bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiorenal effects of dual blockade with Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers in people with CKD: analysis of routinely collected data with emulation of a reference trial (ONTARGET)
Authors: Baptiste Paris J , Wong Angel YS , Schultze Anna , Clase Catherine M , Leyrat Clémence , Williamson Elizabeth , Powell Emma , Mann Johannes FE , Cunnington Marianne , Teo Koon , Bangdiwala Shrikant I , Gao Peggy , Wing Kevin , Tomlinson Laurie
Published: May 2024

We aimed to explore whether the ONTARGET trial results, which led to an end of recommendations of dual angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use, extended to patients with chronic kidney disease (CKD) who were underrepresented in the trial.

We selected people prescribed an ACEi and/or an ARB in the UK Clinical Practice Research Datalink Aurum during 1/1/2001-31/7/2019. We specified an operational definition of dual users and applied ONTARGET eligibility criteria. We used propensity-score—weighted Cox-proportional hazards models to compare dual therapy to ACEi for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), as well as a primary composite renal outcome (≥50% reduction in GFR or end-stage kidney disease), and other secondary outcomes, including hyperkalaemia. Conditional on successfully benchmarking results against the ONTARGET trial, we explored treatment effect heterogeneity by CKD at baseline.

In the propensity-score—weighted trial-eligible analysis cohort (n=412 406), for dual therapy vs ACEi we observed hazard ratio (HR) 0.98 (95% CI: 0.93, 1.03), for the primary composite outcome, consistent with the trial results (ONTARGET HR 0.99, 95% CI: 0.92, 1.07). Dual therapy use was associated with an increased risk of the primary renal composite outcome, HR 1.25 (95% CI: 1.15, 1.36) vs ONTARGET HR 1.24 (1.01, 1.51) and hyperkalaemia, HR 1.15 (95% CI: 1.09, 1.22) in the trial eligible cohort, consistent with ONTARGET. The presence of CKD at baseline had minimal impact on results.

Translational statement

We extended ONTARGET trial findings of the comparative effectiveness of dual ARB and ACEi therapy use compared to ACEi alone for a composite cardiovascular outcome to UK patients at high-risk of cardiovascular disease, including those with CKD. As in ONTARGET, we found an increased risk of a composite renal outcome (≥50% reduction in GFR or end-stage kidney disease) and an increased risk of hyperkalaemia among dual users compared to ACEi alone. Consistent results were observed among patients with CKD at baseline. This is evidence against the hypothesis that dual blockade provides cardiorenal benefits among high-risk cardiovascular patients with CKD.
HYDINvariants cause primary ciliary dyskinesia in the Finnish population
Authors: Burgoyne Thomas , Fassad Mahmoud R , Schultz Rüdiger , Elenius Varpu , Lim Jacqueline S Y , Freke Grace , Rai Ranjit , Mohammed Mai A , Mitchison Hannah M , Sironen Anu I
Published: May 2024

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways, organizing internal organ positioning during embryonic development and gamete transport. PCD is caused by mutations in genes coding for structural or assembly proteins of motile cilia. Thus far, mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported underlining the importance of characterizing gene variants in different populations for development of gene-based diagnostics and management. In this study, we identified disease causing genetic variants in the axonemal central pair component HYDIN. Three Finnish PCD patients carried homozygous loss-of-function variants and one patient had compound heterozygous variants within theHYDINgene. The functional effect of theHYDINvariants was confirmed by immunofluorescence and electron tomography, which demonstrated defects in the axonemal central pair complex. All patients had clinical PCD symptoms including chronic wet cough and recurrent airway infections due to almost static airway cilia. Our results are consistent with the previously identified important role of HYDIN in the axonemal central pair complex and improve specific diagnostics of PCD in different ethnical backgrounds.
MRI-based cortical gray/white matter contrast in young adults who endorse psychotic experiences or are at genetic risk for psychosis
Authors: Naseri Nasimeh , Beck Dani , Ferschmann Lia , Aksnes Eira R. , Havdahl Alexandra , Jalbrzikowski Maria , Norbom Linn B. , Tamnes Christian K.
Published: May 2024

Group-level differences in brain macrostructure between individuals at risk for psychosis and healthy controls have been well documented. However, while differences in cortical grey/white matter contrast (GWC), likely reflecting differences in myelin content, have been reported in clinical populations with psychotic disorders, no studies have explored GWC in individuals at elevated risk for psychosis. In this study, we explored whether brain microstructure, as measured with GWC, differs between young adults who endorsed psychotic experiences or genetic high risk for psychosis and healthy controls, and whether individual differences in GWC in at-risk individuals are associated with the number and psychotic experiences. The sample included individuals from two magnetic resonance imaging (MRI) substudies of the Avon Longitudinal Study of Parents and Children (ALSPAC): the psychotic experiences study and the schizophrenia recall-by-genotype study. The final sample included four groups of young adults 19-24 years old: individuals endorsing psychotic experiences (n=119) and health controls (n=117) and individuals with high (n=95) and low genetic risk for psychosis (n=95). Statistical analyses were performed using FSL’s Permutation Analysis of Linear Models (PALM), controlling for age and sex. The results showed no statistically significant differences in GWC between any of the groups and no significant associations between GWC and the number and experiences of psychotic experiences. In conclusion, the results indicate that GWC is not a sensitive neuroimaging marker for psychosis risk in young adults.
Linear regression reporting practices for health researchers, a cross-sectional meta-research study
Authors: Jones Lee , Barnett Adrian , Vagenas Dimitrios
Published: May 2024

Background

Decisions about health care, such as the effectiveness of new treatments for disease, are regularly made based on evidence from published work. However, poor reporting of statistical methods and results is endemic across health research and risks ineffective or harmful treatments being used in clinical practice. Statistical modelling choices often greatly influence the results. Authors do not always provide enough information to evaluate and repeat their methods, making interpreting results difficult. Our research is designed to understand current reporting practices and inform efforts to educate researchers.

Methods

Reporting practices for linear regression were assessed in 95 randomly sampled published papers in the health field from PLOS ONE in 2019, which were randomly allocated to statisticians for post-publication review. The prevalence of reporting practices is described using frequencies, percentages, and Wilson 95% confidence intervals.

Results

While 92% of authors reported p-values and 81% reported regression coefficients, only 58% of papers reported a measure of uncertainty, such as confidence intervals or standard errors. Sixty-nine percent of authors did not discuss the scientific importance of estimates, and only 23% directly interpreted the size of coefficients.

Conclusion

Our results indicate that statistical methods and results were often poorly reported without sufficient detail to reproduce them. To improve statistical quality and direct health funding to effective treatments, we recommend that statisticians be involved in the research cycle, from study design to post-peer review. The research environment is an ecosystem, and future interventions addressing poor statistical quality should consider the interactions between the individuals, organisations and policy environments. Practical recommendations include journals producing templates with standardised reporting and using interactive checklists to improve reporting practices. Investments in research maintenance and quality control are required to assess and implement these recommendations to improve the quality of health research.
A CROSS-SECTIONAL STUDY OF THE PSYCHOLOGICAL IMPACT OF COVID-19 ON MEDICAL STUDENTS DURING & AFTER RECOVERY FROM COVID-19
Authors: Misra Anushka , Rane Damini , Arun Bhat P.
Published: May 2024

Introduction

Mental health of medical students has been an utmost topic of discussion. It is important to know whether the upcoming doctors are mentally equipped to handle the pressure that comes with the profession. There is substantial literature indicating negative impact on the mental health during COVID-19 pandemic. Studies regarding the same on frontline workers seems scarce. Therefore, it is essential to assess the prevalence of symptoms anxiety and depression among medical students during and after the recovery from COVID-19 infection.

Materials and methods

It is a cross-sectional time bound study on 32 medical undergraduate students with active COVID-19 infection. They were screened using Self-reporting Questionnaire 20 (SRQ). Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D) were administered on those who screened positive on SRQ-20 to assess the severity of anxiety and depressive symptoms. These were administered during and after COVID-19 infection on virtual platform.

Results

In our study, 59.37% population was screened positive for mental health disorder during COVID-19 infection. 89.5% of the positively screened respondents had mild anxiety symptoms and 10.5% had moderate anxiety symptoms. 47.4% of screened respondents had mild depressive symptoms, 31.6% reported moderate depressive symptoms and 21.1% had severe depressive symptoms. Following recovery, there was a reduction in severity of anxiety and depressive symptoms which was statistically significant (p<0.001).

Conclusion

Medical students have a propensity to develop anxiety and depressive symptoms while suffering from COVID-19 infection. Some may continue to have residual anxiety and depressive symptoms after recovery but the severity significantly reduces.
IL-2-mediated CD4 T-cell activation correlates highly with effective serological and T-cell responses to SARS-CoV-2 vaccination in people living with HIV (PLWH)
Authors: Gupta Akshita , Righi Elda , Konnova Angelina , Sciammarella Concetta , Spiteri Gianluca , Averbeke Vincent Van , Berkell Matilda , Hotterbeekx An , Sartor Assunta , Mirandola Massimo , Malhotra-Kumar Surbhi , Azzini Anna Maria , Pezzani Diletta , Monaco Maria Grazia Lourdes , Vanham Guido , Porru Stefano , Tacconelli Evelina , Kumar-Singh Samir
Published: May 2024

People living with HIV (PLWH) despite having appreciable depletion of CD4+T-cell show a good SARS- CoV-2 vaccination response. The underlying mechanism(s) are currently not understood. We studied serological and polyfunctional T-cell responses in PLWH receiving anti-retroviral therapy stratified on CD4+counts as PLWH-high (CD4 ≥500 cells/μL) and PLWH-low (<500 cells/μL). Responses were assessed longitudinally before the first vaccination (T0), 1-month after the first dose (T1), and 3- months (T2), and 6-months (T3) after the second dose. Expectedly, both PLWH-high and -low groups developed similar serological responses after T2, which were also non-significantly different to age and vaccination-matched HIV-negative controls at T3. The IgG titers were also protective showing a good correlation with ACE2-neutralizations (R=0.628, P=0.005). While no difference at T3 was observed between PLWH and controls in activated CD4+CD154+and CD4+memory T-cells, spike- specific CD4+polyfunctional cytokine expression analysis showed that PLWH preferentially express IL-2 (P<0.001) and controls, IFN-γ (P=0.017). CD4+T-cell counts negatively correlated with IL-2- expressing CD4+T-cells including CD4+memory T-cells (Spearman ρ: -0.85 and -0.80, respectively; P<0.001). Our results suggest that the durable serological and CD4+T-cell responses developing in vaccinated PLWH are associated with IL-2-mediated CD4+T-cell activation that likely compensates for CD4+T-cell depletion in PLWH.
Weight Loss-Independent Changes in Human Growth Hormone During Water-Only Fasting: A Secondary Evaluation of a Randomized Controlled Trial
Authors: Horne Benjamin D. , Anderson Jeffrey L. , May Heidi T. , Bair Tami L. , Le Viet T. , Iverson Leslie , Knowlton Kirk U. , Muhlestein Joseph B.
Published: May 2024

Introduction

Water-only fasting for one day or more may provide health benefits independent of weight loss. Human growth hormone (HGH) may play a key role in multiple fasting-triggered mechanisms. Whether HGH changes during fasting are independent of weight loss and how basal HGH and HGH change relate to other fasting-induced changes are unknown.

Methods

Apparently healthy individuals (N=30) were randomized by Latin square to begin two days with either 24-hour water-only fasting or a control of 24-hourad libitumeating. On day 2, subjects were crossed over to control (if day 1 was fasting) or fasting (if they ate on day 1). HGH, weight, and other parameters were measured at baseline and at the end of the first and second days.

Results

Baseline HGH had median 0.50 ng/mL for females (n=20) and 0.04 ng/mL for males (n=10), and correlated inversely with weight, glucose, insulin, and triglycerides and positively with changes in insulin and HOMA-IR. The 24-hour fasting-induced HGH change was uncorrelated with weight loss (r= 0.01, p=0.98), but correlated with changes in glucose, HGB, and IGF-1. The percent increase in HGH was greater (p<0.001) for lower (females ≤0.15 ng/mL, males ≤0.05 ng/mL) vs. higher baseline HGH (median: 1,225% vs. 50.3%, respectively). Subjects with lower baseline HGH had a trend to greater reduction of HOMA-IR (median: −6.15 vs. −1.35 for lower vs. higher HGH, respectively, p=0.08).

Conclusions

Fasting increased HGH and the HGH changes were independent of weight loss. Basal HGH and fasting-induced HGH changes correlated inversely with cardiometabolic risk factors.
Variation in prescription duration for long term conditions: a cohort study in English NHS primary care using OpenPrescribing
Authors: MacKenna Brian , Brown Andrew D , Croker Rich , Walker Alex J , Tsiachristas Apostolos , Evans Dave , Inglesby Peter , Goldacre Ben , Bacon Seb , Curtis Helen J
Published: May 2024

Background

Many patients receive routine medications for long-term conditions (LTCs). Doctors typically issue repeat prescriptions in one to three month durations, but England currently has no national guidance on the optimal duration.

Methods

We calculated the duration of prescriptions for common LTCs in England over a 12-month period (December 2018-November 2019). We assessed the level of variation between regional clinical commissioning groups (CCGs) and determine practice factors associated with different durations.

Results

Of the common medications included, 28-day (one-monthly) prescriptions accounted for 48.5% (2.5 billion) tablets/capsules issued. There was very wide regional variation in the proportion of 28-day prescriptions (7.2% to 95.0%). Practice dispensing status was the most likely predictor of prescription duration. The proportion of patients with LTCs and the electronic health record software used by a practice were also associated with prescription duration.

Conclusions

One month prescription durations are common for patients taking medicines routinely for long term conditions, particularly in dispensing practices. Electronic health record configurations offer an opportunity to implement and evaluate new policies on repeat prescription duration in England.
The effect of mentorship as a means of strengthening leadership in the health system at the operational level: a case study of the Walungu rural health zone in the eastern Democratic Republic of Congo
Authors: Bigirinama Rosine , Bisimwa Ghislain , Makali Samuel , Cikomola Aimé , Barhobagayana Janvier , Lembebu Jean-Corneille , Chiribagula Christian , Mwene-Batu Pacifique , Mukalay Abdon , Porignon Denis , Tambwe Albert
Published: May 2024

Context

In the rural Health Zone (HZ) of Walungu, eastern Democratic Republic of Congo, major constraints impede health outcomes. From 2015 to 2019, the “RIPSEC” program transformed Walungu into a Learning and Research Zone (LRZ) under the mentorship of a local university to enhance the leadership capabilities of HZ managers, focusing on managing challenges including the proliferation of Informal Healthcare Facilities (IHFs).

Objective

This study evaluates the impact of RIPSEC mentorship on leadership development and the performance of the Walungu LRZ, particularly concerning the utilization of integrated curative health services in competition with IHFs.

Methods

We used a mixed method approach, combining retrospective analysis of some key health indicators before (2014) and during RIPSEC program (2015-2019), and in-depth qualitative interviews with members of the HZ management team. Quantitative data were presented as frequencies and proportions. Simple linear regression (p<0.05) measured the influence of IHFs on service use. The functionality and performance of the HZ were assessed using an internal benchmarking approach, with results presented as trend curves. Deductive analysis of interviews allowed for a deeper exploration of quantitative trends.

Results

Despite efforts to manage them, IHFs negatively influenced the use of curative services. RIPSEC mentorship notably enhanced the leadership skills of managers, leading to improved management effectiveness. While the use of curative health services slightly increased during the program, rates remained below 50%, and gains were not sustained post-program.

Conclusion

RIPSEC mentorship has positively impacted leadership and performance in Walungu. However, challenges related to sustainability and financing persist, necessitating comprehensive interventions beyond enhancing managerial leadership solely.
Antibiotic Resistance related Mortality, Length of Hospital Stay, and Disability-Adjusted Life Years at select Tertiary Hospitals in Uganda:A retrospective study
Authors: Mayito Jonathan , Dhikusooka Flavia , Kibombo Daniel , Busuge Andrew , Andema Alex , Yayi Alfred , Obbo Stephen , Walwema Richard , Kakooza Francis
Published: May 2024

Background

Antimicrobial Resistance (AMR) is a major global health threat but its burden has not been extensively described in Uganda. We aimed to investigate the antibiotic resistance related mortality, length of hospital stays (LOS) and Disability Adjusted Life Years (DALYs).

Methods

This was a retrospective study of clinical records of patients with infectious syndromes admitted at Arua, Jinja and Mbale regional referral hospitals between October 2022 and September 2023. Data was abstracted from clinical records and analyzed to derive the mortality, LOS, DALYs, and factors associated with AMR and mortality using the modified Poisson regression model.

Results

Of the 291 participants included in the analysis, 56.6% were males, 10% were living with HIV, and their median age was 35 years (IQR: 21-56). The most common infectious syndromes were sepsis (43.6%) and diarrhea (9.6%). The prevalence of antibiotic-resistant infections (ARI) was 29.6%, while that for multi-drug resistant infections (MDRI) was 17.9%. Patients at Jinja and Mbale RRHs exhibited a 2.42 and 2.65 higher risk of ARI respectively compared to those at Arua RRH. Overall, mortality due to an infectious syndrome was 44.7%, of which 34.9% was due to ARI while 30.8% of the ARI related mortality was due to MDR infections. Most deaths were due to sepsis (42.3%), followed by pneumonia (15.4%) and meningitis (6.2%). Participants with comorbidities had higher risk of mortality due to ARI (45% vs. 31% for those without comorbidities). Among Gram-negative bacteria,Escherichia coliandKlebsiellaspp contributed most to mortality, while among Gram-positives,Staphylococcus aureusandEnterobacterspp contributed equally. Patients with ARI’s LOS was 1.2 times higher than that for those without ARI while a longer LOS was associated with a 21% higher ARI risk but a 24% decline in risk of death. ARI was associated with higher DALYs, 235.4, compared to 147.0 for non-ARI.

Conclusion

The study revealed a high burden of AMR in Uganda, including a high prevalence of MDR and associated mortality, particularly among patients with comorbidities. This indicates an urgent need for stewardship and infection prevention strategies to control the AMR burden.
New WHO guideline on the definition of anemia: implications for 6-35 months old children in Peru 2009-2023
Authors: Campos-Sánchez Miguel , Cordero Muñoz Luis , Velásquez Hurtado Enrique , Baiocchi Ureta Nelly , Miranda-Cuadros Marianella , Sánchez-Griñán María Inés , Valdivia Miranda Walter
Published: May 2024

Introduction

The World Health Organization recently published a guideline updating the cut-off points defining anemia, modifying the age and altitude adjustments and recommending auto-analyzers. We compute in a national sample the magnitude of anemia prevalence with the previous and current guidelines between 6 and 35 months old and discuss the implications.

Methods

Secondary analysis of the Peruvian Demographic and Health Survey 2009-2023, a repeated cross-sectional design upon a national stratified and cluster random sample.

Results

117995 children were included. With the new guideline, the national prevalence is reduced and the regional prevalences are generally reduced (some increased) in variable amounts.

Conclusions and Recommendations

The comparison confirms that the new guideline modifies, mostly reducing, the prevalence in an important and heterogeneous magnitude. Literature supports the direction, but not the magnitude of the correction. We recommend the quick, but cautious and gradual adoption of the new guideline. For analytic calculations, age and altitude formulas (not categories) should be used. Surveillance must be reinforced and control strategies must be reviewed. Case management guidelines must be updated.
High burden of non-adherence to blood pressure-lowering medications: meta-analysis of data from over 34,000 adults with hypertension in Sub-Saharan Africa
Authors: Aminde Leopold Ndemnge , Agbor Valirie Ndip , Fongwen Noah Takah , Ngwasiri Calypse , Nkoke Clovis , Nji Miriam , Dzudie Anastase , Schutte Aletta E.
Published: May 2024

Introduction

Non-adherence to blood pressure (BP)-lowering medication is a strong predictor of poor BP control. Sub-Saharan Africa (SSA) has extremely low BP control rates (∼10%), but it is unclear what the burden of medication non-adherence among Africans with hypertension is. This systematic review estimated the prevalence and determinants of non-adherence to BP-lowering medications in SSA.

Methods

Multiple databases were searched from inception to 6 December 2023. Two reviewers performed independent screening, extraction, and quality assessment of studies. We pooled the prevalence estimates using random effects meta-analyses and summarized the determinants using a narrative synthesis.

Results

From the 1,307 records identified, we included 95 studies published between 1995 and 2023. The overall prevalence of non-adherence to BP-lowering medication among 34,102 people treated for hypertension in 27 countries was 43.5% (95% confidence interval 39.4 to 47.6; I2= 98.3%). There was no change in the prevalence of non-adherence over time. The burden of non-adherence varied by measurement method (p = 0.028) and by median age (38.8%, > 57 years vs. 47.9%, ≤ 57 years; p = 0.015). Socioeconomic and patient-related factors were the most frequent factors that influenced medication adherence. Active patient participation in management, accurate perceptions, and knowledge of hypertension and its treatment predicted good medication adherence, whereas high pill burden, medication cost, side effects, and comorbidities predicted poor adherence.

Conclusions

With the African population projected to increase from 1.4 to ∼2.5 billion by 2050, targeted strategies are urgently needed to optimise medication adherence in people with hypertension in SSA.
Post-stroke delirium and associations with neuroimaging biomarkers on routine Computed Tomography (CT): a cohort study
Authors: Barugh Amanda , Farrall Andrew , Ferguson Karen , Shenkin Susan , MacLullich Alasdair , Mead Gillian
Published: May 2024

Background

Delirium affects a quarter of patients after acute stroke and predicts poorer outcomes. Our aim was to determine whether either qualitative assessment or quantitative assessments of the regional atrophy obtained from routinely performed computed tomography (CT) brain imaging could identify those most at risk of developing delirium.

Methods

We recruited 95 patients with acute stroke (age ≥65) over one year. Follow-up for delirium and cognition was performed at 1, 3, 5, 7, 14, 21, 28 days, 4 months and 12 months. All participants underwent routine CT brain (Toshiba 64-slice or 128-slice scanner). White matter disease and atrophy were rated qualitatively (mild, moderate, severe). Atrophy in multiple specific areas was measured quantitatively.

Results

Twenty-six (27%) developed delirium during the 12 months of follow-up. On univariable analysis, delirium was associated with increasing age, being female, less independent in pre-stroke activities of daily living, pre-existing cognitive impairment, increasing stroke severity, having had a total anterior circulation stroke and global cerebral atrophy on brain CT. Multivariable analysis demonstrated that only global cerebral atrophy, being female and having a more severe stroke predicted delirium. This model accounted for between 38% and 55% of the variance in delirium.

For quantitative CT analysis, on univariable analysis, delirium was associated with atrophy in several specific brain areas. On multivariable analysis, only NIHSS (for every one point increase OR 1.23, 95% CI 1.06-1.43; p=0.006)) and cistern ambiens ratio (OR 1.41, 95% CI 1.48-4.96; p=0.028) were significantly associated. This model accounted for between 35.1% and 51.2% of delirium variance.

Conclusion

Clinical variables together with either qualitative atrophy assessment or cistern ambiens ratio on routine CT brain could identify stroke patients most at risk of delirium and to stratify patients in clinical trials of delirium prevention and treatment.
Personalised interactive music systems for physical activity and exercise: A systematic review and exploratory meta-analysis
Authors: Danso Andrew , Kekäläinen Tiia , Koehler Friederike , Knittle Keegan , Nijhuis Patti , Burunat Iballa , Neto Pedro , Mavrolampados Anastasios , Randall William M. , Hansen Niels Chr. , Ansani Alessandro , Rantalainen Timo , Alluri Vinoo , Hartmann Martin , Schaefer Rebecca S. , Ihalainen Johanna , Rousi Rebekah , Agres Kat , MacRitchie Jennifer , Toiviainen Petri , Saarikallio Suvi , Chastin Sebastien , Luck Geoff
Published: May 2024

Personalised Interactive Music Systems (PIMS) are emerging as promising devices for enhancing physical activity and exercise outcomes. By leveraging real-time data and adaptive technologies, PIMS align musical features, such as tempo and genre with users’ physical activity patterns, including frequency and intensity, enhancing their overall experience. This systematic review and exploratory meta-analysis evaluates the effectiveness of PIMS across physical, psychophysical, and affective domains. Searches across nine databases identified 18 eligible studies, of which six (comprising 17 intervention arms) contained sufficient data for meta-analysis. Random-effects meta-analyses and meta-regression were performed to assess outcomes for physical activity levels, physical exertion, ratings of perceived exertion (RPE), and affective valence. Results showed significant improvements in physical activity levels (g= 0.49, CI [0.07, 0.91],p= .02,k= 4) and affective valence (g= 1.68, CI [0.15, 3.20],p= .03,k= 4), with faster music tempo identified as a significant moderator (p= 0.04). No significant effects were observed for RPE (g= 0.72, CI [-0.14, 1.59],p= .10,k= 3) or physical exertion (g= 0.79, CI [-0.64, 2.10],p= .28,k= 5). Substantial heterogeneity and limited study quality indicate the need for more robust, randomised controlled trials to establish the efficacy of PIMS in diverse populations.
SARS-CoV-2 correlates of protection from infection against variants of concern
Authors: Sun Kaiyuan , Bhiman Jinal N. , Tempia Stefano , Kleynhans Jackie , Madzorera Vimbai Sharon , Mkhize Qiniso , Kaldine Haajira , McMorrow Meredith L , Wolter Nicole , Moyes Jocelyn , Carrim Maimuna , Martinson Neil A , Kahn Kathleen , Lebina Limakatso , du Toit Jacques D. , Mkhencele Thulisa , von Gottberg Anne , Viboud Cécile , Moore Penny L. , Cohen Cheryl ,   PHIRST-C group
Published: May 2024

Serum neutralizing antibodies (nAbs) induced by vaccination have been linked to protection against symptomatic COVID-19 and severe disease. However, much less is known about the efficacy of nAbs in preventing the acquisition of infection, especially in the context of natural immunity and against SARS-CoV-2 immune-escape variants. In this study, we conducted mediation analysis to assess serum nAbs induced by prior SARS-CoV-2 infections as potential correlates of protection (CoPs) against Delta and Omicron BA.1/2 wave infections, in rural and urban household cohorts in South Africa. We find that, in the Delta wave, anti-D614G nAbs mediate 37% (95%CI 34% – 40%) of the total protection against infection conferred by prior exposure to SARS-CoV-2, and that protection decreases with waning immunity. In contrast, anti-Omicron BA.1 nAbs mediate 11% (95%CI 9 – 12%) of the total protection against Omicron BA.1/2 wave infections, due to Omicron’s neutralization escape. These findings underscore that CoPs mediated through nAbs are variant-specific, and that boosting of nAbs against circulating variants might restore or confer immune protection lost due to nAb waning and/or immune escape. However, the majority of immune protection against SARS-CoV-2 conferred by natural infection cannot be fully explained by serum nAbs alone. Measuring these and other immune markers including T-cell responses, both in the serum and in other compartments such as the nasal mucosa, may be required to comprehensively understand and predict immune protection against SARS-CoV-2.
Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility
Authors: McCluskey Kate E. , Stovell Katherine M. , Law Karen , Kostyanovskaya Elina , Schmidt James , Exner Cameron R. T. , Dea Jeanselle , Brimble Elise , State Matthew W. , Willsey A. Jeremy , Willsey Helen Rankin
Published: May 2024

The comorbidity of autism spectrum disorders and severe gastrointestinal symptoms is well-established, yet the molecular underpinnings remain unknown. The identification of high-confidence large-effect autism risk genes offers the opportunity to identify convergent, underlying biology by studying these genes in the context of the gastrointestinal system. Here we show that the expression of these genes is enriched in human prenatal gut neurons as well as their migratory progenitors, suggesting that the development and/or function of these neurons may be disrupted by autism-associated pathogenic variants, leading to gastrointestinal dysfunction. Here we document the prevalence of gastrointestinal issues in patients with large-effect variants in sixteen of these genes, highlighting dysmotility, consistent with potential enteric neuron dysfunction. Using the high-throughput diploid frogXenopus tropicalis, we individually target five of these genes (SYNGAP1, CHD8, SCN2A, CHD2, andDYRK1A) and observe disrupted enteric neuronal progenitor migration for each. More extensive analysis ofDYRK1Areveals that perturbation causes gut dysmotilityin vivo, which can be ameliorated by treatment with a selective serotonin reuptake inhibitor (escitalopram) or a serotonin receptor 6 agonist, identified byin vivodrug screening. This work suggests that atypical development of enteric neurons contributes to the gastrointestinal distress commonly seen in individuals with autism and that increasing serotonin signaling may be a productive therapeutic avenue.
Benchmarking of bioinformatics tools for the hybrid de novo assembly of human whole-genome sequencing data
Authors: Munoz-Barrera Adrian , Rubio-Rodriguez Luis A. , Jaspez David , Corrales Almudena , Marcelino-Rodriguez Itahisa , Lorenzo-Salazar Jose M. , Gonzalez-Montelongo Rafaela , Flores Carlos
Published: May 2024

Accurate and complete de novo assembled genomes sustain variant identification and catalyze the discovery of new genomic features and biological functions. However, accurate and precise de novo assemblies of large and complex genomes remains a challenging task. Long-read sequencing data alone or in hybrid mode combined with more accurate short-read sequences facilitate the de novo assembly of genomes. A number of software exists for de novo genome assembly from long-read data although specific performance comparisons to assembly human genomes are lacking. Here we benchmarked 11 different pipelines including four long-read only assemblers and three hybrid assemblers, combined with four polishing schemes for de novo genome assembly of a human reference material sequenced with Oxford Nanopore Technologies and Illumina. In addition, the best performing choice was validated in a non-reference routine laboratory sample. Software performance was evaluated by assessing the quality of the assemblies with QUAST, BUSCO, and Merqury metrics, and the computational costs associated with each of the pipelines were also assessed. We found that Flye was superior to all other assemblers, especially when relying on Ratatosk error-corrected long-reads. Polishing improved the accuracy and continuity of the assemblies and the combination of two rounds of Racon and Pilon achieved the best results. The assembly of the non-reference sample showed comparable assembly metrics as those of the reference material. Based on the results, a complete optimal analysis pipeline for the assembly, polishing, and contig curation developed on Nextflow is provided to enable efficient parallelization and built-in dependency management to further advance in the generation of high-quality and chromosome-level human assemblies.
Cotranslational membrane insertion of the voltage-sensitive K+channel KvAP
Authors: Westerfield Justin M. , Kozojedová Petra , Juli Cara , Metola Ane , von Heijne Gunnar
Published: May 2024

Voltage-sensor domains (VSDs), found in many voltage-sensitive ion channels and enzymes, are composed of four transmembrane helices (TMHs), including the atypical, highly positively charged S4 helix. VSDs are cotranslationally inserted into the membrane, raising the question of how the highly charged S4 helix is integrated into the lipid bilayer as it exits the ribosome. Here, we have used Force Profile Analysis to follow the cotranslational insertion of the six-TMH KvAP voltage-sensitive ion channel into theE. coliinner membrane. We find that the insertion process proceeds through three semi-independent steps: (i) insertion of the S1-S2 helix hairpin, (ii) insertion of the S3-S5 helices, and (iii) insertion of the Pore and S6 helices. Our analysis highlights the importance of the concerted insertion of helical hairpins, the dramatic influence of the positively charged residues in S4, and the unexpectedly strong forces and effects on downstream TMHs elicited by amphipathic and re-entrant helices.
Comparative genomics studies provide insights into the taxonomic classification and secondary metabolic potential of five bioactiveStreptomycesspecies isolated from the North-Western Himalaya
Authors: Bhat Aasif Majeed , Haneen Mariam Azeezuddin , Hussain Aehtesham , Sharma Gaurav , Hassan Qazi Parvaiz
Published: May 2024

The linear genome of genusStreptomycesmembers has the potential to encode diverse and novel biosynthetic gene clusters of invaluable antimicrobial and therapeutic significance. The use of limited taxonomic markers makes the precise identification of these miracle microbes very challenging. In the ongoing omics era, genome sequencing andin-silicoanalysis of these potential antibiotic producers provide deeper insights into their taxonomy, functional capabilities, and potential for antibiotic production. Here this study presents a multifaceted approach for proper taxonomic identification and genomic and bioinformatic analysis of five bioactiveStreptomycesspecies collected from different sampling sites in the high-altitude oligotrophic North-Western Himalaya, Kashmir, India. We used polyphasic taxonomic classification approaches, such as phylogenetic markers (16S rDNA and gyrase B), average nucleotide identity (ANI) estimation, and digital DNA-DNA hybridization (dDDH), which revealed accurate taxonomic placement of fiveStreptomycesspecies, named as,Streptomyces violarusASQP_29,S. rhizosphaerihabitansASQP_78,S. fulvoviolaceusASQP_80,S. mirabilisASQP_98, andS. thajiwasiensisASQP_92. Amongst these, one notable finding is the discovery of a novel species proposed asStreptomyces thajiwasiensissp. nov. ASQP_92. In addition, our study presents the first genome announcement report and analysis forS. rhizosphaerihabitansASQP_78. Genomic annotation highlighted the presence of an exceptionally high number of poorly characterized genes and hypothetical proteins, indicating their potential for undiscovered biotechnological applications. Clusters of orthologous groups (COG) and gene ontology (GO) analysis provided insights into their varied functional roles in metabolism, signaling, information storage and secondary metabolite biosynthesis. Domain-based functional characterization further detailed their involvement in various biological processes particularly in antibiotic biosynthesis, transport, and resistance. Biosynthetic gene clusters (BGC) analysis demonstrated their diverse metabolite biosynthetic capabilities and identified both unique and conserved BGCs emphasizing the species-specific roles in bioactive metabolite production and the potential of orphan BGCs in novel drug discovery.Graphical abstract:

Genomic analysis and taxonomic affiliations of five bioactiveStreptomycesspecies isolated from high altitudes of the North Western Himalaya
WITHDRAWN: Progressive neural engagement within the IFG-pMTG circuit as gesture and speech entropy and MI advances
Authors: Zhao Wanying , Li Zhouyi , Li Xiang , Du Yi
Published: May 2024

Withdrawal Statement

The authors have withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2022/517759. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi: 10.1101/2022.11.23.517759
Dependence of aerosol-borne influenza A virus infectivity on relative humidity and aerosol composition
Authors: Motos Ghislain , Schaub Aline , David Shannon C. , Costa Laura , Terrettaz Céline , Kaltsonoudis Christos , Glas Irina , Klein Liviana K. , Bluvshtein Nir , Luo Beiping , Violaki Kalliopi , Pohl Marie O. , Hugentobler Walter , Krieger Ulrich K. , Pandis Spyros N. , Stertz Silke , Peter Thomas , Kohn Tamar , Nenes Athanasios
Published: May 2024

We describe a novel biosafety aerosol chamber equipped with state-of-the-art instrumentation for bubble-bursting aerosol generation, size distribution measurement, and condensation-growth collection to minimize sampling artifacts when measuring virus infectivity in aerosol particles. Using this facility, we investigated the effect of relative humidity (RH) in very clean air without trace gases (except ∼400 ppm CO2) on the preservation of influenza A virus (IAV) infectivity in saline aerosol particles. We characterized infectivity in terms of 99%-inactivation time,t99, a metric we consider most relevant to airborne virus transmission. The viruses remained infectious for a long time, namelyt99> 5 h, if RH < 30% and the particles effloresced. Under intermediate conditions of humidity (40% < RH < 70%), the loss of infectivity was the most rapid (t99≈ 15-20 min, and up tot99≈ 35 min at 95% RH). This is more than an order of magnitude faster than suggested by many previous studies of aerosol-borne IAV, possibly due to the use of matrices containing organic molecules, such as proteins, with protective effects for the virus. We tested this hypothesis by adding sucrose to our aerosolization medium and, indeed, observed protection of IAV at intermediate RH (55 %). Interestingly, thet99of our measurements are also systematically lower than those in 1-μL droplet measurements of organic-free saline solutions, which cannot be explained by particle size effects alone.
Activity-Based Protein Profiling IdentifiesKlebsiella pneumoniaeSerine Hydrolases with Potential Roles in Host-Pathogen Interactions
Authors: Uddin Md Jalal , Randall George , Zhu Jiyun , Upadhyay Tulsi , van Eijk Laura , Stege Paul B. , Masson Frerich M. , Viveen Marco C. , Bogyo Matthew , Fellner Matthias , de Zoete Marcel R. , Johannessen Mona , Lentz Christian S.
Published: May 2024

Klebsiella pneumoniaeis a normal resident of the human gastro-intestinal tract and an opportunistic, critical priority pathogen that can cause a variety of severe systemic infections. Due to emerging multi-drug resistance of this pathogen, the discovery and validation of novel targets for the development of new treatment options is an urgent priority. Here, we explored the family of serine hydrolases, a highly druggable and functionally diverse enzyme family which is uncharacterized inK. pneumoniae. Using functionalized covalent fluorophosphonate inhibitors as activity-based probes we identified 10 serine hydrolases by mass spectrometry-based activity-based protein profiling, 7 of which were previously uncharacterized. Functional validation using transposon mutants deficient in either of the putative lysophospholipase PldB, esterase YjfP and patatin-like phospholipase YchK revealed severe growth defects in human colonic organoid co-culture models and reduced virulence duringGalleria mellonellainfection. Mutants deficient in the PldB and YjfP, but not YchK show increased susceptibility to killing by complement and the antimicrobial peptide antibiotic polymyxin B, suggesting a role in maintaining cell envelope integrity. Biochemical characterization and structural analysis of recombinant YjfP suggest this protein is a deacetylase. This study gives important insights into the molecular mechanisms underlying virulence and cell physiology ofK. pneumoniaeat the host-pathogen interface and it positions PldB, YjfP and YchK as potential antimicrobial or anti-virulence target candidates, inhibition of which might synergize with existing antibiotics and human immune defenses.
Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling
Authors: Pérez-Sisqués Leticia , Bhatt Shail U. , Caruso Angela , Ahmed Mohi U. , Gileadi Talia E. , Spring Shoshana , Hendy Eleanor , Taylor-Papadimitriou Joyce , Cash Diana , Clifton Nicholas , Ellegood Jacob , Andreae Laura C. , Lerch Jason P. , Scattoni Maria Luisa , Giese K. Peter , Fernandes Cathy , Basson M. Albert
Published: May 2024

Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for regulating the trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the specific role of H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developingKdm5bmutant neocortex. These included elevated expression ofGrin2d. TheGrin2dgene product NMDAR2D was increased in synaptosomes isolated from theKdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associatedGrin2dgene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.
ActiveE. coliheteromeric acetyl-CoA carboxylase forms polymorphic helical tubular filaments
Authors: Xu Xueyong , Silva de Sousa Amanda , Boram Trevor J. , Jiang Wen , Lohman Jeremy R.
Published: May 2024

TheEscherichia coliheteromeric acetyl-CoA carboxylase (ACC) has four subunits assumed to form an elusive catalytic complex and are involved in allosteric and transcriptional regulation. TheE. coliACC represents almost all ACCs from pathogenic bacteria making it a key antibiotic development target to fight growing antibiotic resistance. Furthermore, it is a model for cyanobacterial and plant plastid ACCs as biofuel engineering targets. Here we report the catalyticE. coliACC complex surprisingly forms tubes rather than dispersed particles. The cryo-EM structure reveals key protein-protein interactions underpinning efficient catalysis and how transcriptional regulatory roles are masked during catalysis. Discovering the protein-protein interaction interfaces that facilitate catalysis, allosteric and transcriptional regulation provides new routes to engineering catalytic activity and new targets for drug discovery.

One-Sentence Summary

Bacterial heteromeric acetyl-CoA carboxylase forms tubes to promote efficient catalysis and mask transcriptional regulation.
High-resolution 2D Solid-State NMR provides insights into Nontuberculous Mycobacteria
Authors: Byeon Chang-Hyeock , Hansen Kasper Holst , DePas William , Akbey Ümit
Published: May 2024

We present a high-resolution magic-angle spinning (MAS) solid-state NMR (ssNMR) study to characterize native nontuberculous mycobacteria (NTM). We studied two different NTM strains,Mycobacterium smegmatis, a model, non-pathogenic strain, andMycobacterium abscessus, an emerging and important human pathogen. Native hydrated NTM samples were studied at natural abundance without isotope-labelling and any chemical or physical modification. We utilized 1D13C and 2D1H-13C ssNMR spectra and peak deconvolution to identify NTM cell-wall chemical sites. More than ∼100 distinct13C signals were identified in the ssNMR spectra. The signals originating from both the flexible and rigid fractions of the native bacteria samples were selectively analyzed by utilizing either CP or INEPT based13C ssNMR spectra. CP buildup curves provide insights into the dynamical similarity of the cell-wall components for NTM strains. Signals from peptidoglycan, arabinogalactan and mycolic acid were identified. We also provide tentative assignments for ∼30 polysaccharides by using well resolved1H/13C chemical shifts from the 2D INEPT-based1H-13C ssNMR spectrum. As an orthogonal way of characterizing the bacteria, electron microscopy (EM) was used to provide spatial characterization. ssNMR and EM data suggest thatM. abscessuscell-wall is composed of a smaller peptidoglycan layer which is more flexible compared toM. smegmatis, which may be related to its higher pathogenicity. Here in this work, we used high-resolution 2D ssNMR first time to characterize native NTM strains and identified chemical sites. These results will aid the development of structure-based approaches to combat NTM infections.