bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute pancreatitis as a rare adverse event among cannabis users: A systematic review
Authors: Jaiswal Vikash , Mukherjee Dattatreya , Batra Nitya , Ruchika FNU , Susheela Ammu Thampi , Chia Jia Ee , Mukherjee Deblina , Naz Sidra , Victor Aguilera-Alvarez , Pokhrel Nishan Babu , Song David , Seen Tasur , Almas Talal , Saleh Mohanmad Abou , Bansrao Amandeep Singh , Mansoor Emad
Published: June 2022

Background:

Cannabis use has been steadily rising in the United States and can have multiple adverse effects, including cannabis-induced acute pancreatitis. This study aims to collate and highlight the significant demographics, clinical presentation, and outcomes in patients with cannabis-induced acute pancreatitis.

Method:

A systematic literature search of electronic databases for peer-reviewed articles was conducted. After an initial search, we found 792 articles through different electronic databases. After manually removing duplicates and articles that did not meet the criteria, 25 articles were included in our review.

Results:

A total of 45 patients were studied, 35 (78%) cases were male and 10 (22%) cases were female, showing male predominance. The mean age of all participants was 29.2 ± 10.3 years. The most common presenting symptoms were abdominal pain 21 of 21 (100%), nausea 17 of 21 (81%), and vomiting 12 of 20 (60%). Ultrasound was normal in the majority of patients, with findings of mild pancreatitis. Computerized tomography scans revealed pancreatic edema and inflammation in 7 of 20 (35%) patients, and findings of necrotizing pancreatitis and complex fluid collection were visualized in 3 of 20 (15%) patients. Dilatation of intrahepatic or extrahepatic biliary ducts was not seen in any patients. The overall prognosis was good, with reported full recovery.

Conclusions:

Cannabis should be included in the differential diagnosis for the etiology of acute pancreatitis, which would help in early intervention and treatment for the mitigation of the rapidly progressive disease.
Cross-sectional area reference values for high-resolution ultrasonography of the lower extremity nerves in healthy Korean adults
Authors: Bae Dae Woong , An Jae Young
Published: June 2022

The cross-sectional area (CSA) reference values of the lower extremity nerves in Asians have been rarely reported. For this study, 107 sex- and age-matched, healthy subjects with a mean age of 46 years (range, 24–75 years) were recruited. All subjects underwent standardized nerve conduction studies of the upper and lower extremities. The CSA was measured unilaterally at 12 sites in the lower extremity nerves, including the femoral, lateral femoral cutaneous, sciatic, common peroneal, superficial peroneal, deep peroneal, tibial, and sural nerves. The CSA significantly correlated with height, weight, and body mass index. The CSA was significantly larger in males than females at most nerves except for the lateral femoral cutaneous, common peroneal (fibular head), and superficial peroneal nerves (distal calf). There was no statistically significant difference between the age groups except for the tibial nerve (ankle). The results of this study provide CSA reference values for the lower extremity nerves including small branches and the values can be useful in the ultrasonographic investigation of various peripheral neuropathies in East Asian populations.
Hereditary Pancreatitis—25 Years of an Evolving Paradigm
Authors: Sahin-Tóth Miklós
Published: June 2022

The identification of the genetic basis of hereditary pancreatitis in 1996 confirmed the critical role of trypsinogen in this disease and opened a new avenue of research on pancreatitis-associated genetic risk factors and their mechanism of action. Through the following 25 years, the ensuing discoveries fundamentally changed our understanding of pancreatitis pathogenesis, clarified the role of trypsinogen autoactivation in disease onset and progression, and set the stage for future therapeutic interventions. This Frank Brooks Memorial Lecture was delivered on November 4, 2021, at the 52nd Annual Meeting of the American Pancreatic Association, held in Miami Beach, Florida.
Feasibility and Satisfaction of Using NET VITALS Self-assessment Tool Among Patients With Neuroendocrine Tumors
Authors: Li Daneng , Imbesi Giovanna J. , Yen Lisa , Kim Heeyoung , Sun Can-Lan , Crook Christiana J. , Ballena Richard , Zhang Ya-Han , Allen Rebecca , Sedrak Mina , Singh Gagandeep
Published: June 2022

Objectives

There is a lack of effective patient education regarding diagnosis/treatment of neuroendocrine tumors (NETs), possibly related to their rare incidence.

Methods

In this cross-sectional survey study, NET patients attending the 2019 Annual Los Angeles NET Education Conference were approached to complete NET VITALS, a self-assessment tool gauging patients’ perception/awareness of their NET diagnosis/treatment, and a satisfaction survey. Feasibility of NET VITALS, patient satisfaction with NET VITALS, and patients’ perception/awareness of their NET diagnosis/treatment were evaluated.

Results

This analysis included 68 patients (median age, 63 years; 47.1% gastrointestinal NETs; 88.2% metastatic disease). Participation was 88.3% (68/77), with a median of 85.7% of items completed (range, 61.9%–100.0%). More than 30% of the patients answered “Don't know/Not familiar”/left blank questions related to tumor characteristics, years of symptoms, and liver-directed therapies. In addition, 69.5% of the patients did not feel sufficient information about NETs was provided at diagnosis. Overall, 67.8% of the patients felt that NET VITALS provides topics to discuss with providers and 76.3% would recommend NET VITALS to others.

Conclusions

NET VITALS is a feasible and acceptable self-assessment tool to potentially help patients improve communication about their NET diagnosis/treatment with their physician. Further studies will examine NET VITALS’ generalizability and discuss its incorporation into clinical care.
Using a Mechanical Lift at Home
Authors: Fields Bronwyn E. , Whitney Robin L. , Bell Janice F.
Published: June 2022

This article is part of a series, Supporting Family Caregivers: No Longer Home Alone, published in collaboration with the AARP Public Policy Institute. Results of focus groups, conducted as part of the AARP Public Policy Institute's No Longer Home Alone video project, supported evidence that family caregivers aren't given the information they need to manage the complex care regimens of family members. This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's health care at home. Nurses should read the articles first, so they understand how best to help family caregivers. Then they can refer caregivers to the informational tear sheet—Information for Family Caregivers—and instructional videos, encouraging them to ask questions. For additional information, see Resources for Nurses.
Introducing a Resiliency Bundle for Home Care Nurses
Authors: Unger Candace
Published: June 2022

Home healthcare (HHC) nurses are experiencing stress and burnout related to high workloads, isolation on the job, and COVID-19 restrictions. A literature review found numerous interventions effective in reducing nurse burnout through building resiliency and decreasing moral distress. The purpose of this evidence-based project was to improve resiliency and decrease the risk of burnout in HHC nurses through the introduction of a resiliency bundle. The following resiliency bundle interventions were implemented: a) gratitude strategies, b) connecting with co-workers, c) storytelling, and d) resiliency training. Duffy's Quality-Caring Model and Neal's Theory of Home Health Nursing Practice framed the project. The interventions were implemented in an HHC department at a large Midwestern pediatric hospital. Outcomes were measured using a pre- and postimplementation resiliency and burnout survey, which used a Likert scale to allow for quantitative analysis. Fourteen nurses completed the presurvey, 11 completed the postsurvey, and 10 completed both pre- and postsurveys. Results showed no statistically significant change in resiliency or burnout after implementation; however, nurses expressed desire to continue using the bundle pieces, especially the gratitude strategies, connecting with co-workers, and sharing stories. Leadership should take burnout risk in HHC nurses seriously and look for innovative ways to promote resiliency.
Multivariate morphometry statistics reveal the morphological change pattern of hippocampus during normal aging
Authors: Chai Hong , Sun Jianhua , Zhou Peng , Zhang Lingyu ,   for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: June 2022

There have been numerous studies focusing on normal aging in previous decades which is accompanied by the structural and functional decline in the hippocampus, while the pattern of hippocampal alteration with age remains unclear. Figuring out the mechanism of hippocampal changes precisely is beneficial for a better understanding of the aging process. In this study, we included a total of 451 T1 MRI scans of subjects of age 50–90 who were labeled as normal in the Alzheimer’s Disease Neuroimaging Initiative. Taking 10 years of age as an age band, we divided the subjects into four groups (denoted as HC1, HC2, HC3, and HC4, respectively), with the youngest being 50–60 and the oldest 81–90. Then the Multivariate Morphometry Statistics (MMS) of the hippocampus segmented from the four groups were extracted by surface reconstruction, mesh generation, and surface registration. Finally, the significant differences between the youngest group and the other three were statistically analyzed. Results showed that the earliest deformation region of the left hippocampus located in the frontal subiculum and the dorsal CA1 of the tail part and gradually expanded with aging, while the right hippocampal deformation mainly concentrated in the dorsal CA1 and spread to the posterior CA2-3, which occurred later than that of the left. All the results illustrated that the hippocampus is truly a vulnerable structure in the course of aging, and the MMS are sensitive metrics for detecting the changes in the subcortical convex structure.
Vaccine-induced neutralizing antibodies against SARS-CoV-2 Omicron variant isolated in Osaka, Japan
Authors: Hiroi Satoshi , Morikawa Saeko , Motomura Kazushi , Mori Haruyo
Published: June 2022

To study vaccine-induced neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants isolated in Osaka, Japan, microneutralization tests were performed on serum samples from 32 subjects who received a second dose of vaccination, and 10 of those who received the third dose of vaccination. Geometric Mean Titres (GMTs) for the D614G strain, Alpha variant, Delta variant, and Omicron BA.1 of the subjects after the second dose of vaccination were 19.5, 21.8, 6.3, and 2.0, respectively. The GMT for the Delta variant was significantly lower than that for the D614G strain and Alpha variant, and the GMT for the Omicron BA.1 was significantly lower than that for the Delta variant. Among the subjects who received three doses of vaccination, the GMTs for the Omicron BA.1 (62.8) and BA.2 (38.6) were significantly higher than that for the Omicron BA.1 after the second dose. Thus, in the present study, the second dose of vaccination induced neutralizing antibodies against SARS-CoV-2 strains, and the reactivity of neutralizing antibodies to the variants was thought to be enhanced by the third dose of vaccination. The serum samples used in this study will be useful in evaluating the reactivity of vaccine-induced antibodies to newly emerging variants.
Practical checklist for implementation of antifungal stewardship programmes
Authors: Bienvenu Anne-Lise , Pavese Patricia , Leboucher Gilles , Berger Pierre , Roux Sandrine , Charmillon Alexandre , Foroni Luc , Menotti Jean , Lebeaux David , Mayan Rémi , Mondain Véronique , Robin Christine , Lesprit Philippe , Alfandari Serge , Kernéis Solen
Published: June 2022

Introduction. Antifungal stewardship programmes are needed in healthcare facilities to limit the overuse or misuse of antifungals, which are responsible for an increase in antifungal resistance.

Hypothesis/Gap Statement. Core recommendations for antifungal stewardship were published by the Mycoses Study Group Education and Research Consortium, while the Centers for Disease Control and Prevention (CDC) provided a Core Elements of Hospital Antibiotic Stewardship Programs checklist. The recommendations offer global core elements for best practices in antifungal stewardship, but do not provide a framework for the implementation of antifungal stewardship programmes in healthcare facilities.

Aim. In line with the recommendations, it is of the utmost importance to establish a practical checklist that may be used to implement antifungal stewardship programmes.

Methodology. The practical checklist was established by a national consensus panel of experts involved in antifungal stewardship activities. A preliminary checklist was sent to all experts. The final document was approved by the panel after discussion and the resolution of any disagreements by consensus.

Results. The final checklist includes the following items: leadership support; actions to support optimal antifungal use; actions to monitor antifungal prescribing, use and resistance; and an education programme.

Conclusion. This antifungal stewardship checklist offers opportunities for antifungal resistance containment, given that antifungal stewardship activities promote the optimal use of antifungals.
Catwalk: identifying closely related sequences in large microbial sequence databases
Authors: Volk Denis , Yang-Turner Fan , Didelot Xavier , Crook Derrick W. , Wyllie David
Published: June 2022

There is a need to identify microbial sequences that may form part of transmission chains, or that may represent importations across national boundaries, amidst large numbers of SARS-CoV-2 and other bacterial or viral sequences. Reference-based compression is a sequence analysis technique that allows both a compact storage of sequence data and comparisons between sequences. Published implementations of the approach are being challenged by the large sample collections now being generated. Our aim was to develop a fast software detecting highly similar sequences in large collections of microbial genomes, including millions of SARS-CoV-2 genomes. To do so, we developed Catwalk, a tool that bypasses bottlenecks in the generation, comparison and in-memory storage of microbial genomes generated by reference mapping. It is a compiled solution, coded in Nim to increase performance. It can be accessed via command line, rest api or web server interfaces. We tested Catwalk using both SARS-CoV-2 and

Mycobacterium tuberculosis

genomes generated by prospective public-health sequencing programmes. Pairwise sequence comparisons, using clinically relevant similarity cut-offs, took about 0.39 and 0.66 μs, respectively; in 1 s, between 1 and 2 million sequences can be searched. Catwalk operates about 1700 times faster than, and uses about 8 % of the RAM of, a Python reference-based compression and comparison tool in current use for outbreak detection. Catwalk can rapidly identify close relatives of a SARS-CoV-2 or

M. tuberculosis

genome amidst millions of samples.
The Cohesin ATPase cycle is mediated by specific conformational dynamics and interface plasticity of SMC1A and SMC3 ATPase domains
Authors: Gomes Marina Vitoria , Landwerlin Pauline , Diebold-Durand Marie-Laure , Shaik Tajith B. , Durand Alexandre , Troesch Edouard , Weber Chantal , Brillet Karl , Lemée Marianne , Decroos Christophe , Dulac Ludivine , Antony Pierre , Watrin Erwan , Ennifar Eric , Golzio Christelle , Romier Christophe
Published: June 2022

Cohesin is key to eukaryotic genome organization and acts throughout the cell cycle in an ATP- dependent manner. The molecular mechanisms underlying the Cohesin ATPase activity are poorly understood. Here, we have characterized distinct steps of the human Cohesin ATPase cycle and show that the SMC1A and SMC3 ATPase domains undergo specific but concerted structural rearrangements along this cycle. Specifically, while the proximal coiled coil of the SMC1A ATPase domain remains conformationally stable, that of SMC3 displays an intrinsic flexibility. The ATP-dependent formation of the heterodimeric SMC1A/SMC3 ATPase module (engaged state) favours this flexibility, while it is counteracted by binding of NIPBL and DNA (clamped state). Opening of the SMC3/RAD21 interface (open-engaged state) leads to a stiffening of the SMC3 proximal coiled coil that constricts, together with that of SMC1A, the DNA binding chamber of the ATPase module. Our results reveal that the plasticity of the ATP-dependent interface between the SMC1A and SMC3 ATPase domains enables the structural rearrangements occurring between the engaged, clamped and open-engaged states, while keeping the ATP gate shut.
CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1
Authors: Xu Zhihao , Deng Shasha , Huang Yuluo , Yang Yunru , Sun Liangqi , Liu Hanyuan , Zhao Dan , Zeng Weihong , Yin Xueying , Zheng Peiyi , Liu Muziying , Zhao Weidong , Zhou Ying , Jin Tengchuan
Published: June 2022

NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that the different ASC preference in three types of inflammasomes, namely ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that the signal transduction of NLRP1 inflammasome relies on multiple interaction surfaces on its death domain superfamily member CARD domain. Finally, our results partly explain the mechanism of the NLRP1 mutation-derived auto-inflammatory diseases caused by the overactivation of the NLRP1 inflammasome. In conclusion, our study not only reveals how CARD8 downregulates NLRP1 inflammasome activation, but also provides insights into the mechanisms of CARD-containing inflammasome assembly.
YAP and collagen remodelling support cell proliferation and tumour aggressiveness in uterine leiomyosarcoma
Authors: Gonzalez-Molina Jordi , Hahn Paula , Falcão Raul Maia , Gultekin Okan , Kokaraki Georgia , Zanfagnin Valentina , Petta Tirzah Braz , Lehti Kaisa , Carlson Joseph W.
Published: June 2022

Fibrillar collagen deposition, stiffness, and downstream signalling support the development of leiomyomas (LM), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared to epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (LMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression of LMS, LM and normal myometrium (MM). We find that, in contrast to LM, LMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that the activity of MMP14, a central protein with collagen-remodelling functions particularly overexpressed in LMS, is necessary for LMS cell proliferation. In addition, we find that, unlike MM and LM cells, LMS proliferation and migration are not affected by collagen substrate stiffness. We demonstrate that LMS cell growth in low matrix adhesion microenvironments is supported by an enhanced basal YAP activity. Altogether, our results indicate that LMS cells acquire high collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease.
Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe
Authors: Rapan Lucija J. , Froudist-Walsh Sean , Niu Meiqi , Xu Ting , Zhao Ling , Funck Thomas , Wang Xiao-Jing , Amunts Katrin , Palomero-Gallagher Nicola
Published: June 2022

Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas and introduced a novel subdivision of Walker’s areas 10, 9, 8B and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Since structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains, and revealed five clusters encompassing frontal lobe areas. Based on the functional connectivity analysis, clustered areas showed similar connectivity distribution pattern. In particular, rostrally located areas (in clusters 1-2) were characterized by bigger fingerprints, i.e., higher receptor densities, and stronger regional interconnections. Whereas, more caudal areas (in clusters 3-5) had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, present study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.
Mitochondrial network structure controls cell-to-cell mtDNA variability generated by cell divisions
Authors: Glastad Robert C. , Johnston Iain G.
Published: June 2022

Mitochondria are highly dynamic organelles, containing vital populations of mitochondrial DNA (mtDNA) distributed throughout the cell. Mitochondria form diverse physical structures in different cells, from cell-wide reticulated networks to fragmented individual organelles. These physical structures are known to influence the genetic makeup of mtDNA populations between cell divisions, but their influence on the inheritance of mtDNA at divisions remains less understood. Here, we use statistical and computational models of mtDNA content inside and outside the reticulated network to quantify how mitochondrial network structure can control the variances of inherited mtDNA copy number and mutant load. We assess the use of moment-based approximations to describe heteroplasmy variance and identify several cases where such an approach has shortcomings. We show that biased inclusion of one mtDNA type in the network can substantially increase heteroplasmy variance (acting as a genetic bottleneck), and controlled distribution of network mass and mtDNA through the cell can conversely reduce heteroplasmy variance below a binomial inheritance picture. Network structure also allows the generation of heteroplasmy variance while controlling copy number inheritance to sub-binomial levels, reconciling several observations from the experimental literature. Overall, different network structures and mtDNA arrangements within them can control the variances of key variables to suit a palette of different inheritance priorities.
AGO1 and HSP90 buffer different genetic variants in Arabidopsis thaliana
Authors: Lemus Tzitziki , Mason G. Alex , Bubb Kerry L. , Alexandre Cristina M. , Queitsch Christine , Cuperus Josh T.
Published: June 2022

Argonaute 1 (AGO1), the principal protein component of microRNA-mediated regulation, plays a key role in plant growth and development. AGO1 physically interacts with the chaperone HSP90, which buffers cryptic genetic variation in plants and animals. We sought to determine whether genetic perturbation of AGO1 in Arabidopsis thaliana would also reveal cryptic genetic variation, and if so, whether AGO1-dependent loci overlap with those dependent on HSP90. To address these questions, we introgressed a hypomorphic mutant allele of AGO1 into a set of mapping lines derived from the commonly used Arabidopsis strains Col-0 and Ler. Although we identified several cases in which AGO1 buffered genetic variation, none of the AGO1-dependent loci overlapped with those buffered by HSP90 for the traits assayed. We focused on one buffered locus where AGO1 perturbation uncoupled the traits days to flowering and rosette leaf number, which are otherwise closely correlated. Using a bulk segregant approach, we identified a non-functional Ler hua2 mutant allele as the causal AGO1-buffered polymorphism. Introduction of a non-functional hua2 allele into a Col-0 ago1 mutant background recapitulated the Ler-dependent ago1 phenotype, implying that coupling of these traits involves different molecular players in these closely related strains. Taken together, our findings demonstrate that even though AGO1 and HSP90 buffer genetic variation in the same traits, these robustness regulators interact epistatically with different genetic loci, suggesting that higher-order epistasis is uncommon.

Article Summary

Argonaute 1 (AGO1), a key player in plant development, interacts with the chaperone HSP90 which buffers environmental and genetic variation. We found that AGO1 buffers environmental and genetic variation in the same traits; however, AGO1-dependent and HSP90-dependent loci do not overlap. Detailed analysis of a buffered locus found that a non-functional HUA2 allele decouples days to flowering and rosette leaf number in an AGO1-dependent manner, suggesting the AGO1-dependent buffering acts at the network level.
mBAT-combo: a more powerful test to detect gene-trait associations from GWAS data
Authors: Li Ang , Liu Shouye , Bakshi Andrew , Jiang Longda , Chen Wenhan , Zheng Zhili , Sullivan Patrick F. , Visscher Peter M. , Wray Naomi R. , Yang Jian , Zeng Jian
Published: June 2022

Gene-based association tests aggregate multiple SNP-trait associations into sets defined by gene boundaries. Since genes have a direct biological link to downstream function, gene-based test results are widely used in post-GWAS analysis. A common approach for gene-based tests is to combine SNPs associations by computing the sum of χ2 statistics. However, this strategy ignores the directions of SNP effects, which could result in a loss of power for SNPs with masking effects (e.g., when the product of the effects of two SNPs and their linkage disequilibrium (LD) correlation is negative). Here, we introduce “mBAT-combo”, a new set-based test that is better powered than other methods to detect multi-SNP associations in the context of masking effects. We validate the method through simulations and applications to real data. We find that of 35 blood and urine biomarker traits in the UK Biobank, 34 traits show evidence for masking effects in a total of 4,175 gene-trait pairs, indicating that masking effects in complex traits is common. We further validate the improved power of our method in height, body mass index and schizophrenia with different GWAS sample sizes and show that on average 95.7% of the genes detected only by mBAT-combo with smaller sample sizes can be identified by the single-SNP approach with larger sample sizes (average sample size increased by 1.7-fold). For instance, LRRC4B is significant only in our method for schizophrenia, which has been shown to play a role in presynaptic pathology using genetic fine-mapping and evidence-based synaptic annotations. As a more powerful gene-based method, mBAT-combo is expected to improve the downstream pathway analysis or tissue and cell-type enrichment analysis that takes genes identified from GWAS data as input to understand the biological mechanisms of the trait or disease. Despite our focus on genes in this study, the framework of mBAT-combo is general and can be applied to any set of SNPs to refine trait-association signals hidden in genomic regions with complex LD structures.
Natural products lysobactin and sorangicin A show in vitro activity against Mycobacterium abscessus complex
Authors: Sullivan Jaryd R. , Yao Jacqueline , Courtine Christophe , Lupien Andréanne , Herrmann Jennifer , Müller Rolf , Behr Marcel A.
Published: June 2022

The prevalence of lung disease caused by Mycobacterium abscessus is increasing among patients with cystic fibrosis. M. abscessus is a multidrug resistant opportunistic pathogen that is notoriously difficult to treat due to a lack of efficacious therapeutic regimens. Currently, there are no standard regimens, and treatment guidelines are based empirically on drug susceptibility testing. Thus, novel antibiotics are required. Natural products represent a vast pool of biologically active compounds that have a history of being a good source of antibiotics. Here, we screened a library of 517 natural products purified from fermentations of various bacteria and fungi against M. abscessus ATCC 19977. Lysobactin and sorangicin A were active against the M. abscessus complex and drug resistant clinical isolates. These natural products merit further consideration to be included in the M. abscessus drug pipeline.
Effectiveness of vaccines in preventing hospitalization due to COVID-19: A multicenter hospital-based case-control study, Germany, June 2021 to January 2022
Authors: Stoliaroff-Pepin Anna , Peine Caroline , Herath Tim , Lachmann Johannes , Perriat Delphine , Dörre Achim , Nitsche Andreas , Michel Janine , Grossegesse Marica , Hofmann Natalie , Rinner Thomas , Kohl Claudia , Brinkmann Annika , Meyer Tanja , Dorner Brigitte G. , Stern Daniel , Treindl Fridolin , Hein Sascha , Werel Laura , Hildt Eberhard , Gläser Sven , Schühlen Helmut , Isner Caroline , Peric Alexander , Ghouzi Ammar , Reichardt Annette , Janneck Matthias , Lock Guntram , Schaade Lars , Wichmann Ole , Harder Thomas
Published: June 2022

We included 852 patients in a prospectively recruiting multicenter matched case-control study in Germany to assess vaccine effectiveness (VE) in preventing COVID-19-associated hospitalization (Delta-variant dominance). Two-dose VE was 89% (95%CI 84-93%) overall, 79% in patients with >2 comorbidities and 77% in adults aged 60-75 years. A third dose increased VE to >93% in all patient-subgroups.
Maternal diagnoses around pregnancy and risk of autism spectrum disorder – A population-based study
Authors: Khachadourian Vahe , Arildskov Elias , Grove Jakob , O’Reilly Paul F , Kodesh Arad , Levine Stephen Z , Buxbaum Joseph D , Reichenberg Abraham , Croen Lisa A. , Schendel Diana , Sandin Sven , Hansen Stefan Nygaard , Janecka Magdalena
Published: June 2022

Background

There is growing interest in the potential effects of maternal health in pregnancy on the risk for autism spectrum disorder (ASD) in the offspring. Studies to date have examined only a few maternal diagnoses in pregnancy and did not account for the potential effects of co-occurring conditions. This study systematically investigates the associations between maternal diagnoses in pregnancy and the risk of ASD in the offspring, addressing comorbidity and familial confounding.

Methods

The study sample included all children born in Denmark in 1998-2007 (N=653,580) and their mothers. We fitted Cox proportional hazard regression models to estimate the risk of ASD associated with maternal chronic and non-chronic ICD-10 diagnoses. We further examined the evidence for potential familial confounding using discordant sibling and negative control designs.

Results

The analytic sample included 7,866 ASD cases (1.2%) and 645,714 controls, born to 425,399 mothers. We tested 241 non-chronic, and 90 chronic maternal conditions for an association with ASD. In a multivariable model, adjusting for maternal comorbidities, 15 of the non-chronic and 5 of the chronic diagnoses were significantly associated with ASD after correcting for multiple testing. Pregnancy complications and injuries accounted for a major portion of the non-chronic maternal diagnoses associated with risk of ASD (e.g., diabetes mellitus in pregnancy: HR=1.27, 95%CI: 1.07-1.51; fracture of skull and facial bones: HR=1.61, 95%CI: 1.09-2.38), and maternal psychiatric diagnoses were most strongly associated with ASD among the chronic conditions (e.g., major depressive disorder: HR=1.89, 95%CI: 1.39, 2.56). Results from negative control (timing of diagnosis, before vs. during pregnancy) and sibling analyses provide limited evidence for the role of familial confounding in the observed associations.

Conclusions

Our findings highlight the potential relevance of maternal health around pregnancy for offspring long-term neurodevelopmental outcomes and offer insights into the ASD etiology – necessitating further dissection of the mechanisms underlying the observed associations.
Multiple Long-Term Conditions (MLTC) and the environment: A scoping review
Authors: Dambha-Miller Hajira , Cheema Sukhmani , Saunders Nile , Simpson Glenn
Published: June 2022

Background

Multiple Long Term conditions (MLTC), the coexistence of two or more health conditions, is a major health care challenge associated with high service utilisation and expenditure. Once established, the trajectory to an increased number and severity of conditions, hospital admission, increased social care need and mortality is multifactorial. The role of wider environmental determinants in the MLTC sequelae is unclear.

Aim

The aim of this review was to summarise and collate existing evidence on environmental determinants on established MLTC.

Methods

A comprehensive search of Medline, Embase, Cochrane, CINAHL and Bielefeld Academic Search Engine (BASE) from inception to 4th June 2022 in addition to grey literature. Two authors independently screened and extracted papers. Disagreements were resolved with a third author.

Results

The search yielded 9,079 articles of which 12 were included. Five studies considered the effect of urban built environments and neighbourhood characteristics on MLTC. Two studies examined both the built and social environments. The social environment was considered by four studies. One study examined the natural environment. Evidence of correlations between some environmental determinants and increased or decreased risks of MLTC were found, including the quality of internal housing/living environments, exposure to airborne environmental hazards and a beneficial association with socially cohesive, accessible and greener neighbourhood environments.

Conclusions

Only 12 relevant papers were identified, with the majority focused on the built and social environments. Overall, the review uncovered very limited evidence and this finding indicates a need for further research to understand the role of environmental determinants in MLTC.
Validation of a Multivariate Prediction Model of the Clinical Progression of Alzheimer’s Disease in a Community-Dwelling Multiethnic Cohort
Authors: Stallard Eric , Kociolek Anton , Jin Zhezhen , Ryu Hyunnam , Lee Seonjoo , Cosentino Stephanie , Zhu Carolyn , Gu Yian , Fernandez Kayri , Hernandez Michelle , Kinosian Bruce , Stern Yaakov
Published: June 2022

Background

The major aims of the three Predictors Studies have been to further our understanding of Alzheimer’s disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD.

Objectives

To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N=211) and non-Hispanic (N=62) older adults from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI).

Methods

The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm.

Results

Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer’s centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except forN=32 subjects initially diagnosed with AD who reverted to a non-AD diagnosis on follow-up.

Conclusions

These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time.
Protection from Omicron infection in residents of nursing and retirement homes in Ontario, Canada
Authors: Breznik Jessica A. , Rahim Ahmad , Kajaks Tara , Hagerman Megan , Bilaver Lucas , Colwill Karen , Dayam Roaya M. , Gingras Anne-Claude , Verschoor Chris P. , McElhaney Janet E. , Bramson Jonathan L. , Bowdish Dawn M. E. , Costa Andrew P.
Published: June 2022

Objectives

To identify factors that contribute to protection from infection with the Omicron variant of SARS-CoV-2 in older adults in nursing and retirement homes.

Design

Longitudinal cohort study with retrospective analysis of infection risk.

Setting and Participants

997 residents of nursing and retirement homes from Ontario, Canada, in the COVID-in-LTC study.

Methods

Residents with three mRNA dose vaccinations were included in the study. SARS-CoV-2 infection was determined by positive nasopharyngeal PCR test and/or circulating anti-nucleocapsid IgG antibodies. Cumulative probability of Omicron infection after recent COVID-19 was assessed by log-rank test of Kaplan-Meier curves. Cox regression was used to assess risk of Omicron infection by age, sex, mRNA vaccine combination, whether individuals received a fourth dose, as well as recent COVID-19.

Results

171 residents (17.2%) had a presumed Omicron variant SARS-CoV-2 infection between December 15, 2021 (local start of the first Omicron wave) and May 3, 2022. Risk of Omicron infection was not different by age [hazard ratio (95% confidence interval): 1.01 (0.99-1.02)], or in women compared to men [0.97 (0.70-1.34)], but infection risk decreased 47% with three vaccine doses of mRNA-1273 (Moderna) compared to BNT162b2 (Pfizer) [0.53 (0.31-0.90)], 81% with any fourth mRNA vaccine dose [0.19 (0.12-0.30)], and 48% with SARS-CoV-2 infection in the 3 months prior to beginning of the Omicron wave [0.52, (0.27-0.99)].

Conclusions and Implications

Vaccine type (i.e., mRNA-1273/Spikevax vs BNT162b2/Cominarty), any fourth vaccine dose, and hybrid immunity from recent COVID-19, were protective against infection with the Omicron variant. These data emphasize the importance of vaccine type, and number of vaccine doses, in maintenance of protective immunity and reduction of risk of Omicron variant breakthrough infection. These findings promote continued public health efforts to support vaccination programs and monitor vaccine immunogenicity in older adults.

Brief summary

Risk of infection with the SARS-CoV-2 Omicron variant in older adults in early 2022 was reduced with triple mRNA-1273 vaccination, any fourth dose vaccine, and within three months of prior COVID-19.
Retention of Female Sex Workers at one month taking oral Pre-exposure prophylaxis for HIV prevention in selected Public Health facilities in Kampala, Uganda
Authors: Wanyama James , Atuhairwe Christine , Alege John Bosco
Published: June 2022

Rationale

Retention of Female sex workers at one month of PrEP is critical as low retention may lead to sub-optimal protection and increased HIV incidence rates in this sub-population. We determined factors associated with retention at one month among Female Sex workers on Pre-Exposure Prophylaxis for HIV prevention in selected health facilities in Kampala Capital City Authority, Uganda.

Methods

In this retrospective cohort study we followed 350 FSWs from September to December 2021; and 30 women underwent in-depth interviews. Retention was categorically defined as the number of FSWs who adhered to their clinic appointments got refills over the total number of FSWs expected to come for a refill. Poisson regression was used for multivariate analysis and thematic data analysis was conducted for the quantitative and qualitative data respectively.

Results

The median age of the FSWs was 25 years. 40.9% of the FSWs had attended primary level, 43.7% secondary level, 3.4% tertiary level education respectively, and 12% had no education. The mean duration of sex work was 3 years.On average, the FSWs had 14 sex partners in the past week. 59.4% reported lubricant use on the last sexual encounter compared to 40.6% who did not use lubricants. Factors associated with retention to PrEP at bivariate level were religion, place of work, lubricant use, use of drugs, received PrEP counselling at initiation, the color of PrEP tablet, pill size and attitude of health care workers. The Poisson regression showed that Retention to PrEP was 7% higher among sex workers that use lubricants compared to those that don’t use holding other factors constant (adjusted 0.02 [1.01, 1.14] IRR 1.07) and retention to PrEP among sex workers that think the health care workers had a good attitude was 23% higher than those that think HCW had fair attitude holding other factors constant (adjusted 0.012 [1.05, 1.44] IRR 1.23). FSWs who had no stigma had 90% higher retention than those who had stigma) (adjusted 0.04 [0.814, 0.996] IRR 0.90).No drugs at the facility affected PrEP retention by about 76% among FSWs (adjusted 0.003 [0.67, 0.922] IRR 0.76). FSWs were retained to PrEP because they felt at risk when they experienced condom breaks during intercourse or they failed to use condoms with a client. Barriers to PrEP retention included drug side effects, lack of financial resources, food insecurity, stigma, and doubts about PrEP efficacy, travel and health system factors.

Conclusion

A high proportion of FSWs were retained on PrEP. FSWs considered PrEP as a reliable method of protection against HIV in cases of condom breaks or if they had sex without a condom. A number of barriers to PrEP retention at both personal and systems-level need to be addressed for successful PrEP implementation.
Triglyceride-glucose index and the risk of heart failure: evidence from two large cohorts and a Mendelian randomization analysis
Authors: Li Xintao , Chan Jeffrey Shi Kai , Guan Bo , Peng Shi , Wu Xiaoyu , Zhou Jiandong , Hui Jeremy Man Ho , Lee Yan Hiu Athena , Satti Danish Iltaf , Tsang Shek Long , Wu Shouling , Chen Songwen , Tse Gary , Liu Shaowen
Published: June 2022

Background

The relationship between triglyceride-glucose (TyG) index, an emerging marker of insulin resistance, and the risk of incident heart failure (HF) was unclear. This study thus aimed to investigate this relationship.

Methods

Subjects without prevalent cardiovascular diseases from the prospective Kailuan cohort (recruited during 2006-2007) and a retrospective cohort of family medicine patients from Hong Kong (recruited during 2000-2003) were followed up until December 31st, 2019 for the outcome of incident HF. Separate adjusted hazard ratios (aHRs) summarizing the relationship between TyG index and HF risk in the two cohorts were combined using a random-effect meta-analysis. Additionally, a two-sample Mendelian randomization (MR) of published genome-wide association study data was performed to assess the causality of observed associations.

Results

In total, 95,996 and 19,345 subjects from the Kailuan and Hong Kong cohorts were analyzed, respectively, with 2,726 cases (2.8%) of incident HF in the former and 1,709 (7.0%) in the latter. Subjects in the highest quartile of TyG index had the highest risk of incident HF in both cohorts (Kailuan: aHR 1.23 (95% confidence interval: 1.09-1.39), PTrend <0.001; Hong Kong: aHR 1.21 (1.04-1.40), PTrend =0.007; both compared with the lowest quartile). Meta-analysis showed similar results (highest versus lowest quartile: HR 1.22(1.11-1.34), P<0.0001). Findings from MR analysis, which included 47,309 cases and 930,014 controls, supported a causal relationship between higher TyG index and increased risk of HF (odds ratio 1.27(1.15-1.40), P<0.001).

Conclusion

A higher TyG index is an independent and causal risk factor for incident HF in the general population.

Clinical Perspective

What is new?

In 115,341 subjects from two large cohorts in China, an elevated triglyceride-glucose (TyG) index was independently associated with an increased risk of incident heart failure (HF).

Two-sample Mendelian randomization analysis based on published genome-wide association studies found significant association between genetically determined TyG index and the risk of HF.

Together, these findings suggest that a higher TyG index is an independent and causal risk factor of incident HF in the general population.

What are the clinical implications?

The TyG index may facilitate recognition of individuals at elevated risk of incident HF and allow early preventive interventions.

The demonstrated causal effect of TyG index on incident HF warrants further research to fully understand the underlying mechanisms.
Function and phylogeny support the independent evolution of acid-sensing ion channels in the Placozoa
Authors: Elkhatib Wassim , Yanez-Guerra Luis , Mayorova Tatiana D. , Currie Mark A. , Perera Maria , Singh Anhadvir , Gauberg Julia , Senatore Adriano
Published: June 2022

Acid-sensing ion channels (ASICs) are proton-gated cation channels that are part of the Deg/ENaC ion channel family, which also includes neuropeptide-, bile acid-, and mechanically-gated channels. Despite sharing common tertiary and quaternary structures, strong sequence divergence within the Deg/ENaC family has made it difficult to resolve their phylogenetic relationships, and by extension, whether channels with common functional features, such as proton-activation, share common ancestry or evolved independently. Here, we report that a Deg/ENaC channel from the early diverging placozoan species Trichoplax adhaerens, named TadNaC2, conducts proton-activated currents in vitro with biophysical features that resemble those of the mammalian ASIC1 to ASIC3 channels. Through a combined cluster- based and phylogenetic analysis, we successfully resolve the evolutionary relationships of most major lineages of metazoan Deg/ENaC channels, identifying two subfamilies within the larger Deg/ENaC family that are of ancient, pre-bilaterian origin. We also identify bona fide Deg/ENaC channel homologues from filasterean and heterokont single celled eukaryotes. Furthermore, we find that ASIC channels, TadNaC2, and various other proton-activated channels from vertebrates and invertebrates are part of phylogenetically distinct lineages. Through structural modelling and mutation analysis, we find that TadNaC2 proton-activation employs fundamentally different molecular determinants than ASIC channels, and identify two unique histidine residues in the placozoan channel that are required for its proton-activation. Together, our phylogenetic and functional analyses support the independent evolution of proton-activated channels in the phylum Placozoa. Spurred by our discovery of pH sensitive channels, we discovered that despite lacking a nervous system, Trichoplax can sense changes in extracellular pH to coordinate its various cell types to locomote away from acidic environments, and to contract upon rapid exposure to acidic pH in a Ca2+-dependent manner. Lastly, via yeast 2 hybrid screening, we find that the Trichoplax channels TadNaC2 and TadNaC10, belonging to the two separate Deg/ENaC subfamilies, interact with the cytoskeleton organizing protein filamin, similar to the interaction reported for the human ENaC channels.