bluuebunny/crossref_metadata_2025 huggingface dataset:
A unified framework for estimating country-specific cumulative incidence for 18 diseases stratified by polygenic risk
Authors: Jermy Bradley , Läll Kristi , Wolford Brooke , Wang Ying , Zguro Kristina , Cheng Yipeng , Kanai Masahiro , Kanoni Stavroula , Yang Zhiyu , Hartonen Tuomo , Monti Remo , Wanner Julian , Youssef Omar ,   Estonian Biobank research team,   FinnGen, Lippert Christoph , van Heel David , Okada Yukinori , McCartney Daniel L. , Hayward Caroline , Marioni Riccardo E. , Furini Simone , Renieri Alessandra , Martin Alicia R. , Neale Benjamin M. , Hveem Kristian , Mägi Reedik , Palotie Aarno , Heyne Henrike , Mars Nina , Ganna Andrea , Ripatti Samuli
Published: June 2023

Polygenic Scores (PGSs) offer the ability to predict genetic risk for complex disease across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant for clinical and public health decision making, it is important to account for any varying effects due to common risk factors such as age and sex. Here, we develop a novel framework to estimate for cumulative incidences over the life course and produce country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases by integrating PGS associations from 7 studies in 4 countries (N=1,197,129) with disease incidences from the Global Burden of Disease. PGSs had a significant sex-specific effect for 5 diseases (asthma, hip osteoarthritis, gout, coronary heart disease, type 2 diabetes) with all but type 2 diabetes exhibiting a larger effect in men. PGS had a larger effect in younger individuals for 13 diseases, with the effects decreasing linearly with age. We showed for breast cancer that, relative to individuals in the bottom 20% of polygenic risk, the top 5% attain an absolute risk for screening eligibility 16.3 years earlier. For T2D, men and women in the top 1% reached the threshold aged 24.8 (95% CI: 22.5 – 27.6) and 22.3 (95% CI: 20.0 – 25.3) respectively. Individuals in the bottom 1% of PGS did not reach the risk threshold by age 80. Our easily extendable framework increases the generalizability of results from biobank studies and the accuracy of absolute risk estimates by appropriately accounting age and sex-specific PGS effects. Our results highlight the potential of PGS as a screening tool which may assist in the early prevention of common disease.
Therapeutic potential of a modified Mediterranean ketogenic diet in reversing the peripheral lipid signature of Alzheimer’s disease
Authors: Neth Bryan J , Huynh Kevin , Giles Corey , Wang Tingting , Mellett Natalie A , Duong Thy , Blach Colette , Schimmel Leyla , Register Thomas C , Blennow Kaj , Zetterberg Henrik , Batra Richa , Schweickart Annalise , Dilmore Amanda Hazel , Martino Cameron , Arnold Matthias , Krumsiek Jan , Han Xianlin , Dorrestein Pieter C , Knight Rob , Meikle Peter J , Craft Suzanne , Kaddurah-Daouk Rima
Published: June 2023

Alzheimer’s disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear. In this randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome, analyzing 784 lipid species across 47 classes. We identified substantial changes in response to intervention, notably a global elevation across all plasmanyl and plasmenyl ether lipid species among others, with many changes linked with changes to clinical and biochemical markers of AD. Leveraging our prior clinical studies on AD (n = 1,912), we found that MMKD was inversely associated with the lipidomic signature of prevalent and incident AD. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD.
Exclusive heat-not-burn cigarette smoking alters the profile of circulating microRNAs
Authors: Picchio Vittorio , Ferrero Giulio , Cozzolino Claudia , Pardini Barbara , Floris Erica , Tarallo Sonia , Dhori Xhulio , Nocella Cristina , Loffredo Lorenzo , Biondi-Zoccai Giuseppe , Carnevale Roberto , Frati Giacomo , Chimenti Isotta , Pagano Francesca
Published: June 2023

Background

Traditional combustion cigarette (TCC) smoking is an established risk factor for several types of cancer and cardiovascular diseases. Circulating microRNAs (miRNAs) represent key molecules mediating pathogenetic mechanisms, and potential biomarkers for personalized risk assessment. TCC smoking globally changes the profile of circulating miRNAs. The use of heat-not-burn cigarettes (HNBCs) as alternative smoking devices is rising exponentially worldwide, and the circulating miRNA profiles in chronic HNBC smokers are unknown.

We aimed at defining the circulating miRNA profile of chronic exclusive HNBC smokers, and identifying potentially pathogenetic signatures.

Methods

Serum samples were obtained from 60 healthy young subjects, stratified in chronic HNBC smokers, TCC smokers, and Non Smokers (20 subjects each). Three pooled samples per group were used for small RNA sequencing, and the fourth sub-group constituted the validation set.

Findings

Differential expression analysis revealed 108 differentially expressed miRNAs; 72 exclusively in TCC, 10 exclusively in HNBC, and 26 in both smoker groups. KEGG pathway analysis on target genes of the commonly modulated miRNAs returned cancer and cardiovascular disease associated pathways. Stringent abundance and fold-change criteria nailed down our functional bioinformatic analyses to a network where miR-25-3p and miR-221-3p are main hubs.

Interpretation

Our results define for the first time the miRNA profile in the serum of exclusive chronic HNBC smokers and suggest a significant impact of HNBCs on circulating miRNAs.

Funding

Sapienza University of Rome grant 2019, # RG11916B8621D7FF to GBZ and grant 2021 # RM12117A5D7688BC to RC. IC is supported by grants # RM12117A805ED2FD and # RG11916B85CDBF76 from Sapienza University of Rome, and by grant # RG1221816BC8E766 from the Italian Health Ministry. FP is supported by Grant # A0375-2020-36621 from Regione Lazio (POR-FESR 2014-2021).
Associations of hypertension and antenatal care-seeking with perinatal mortality: A nested case-control study in rural Bangladesh
Authors: Bear Allyson P. , Bennett Wendy L. , Katz Joanne , Lee Kyu Han , Chowdhury Atique Iqbal , Bari Sanwarul , El Arifeen Shams , Gurley Emily S.
Published: June 2023

Maternal hypertension may be an underrecognized but important risk factor for perinatal death in low resource settings. We investigated the association of maternal hypertension and perinatal mortality in rural Bangladesh.

This nested, matched case-control study used data from a 2019 cross-sectional survey and demographic surveillance database in Baliakandi, Bangladesh. We randomly matched each pregnancy ending in perinatal death with five pregnancies in which the neonate survived beyond seven days based on maternal age, education, and wealth quintile. We estimated associations of antenatal care-seeking and self-reported hypertension with perinatal mortality using conditional logistic regression and used median and interquartile ranges to assess the mediation of antenatal care by timing or frequency.

Among 191 cases and 934 matched controls, hypertension prevalence was 14.1% among cases and 7.7% among controls. Compared with no diagnosis, the probability of perinatal death was significantly higher among women with a pre-gestational hypertension diagnosis (OR 2.90, 95% CI 1.29, 6.57), but not among women with diagnosis during pregnancy (OR 1.68, 95% CI 0.98, 2.98). We found no association between the number of antenatal care contacts and perinatal death (p=0.66). Among women with pre-gestational hypertension who experienced a perinatal death, 78% had their first antenatal contact in the sixth or seventh month of gestation.

Hypertension was more common among rural women who experience a perinatal death. Greater effort to prevent hypertension prior to conception and provide early maternity care to women with hypertension could improve perinatal outcomes in rural Bangladesh.
Individual healthcare-seeking pathways for tuberculosis in Nigeria’s private sector during the COVID-19 pandemic
Authors: Oga-Omenka Charity , Rosapep Lauren , Huria Lavanya , Vasquez Nathaly Aguilera , Olusola-Faleye Bolanle , Kafi Mohammad Abdullah Heel , Sassi Angelina , Nwosu Chimdi , Johns Benjamin , Adamu Abdu , Chijioke-Akaniro Obioma , Anyaike Chukwuma , Pai Madhukar
Published: June 2023

Background

Pre-COVID-19, individuals with TB in Nigeria were often underdiagnosed and untreated. Care for TB was mostly in the public sector while only 15% of new cases in 2019 were from the private sector. Reports highlighted challenges in accessing care in the private sector, which accounted for 67% of all initial care-seeking. Our study examined patients’ health seeking pathways for TB in Nigeria’s private sector, and explored any changes to care pathways during COVID, based on patients’ perspectives.

Design/Methods

We conducted 180 cross-sectional surveys and 20 in-depth interviews with individuals having chest symptoms attending 18 high volume private clinics and hospitals in Kano and Lagos States. Questions focused on sociodemographic characteristics, health-seeking behavior and pathways to care during the COVID-19 periods. All surveys and interviews were conducted in May 2021.

Results

Most participants were male (n=111, 62%), with average age of 37. Half (n=96, 53.4%) sought healthcare within a week of symptoms, while few (n=20, 11.1%) waited over 2 months. TB positive individuals had more health-seeking delays, and TB negative had more provider delays. On average, participants visited 2 providers in Kano and 1.69 in Lagos, with 61 (75%) in Kano and 48 (59%) in Lagos visiting other providers before the recruitment facility. Private providers were the initial encounters for most participants (n=60 or 66.7% in Kano, n-83 or 92.3% in Lagos). Most respondents (164 or 91%) experienced short-lived pandemic-related restrictions, particularly during the lockdowns, affecting access to transportation, and closed facilities.

Conclusions

This study showed a few challenges in accessing TB healthcare in Nigeria, necessitating continued investment in healthcare infrastructure and resources, particularly in the private sector. Understanding the different care pathways and delays in care provides opportunities for targeted interventions to improve deployment of services closer to where patients first seek care.
A human pan-genomic analysis reconfigures the genetic and epigenetic make up of facioscapulohumeral muscular dystrophy
Authors: Salsi Valentina , Chiara Matteo , Pini Sara , Kuś Paweł , Ruggiero Lucia , Bonanno Silvia , Rodolico Carmelo , Previtali Stefano C. , D’Angelo Maria Grazia , Maggi Lorenzo , Lopergolo Diego , Kimmel Marek , Santorelli Filippo M. , Pesole Graziano , Tupler Rossella G.
Published: June 2023

Facioscapulohumeral muscular dystrophy (FSHD) is the only human disease associated with epigenetic changes at a macrosatellite array. Almost 95% of FSHD cases carry a reduced number (≤10) of tandem 3.3 kilobase repeats, termed D4Z4, on chromosome 4q35; remaining cases bear variants in chromatin remodeling factors, such as SMCHD1, DNMT3B, LRIF1. Reduced CpG methylation is used for the molecular diagnosis of FSHD, but D4Z4-like sequences dispersed in the genome can generate ambiguous results. By analyzing complete haplotype level assemblies from the T2T-CHM13 human genome and 86 haploid genomes from the human pangenome project, we uncovered the extensive number of D4Z4-like elements and their widespread inter- and intra-individual variability. An original analytical approach was developed to elucidate this previously unaccounted wealth of D4Z4-like elements and to analyze CpG methylation at D4Z4 in bisulfite-treated DNA from 29 FSHD index cases and 15 relatives. Integrated analysis of clinical phenotype, D4Z4 CpG methylation level and gene variants showed that low D4Z4 methylation was associated with variants in theSMCHD1gene, but not with the patients’ clinical phenotypes. This is the first study showing the relevance of the pangenome and T2T-CHM13 assemblies for investigating the genotype-phenotype correlation in genetic diseases. The extension and the variability of D4Z4-like elements scattered throughout the human genome and the inconsistent association of phenotypes with methylation profiles advocate for a critical revision of FSHD diagnostic tests based on D4Z4 CpG methylation assays and indicate that molecular investigations must be complemented by family studies for the proper interpretation of results.
Vagus nerve inflammation contributes to dysautonomia in COVID-19
Authors: Woo Marcel S. , Shafiq Mohsin , Fitzek Antonia , Dottermusch Matthias , Altmeppen Hermann , Mohammadi Behnam , Mayer Christina , Bal Lukas C. , Raich Lukas , Matschke Jakob , Krasemann Susanne , Pfefferle Susanne , Brehm Thomas Theo , Lütgehetmann Marc , Schädler Julia , Addo Marylin M. , Schulze Zur Wiesch Julian , Ondruschka Benjamin , Friese Manuel A. , Glatzel Markus
Published: June 2023

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we show that SARS-CoV-2 is detectable inpostmortemvagus nerve specimen together with inflammatory cell infiltration derived primarily from monocytes. This is associated with a decreased respiratory rate in non-survivors of critical COVID-19. Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction.
Test-retest reliability of a 2-dimensional and 3-dimensional visual assessment of body image disturbance in anorexia nervosa
Authors: Ralph-Nearman Christina , Arevian Armen C. , Karem Andrew , Llano-Rios Tomas F. , Sinik Megan , Moseman Scott , Feusner Jamie D. , Khalsa Sahib S.
Published: June 2023

Body image disturbance (BID) is a diagnostic feature of anorexia nervosa (AN), with few reliable visual perceptual or attitudinal markers.Somatomapis a 2-dimensional (2D) and 3-dimensional (3D) digital assessment of BID, which has demonstrated utility. Test-retest reliability ofSomatomap2D and 3D digital assessment of BID in AN was examined. Fifty-nine inpatient participants with AN performed test-retest by a) outlining body concern areas on a 2D avatar for each independent area of concern; and b) sculpting 23 independent body parts on a randomized 3D avatar to reflect their perceived body size in length and girth. Participants corresponding body parts were physically measured to calculate discrepancy scores (i.e., 3D perceived minus measured values). Regional 2D BID test-retest differences were evaluated using z-scores to generate statistical visual body maps. Test-retest of 3D assessment reliability was evaluated by Intraclass Correlation Coefficient for individual and aggregated body parts. Somatomap 2D demonstrated excellent test-retest reliability with no statistical differences between test and retest z-scores. All 23 body parts on Somatomap 3D demonstrated statistically significant fair-to-excellent test-retest reliability in AN. Regions that are commonly of concern in AN, and combined measures, showed the highest reliability. Results suggest that Somatomap 2D and 3D may provide a reliable perceptual marker of visual BID in AN.
Understanding the cervical cancer self-collection preferences of women living in urban and rural Rwanda
Authors: Nair Varun , Dau Hallie , Vidler Marianne , AboMoslim Maryam , Mutamba Barbra , Scott McKerron , Nesbitt Zoey , Deodatha John , Byiringiro Schadrack Danson , Niyotwiringiye Charles , Mithani Nadia , Smith Laurie , Ogilvie Gina , Rulisa Stephen
Published: June 2023

PURPOSE

Cervical cancer is a leading cause of cancer among women in low- and middle-income countries. Women in Rwanda have high rates of cervical cancer due to limited access to effective screening methods. Research in other low-resource settings similar to Rwanda has shown that HPV-based self-collection is an effective cervical cancer screening method. This study aims to compare the preferences of Rwandan women in urban and rural settings toward self-collection and to report on factors related to self-collection amenability.

METHODS

A cross-sectional survey was conducted from June 1-9, 2022. Women were recruited from one urban and one rural clinic in Rwanda. Women were eligible for the study if they were ≥ 18 years and spoke Kinyarwanda or English. The survey consisted of 51 questions investigating demographics and attitudes towards self-collection for cervical cancer screening. We reported descriptive statistics stratified by urban and rural sites.

RESULTS

In total, 169 urban and 205 rural women completed the survey. The majority of respondents at both sites had a primary school or lower education and were in a relationship. Both urban and rural respondents were open to self-collection; however, rates were higher in the rural site (79.9% urban and 95.6% rural; p-value<0.001). Similarly, women in rural areas were more likely to report feeling unembarrassed about self-collection (65.3% of urban, 76.8% of rural; p-value<0.001). Notably, almost all urban and rural respondents (97.6% urban and 98.5% rural) stated they would go for a cervical cancer pelvic examination to a nearby health center if their self-collected results indicated any concern (p-value=0.731).

CONCLUSION

Rwandan women in both urban and rural areas largely support self-collection for cervical cancer screening. Further research is needed to better understand how to implement self-collection screening services in Rwanda.
HPV Vaccination in immunosuppressed patients with established skin warts and non-melanoma skin cancer: A single-institutional cohort study
Authors: Bossart Simon , Daneluzzi Cloé , Moor Matthias B. , Hirzel Cédric , Seyed Jafari S. Morteza , Hunger Robert E. , Sidler Daniel
Published: June 2023

Background

cSCC (cutaneous squameous cell carcinom) and its precursors are a major cause of morbidity especially in immunosuppressed patients and are frequently associated with human papilloma virus (HPV) infections.

Objective

The purpose of this study is to investigate the therapeutically potential of alpha-HPV vaccination for immunosuppressed patients with established cSCC and its precursors.

Methods

In this retrospective study, all patients who received Gardasil-9®, a nonavalent HPV vaccine, as secondary prophylaxis were examined. Dermatologic interventions in both the pre- and post-vaccination periods were analyzed with zero-inflated poisson regression and a proportional intensity model for repeated events with consideration of the clinically relevant cofactors.

Results

The hazard ratio for major dermatologic interventions was 0.27 (CI 0.14-0.51, p <0.001) between pre- and post Gardasil-9® intervention. Gardasil-9® vaccination showed good efficacy in reducing major dermatologic interventions even after correction of relevant cofactors and national COVID-19 case loads during the observational period.

Limitation

The retrospective study design and the rather low number of patients may influence study results. Furthermore, analysis of HPV types and data collection on vaccine-specific HPV antibody measurements was not possible.

Conclusion

Alpha-HPV vaccination may potentially cause a significant decrease in dermatologic interventions in immunosuppressed patients with high skin tumor burden.

Capsule summary

Little is known about a possible immunizing effect of alpha-vaccines in immunosuppressed patients with high skin tumor burden

Alpha-HPV vaccination such as Gardasil-9® may potentially cause a significant decrease in dermatologic interventions in IS patients with high skin tumor burden.
Topologic Parametric Response Mapping Identifies Tissue Subtypes Associated with Emphysema Progression
Authors: Wang Jennifer M. , Bell Alexander J. , Ram Sundaresh , Labaki Wassim W. , Hoff Benjamin A. , Murray Susan , Kazerooni Ella , Galban Stefanie , Hatt Charles R. , Han MeiLan K. , Galban Craig J.
Published: June 2023

Rationale and Objectives

Small airways disease (SAD) and emphysema are significant components of COPD, a heterogenous disease where predicting progression is difficult. SAD, a principal cause of airflow obstruction in mild COPD, has been identified as a precursor to emphysema. Parametric Response Mapping (PRM) of chest computed tomography (CT) can help distinguish SAD from emphysema. Specifically, topologic PRM can define local patterns of both diseases to characterize how and in whom COPD progresses. We aimed to determine if distribution of CT-based PRM of functional SAD (fSAD) is associated with emphysema progression.

Materials and Methods

We analyzed paired inspiratory-expiratory chest CT scans at baseline and 5-year follow up in 1495 COPDGene subjects using topological analyses of PRM classifications. By spatially aligning temporal scans, we mapped local emphysema at year 5 to baseline lobar PRM-derived topological readouts. K-means clustering was applied to all observations. Subjects were subtyped based on predominant PRM cluster assignments and assessed using non-parametric statistical tests to determine differences in PRM values, pulmonary function metrics and clinical measures.

Results

We identified distinct lobar imaging patterns and classified subjects into three radiologic subtypes: emphysema-dominant (ED), fSAD-dominant (FD), and fSAD-transition (FT: transition from healthy lung to fSAD). Relative to year 5 emphysema, FT showed rapid local emphysema progression (−57.5% ± 1.1) compared to FD (−49.9% ± 0.5) and ED (−33.1% ± 0.4). FT consisted primarily of at-risk subjects (roughly 60%) with normal spirometry.

Conclusion

The FT subtype of COPD may allow earlier identification of individuals without spirometrically-defined COPD at-risk for developing emphysema.
U-shaped Association Between Mean Platelet Volume And Short-term Survival In Chinese Patients With Heart Failure
Authors: Huang Yuan-lei , Zhou Qi , Zheng Tao
Published: June 2023

Background

Mean Platelet Volume (MPV) has been proposed as a potential predictor of increased mortality risk at 6 months among Chinese patients with heart failure (HF). However, the current evidence supporting this association is limited.

Methods

This study aimed to investigate the relationship between MPV and HF short-term survival status. The data was obtained from a publicly accessible HF database in Zigong, Sichuan, and included information on 2008 Chinese patients. Baseline MPV was considered as the exposure while HF short-term survival status was the outcome. Two models, a binary logistic regression model and a two-piecewise linear model, were used to analyze the data.

Results

The study revealed a U-shaped relationship between MPV and all-cause mortality in HF patients. When MPV levels were less than 9.8, every unit increase in MPV was associated with a 91% reduction (RR: 0.09; 95% CI: 0.03-0.24; P=0.0001) in the risk of death over the next six months. In contrast, at MPV levels above 9.8, each unit increase in MPV was linked to a 27% increase (RR: 1.27; 95% CI: 1.01-1.61; P=0.0434) in the probability of dying within the same period. Stratification by obesity status revealed no significant association between MPV and death in the obese population, while the same U-shaped association was observed among non-obese participants.

Conclusion

The present study provides evidence of a U-shaped association between MPV and short-term survival in Chinese patients with heart failure. These findings suggest that MPV may serve as a potential prognostic marker for HF. However, further studies are needed to validate these results and to explore the underlying mechanisms of this association. The observed U-shaped association did not apply to obese patients, suggesting that the effect of MPV on mortality risk in HF patients may be influenced by body weight.
Crykey: Rapid Identification of SARS-CoV-2 Cryptic Mutations in Wastewater
Authors: Liu Yunxi , Sapoval Nicolae , Gallego-García Pilar , Tomás Laura , Posada David , Treangen Todd J. , Stadler Lauren B.
Published: June 2023

We present Crykey, a computational tool for rapidly identifying cryptic mutations of SARS-CoV-2. Specifically, we identify co-occurring single nucleotide mutations on the same sequencing read, called linked-read mutations, that are rare or entirely missing in existing databases, and have the potential to represent novel cryptic lineages found in wastewater. While previous approaches exist for identifying cryptic linked-read mutations from specific regions of the SARS-CoV-2 genome, there is a need for computational tools capable of efficiently tracking cryptic mutations across the entire genome and for tens of thousands of samples and with increased scrutiny, given their potential to represent either artifacts or hidden SARS-CoV-2 lineages. Crykey fills this gap by identifying rare linked-read mutations that pass stringent computational filters to limit the potential for artifacts. We evaluate the utility of Crykey on >3,000 wastewater and >22,000 clinical samples; our findings are three-fold: i) we identify hundreds of cryptic mutations that cover the entire SARS-CoV-2 genome, ii) we track the presence of these cryptic mutations across multiple wastewater treatment plants and over a three years of sampling in Houston, and iii) we find a handful of cryptic mutations in wastewater mirror cryptic mutations in clinical samples and investigate their potential to represent real cryptic lineages. In summary, Crykey enables large-scale detection of cryptic mutations representing potential cryptic lineages in wastewater.
Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome
Authors: Matsui Maiko , Lynch Lauren E. , Distefano Isabella , Galante Allison , Gómez-Banoy Nicolas , Wang Hong-Gang , Gade Aravind R. , Sinden Daniel S. , Wei Eric Q. , Barnett Adam S. , Johnson Kenneth , Rubio-Navarro Alfonso , Li Ang K. , Marx Steven O. , McGraw Timothy E. , Thornton Paul , Timothy Katherine W. , Lo James C. , Pitt Geoffrey S.
Published: June 2023

The canonical G406R gain of function mutation that reduces inactivation and increases Ca2+influx through theCACNA1C-encoded CaV1.2 voltage gated Ca2+channel underlies the multisystem disorder Timothy syndrome (TS), characterized by invariant Long QT syndrome and consequent life-threatening arrhythmias. Severe episodic hypoglycemia, which exacerbates arrhythmia risk, is among the myriad non-cardiac TS pathologies that are poorly characterized. While hypoglycemia is thought to result from increased Ca2+influx through CaV1.2 channels in pancreatic beta cells and consequent hyperinsulinism, this mechanism has never been demonstrated due to a lack of informative animal models, thus hampering development of preventive strategies. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features including hypoglycemia. Unexpectedly, these mice did not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. We discovered multiple alternative contributors to hypoglycemia, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic glucose sensing. Together, these data provide new insights into physiological contributions of the broadly expressed CaV1.2 channel and reveal integrated consequences of the mutant channel that underlie the life-threatening events in TS.

Brief Summary

Gain of function mutant CaV1.2 channels drive hypoglycemia through adverse effects on counterregulatory hormones and central nervous system glucose sensing
Sex-Specific Clinical and Genetic Factors Associated with Adverse Outcomes in Hypertrophic Cardiomyopathy
Authors: Butters Alexandra , Arnott Clare , Sweeting Joanna , Claggett Brian , Cuomo Anna , Abrams Dominic , Ashley Euan A. , Day Sharlene M. , Helms Adam S. , Lampert Rachel , Lin Kim , Michels Michelle , Miller Erin M. , Olivotto Iacopo , Owens Anjali , Parikh Victoria N. , Pereira Alexandre C. , Rossano Joseph W. , Ryan Thomas D. , Saberi Sara , Stendahl John C. , Ware James S. , Atherton John , Semsarian Christopher , Lakdawala Neal K. , Ho Carolyn Y. , Ingles Jodie
Published: June 2023

Background

Women with HCM present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors contributing to these differences are unclear. We aimed to investigate sex differences in clinical and genetic factors associated with adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry (SHaRe).

Methods

Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for women and men to find the sex-specific hazard ratio.

Results

After a mean follow-up of 6.4 years, women had a higher risk of heart failure (HR 1.51; 95% CI 1.21-1.88, p=0.0003) but a lower risk of atrial fibrillation (0.74; 0.59-0.93; p<0.0001) and ventricular arrhythmia (0.60; 0.38-0.94; p=0.027) than men. No sex difference was observed for death (p=0.84). Sarcomere-positive men had a higher risk of heart failure and death, not seen in women (p-heterogeneity=0.006 & p-heterogeneity=0.035, respectively).MYBPC3variants were associated with lower heart failure risk in women than other HCM subgroups, with no significant change for men (p-heterogeneity <0.0001). Women with moderate risk of ventricular arrhythmia (4% to <6% ESC risk score) were at a higher risk of ventricular arrhythmia than those scoring <4%, not observed in men (p-heterogeneity= 0.019).

Conclusion

Clinical and genetic factors contributing to adverse outcomes in HCM affect women and men differently. Research to inform sex-specific management of HCM could improve outcomes for both sexes.
Hypertension Among Adults With HIV Initiating Antiretroviral Therapy in Freetown, Sierra Leone: A Cross-sectional Study
Authors: Yendewa George A. , Jiba Darlinda F. , Sesay Daniel , Namanga Enanga Sonia , Yendewa Sahr A. , Barrie Umu , Deen Gibrilla F. , Sahr Foday , Salata Robert A. , Russel James B.W. , Lakoh Sulaiman
Published: June 2023

Background

Hypertension is a major contributor to cardiovascular morbidity and mortality in people with HIV (PWH). However, screening and identification among PWH initiating antiretroviral therapy (ART) in sub-Saharan Africa is understudied.We aimed to assess the prevalence of hypertension and its associated factors among newly diagnosed PWH in Freetown, Sierra Leone.

Methods

We used a cross-sectional study design to assess the baseline characteristics of newly diagnosed ART-naïve PWH at Connaught Hospital in Freetown from March 2021 to March 2022. We categorized patients as having normal blood pressure (<120/80mmHg), pre-hypertension (systolic 120-139 mmHg or diastolic 80-89 mmHg), and hypertension (systolic ≥140 mmHg or diastolic ≥90 mmHg). We used logistic regression models to identify factors independently associated with hypertension.

Results

918 PWH were studied (55.0% female, median age 33 years). The prevalence of hypertension was 20.0% and 29.5% were pre-hypertensive. In univariate analysis, hypertension prevalence increased with age, body mass index (BMI), smoking, alcohol consumption, and being Christian (all p < 0.05). In multivariate logistic regression analysis, ages 40-49 years (aOR 2.15, 95% CI 1.30-3.57), 50-59 years (aOR 2.30, 95% CI 1.26-4.18), ≥ 60 years (aOR 3.08, 95% CI 1.28-7.41), BMI ≥ 30 kg/m2(aOR 2.34, 95% CI 1.11-4.93), identifying as a Christian (aOR 1.45, 95% CI 1.01-2.11), and smoking (aOR 1.67, 95% CI 1.04-2.69) were significantly associated with hypertension.

Conclusions

We observed a significant burden of hypertension among ART-naïve PWH in Sierra Leone, emphasizing the importance of early identification and management to help reduce cardiovascular morbidity and mortality.
Interaction of spatial attention and the associated reward value of audiovisual stimuli
Authors: Vakhrushev Roman , Pooresmaeili Arezoo
Published: June 2023

Reward value and selective attention both enhance the representation of sensory stimuli at the earliest stages of processing. It is still debated whether and how reward-driven and attentional mechanisms interact to influence perception. Here we ask whether the interaction between reward value and selective attention depends on the sensory modality through which the reward information is conveyed. Human participants first learned the reward value of uni-modal visual and auditory stimuli during a conditioning phase. Subsequently, they performed a target detection task on bimodal stimuli containing a previously rewarded stimulus in one, both, or neither of the modalities. Additionally, participants were required to focus their attention on one side and only report targets on the attended side. Our results showed a strong modulation of visual and auditory event-related potentials (ERPs) by spatial attention. We found no main effect of reward value but importantly an interaction effect was found as the strength of attentional modulation of the ERPs was significantly affected by the reward value. When reward effects were inspected separately with respect to each modality, auditory value-driven modulation of attention was found to dominate the ERP effects whereas visual reward value on its own led to no effect, likely due to its interference with the target processing. These results inspire a two-stage model where first the salience of a high reward stimulus is enhanced on a local priority map specific to each sensory modality, and at a second stage reward value and top-down attentional mechanisms are integrated across sensory modalities to affect perception.
Single-neuron and population measures of neuronal activity in working memory tasks
Authors: Mozumder Rana , Constantinidis Christos
Published: June 2023

Information represented in working memory is reflected in the firing rate of neurons in the prefrontal cortex and brain areas connected to it. In recent years, there has been an increased realization that population measures capture more accurately neural correlates of cognitive functions. We examined how single neuron firing in the prefrontal and posterior parietal cortex of two male monkeys compared with population measures in spatial working memory tasks. Persistent activity was observed in the dorsolateral prefrontal and posterior parietal cortex and firing rate predicted working memory behavior, particularly in the prefrontal cortex. These findings had equivalents in population measures, including trajectories in state space that became less separated in error trials. We additionally observed rotations of the stimulus space for different task conditions, which was not obvious in firing rate measures. These results suggest that population measures provide a richer view of how neuronal activity is associated with behavior, however, largely confirm that persistent activity is the core phenomenon that maintains visual-spatial information in working memory.

NEW & NOTEWORTHY

Recordings from large numbers of neurons led to a re-evaluation of neural correlates of cognitive functions, which traditionally were defined based on responses of single neurons, or averages of firing rates. Analysis of neuronal recordings from the dorsolateral prefrontal and posterior parietal cortex revealed that properties of neuronal firing captured in classical studies of persistent activity can account for population representations, though some population characteristics did not have clear correlates in single neuron activity.
A multicenter review of histopathology of variants in the context of upper urinary tract urothelial carcinoma and their impact on clinical outcomes
Authors: Giudici N , Schoch A , Genitsch V , Rodriguez-Calero JA , Thalmann GN , Seiler R
Published: June 2023

Introduction

Similar to bladder cancer, about one third of upper tract urothelial carcinoma (UTUC) present variant histology (VH). We aim to evaluate the incidence, clinical characteristics and the impact on outcomes of VH in UTUC.

Methods

We consecutively enrolled 77 patients from 2009-2022 treated with radical surgery for UTUC from a secondary and a tertiary referral center. A central pathology review of all specimens was performed by one independent uropathologist for each center. We compared pure UTUC and UTUC with VH and the accuracy of endoscopic biopsy. Descriptive and comparative analysis were used to assess association with clinical characteristics and the Kaplan-Meier estimator to compare outcomes.

Results

Median follow-up after surgery was 51 months. VH was present in 21/77 (28%) patients and 4/21 (19%) patients had multiple variants. The most frequent VH was squamous 12/21 (57%), followed by glandular 6/21 (29%) and micropapillary 3/21 (14%). Small cell neuroendocrine bladder carcinoma was present in two patients. Nested variant was found in one patient.

Muscle invasive tumor (≥pT2) was present in 29/56 (52%) patients with pure UTUC and in 18/21 (86%) patients with VH (p <0.05). Presence of carcinoma in situ was seen in 14/56 (25%) patients with pure UTUC and in 15/21 (71%) with VH (p <0.05). Cumulative 8/56 (14%) with pure UTUC had a non-intravesical recurrence (6 patients with local and 2 distant recurrence) compared to 8/21 (38%) (3 local, 3 nodal, 2 distant) in the subgroup with VH (p <0.05). Opposite effect was noted for bladder recurrence: 60% for pure UTUC vs. 29% for tumors with VH (p <0.05). Review of preoperative endoscopic biopsy did not show the presence of VH in any patients. Differences in outcomes did not reach significance: 3yr-OS 63% vs 42% (p 0.28) and 3yr-CSS 77% vs. 50% (p 0.7).

Conclusion

Almost a third of UTUC present VH. Presence of VH is related to more aggressive tumor characteristics and associated with unfavorable outcomes. Due to a higher rate of extravesical recurrences in UTUC with VH, Follow-up controls should include cross sectional imaging and cystoscopy.
Decentralisation of the compliance of anti-tobacco law in India: The case of higher educational institutions in New Delhi, India
Authors: Singh Raja
Published: June 2023

This paper studies the decentralised compliance responsibility of India’s tobacco control legislation that the government has outsourced to higher educational institutions through an example of New Delhi. 36 higher educational institutions, including universities, are selected and studied through a unique methodology using India’s transparency law, i.e., the Right to Information Act 2005. The study looks into the three most important parameters of decentralised compliance. Two of these require the installation of signboards by educational institutions, and the third involves imposing and collecting fines against persons found smoking within the educational institutions. Regarding the boards, the first board is about the warning prohibiting the sale within 100 yards of educational institutions, and the second one prohibits smoking in educational institutions. The study also asks the educational institutions whether there is a presence of cigarette and tobacco product vendors within 100 yards of the institution, where the sale of such products has been banned by law. The study also found educational activities to create awareness in the institutions for tobacco control and cessation. The results show that the intent to decentralise the compliance of the tobacco control law in New Delhi has not been universally successful and requires much effort.t for its on-ground penetration. Such studies have a policy impact as they serve as an example for the generalisability of such statutes, which only work when there is implementation from the bottom-up and when the deterrent is also strong with incentivisation to the educational institutions to implement tobacco control with vigour.
Profiling of theHelicobacter pyloriredox switch HP1021 regulon using a multi-omics approach
Authors: Noszka Mateusz , Strzałka Agnieszka , Muraszko Jakub , Kolenda Rafał , Meng Chen , Ludwig Christina , Stingl Kerstin , Zawilak-Pawlik Anna
Published: June 2023

The gastric human pathogenHelicobacter pylorihas developed mechanisms to combat stress factors, including reactive oxygen species (ROS), which are present in the stomach’s harsh environment. Here, we present a comprehensive study on the redox switch protein HP1021 regulon combining transcriptomic, proteomic and DNA-protein interactions analyses. Our results indicated that HP1021 decides aboutH. pyloriresponse to oxidative stress. HP1021 regulon included 498 genes, of which 411 responded to oxidative stress. HP1021 controlled typical ROS response pathways (katA,rocF) and less canonical ones, particularly DNA uptake and central carbohydrate metabolism. We identified HP1021 as the first molecular regulator of competence inH. pylori, as HP1021-dependent repression of thecomBDNA uptake genes was relieved under oxidative conditions, increasing natural competence. Furthermore, HP1021 controlled glucose consumption by directly regulating thegluPtransporter and had an important impact on maintaining the energetic balance in the cell.
Disposition and Metabolomic Effects of 2,2’,5,5’-Tetrachlorobiphenyl in Female Rats Following Intraperitoneal Exposure
Authors: Bullert Amanda , Li Xueshu , Zhang Chunyun , Lee Kendra , Pulliam Casey F. , Cagle Brianna S. , Doorn Jonathan A. , Klingelhutz Aloysius J. , Robertson Larry W. , Lehmler Hans-Joachim
Published: June 2023

The disposition and toxicity of lower chlorinated PCBs (LC-PCBs) with less than five chlorine substituents have received little attention. This study characterizes the distribution and metabolomic effects of PCB 52, an LC-PCB found in indoor and outdoor air, three weeks after intraperitoneal exposure of female Sprague Dawley rats to 0, 1, 10, or 100 mg/kg BW. PCB 52 exposure did not affect overall body weight. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis identified PCB 52 in all tissues investigated. Hydroxylated, sulfated, and methylated PCB metabolites, identified using GC-MS/MS and nontarget liquid chromatography-high resolution mass spectrometry (Nt-LCMS), were primarily found in the serum and liver of rats exposed to 100 mg/kg BW. Metabolomic analysis revealed minor effects on L-cysteine, glycine, cytosine, sphingosine, thymine, linoleic acid, orotic acid, L-histidine, and erythrose serum levels. Thus, the metabolism of PCB 52 and its effects on the metabolome must be considered in toxicity studies.

Highlights

PCB 52 was present in adipose, brain, liver, and serum 3 weeks after PCB exposure

Liver and serum contained hydroxylated, sulfated, and methylated PCB 52 metabolites

Metabolomics analysis revealed minor changes in endogenous serum metabolites

Levels of dopamine and its metabolites in the brain were not affected by PCB 52
Humanized yeast to study the role of human ECE-1 isoforms in apoptosis in congenital heart disease
Authors: Xie Hanhui , Huang Yan , Louis Edward J. , Xie Xiaodong
Published: June 2023

Endothelin convert enzyme-1(ECE-1) plays a significant role in cardiovascular development including four isoforms with unclear function. Therefore, we are interested in studying the function of ECE-1 isoforms through mitochondria due to the high correlation between congenital heart disease (CHD) and apoptosis. Since the expression of human Bax and Bcl-xL in budding yeast (Saccharomyces cerevisiae) results in similar effects in mammalian cells, a yeast system was generated for mimicking human Bax-induced apoptosis and the expression of human ECE-1 isoforms was involved. The correlation between Bax-induced growth defect and the candidates of apoptosis via mitochondrial pathway was preliminarily investigated in this system. Furthermore, the phenotypes of ECE-1 isoforms have been identified through yeast growth defect. Individual ECE-1 isoform does not affect yeast growth but act as enhancers for the Bax-induced growth defect. ECE-1c is the strongest enhancer that affect the expression of candidates of outer membrane translocases. This study indicates that ECE-1 might play an important role in inducing apoptosis and we speculate these findings are possible to provide new perspectives with clarifying the mechanism of CHD.
The membrane-cytoplasmic linker defines activity of FtsH proteases inPseudomonas aeruginosaclone C
Authors: Mawla Gina D , Mansour Kamal Shady , Cao Lianying , Purhonen Pasi , Hebert Hans , Sauer Robert T , Baker Tania A , Römling Ute
Published: June 2023

PandemicPseudomonas aeruginosaclone C strains encode a xenolog of FtsH (PaFtsH2), an inner-membrane associated ATP-dependent protease.FtsH1supports growth and intrinsic antibiotic resistance but cannot be replaced byftsH2. We show that purified PaFtsH2 degrades fewer substrates than PaFtsH1. Swapping residues of a short MC peptide that links transmembrane helix-2 with the cytosolic AAA+ ATPase module from PaFtsH1 into PaFtsH2 improves hybrid-enzyme substrate processingin vitroand enables PaFtsH2 to substitute for PaFtsH1in vivo. FtsH1 MC peptides are glycine rich. Introducing three glycines into the membrane-proximal end of PaFtsH2’s MC linker is sufficient to elevate activityin vitroandin vivo. Electron microscopy including PaFtsH2 indicates that MC linker identity influences FtsH flexibility. Our findings establish that the efficiency of substrate processing by two PaFtsH isoforms depends on how they are attached to the membrane and suggest that greater linker flexibility/length allows FtsH to degrade a wider spectrum of substrates. As FtsH2 homologs occur across bacterial phyla, we hypothesize that FtsH2 is not a latent enzyme, rather recognizes specific substrates or is activated in specific contexts or biological niches. We hypothesize that such linkers might play a more determinative role in functionality and physiological impact of FtsH proteases than previously thought.
Regional pulmonary perfusion, blood volume, and their relationship change during early ARDS in an experimental study
Authors: Santos Arnoldo , Motta-Ribeiro Gabriel C. , De Prost Nicolas , Tucci Mauro R. , Wellman Tyler J. , Vidal Melo Marcos F. , Winkler Tilo
Published: June 2023

Regional pulmonary perfusion (Q) has been investigated using blood volume (Fb) imaging as an easier-to-measure surrogate. However, it is unclear if changing pulmonary conditions could affect their relationship. We hypothesized that vascular changes in early acute respiratory distress syndrome (ARDS) affect Q and Fbdifferently. Five sheep were anesthetized and received protective mechanical ventilation for 20 hours while endotoxin was continuously infused. Using dynamic18F-FDG and13NN Positron Emission Tomography (PET), regional Fband Q were analysed in 30 regions of interest (ROIs) and normalized by tissue content (Fbnand Qn, respectively). After 20 hours, the animals’ lung injury showed characteristics of early ARDS, including gas exchange and lung mechanics. PET images of Fbnand Qnshowed substantial differences between baseline and lung injury. Lung injury caused a significant change in the Fbn-Qnrelationship compared to baseline (p<0.001). The best models at baseline and lung injury were Fbn=0.32+0.690Qnand Fbn=1.684Qn–0.538Qn2, respectively. Early ARDS changed the relationship between Fband Q from linear to curvilinear. Effects of endotoxin exposure on the vasoactive blood flow regulation were most likely the key factor for this change limiting the quantitative accuracy of Fbimaging as a surrogate for regional Q.