bluuebunny/crossref_metadata_2025 huggingface dataset:
The progress of percutaneous left atrial appendage occlusion: A bibliometric analysis from 1994 to 2022
Authors: Zhai Huiqi , Kang Liang , Li Yihua , Zhao Xinjun , Chu Qingmin , Li Rong
Published: April 2024

Background:

Atrial fibrillation is the most common cardiac arrhythmia, affecting 32 million individuals worldwide. Although atrial fibrillation has been studied for decades, a comprehensive analysis using bibliometrics has not been performed for atrial fibrillation-left atrial appendage occlusion (LAAO). Therefore, we analyzed the scientific outputs of global LAAO research and explored the current research status and hotpots from 1994 to 2022.

Methods:

We searched the Web of Science core collection for publications related to LAAO that were published between 1994 and 2022. We then performed bibliometric analysis and visualization using Microsoft Excel 2021, Bibliometric (https://bibliometric.com), VOSviewer (version 1.6.19), CiteSpace (version 6.2. R2), and the Bibliometrix 4.0.0 Package (https://www.bibliometrix.org) based on the R language were used to perform the bibliometric analysis, trend and emerging foci of LAAO in the past 29 years, including author, country, institution, journal distribution, article citations, and keywords. In total, we identified 1285 eligible publications in the field of LAAO, with an increasing trend in the annual number of publications.

Results:

The United States is the country with the most published articles in this field, while the United Kingdom is the country with the most cited literature. Mayo Clinic, from the United States, has the most publications in this area and Horst Sievert from Germany had the highest number of individual publications. The analysis of keywords showed that fibrillation, stroke, safety, oral anticoagulants, and watchman were the main hotpots and frontier directions of LAAO. Surgical treatment of nonvalvular atrial fibrillation, upgrading of related surgical instruments, and anticoagulation regimen after surgical treatment are the major research frontiers.

Conclusion:

We show that the research of percutaneous LAAO has been increasing rapidly over the last decade. Our aim was to overview past studies in the field of LAAO, to grasp the frame of LAAO research, and identify new perspectives for future research.
Prevalence of common risk factors of major noncommunicable diseases among sexual and gender minorities in Kathmandu valley, Nepal
Authors: Poudel Bikram , Paudel Kiran , Adhikari Bikram , Paudel Rajan , Bhusal Sandesh , Adhikari Nabin , Adhikari Tara Ballav , Sapkota Vishnu Prasad , Shrestha Roman
Published: April 2024

Four noncommunicable diseases (NCDs): cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes, account for 71% of global deaths. However, little is known about the NCDs risk profile of sexual and gender minorities (SGMs). This study aimed to determine the prevalence of NCDs risk factors among the SGMs of Kathmandu valley, Nepal. A cross-sectional study was conducted among SGMs in the Kathmandu valley, Nepal. We recruited 140 participants using the snowball sampling method. A face-to-face interview was done using a structured questionnaire adapted from World Health Organization Step Wise Approach to Surveillance (STEPS instruments V2.2 2019) along with blood pressure and anthropometric measurements. Data were analyzed using Statistical Package for Social Science (SPSS.v20). More than two-thirds of the participants, 96 (68.6%), had co-occurrence of NCDs risk factors. The prevalence of insufficient fruits and vegetables consumption, current smoking, harmful alcohol consumption, overweight/obesity, and hypertension were 95.7%, 40.0%, 32.9%, 28.5%, and 28.6%, respectively. There was a significant association between hypertension, harmful alcohol consumption, and overweight/obesity with the participants’ age, employment status, and marital status, respectively. Study findings indicated a higher prevalence of NCDs risk factors among SGMs. National-level NCDs surveillance, policy planning, prevention, and targeted health interventions should prioritize the SGMs.
JAKCalc: A machine-learning approach to rationalized JAK2 testing in patients with elevated hemoglobin levels
Authors: Koseoglu Fatos Dilan , Keklik Karadag Fatma , Bulbul Hale , Alici Erdem Ugur , Ozyilmaz Berk , Ozdemir Taha Resid
Published: April 2024

The demand for Janus Kinase-2 (JAK2) testing has been disproportionate to the low yield of positive results, which highlights the need for more discerning test strategies. The aim of this study is to introduce an artificial intelligence application as a more rational approach for testing JAK2 mutations in cases of erythrocytosis. Test results were sourced from samples sent to a tertiary hospital’s genetic laboratory between 2017 and 2023, meeting 2016 World Health Organization criteria for JAK2V617F mutation testing. The JAK2 Somatic Mutation Screening Kit was used for genetic testing. Machine learning models were trained and tested using Python programming language. Out of 458 cases, JAK2V617F mutation was identified in 13.3%. There were significant differences in complete blood count parameters between mutation carriers and non-carriers. Various models were trained with data, with the random forest (RF) model demonstrating superior precision, recall, F1-score, accuracy, and area under the receiver operating characteristic, all reaching 100%. Gradient boosting (GB) model also showed high scores. When compared with existing algorithms, the RF and GB models displayed superior performance. The RF and GB models outperformed other methods in accurately identifying and classifying erythrocytosis cases, offering potential reductions in unnecessary testing and costs.
Congenital trans-mesentric internal hernia: a rare cause of acute intestinal obstruction in adult
Authors: Yasin Nor A. , Ahmed Mohamed R. , Mohammed Abdulkadir N. , Ali Abdihamid M.
Published: April 2024

Introduction and Importance:

Internal hernia is responsible for 0.6–5.8% of all small intestinal obstructions. Only 8% of internal hernias are of the congenital trans mesenteric variant. Urgent surgical intervention should be considered in individuals who exhibit intestinal obstruction before the development of irreversible bowel ischemia and necrosis.

Case Presentation:

The authors report a 38-year-old male patient who presented to the emergency department with abdominal pain, distension, and vomiting for the last three days. After an explorative laparotomy, it was confirmed that there was a trans mesenteric hernia defect with strangulated distal ileal loops. End-to-end ileo-ileal anastomosis was done.

Clinical Discussion:

Early recognition and subsequent surgical treatment permit proper management and prevent complications. There should be a differential diagnosis. In this case, there is no prior history of abdominal surgery, and the patient presents with recurrent abdominal pain and intestinal obstruction.

Conclusion:

Early diagnosis and emergency laparotomy can save the intestine before gangrene, lowering morbidity and mortality, correcting the mesenteric defect to prevent recurrences, and enhancing clinical outcomes because many studies have shown that some cases are missed before radiological investigation. Laparotomy is still the method of choice for acute cases of incarceration with bowel obstruction, strangulation, and ischemia. The entire mesentery needs to be evaluated, and all mesenteric defects need to be sutured to prevent recurrence.
The equation for medical multiple-choice question testing time estimation
Authors: Kreepala Chatchai , Keeratibharat Nattawut , Aekgawong Sekdusit , Wattanavaekin Krittanont , Danjittrong Taechasit , Juntararuangtong Thitikorn , Chombandit Theetad
Published: April 2024

Introduction and importance:

Multiple-choice questions (MCQs) offer a suitable means to assess the cognitive domain of learners with a high degree of objectivity. The study's objective is to formulate an equation for determining the ideal timing for MCQ examinations, thereby inspiring the development of a model to estimate the duration of these examinations.

Methods:

The authors generated a specific computer program that integrated with the operating system of the examination. Technical-specific features included the ability to calculate the speed of students taking examinations with images or videos in the questions or options. This bespoke computer program was designed specifically for assessing individual students' MCQ test-taking pace and generating a proctor report in a computer-readable format. Subsequently, data derived from this program underwent regression analysis to determine the speed at which students completed MCQ examinations.

Outcomes:

The data were collected from a total of 1035 examinees, all of whom were non-native English speakers. The average reading rate was 62.38±20.4 words/min. It was found that the rate decreased significantly in difficult (50.65±6.9 words/min) items compared to easy (82.29±21.3 words/min) and intermediate (60.56±19.1 words/min) items (p<0.001), respectively. The linear regression analysis predicted option selection (words/min) as; 33.92+1.93(%tables/figures)+0.14(%recall)–0.37(%application), r2=0.45, p<0.001.

Conclusion:

It is not advisable to base the decision solely on reading time or time allocation. Examination administrators are advised to proactively plan ahead, with particular emphasis on establishing a well-defined taxonomy, as it constitutes a fundamental cornerstone in the utilization of the estimation equation.
Liver pucker sign: predictor of difficult laparoscopic cholecystectomy: a case series
Authors: Laudari Uttam , Acharya Suyash , Malla Bala Ram
Published: April 2024

Introduction:

Pucker sign is the depression of the liver in the region of the gallbladder due to a high degree of chronic contractive inflammation of the gallbladder. It usually develops in patients who have a delayed cholecystectomy after acute cholecystitis due to a high degree of chronic contractive inflammation of the gallbladder and contraction of the cystic plate. It is an essential finding either preoperatively or intraoperatively as it can act as a stopping rule during cholecystectomy (act as a guide that cholecystectomy will be difficult).

Case series:

The authors here report three cases of pucker sign that were incidentally discovered during laparoscopy.

Discussion:

Chronic cholecystitis is a prolonged, subacute condition caused by inflammation of the gallbladder, which mostly occurs in the setting of cholelithiasis. Laparoscopic cholecystectomy is the procedure of choice for symptomatic cholelithiasis. Hence, it would be beneficial to be aware of reliable signs that predict difficult Laparoscopic cholecystectomy. Pucker sign usually predicts increased operative difficulty as there is an operative danger of biliary or vascular injury.

Conclusion:

The pucker sign is a novel indicator of significant persistent inflammation and heightened difficulty during surgery. It might establish a halting rule that modifies the procedure's management and raises its level of safety.
Long-term outcomes of converting fused hips to total hip arthroplasty are satisfactory: a systematic review and meta-analysis
Authors: Abrishami Ramin , Aghili Seyed Hadi , Afshar Cyrus , Farhang Ranjbar Mehri , Nasrollahizadeh Amir , Poursalehian Mohammad
Published: April 2024

Background:

Although conversion arthroplasty of fused hips can relieve pain and provide patient satisfaction, long-term outcomes of total hip arthroplasty (THA) after hip fusion remain a subject of debate. This meta-analysis aimed to assess the effectiveness of THA for fused hips over a long period with concerns over potential complications.

Methods:

A systematic search of five databases from 2000 until 2023 identified English studies evaluating THA for fused hips with at least 100 months of follow-up. Meta-analyses were conducted using random-effect models via the comprehensive meta-analysis software. Sensitivity analysis, in-depth meta-regression, Egger's test, and the trim-and-fill method were performed appropriately

Results:

The meta-analysis assessed 790 patients and 889 hips with a mean follow-up of 11 years. At the final follow-up, the mean Harris Hip Score (HHS) and leg length discrepancy (LLD) improved by 34.755 and 2.3 cm from the baseline, respectively. Regarding survival of hip fusion conversion to THA, most studies (88.8%) reported a 5-year implant survival rate of at least 90%, and the 15-year and 20-year implant survival rates, ranged between 80–90% and 70–90%, respectively. Subjective dissatisfaction with the conversion of hip fusion to THA was only 5.3%. Composite rates of revision, instability, and aseptic loosening were 13.6%, 3.8%, and 8.8%, respectively.

Conclusions:

Conversion of fused hips to THA results in favourable long-term outcomes regarding HHS, LLD, survival rates, and subjective satisfaction, leading to improved quality of life in properly selected patients. However, the presence of complications should be considered when evaluating the overall success of the procedure.
Enhanced Free-Text Search for Aggregated Medication Error Report Analysis and Risk Detection
Authors: Valkonen Ville , Saano Susanna , Haatainen Kaisa , Tiihonen Miia
Published: April 2024

Objectives

Detecting medication errors (MEs) and learning from them are the key elements of medication safety management in health care. While the aggregation of the data and learning across the ME reports could help detect and manage organizational risks, the inconsistent and partly missing structural data complicate the analysis. The objective of this study was to examine whether an analysis of free-text data of aggregated ME reports could contribute to the detection of organizational risks.

Methods

A retrospective, cross-sectional analysis of ME reports from a patient safety incident reporting system in a tertiary hospital 2017–2021. Clustering of characteristics and variables of ME reports with an enhanced free-text search of the 10 most frequent active substances (TOP10) related to ME reports using Microsoft Excel. Validity analysis of the four most frequent active substances of the search results (TOP4). Evaluation of the possible impact of the enhanced free-text search method on ME report analysis and risk detection.

Results

The enhanced free-text search increased significantly the number of relevant ME reports of TOP10 active substances from 698 reports to 1578 reports. The validity of the enhanced free-text search results in TOP4 active substances was more than 74%. The enhanced free-text search revealed also new ME findings.

Conclusions

Enhanced free-text search can contribute to the aggregate analysis of clustered ME reports and to the improvement of ME risk detection. The enhanced free-text search method enables more comprehensive analysis of the free-text data with commonly available software and provides new insights into medication safety improvement.
Efficacy of hinged and carbon fiber ankle-foot orthoses in children with unilateral spastic cerebral palsy and drop-foot gait pattern
Authors: Dobler Florian , Mayr Robin , Lengnick Harald , Federolf Peter , Alexander Nathalie
Published: April 2024

Background:

In children with unilateral spastic cerebral palsy (USCP), ankle-foot orthoses (AFOs) are widely used to correct common gait deviations such as a drop-foot pattern. Most studies on this topic have investigated specific time points while omitting other parts of the gait cycle.

Objectives:

This study investigated the separate effects of prefabricated carbon fiber AFOs and custom-made hinged AFOs compared with barefoot walking in children with USCP with a drop-foot gait pattern using statistical parametric mapping.

Study design:

Retrospective, cross-sectional, repeated measures study.

Methods:

Twenty ambulatory children (9.9 ± 2.5 years) with USCP and a drop-foot gait pattern were included. Kinematics, kinetics, and spatiotemporal parameters assessed during 3-dimensional gait analysis were compared between barefoot and AFO walking. Statistical parametric mapping was used to compare joint angles and moment waveforms. Kinematics, kinetics and spatiotemporal parameters assessed during 3-dimensional gait analysis were compared between barefoot and AFO walking for each AFO type but not between the 2 AFO types.

Results:

Compared with barefoot walking, there was a steeper sole angle at initial contact, corresponding to a heel strike pattern, and an increased ankle dorsiflexion in swing with the use of both AFOs. The ankle plantar flexion moment during loading response increased. Ankle power generation during pre-swing decreased in the carbon fiber AFO group when walking with AFOs.

Conclusions:

Both AFOs were beneficial for improving a drop-foot gait pattern in these small patient groups and can, therefore, be recommended to treat this gait deviation in patients with unilateral cerebral palsy. However, the reduction in ankle power generation during push-off and additional goals targeted by AFOs, such as correction of structural or flexible foot deformities, should be considered for prescription.
The Evaluation of Condylar Position Change in the Asymmetric Mandible Following Sagittal Split Osteotomy
Authors: Tabrizi Reza , Amini Ehsan , Hormozi Behnoush , Behnia Parsa , Aboul Hosn Centenero Samir
Published: April 2024

Background:

The change of condyle position following orthognathic surgery affects the stability of treatments. This study aims to assess the correlation between the amount of condyles’ position change and the severity of mandibular asymmetry following BSSO.

Materials and Methods:

This is a cross-sectional study. Subjects with asymmetric mandibular prognathism following BSSO were studied. Subjects were classified into 2 groups: group 1, subjects had mandibular asymmetry without occlusal cant and underwent BSSO. Group 2, subjects had mandibular asymmetry with occlusal cant and underwent BSSO+ Lefort I osteotomy. The condyle position was evaluated using cone-beam computer tomography (CBCT). Pearson’s correlation test was used to assess any correlation between the condyle changes and the change in the mandible in sagittal and anterior–posterior directions.

Results:

A total of 44 subjects were studied. In group 1, the condyle tilted outward in the deviated condyle and inward in the non-deviated condyle immediately after osteotomy. After 12 months, both condyles showed a rotation relative to the original position. In group 2, the condyles of the deviated sides and non-deviated sides moved inferiorly after surgery (condylar sagging), which was more significant in the non-deviated sides. The condyle rotation was similar to group 1. The severity of asymmetry and occlusal cant correlate with the condylar position change in the two groups.

Conclusion:

The severity of mandibular asymmetry correlates with the amount of condyles’ position change immediately after BSSO. However, the condyles tend to return to their original position 12 months later.
Microbial Primer: Cooperation in bacteria
Authors: West Stuart A. , Griffin Ashleigh S.
Published: April 2024

The growth and success of many bacteria appear to rely on a stunning range of cooperative behaviours. But what is cooperation and how is it studied?
Reference equations for peak oxygen uptake for treadmill cardiopulmonary exercise tests based on the NHANES lean body mass equations, a FRIEND registry study
Authors: Santana Everton J. , Kim Daniel Seung , Christle Jeffrey W , Cauwenberghs Nicholas , Celestin Bettia E. , Tso Jason V. , Wheeler Matthew T , Ashley Euan A , Peterman James E. , Arena Ross , Harber Matthew , Kaminsky Leonard A. , Kuznetsova Tatiana , Myers Jonathan N. , Haddad Francois
Published: April 2024

BACKGROUND

Cardiorespiratory fitness (CRF), measured by peak oxygen uptake (VO2peak), is a strong predictor of mortality. Despite its widespread clinical use, current reference equations for VO2peak show distorted calibration in obese individuals. Using data from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we sought to develop novel reference equations for VO2peak better calibrated for overweight/obese individuals - in both males and females, by considering body composition metrics.

METHODS AND RESULTS

Graded treadmill tests from 6,836 apparently healthy individuals were considered in data analysis. We used the National Health and Nutrition Examination Survey equations to estimate lean body mass (eLBM) and body fat percentage (eBF).

Multivariable regression was used to determine sex-specific equations for predicting VO2peak considering age terms, eLBM and eBF. The resultant equations were expressed as VO2peak (male) = 2633.4 + 48.7✕eLBM (kg) - 63.6✕eBF (%) - 0.23✕Age2(R2=0.44) and VO2peak (female) = 1174.9 + 49.4✕eLBM (kg) - 21.7✕eBF (%) - 0.158✕Age2(R2=0.53). These equations were well-calibrated in subgroups based on sex, age and body mass index (BMI), in contrast to the Wasserman equation. In addition, residuals for the percent-predicted VO2peak (ppVO2) were stable over the predicted VO2peak range, with low CRF defined as < 70% ppVO2and average CRF defined between 85-115%.

CONCLUSIONS

The derived VO2peak reference equations provided physiologically explainable and were well-calibrated across the spectrum of age, sex and BMI. These equations will yield more accurate VO2peak evaluation, particularly in obese individuals.
Early sports specialization in Japanese young soccer players and related factors
Authors: Nagano Yasuharu , Sasaki Shogo , Higashihara Ayako , Oyama Takashi
Published: April 2024

Although understanding the status of sports participation is essential for preventing injuries in young athletes, the level of specialization and relevant information in Japan is unknown. This study aimed to clarify the status of sports specialization and examine the relationships between specialization and training status in Japanese young soccer players.Four hundred Japanese young male soccer players were included. The players’ parents completed a web questionnaire that consisted of three-point questions regarding specialization and training status (year, days of playing soccer, age when starting soccer). The level of specialization and accompanying information were calculated, and data were compared by specialization status. Of the participants, 53.8% demonstrated a high level of specialization. In addition, 74.5% considered soccer more important than other sports, 89.0% trained in soccer for more than 8 months of the year, and 74.0% had quit other sports to focus on soccer or played only soccer. The proportion of participants who played only soccer was significantly higher in the high-specialization group (37.6%) than in the moderate-specialization (22.5%;P< .01) and low-specialization (7.1%;P< .01) groups. By specialization status at grades 4 to 6 (9–12 years), 40.3% of participants demonstrated a high level of specialization. Young Japanese soccer players tend toward early specialization. Factors contributing to the high-specialization level are being active throughout the year and rarely playing other sports. Training volume should be controlled in children of this age with avoidance of early specialization.
Incidence and risk factors of omicron variant SARS-CoV-2 breakthrough infection among vaccinated and boosted individuals
Authors: Moreno-Echevarria Fabiola M. , Caputo Mathew T. , Camp Daniel M. , Reddy Susheel , Achenbach Chad J.
Published: April 2024

Background

SARS-CoV-2 vaccines have been shown to be safe and effective against infection and severe COVID-19 disease worldwide. Certain co-morbid conditions cause immune dysfunction and may reduce immune response to vaccination. In contrast, those with co-morbidities may practice infection prevention strategies. Thus, the real-world clinical impact of co-morbidities on SARS-CoV-2 infection in the recent post-vaccination period is not well established. We performed this study to understand the epidemiology of Omicron breakthrough infection and evaluate associations with number of comorbidities in a vaccinated and boosted population.

Methods and Findings

We performed a retrospective clinical cohort study utilizing the Northwestern Medicine Enterprise Data Warehouse. Our study population was identified as fully vaccinated adults with at least one booster. The primary risk factor of interest was the number of co-morbidities. Our primary outcome was incidence and time to first positive SARS-CoV-2 molecular test in the Omicron predominant era. We performed multivariable analyses stratified by calendar time using Cox modeling to determine hazard of SARS-CoV-2. In total, 133,191 patients were analyzed. Having 3+ comorbidities was associated with increased hazard for breakthrough (HR=1.2 CI 1.2-1.6). During the second half of the study, having 2 comorbidities (HR= 1.1 95% CI 1.02-1.2) and having 3+ comorbidities (HR 1.7, 95% CI 1.5-1.9) were associated with increased hazard for Omicron breakthrough. Older age was associated with decreased hazard in the first 6 months of follow-up. Interaction terms for calendar time indicated significant changes in hazard for many factors between the first and second halves of the follow-up period.

Conclusions

Omicron breakthrough is common with significantly higher risk for our most vulnerable patients with multiple co-morbidities. Age related behavioral factors play an important role in breakthrough infection with the highest incidence among young adults. Our findings reflect real-world differences in immunity and exposure risk behaviors for populations vulnerable to COVID-19.
Examining the Prevalence and Risk Factors of Genital Warts among HIV-Infected and HIV-Negative Women: A Cross-Sectional Study in Cameroon
Authors: Fougang Daina Charnelle , Kuete Martin
Published: April 2024

Background

Current research primarily focuses on high-risk strains of HPV associated with cervical cancer, overlooking risk factors for low-risk HPV infections like genital warts among vulnerable women, especially concerning their HIV serology. Understanding the interplay between genital warts, HIV status, and socio-cultural factors is crucial for informing targeted prevention to alleviate the burden of genital warts in vulnerable populations.

Aims

The purpose of this study is to determine the prevalence and risk factors of genital warts among women based on their HIV serostatus.

Materials and Methods

A cross-sectional study was conducted among women seeking gynecological consultation at a public Hospital in Cameroon. Data were collected through a survey and medical records, then analyzed using SPSS version 18.0.

Results

Among 257 women attending the hospital, 60 had genital warts, with the majority being HIV-positive (63.33%). Notably, 67% of these women sought gynecology consultation for the first time for genital warts. The location and types of genital warts were associated with HIV status, with papule genital warts being more prevalent among HIV-infected women and acuminate warts among non-infected women. Additionally, associations were found between smoking, multiple sexual partners, and genital warts among HIV-positive women. The reliance on traditional medicine or homemade remedies (85%) and the high prevalence of self-medication (75%) were also observed.

Conclusions

Addressing socio-cultural barriers is essential to enhance healthcare-seeking behaviour, facilitate early detection and treatment, and alleviate the burden of genital warts and HIV. Efforts should prioritize awareness-raising, enhancing healthcare access, and integrating traditional medicine into comprehensive healthcare systems.
Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19
Authors: Lu Yongzhi , Yang Qi , Ran Ting , Zhang Guihua , Li Wenqi , Zhou Peiqi , Tang Jielin , Dai Minxian , Zhong Jinpeng , Chen Hua , He Pan , Zhou Anqi , Xue Bao , Chen Jiayi , Zhang Jiyun , Yang Sidi , Wu Kunzhong , Wu Xinyu , Tang Miru , Zhang Wei K. , Guo Deyin , Chen Xinwen , Chen Hongming , Shang Jinsai
Published: April 2024

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLproinhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLprofrom SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discovered a series of novel potent non-covalent PLproinhibitors with remarkablein vitropotency andin vivoPK properties. The co-crystal structures of PLprowith leads revealed that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor’s potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 μM, respectively. Oral administration of the compound resulted in significantly improved survival and notable reductions in lung viral loads and lesions in SARS- CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLproinhibitor is a promising SARS-CoV-2 therapy.
Structurally informed resting-state effective connectivity recapitulates cortical hierarchy
Authors: Greaves Matthew D. , Novelli Leonardo , Razi Adeel
Published: April 2024

Neuronal communication relies on the anatomy of the brain, yet it remains unclear whether, at the macroscale, structural (or anatomical) connectivity provides useful constraints on effective connectivity. Here, we assess a hierarchical empirical Bayes model that builds on a well-established dynamic causal model by integrating structural connectivity into resting-state effective connectivity via priors. In silico analyses show that the model successfully recovers ground-truth effective connectivity and compares favorably with a prominent alternative. Analyses of empirical data reveal that a positive, monotonic relationship between structural connectivity and the prior probability of group-level effective connectivity generalizes across sessions and samples. Finally, attesting to the model's biological plausibility, we show that inter-network differences in the coupling between structural and effective connectivity recapitulate a well-known unimodal-transmodal hierarchy. These findings underscore the value of integrating structural and effective connectivity to enhance the understanding of functional integration in health and disease.
Wolbachiaas agents of extensive mtDNA lineage sharing between species through multiple infection
Authors: Noguerales Víctor , Emerson Brent C.
Published: April 2024

Wolbachiacan manipulate arthropod host reproduction, triggering the homogenisation of mtDNA variation within species and introgression between hybridising species through indirect selection. While fixation within species of mtDNA variants linked toWolbachiainfections has been documented, a broader understanding of the potential consequences ofWolbachiainfection through hybridisation is limited. Here we evaluateWolbachiatransmission through hybridisation as a mechanistic explanation for extensive mtDNA paraphyly between two species of iron-clad beetle (Zopheridae). Our analyses reveal a complex pattern of mitochondrial variation, supporting the introgression of at least five mtDNA lineages fromTarphius canariensisintoT. simplex, in a background of a sharedWolbachiainfection across both species. Genetic clustering and demographic simulations reveal a clear pattern of nuclear differentiation between species, a limited signature of historical gene flow, and the eastwards range expansion ofT. simplexacross the existing distribution ofT. canariensis.These results are consistent with hybridisation during early stages of secondary contact, during whichWolbachiainfection facilitated recurrent mtDNA introgression events. These results highlight the complex restructuring of mitochondrial differentiation across invertebrate species that can result from bacterial endosymbiotic infections, a phenomena with potentially profound impacts for the disciplines of phylogeography and species delimitation.
Unique functional neuroimaging signatures of genetic versus clinical high risk for psychosis
Authors: Schleifer Charles H. , Chang Sarah E. , Amir Carolyn M. , O’Hora Kathleen P. , Fung Hoki , Kang Jee Won D. , Kushan-Wells Leila , Daly Eileen , Fabio Fabio Di , Frascarelli Marianna , Gudbrandsen Maria , Kates Wendy R. , Murphy Declan , Addington Jean , Anticevic Alan , Cadenhead Kristin S. , Cannon Tyrone D. , Cornblatt Barbara A. , Keshavan Matcheri , Mathalon Daniel H. , Perkins Diana O. , Stone William , Walker Elaine , Woods Scott W. , Uddin Lucina Q. , Kumar Kuldeep , Hoftman Gil D. , Bearden Carrie E.
Published: April 2024

Background

22q11.2 Deletion Syndrome (22qDel) is a copy number variant (CNV) associated with psychosis and other neurodevelopmental disorders. Adolescents at clinical high risk for psychosis (CHR) have subthreshold psychosis symptoms without known genetic risk factors. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped results to biological pathways.

Methods

We analyzed two large multi-site cohorts with resting-state functional MRI (rs-fMRI): 1) 22qDel (n=164, 47% female) and typically developing (TD) controls (n=134, 56% female); 2) CHR individuals (n=244, 41% female) and TD controls (n=151, 46% female) from the North American Prodrome Longitudinal Study-2. We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions, testing case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation.

Results

BSV, LC, and GBC are significantly disrupted in 22qDel compared with TD controls (False Discovery Rate q<0.05). Spatial maps of BSV and LC differences are highly correlated with each other, unlike GBC. In CHR, only LC is significantly altered versus controls, with a different spatial pattern compared to 22qDel. Group differences map onto biological gradients, with 22qDel effects strongest in regions with high predicted blood flow and metabolism.

Conclusion

22qDel and CHR exhibit divergent effects on fMRI temporal variability and multi-scale functional connectivity. In 22qDel, strong and convergent disruptions in BSV and LC not seen in CHR individuals suggest distinct functional brain alterations.
Sleep disturbance in people with anxiety or depressive disorders over 30 years, and the influence of personality disorder
Authors: King Jacob D , Yang Min , Tyrer Helen , Tyrer Peter
Published: April 2024

Objectives

Sleep disturbance is commonly reported by people with anxiety, depressive and personality disorders, but longitudinal studies exploring the interplay of the three with disturbed sleep have not previously been described.

Methods

In this study sleep disturbance was examined among 89 patients initially presenting with anxiety or depressive disorders who provided follow-up at 12 and 30 year timepoints in The Nottingham Study of Neurotic Disorder. Multiple regression models were used to identify factors most predictive of poor sleep, and changes in sleep quality over time.

Results

There were strong associations between poor sleep and contemporaneous severity of personality disorder and the presence of other mental disorders at 12 and 30 years follow-up, but not with disorder presence at other time points. Improvements in personality disorder were associated with improvements in sleep between time points, and attenuated the positive unadjusted effects of recovery from anxiety or depressive disorders to insignificance. Relapse into further episodes of mental disorder predicted poorer sleep, whereas worsening personality disorder was not predictive of significant changes when adjusting for other factors.

Conclusions

This study demonstrates the complex interplay between anxiety, depressive and personality disorders and sleep disturbance over a long follow-up period. Future research might look to examine the relationship between personality disorder and disturbed sleep with interventional studies and by integrating personality trait research.
Cost-effectiveness of mass drug administration with ivermectin against strongyloidiasis: a modelling study
Authors: Coffeng Luc E. , Lo Nathan C. , de Vlas Sake J.
Published: April 2024

Background

Strongyloidiasis, caused by the parasitic intestinal wormStrongyloides stercoralis, infects hundreds of millions of people globally. Current school-based preventive chemotherapy (PC) programs that use benzimidazole derivatives (e.g., albendazole) against soil-transmitted helminths do not effectively treat strongyloidiasis, which requires treatment with ivermectin. We estimate the cost-effectiveness of mass drug administration with ivermectin for the control of strongyloidiasis.

Methods

We developed a mathematical model to simulate the population dynamics ofS. stercoralisand the impact of school-based and community-wide PC across a range of epidemiological settings. We simulated 10-year PC programs with varying treatment coverages. We estimated a primary outcome of disability-adjusted life years (DALYs) averted by each PC strategy and calculate the programmatic cost (US$) of each strategy. We estimated cost-effectiveness by comparing strategies by their incremental cost-effectiveness ratios (US$/averted DALY) and expected loss curves.

Findings

The model found community-based PC was the most cost-effective strategy (≤600 US$ / DALY averted), despite costing approximately 5 times as much as school-based PC. Community-based PC targeted at ages 5 and above reduced infection levels close to 0% within 5 to 6 years. School-based PC was predicted to have very little impact. These results were robust across a range of epidemiologic settings above a measured prevalence of 2-5% in school age children.

Interpretation

Annual community-based PC is the most cost-effective public health strategy to control strongyloidiasis, being superior to school-based PC due to most of the infections and mortality occurring in adults. A baseline prevalence of 2% of infection in school age children, as measured by Baermann or stool culture, is a suitable minimum threshold for cost-effective implementation of community-based PC.

Funding

World Health Organization.
Is exposure to pesticides associated with biological aging? A systematic review and meta-analysis
Authors: Zuo Shanshan , Sasitharan Vidhya , Di Tanna Gian Luca , Vonk Judith M. , Vries Maaike De , Sherif Moustafa , Ádám Balázs , Rivillas Juan Carlos , Gallo Valentina
Published: April 2024

Objective

Exposure to pesticides is a risk factor for various diseases, yet its association with biological aging remains unclear. We aimed to systematically investigate the relationship between pesticide exposure and biological aging.

Methods

PubMed, Embase and Web of Science were searched from inception to August 2023. Observational studies investigating the association between pesticide exposure and biomarkers of biological aging were included. Three-level random-effect meta-analysis was used to synthesize the data. Risk of bias was assessed by the Newcastle-Ottawa Scale.

Results

Twenty studies evaluating the associations between pesticide exposure and biomarkers of biological aging in 10,368 individuals were included. Sixteen reported telomere length and four reported epigenetic clocks. Meta-analysis showed no statistically significant associations between pesticide exposure and the Hannum clock (pooled β = 0.27; 95%CI: -0.25, 0.79), or telomere length (pooled Hedges’g = -0.46; 95%CI: -1.10, 0.19). However, the opposite direction of effect for the two outcomes showed an indication of possible accelerated biological aging. After removal of influential effect sizes or low-quality studies, shorter telomere length was found in higher-exposed populations.

Conclusion

The existing evidence for associations between pesticide exposure and biological aging is limited due to the scarcity of studies on epigenetic clocks and the substantial heterogeneity across studies examining telomere length. High-quality studies incorporating more biomarkers of biological aging, focusing more on active chemical ingredients of pesticides and accounting for potential confounders are needed to enhance our understanding of the impact of pesticides on biological aging.
Overexpression of Fibroblast Activation Protein (FAP) in stroma of proliferative inflammatory atrophy (PIA) and primary adenocarcinoma of the prostate
Authors: Caramella-Pereira Fernanda , Zheng Qizhi , Hicks Jessica L. , Roy Sujayita , Jones Tracy , Pomper Martin , Antony Lizamma , Meeker Alan K. , Yegnasubramanian Srinivasan , De Marzo Angelo M. , Brennen W. Nathaniel
Published: April 2024

Fibroblast activation protein (FAP) is a serine protease upregulated at sites of tissue remodeling and cancer that represents a promising therapeutic and molecular imaging target. In prostate cancer, studies of FAP expression using tissue microarrays are conflicting, such that its clinical potential is unclear. Furthermore, little is known regarding FAP expression in benign prostatic tissues. Here we demonstrated, using a novel iterative multiplex IHC assay in standard tissue sections, that FAP was nearly absent in normal regions, but was increased consistently in regions of proliferative inflammatory atrophy (PIA). In carcinoma, FAP was expressed in all cases, but was highly heterogeneous. High FAP levels were associated with increased pathological stage and cribriform morphology. We verified that FAP levels in cancer correlated with CD163+ M2 macrophage density. In this first report to quantify FAP protein in benign prostate and primary tumors, using standard large tissue sections, we clarify that FAP is present in all primary prostatic carcinomas, supporting its potential clinical relevance. The finding of high levels of FAP within PIA supports the injury/regeneration model for its pathogenesis and suggests that it harbors a protumorigenic stroma. Yet, high levels of FAP in benign regions could lead to false positive FAP-based molecular imaging results in clinically localized prostate cancer.
Investigating the biosynthesis and roles of the auxin phenylacetic acid duringPseudomonas syringae-Arabidopsis thalianapathogenesis
Authors: Lee Chia-Yun , Harper Christopher P. , Lee Soon Goo , Qi Yunci , Clay Taylor , Aoi Yuki , Jez Joseph M. , Kasahara Hiroyuki , Blodgett Joshua A. V. , Kunkel Barbara N.
Published: April 2024

Several plant-associated microbes synthesize the auxinic plant growth regulator phenylacetic acid (PAA) in culture; however, the role of PAA in plant-pathogen interactions is not well understood. In this study, we investigate the role of PAA during interactions between the phytopathogenic bacteriumPseudomonas syringaestrainPtoDC3000 (PtoDC3000) and the model plant host,Arabidopsis thaliana. Previous work demonstrated that indole-3-acetaldehyde dehydrogenase A (AldA) ofPtoDC3000 converts indole-3-acetaldehyde (IAAld) to the auxin indole-3-acetic acid (IAA). Here, we further demonstrate the biochemical versatility of AldA, as it can use both IAAld and phenylacetaldehyde as substrates to produce IAA and PAA, respectively. We also show that during infection AldA-dependent synthesis of either IAA or PAA byPtoDC3000 does not contribute significantly to the increase in auxin levels inA. thalianaleaves. Using availablearogenate dehydratase(adt) mutant lines ofA. thalianacompromised for PAA synthesis, we observed that a reduction in PAA-Asp and PAA-Glu is correlated with elevated levels of IAA and increased susceptibility. These results provide evidence that PAA/IAA homeostasis inA. thalianainfluences the outcome of plant-microbial interactions.
Quantitative metabolic reference for healthy human cerebrum derived from group averaged 9.4T1H MRSI data
Authors: Wright Andrew Martin , Ziegs Theresia , Henning Anke
Published: April 2024

Drawing inspiration from previous works using1H FID MRSI, this study quantifies metabolite concentrations at 9.4 T in the human cerebrum of a volunteer cohort and performs a respective group analysis to derive region specific metabolite concentrations. Voxel-specific corrections were performed for both water and individual metabolites, as well as used tissue specific T1-relaxation times. Anatomical and magnetic resonance spectroscopic imaging data were collected using MP2RAGE and FID MRSI sequences, and subsequent data underwent a series of preprocessing techniques. Results showed consistent metabolite maps for key metabolites (NAA, tCr, Glu, tCho and mI), while instability in data quality was noted for lower slices. This study not only showcases the potential of metabolite quantification and mapping at 9.4 T but also underscores the necessity for meticulous data processing to ensure accurate metabolite representations. Comparisons with earlier works and single voxel results validate the methodologies adopted.

Highlights

Quantitative whole cerebrum metabolite maps in the human brain acquired at 9.4 T.

Group averaged regional metabolite concentrations.

Group summed regional metabolite spectra.
Brain-wide monosynaptic connectivity mapping with ROInet-seq
Authors: Lin Zhige , Ophir Osnat , Trimbuch Thorsten , Brokowski Bettina , Tibi Muhammad , Pavletsov Polina , Schmidt Hermann , Rosenmund Christian , Hochgerner Hannah , Zeisel Amit
Published: April 2024

Viral projection tracing strategies help establish regional connectomes of mammalian brains. Monosynaptic connectivity tracing with G-deleted rabies virus (RV) establishes retrograde synaptic connectivity, but cannot distinguish networks at cell resolution. We developed ROInet-seq, an accessible spatial method using barcoded ΔG rabies virus, amenable to readout by RNA-sequencing. We optimized library complexity and uniformity, such that detection of specific barcodes can reliably distinguish multiple infected neurons, and their individual monosynaptic input networks. In cortical brain areas we found preserved regional network motives, including co-inputs to single cortical neurons from distant and local sites. Towards improved spatial resolution and simultaneous detection of the single cells’ transcriptomes and networks, we finally sampled barcoded ΔG rabies virus infected hippocampus on a commercial spatial transcriptomics assay and reveal details of the regions’ neurons local network architecture.