Google-Apple exposure notification framework has hindered assessment of its effectiveness. Between October 2021 and January 2022, we systematically collected app use and notification receipt data within a test and trace programme for university students in Leuven, Belgium. Due to low success rates in each studied step of the digital notification cascade, only 4.3% of exposed contacts (CI: 2.8-6.1%) received such notifications, resulting in 10 times more cases detected through conventional contact tracing. Moreover, the infection risk of digitally traced contacts (5.0%; CI: 3.0-7.7%) was lower than that of conventionally traced non-app users (9.8%; CI: 8.8-10.7%; p=0.002). Contrary to common perception as near instantaneous, there was a 1.2-day delay (CI: 0.6-2.2) between case PCR result and digital contact notifications. These results highlight major limitations of the dominant digital proximity tracing framework.
The whole day matters after stroke: Study protocol for a randomized controlled trial investigating the effect of a ‘sit less, move more, sleep better’ program early after stroke
Authors: Okusanya Deborah , Ezeugwa Joy , Khan Aiza , Buck Brian , Jickling Glen , Ezeugwu Victor
Published: August 2023

Background

Movement-related behaviours, including prolonged sedentary behaviour, physical inactivity, and sleep disorders, are associated with worse functional outcomes poststroke. Addressing these co-dependent behaviours early after stroke may help to optimize recovery and improve overall quality of life for individuals with stroke.

Objective

This study aims to determine the feasibility and effect of a ‘sit less, move more, sleep better’ program early after stroke on functional mobility and global disability outcomes, while also exploring imaging and behavioral markers that may influence walking recovery.

Methods

The study is a single-blind (outcome assessor), single-center, parallel-group, randomized controlled trial. We will enroll 50 patients with acute ischemic stroke within 7 days from symptom onset, aged 18 years or older, and with ongoing walking goals. Demographic and stroke characteristics, including stroke risk factors, neuroimaging, and acute stroke treatments, will be determined and documented. All participants will wear an accelerometer for one week at three different time-points (baseline, 6, and 12 weeks) to assess movement-related behaviours.

Following randomization, participants in the intervention arm will receive a ‘sit less, move more, sleep better’ program for up to 1 hour/day, 5 days/week, for 6 weeks to enhance self-efficacy for change. Participants in the control arm will receive usual inpatient and early supported stroke discharge care. The feasibility outcomes will include reach (enrolled/eligible), retention (completed/enrolled), adverse events, and program adherence. Other outcomes at 6 and 12 weeks include the modified Rankin Scale, Timed-Up and Go, movement-related behaviours, walking endurance, gait speed, cognition, stroke severity and quality of life.

Discussion

Adopting a whole-day approach to poststroke rehabilitation will provide valuable insights into the relationship between optimizing movement-related behaviours early after stroke and their impact on functional outcomes. Through exploring person-specific behavioural and imaging markers, this study may inform precision rehabilitation strategies, and guide clinical decision making for more tailored interventions.
Preventable Deaths involving Sepsis in England and Wales, 2013-2022: A Systematic Case Series of Coroners’ Reports
Authors: Jindal Jessy , Launer David , France Harrison S , Hey Molly , Song Kaiyang , Portwood Clara , Richards Georgia , Dernie Francesco
Published: August 2023

Purpose

Coroners’ Prevention of Future Death (PFDs) reports are an under-utilised resource to learn about preventable deaths in England and Wales. We aimed to identify sepsis-related PFDs and explore the causes and concerns in this subset of preventable sepsis deaths.

Methods

4305 reports were acquired from the Courts and Tribunals Judiciary website between July 2013 and November 2022, which were screened for sepsis. Demographic information, coroners concerns and responses to these reports were extracted and analysed, including a detailed paediatric subgroup analysis.

Results

265 reports (6% of total PFDs) involved sepsis-related deaths. The most common cause of death in these reports was “sepsis without septic shock” (42%) and the most common site of infection was the respiratory system (18%) followed by gastrointestinal (16%) and skin (13%) infections. Specific pathogens were named in few reports (27%). Many deaths involved multimorbid patients (49%) or those with recent surgery (26%). Coroners named 773 individual concerns, the most frequent were: a failure to keep accurate records or notes (28%), failure in communication or handover (27%) or failure to recognise risk factors or comorbidities (20%). Paediatric cases frequently reported issues with sepsis screening tools (26%). Sepsis PFDs resulted in 421 individual reports being sent, of which 45% received no response. Most organisations who did respond acknowledged concerns and initiated a new change (74%).

Conclusion

Sepsis-related PFDs provide valuable insights into preventable causes of sepsis and identify important sources of improvement in sepsis care. Wider dissemination of findings is vital to learn from these reports.
Projecting Omicron scenarios in the US while tracking population-level immunity
Authors: Bouchnita Anass , Bi Kaiming , Fox Spencer , Meyers Lauren Ancel
Published: August 2023

Throughout the COVID-19 pandemic, changes in policy, shifts in behavior, and the emergence of new SARS-CoV-2 variants spurred multiple waves of transmission. Accurate assessments of the changing risks were vital for ensuring adequate healthcare capacity, designing mitigation strategies, and communicating effectively with the public. Here, we introduce a model of COVID-19 transmission and vaccination that provided rapid and reliable projections as the BA.1, BA.4 and BA.5 variants emerged and spread across the US. For example, our three-week ahead national projection of the early 2021 peak in COVID-19 hospitalizations was only one day later and 11.6-13.3% higher than the actual peak, while our projected peak in mortality was two days earlier and 0.22-4.7% higher than reported. We track population-level immunity from prior infections and vaccination in terms of the percent reduction in overall susceptibility relative to a completely naive population. As of October 1, 2022, we estimate that the US population had a 36.52% reduction in overall susceptibility to the BA.4/BA.5 variants, with 61.8%, 15.06%, and 23.54% of immunity attributable to infections, primary series vaccination, and booster vaccination, respectively. We retrospectively projected the potential impact of expanding booster coverage starting on July 15, 2022, and found that a five-fold increase in weekly boosting rates would have resulted in 70% of people over 65 vaccinated by Oct 10, 2022 and averted 25,000 (95% CI: 14,400-35,700) deaths during the BA.4/BA.5 surge. Our model provides coherent variables for tracking population-level immunity in the increasingly complex landscape of variants and vaccines and enables robust simulations of plausible scenarios for the emergence and mitigation of novel COVID variants.
High amino-acid intake in early life is associated with systolic but not diastolic arterial hypertension at 5-years of age in children born very preterm
Authors: Rozé Jean-Christophe , Bacchetta Justine , Lapillonne Alexandre , Boudred Farid , Picaud Jean-Charles , Marchand-Martin Laetitia , Bruel-Tessoulin Alexandra , Haramba Jérome , Biran Valérie , Darmaun Dominique , Ancel Pierre-Yves
Published: August 2023

BACKGROUND

The life course of individuals born very premature is a topic of increasing concern as their neonatal survival has dramatically increased. In a national, prospective, population-based birth cohort, EPIPAGE-2, we observed that amino-acid intakes greater than 3.5 g/kg/day at day 7 after birth were independently associated with higher intelligence quotient at 5 years. As the association between high early amino-acid intake and later HBP in this population is debated, we assessed blood pressure (BP) at 5 years.

METHODS

This cohort was initiated in 2011, and approved by ethics committees. Eligible infants were those born between 24 and 29 weeks of gestation and alive on day7 after birth. Infants were distributed in two groups of 717 infants matched on propensity score on whether or not they were exposed to high amino-acid intake (>3.5 g/kg/d at Day7); 455 control term infants were also enrolled. Assessment at 5-year occurred from September 2016 to December 2017. A value>95thpercentile of reference values for age and height defined systolic and/or diastolic HBP.

RESULTS

BP at five years of age was assessed for 389 and 385 children in exposed and non-exposed groups. Rates (%) of systolic HBP were 18.0% (95%CI, 14.5 to 22.2), 13.3% (95%CI, 10.3 to 17.0), and 8.5% (95%CI, 6.5 to 11.1) in exposed, non-exposed preterm infants, and term infants, respectively; and 9.0% (95%CI, 6.6 to 12.3), 10.2% (95%CI, 7.5 to 13.6), 5.4% (95%CI, 3.8 to 7.6) % for diastolic HBP, in exposed, non-exposed and term-born groups, respectively. Perinatal characteristics of exposed and non-exposed infants were similar, except for nutrition intake at day3 and day7 after birth. Exposure to high early amino-acid intake, and maximal serum creatinine between day3 and day7 were two independent risk factors for systolic HBP (aOR, 1.60 [95% CI, 1.05 to 2.43] and aOR, 1.59 [95% CI, 1.12 to 2.26] by 50 µmol/L, respectively) but not for diastolic HBP (aOR, 0.84 [95% CI, 0.50 to 1.39] and aOR, 1.09 [95% CI, 0.71 to 1.67] by 50 µmol/L, respectively).

CONCLUSIONS

These observations confirm the risk for HBP in young children born very preterm. Higher amino-acid intake and creatinine values in the first week of life were associated with childhood systolic HBP. These results suggest that mechanisms to childhood systolic HBP involves neonatal renal challenge by high amino-acid intake or dysfunction.
Genetic variants associated with the risk of stroke in sickle cell disease: a systematic review and meta-analysis
Authors: Kumari Aradhana , Chauhan Ganesh , Chaudhuri Partha Kumar , Prasad Anupa
Published: August 2023

Background

Sickle cell disease (SCD) is the commonest cause of stroke in children. As it is a rare disease, studies investigating the association with complications like stroke in SCD have small sample sizes. Here, we performed a systematic review and meta-analysis of the studies exploring an association of genetic variants with stroke to get a better indication of their association with stroke.

Methods

PubMed and Google Scholar were searched to identify studies that had performed an association analysis of genetic variants for the risk of stroke in SCD patients. After screening of eligible studies, summary statistics of association analysis with stroke and other general information were extracted. Meta-analysis was performed using the fixed effect method on the tool METAL and forest plots were plotted using the R program. The random effect model was performed as a sensitivity analysis for loci where significant heterogeneity was observed.

Results

408 studies were identified using the search term and after screening 39 studies that cumulatively analysed 11,780 SCD patients were included. These 39 studies included a total of 2,401 SCD patients with stroke, predominantly included individuals of African ancestry (N=16). Three of these studies performed whole exome sequencing while 36 performed single nucleotide-based genotyping. Though the studies reported association with 109 loci, meta-analyses could be performed only for 12 loci that had data from two or more studies. After meta-analysis we observed that four loci were significantly associated with risk for stroke: -α3.7kbAlpha-thalassemia deletion(P= 0.00000027), rs489347-TEK(P= 0.00081), rs2238432-ADCY9 (P= 0.00085) and rs11853426-ANXA2(P= 0.0034).

Conclusion

Ethnic representation of regions with a high prevalence of SCD like the Mediterranean basin and India needs to be improved for genetic studies on associated complications like stroke. Larger genome-wide collaborative studies on SCD and associated complications including stroke needs to be performed.
Scanning electron microscopy observations on the surface morphology of placenta villi from HIV-positive women having preterm birth while receiving antiretroviral therapy
Authors: Obimbo Moses M. , Ochieng’ Shem , Gesaka Samwel R. , Ogeng’o Julius
Published: August 2023

Background

Preterm birth is a significant global issue. Antiretroviral therapy (ART) use and human immunodeficiency virus (HIV) infection have both been linked in recent research as independent risk factors for preterm birth. Although there has been evidence linking preterm delivery to significant pathological alterations in the placenta, it is still unclear how exactly HIV and ART harm the placenta and raise the risk of prematurity. To explain the increased risk of preterm birth (PTB), we set out to describe the surface morphological alterations in placenta villi associated with HIV and ART.

Methods and materials

We collected and processed 160 placentas from 40 HIV-positive women on ART and 40 HIV-negative women who had preterm deliveries, 40 HIV-positive women and 40 HIV - negative women with term delivery in Nairobi, Kenya. The placenta biopsies were harvested, washed in phosphate buffer solution, and processed for scanning electron microscopy. The dried tissue was mounted onto specimen stubs, sputter coated with gold and visualized using Zeiss Merlin FESEM in-lens. Forty representative samples, 10 from each group, were randomly selected and examined by investigators who were blinded to maternal HIV serostatus.

Results

The average gestational age for preterm and term births was 34 and 39 weeks, respectively. The average age of the mothers of preterm and term babies was 26.8 + 4.6 years and 24.3 + 4.3 years, respectively. The villous core of the placenta from HIV-negative patients was covered with microvilli that varied in size and appearance, and there were hardly any residual red blood cells. Placenta from HIV-positive women with preterm birth had widespread damage with shrunken and wrinkled villi, predominant blunting of the microvilli, with attendant syncytiotrophoblast disruption, and significant erythrocyte adhesion within extensive fibrillar meshwork and on surface of the syncytium.

Conclusion

Our results show distinctive alterations in the placenta of HIV-positive mothers who gave birth prematurely, which may impair the syncytium’s ability to function normally. Microvilli blunting, syncytial disruptions, and syncytial erythrocyte adhesion might be the symptoms of a deeper biological process. Further work to understand the effect of HIV/ART on the syncytiotrophoblast in relation to prematurity is recommended.
Longitudinal genomic surveillance of multidrug-resistantEscherichia colicarriage in critical care patients
Authors: Chaar Mira El , Khoury Yaralynn , Douglas Gavin M. , Kazzi Samir El , Jisr Tamima , Soussi Shatha , Merhi Georgi , Moghnieh Rima A. , Shapiro B. Jesse
Published: August 2023

Background

Colonization with multidrug resistantE. colistrains causes a substantial health burden in hospitalized patients. We performed a longitudinal genomics study to investigate the colonization of resistantE. colistrains in critically ill patients, and to identify evolutionary changes and strain replacement events within patients.

Methods

Patients were admitted to the intensive care unit and haematology wards at a major hospital in Lebanon. Perianal swabs were collected from participants on admission and during hospitalization, which were screened for extended-spectrum beta-lactamases and carbapenem-resistant Enterobacterales. We performed whole-genome sequencing and analysis onE. colistrains isolated from patients at multiple time points.

Results

TheE. coliisolates were genetically diverse, with 13 sequence types (STs) identified among 21 isolates sequenced. Five patients were colonized by ST131 encoding CTX-M-27, a type of beta-lactamase gene not previously been observed in Lebanon. Among the eight patients whose residentE. colistrains were tracked over time, five harbored the sameE. colistrain with relatively few mutations over the 5 to 10 days of hospitalization. The other three patients were colonized by differentE. colistrains over time.

Conclusion

Our study provides evidence of strain diversity within patients during their hospitalization. While strains varied in their antimicrobial resistance profiles, the number of resistance genes did not increase over time. We also show that ST131 encoding CTX-M-27, which appears to be emerging as a globally important multidrug resistantE. colistrain, is also prevalent among critical care patients and deserves further monitoring.
Association of polypharmacy and burden of comorbidities on COVID-19 adverse outcomes in people with type 1 or type 2 diabetes
Authors: Gupta Juhi K , Ravindrarajah Rathi , Tilston George , Ollier William , Ashcroft Darren M , Heald Adrian H
Published: August 2023

Aim: To investigate whether polypharmacy and comorbidities conveyed more risk of adverse health outcomes following COVID-19 infection in people with type 1 diabetes (T1DM) or type 2 diabetes (T2DM). Materials and methods: The Greater Manchester Care Record (GMCR) is an integrated database of electronic health records containing data collected from 433 general practices in Greater Manchester. Baseline demographic information (age, BMI, gender, ethnicity, smoking status, deprivation index), hospital admission or death within 28 days of infection were extracted for adults (18+) diagnosed with either T1DM or T2DM. Results: For T2DM, 16 to 20 medications (p=0.005; OR [95% CI]=2.375 [1.306 to 4.319]) and > 20 medications (p<0.001; OR [95% CI]=3.141 [1.755 to 5.621]) were associated with increased risk of death following COVID-19 infection. Increased risk of hospital admissions in T2DM individuals was associated with 11 to 15 medications (p=0.013; OR [95% CI]=1.341 [1.063 to 1.692]) and above. This was independent of comorbidities, metabolic and demographic factors. For T1DM there was no association of polypharmacy with hospital admission. Respiratory, cardiovascular/cerebrovascular and gastrointestinal conditions were associated with increased risk of hospital admissions and deaths in T2DM (p<0.001). Conclusion: We have shown in T2DM an independent association of multiple medications taken from 11 upwards with adverse health consequences following COVID-19 infection. We also found that individuals with diabetes develop comorbidities that were common across both T1DM and T2DM. This study has laid the foundation for future investigations into the way that complex pharmacological interactions may influence clinical outcomes in people with T2DM.
Diagnosing Epilepsy with Normal Interictal EEG Using Dynamic Network Models
Authors: Myers Patrick , Gunnarsdottir Kristin , Li Adam , Razskazovskiy Vlad , Wyeth Dale , Wyeth Edmund , Tillery Alana , Zaghloul Kareem , Inati Sara , Hopp Jennifer , Haridas Babitha , Gonzalez-Martinez Jorge , Bagíc Anto , Kang Joon-yi , Sperling Michael , Barot Niravkumar , Sarma Sridevi V. , Husari Khalil S.
Published: August 2023

Objective

While scalp EEG is important for diagnosing epilepsy, a single routine EEG is limited in its diagnostic value. Only a small percentage of routine EEGs show interictal epileptiform discharges (IEDs) and overall misdiagnosis rates of epilepsy are 20-30%. We aim to demonstrate how analyzing network properties in EEG recordings can be used to improve the speed and accuracy of epilepsy diagnosis - even in the absence of IEDs.

Methods

In this multicenter study, we analyzed routine scalp EEGs from 198 patients with suspected epilepsy and normal initial EEGs. The patients’ diagnoses were later confirmed based on an epilepsy monitoring unit (EMU) admission. About 46% ultimately being diagnosed with epilepsy and 54% with non-epileptic conditions. A logistic regression model was trained using spectral and network-derived EEG features to differentiate between epilepsy and non-epilepsy. The model was trained using 10-fold cross-validation on 70% of the data, which was stratified to include equal numbers of epilepsy and non-epilepsy patients in both training and testing groups. The resulting tool was named EpiScalp.

Results

EpiScalp achieved an area under the curve (AUC) of 0.940. The model had an accuracy of 0.904, a sensitivity of 0.835, and a specificity of 0.963 in classifying patients as having epilepsy or not.

Interpretation

EpiScalp provides accurate diagnostic aid from a single initial EEG recording, even in more challenging epilepsy cases with normal initial EEGs. This may represent a paradigm shift in epilepsy diagnosis by deriving an objective measure of epilepsy likelihood from previously uninformative EEGs.
Investigating the role of the relaxin-3/RXFP3 system in neuropsychiatric disorders and metabolic phenotypes: a candidate gene approach
Authors: Wong Win Lee Edwin , Arathimos Ryan , Lewis Cathryn M. , Young Allan H. , Dawe Gavin Stewart
Published: August 2023

The relaxin-3/RXFP3 system has been implicated in the modulation of depressive- and anxiety-like behaviour in the animal literature; however, there is a lack of human studies investigating this signalling system. We seek to bridge this gap by leveraging the large UK Biobank study to retrospectively assess genetic risk variants linked with this neuropeptidergic system. Specifically, we conducted a candidate gene study in the UK Biobank to test for potential associations between a set of functional, candidate single nucleotide polymorphisms (SNPs) pertinent to relaxin-3 signalling, determined usingin silicotools, and several outcomes, including depression, atypical depression, anxiety and metabolic syndrome. For each outcome, we used several rigorously defined phenotypes, culminating in subsample sizes ranging from 85,881 to 386,769 participants. Across all outcomes, there were no associations between any candidate SNP and any outcome phenotype, following corrections for multiple testing burden. Regression models comprising several SNPs per relevant candidate gene as exploratory variables further exhibited no prediction of outcome. Our findings corroborate conclusions from previous literature about the limitations of candidate gene approaches, even when based on firm biological hypotheses, in the domain of genetic research for neuropsychiatric disorders.
Temporal trends of dengue seroprevalence among children in coastal Kenya, 1998–2018: a longitudinal cohort study
Authors: Karanja Henry K. , Orindi Benedict , Gitonga John N. , Mugo Daisy , Mwai Kennedy , Nyamwaya Doris K. , Omuoyo Donwilliams , Kitsao Barnes S. , Musyoki Jennifer N. , Wambua Julianna , Otieno Edward , Ochola-Oyier Lynette Isabella , Bejon Philip , Warimwe George M.
Published: August 2023

Serosurveys suggest widespread dengue virus (DENV) transmission in Africa but there is limited information on the temporal patterns of exposure. Here, we estimated the prevalence and incidence of DENV infections in coastal Kenya over a 20-year period (1998–2018). Sera (n=8038) obtained annually from a longitudinal cohort of 1847 children aged 15 years and below were screened for anti-DENV IgG antibodies. Anti-DENV IgG seroprevalence increased with age and peaked during outbreak years. Among 1354 children who were seronegative at recruitment, we observed an overall incidence (seroconversion) rate of 129.5 (95% CI 118.7–141.4) DENV infections per 1000 person-years. The highest incidence was observed in 2013 at 520 infections per 1000 person-years (95% CI 443.6–610.2) coinciding with a large DENV outbreak in coastal Kenya. Our data suggest long-term DENV exposure among children in coastal Kenya highlighting an urgent need for clinical surveillance to determine the associated health burden in this setting.
Does screening forNeisseria gonorrhoeaeandChlamydia trachomatisaffect the incidence of these infections in men who have sex with men taking HIV pre-exposure prophylaxis (PrEP)Results from a randomized, multicentre controlled trial (the Gonoscreen study)
Authors: Vanbaelen Thibaut , Tsoumanis Achilleas , Florence Eric , Van Dijck Christophe , Huis in ‘t Veld Diana , Sauvage Anne-Sophie , Herssens Natacha , De Baetselier Irith , Rotsaert Anke , Verhoeven Veronique , Henrard Sophie , Van Herrewege Yven , Van den Bossche Dorien , Goffard Jean-Christophe , Padalko Elizaveta , Reyniers Thijs , Vuylsteke Bea , Hayette Marie-Pierre , Libois Agnes , Kenyon Chris
Published: August 2023

Background

Guidelines recommend three-site (urine, anal, pharynx) three-monthly (3X3 screening) screening for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) in men who have sex with men (MSM) taking HIV pre-exposure prophylaxis (PrEP). We present the first randomized controlled trial to compare the effect of screening versus non-screening for NG/CT on the incidence of these infections in MSM taking PrEP.

Methods

A multicenter, randomized, controlled trial of 3X3 screening for NG/CT versus non-screening was conducted among MSM taking PrEP in five HIV reference centers in Belgium. Participants attended the PrEP clinics quarterly for 12 months. NG/CT was tested at each visit in both arms, but results were not provided to the non-screening arm. The primary outcome was the incidence rate (IR) of NG/CT infections in each arm, assessed in the per-protocol population. Non-inferiority of the non-screening arm was proven if the upper limit of the 95% confidence interval of the IR ratio (IRR) was lower than 1.25. The trial protocol was registered atclinicaltrials.gov(NCT04269434).

Findings

Between September 2020 and June 2021, 508 subjects were randomized to the 3X3 screening arm and 506 to the non-screening arm. The overall IR of NG/CT was 0.155 cases/100 person-days (95%CI 0.128-0.186) in the 3×3 screening arm and 0.205 (95%CI 0.171-0.246) in the non-screening arm. The IR was significantly higher in the non-screening arm (IRR 1.318, 95%CI 1.068-1.627). Participants in the non-screening arm had a higher incidence of CT infections and symptomatic CT infections. There were no significant differences in NG infections. Participants in the non-screening arm consumed significantly less antimicrobials. No serious adverse events were reported.

Interpretation

We failed to show that non-screening for NG/CT is non-inferior to 3-site 3-monthly screening in MSM taking PrEP in Belgium. However, screening was associated with higher antibiotic consumption and had no effect on the incidence of NG. Therefore, our findings do not provide strong support for screening for NG/CT in this population.

Funding

Belgian Healthcare Knowledge Center (KCE - INV18-1133)
Effect of Daytime Nap on Attention, Working Memory, and Recognition Memory
Authors: Zare Shahab , Dortaj Fariborz , Setareh Javad
Published: August 2023

Daytime napping has gained attention for its potential to enhance cognitive functions. While the positive impact of nocturnal sleep on cognitive functions is widely acknowledged, limited research has focused on the effects of daytime naps. In this study, we investigated the influence of a 30-minute afternoon nap on cognitive functions in healthy adults.

Ten participants (4 females) were involved in both nap and non-nap (control) conditions. Participants were randomly selected from the sleep department of Zare Hospital. During the nap condition, participants engaged in a 30-minute nap at approximately 14:00. Cognitive assessments were performed 30 minutes after the nap to reduce the effects of sleep inertia. Three days after nap condition, cognitive evaluations were conducted again at approximately 15:00, in the non-nap condition.

Working memory, evaluated using the Backward Digit Span Task using a paired sample t-test, exhibited significant improvement during napping (p = 0.0164, d = 0.459), highlighting its practical significance. Attention, assessed with the Stroop test, and the Wilcoxon signed-rank test showed significant differences between nap and non-nap conditions, emphasizing napping’s role in sustaining attention and alertness. Recognition memory, gauged through the Auditory Verbal Learning Test, revealed superior performance in the nap condition, particularly in False Alarm scores.

Despite limitations such as sample size and nap monitoring, our study contributes valuable insights into the cognitive benefits of daytime napping. By refining our understanding of napping’s effects, tailored interventions can be developed, promoting cognitive health and performance enhancement across various contexts.

Iranian Registry of Clinical Trials (IRCT) registration number 66862. Date of registration: 12/31/2022

The study was approved by the Research Ethics Committee of Allameh Tabataba’i University (IR.ATU.REC.1401.030).

Statements and Declarations

The writers confirm that they have no affiliations or engagements with any organization or institution that holds any financial or non-financial interest in the subject matter or materials addressed in this publication.