bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perioperative Opioid Dispensing and Persistent Use After Benign Hysterectomy: A Systematic Review and Meta-analysis
Authors: Hessami Kamran , Welch Jennifer , Frost Anja , AlAshqar Abdelrahman , Arian Sara E. , Gough Ethan , Borahay Mostafa A. 
Published: June 2023

(Abstracted from Am J Obstet Gynecol 2022; doi: 10.1016/j.ajog.2022.12.015
Between 1999 and 2019, the opioid epidemic claimed the lives of nearly 250,000 individuals in the United States. Many patients first opioid prescription is dispensed in a surgical setting, and hysterectomy is the second most common surgical procedure in women.
Predictive Value of New Onset Versus Primary Meconium-Stained Amniotic Fluid
Authors: Shai Daniel , Mazaki-Tovi Shali , Hendler Israel , Meyer Raanan , Cahan Tal , Shapira Moran , Sivan Eyal , Barzilay Eran , Haas Jigal 
Published: June 2023

(Abstracted from Birth 2022;49:805–811
Meconium-stained amniotic fluid (MSAF) occurs in up to 52% of postterm pregnancies, 25% of term pregnancies, and 5% of pregnancies <37 weeks of gestation. As a sign of fetal maturity, MFAS may also help signal fetal distress.
“Urinary Reconstruction in Genital Gender-Affirming Surgery: Checking Our Surgical Complication Blind Spots”
Authors: Blasdel Gaines , Dy Geolani W. , Nikolavsky Dmitriy , Ferrando Cecile A. , Bluebond-Langner Rachel , Zhao Lee C. 
Published: June 2023

Background:
Urologic complications in genital gender-affirming surgery (GGAS) are imperfectly measured, with existing evidence limited by “blind spots” which will not be resolved through implementation of patient-reported outcomes alone. Some blind spots are expected in a surgical field with rapidly expanding techniques, and may be exacerbated by factors related to transgender health.

Methods:
We provide a narrative review of systematic reviews published in the last decade to describe the current options for genital gender-affirming surgery and surgeon-reported complications, as well as contrasting peer-reviewed sources with data not reported by primary surgeon. In combination with expert opinion, these findings describe complication rates.

Results:
Eight systematic reviews describe complications in vaginoplasty patients, including 5%-16.3% mean incidence of meatal stenosis and 7%-14.3% mean incidence of vaginal stenosis. Compared to surgeon-reported cohorts, vaginoplasty and vulvoplasty patients in alternate settings report higher rates of voiding dysfunction (47%-66% vs 5.6%-33%), incontinence (23%-33% vs. 4%-19.3%) and misdirected urinary stream (33%-55% vs 9.5%-33%). Outcomes in six reviews of phalloplasty and metoidioplasty included urinary fistula (14%-25%), urethral stricture and/or meatal stenosis (8%-12.2%), and ability to stand to void (73%-99%). Higher rates of fistula (39.5%-56.4%) and stricture (31.8%-65.5%) were observed in alternate cohorts, along with previously unreported complications such as vaginal remnant requiring reoperation.

Conclusion:
The extant literature does not completely describe urologic complications of GGAS. In addition to standardized, robustly validated patient-reported outcome measures, future research on surgeon-reported complications would benefit from using the IDEAL (Idea, Development, Exploration, Assessment, and Long-term Study) framework for surgical innovation.
Distally Based Anterolateral Thigh Flap Algorithm for Unexpected Situations during Soft-Tissue Defect Reconstruction around the Knee
Authors: Du Qingyan , Liu Yuanbo , Zang Mengqing , Zhu Shan , Li Shanshan , Chen Zixiang , Han Tinglu 
Published: June 2023

Background:
The distally based anterolateral thigh (dALT) flap is an effective option for soft-tissue reconstruction around the knee; however, unexpected situations may occur intraoperatively, impeding the flap harvest. We proposed an algorithm for surgical conversion for unexpected situations encountered intraoperatively.

Methods:
Between 2010 and 2021, 61 dALT flap harvests were attempted for soft-tissue defect reconstruction around the knee; 25 patients underwent surgical conversion for anomalies, including lack of a suitable perforator, hypoplasia of the descending branch, and compromised reverse flow from the descending branch. After excluding improper cases, 35 flaps were harvested as planned (group A) and 21 surgical conversion cases (group B) were finally enrolled for analysis. An algorithm was developed based on the cases in group B. Outcomes, including complication and flap loss rates, were compared between groups to verify the algorithm’s rationality.

Results:
In group B, the dALT flap was converted to a distally based anteromedial thigh flap (n=8), bi-pedicled dALT flap (n=4), distally based rectus femoris muscle flap (n=3), free anterolateral thigh flap (n=2), or other locoregional flap that required additional incision (n=4). No differences in outcomes were observed between the two groups.

Conclusions:
The proposed contingency planning algorithm for dALT flap surgery proved rational, as surgical conversion could be made via the same incision in most cases, and outcomes generated by the algorithm were acceptable.
Antibiotic Use and Antimicrobial Resistance: KAP survey of medical students to evaluate undergraduate training curriculum
Authors: Saksena Rushika , Parida Annapurna , Jain Madhura , Gaind Rajni 
Published: June 2023

Introduction: A better understanding of knowledge, attitude and practices of undergraduate medical students towards antimicrobial resistance (AMR) is necessary to identify gaps in current training curriculum.
Methods: A 20-point Likert scale-based questionnaire divided three parts on knowledge, attitude and practices relating to antibiotic use and resistance was devised. Students attending each year of undergraduate medical program were approached to participate in the study over a one-week-period. KAP scores of each year were compared through logistic ordinal regression and Kruskal-Wallis (KW) test.
Results: Two hundred and eight students participated in the study. Overall, knowledge of about intended use of antibiotics, fixed drug combinations and awareness about AMR was good (average score of 5.9 out of a 8). Steady improvement in knowledge scores was observed from first year (-0.441) to final year (0.00). The medical students had favorable attitude towards rational antimicrobial use (Likert score ³4) including the need to spread awareness about AMR amongst students and public and following doctor’s prescription. Self-medication was reported by 28.4% of students and hoarding of leftover doses by 49.1%. Attitude score had a direct correlation with the knowledge score on KW test (χ2 =29.6, p≤0.5) but had no significant correlation with antimicrobial practices (χ2 =3.9, p≥0.5).
Conclusion: The gaps identified in students’ practices included self-medication, skipping of dosing, hoarding of leftover medication. As improvement in knowledge did not correlate with that of practices, current curriculum needs to include AMR as a focus area to ensure good antibiotic prescribing practices in future practitioners.
Clinical impact and public health challenges of a PVL- MRSA bacteraemia outbreak amongst people who inject drugs in South Yorkshire.
Authors: Beaumont Matthew , Subramanian Bala , Agwuh Ken , Pichon Bruno , Ryan Yan 
Published: June 2023

Background: Panton-Valentine leukocidin (PVL) Staphylococcus aureus (SA) is an emergent public health concern. PVL toxin has been mostly associated with methicillin-sensitive Staphylococcus aureus (MSSA) related skin and soft tissue infections occurring in high-risk groups such as people who inject drugs (PWID). The emergence of PVL- methicillin resistant Staphylococcus aureus (MRSA) infection is causing severe and life-threatening disease in PWID.
Clinical cases: we present an outbreak of eight PVL-MRSA bacteraemias at a UK teaching hospital between 2018 and 2022. An additional four patients developed bacteraemias with PVL-negative MRSA of the same multi-locus sequence type (MLST). All patients were PWID and aged between 33- 51 years old. Four patients developed MRSA bacterial endocarditis. Three patients died. These cases represent the initial cases detected at Doncaster and Bassetlaw Teaching Hospitals of what is an ongoing and developing outbreak.
Management: an outbreak investigation has been undertaken in association with the UK Health Security Agency. Epidemiological factors have been explored, including via direct contact at a local sheltered accommodation and the possibility of a contaminated drug supply. Whole-genome sequencing confirmed that all isolates were closely related and of the same MLST (sequence type 5). A community substance misuse group disseminated health education on the prevention of PVL-MRSA. Preventing infection in PWID presents a major challenge due to the impact of addiction on engagement with services and the significant barriers faced by our patients to observing infection prevention measures.
Conclusion: PVL-MRSA is of major public health concern and outbreak investigation and mapping out local epidemiological patterns plays a vital role in preventing further spread throughout the community. Additionally, this work enables targeted and early treatment in patients in high-risk categories for disease. These cases of PVL-MRSA infection in PWID highlights the transmissibility, pathogenic potential and severe clinical disease spectrum within this population. Further work is required to tackle transmission and infection from this pathogenic strain.
Imageless navigation system (Naviswiss) provides accurate component position in total hip arthroplasty with lateral decubitus position for end-stage hip osteoarthritis: A prospective cohort study with CT-validation
Authors: Scholes Corey , Fatima Manaal , Schwagli Tobias , Liu David 
Published: June 2023

AbstractAimsThe Naviswiss system (Naviswiss AG, Brugg, Switzerland) is a handheld imageless navigation device used to improve the accuracy of implant positioning in total hip arthroplasty (THA). However, clinical data for leg length discrepancy and femoral offset is lacking, and the validity of the system has not been reported for patients undergoing THA in the lateral decubitus position. This study aimed to report the accuracy of the device in this patient population.MethodsPatients underwent THA in the lateral decubitus position by a single surgeon. Component positioning measured by the device intraoperatively was compared to postoperative measurements on computed tomography (CT) scans. Agreement between the navigation system and postoperative measurements was reported with respect to acetabular cup inclination, acetabular cup version, femoral offset and leg length discrepancy.ResultsThe mean difference between intraoperative and postoperative CT measurements was within 2° for angular measurements and 2mm for leg length. Absolute differences for the two indices were within 5° and 4mm. Mean bias was 1-2° overestimation for cup orientation and up to 2mm overestimation for leg length change, but 95% limits of agreement did not exceed absolute thresholds of 10° and 10mm, especially after correction for bias. Four cases (12%) were declared intraoperatively for issues with fixation on the greater trochanter. While inclusion of these cases generated acceptable accuracy overall, their omission improved between-case variability in accuracy and reduced the LOA for both offset and leg length.ConclusionsThe accuracy of the Naviswiss system falls within clinically acceptable recommendations for acetabular cup placement, femoral offset and length length. The system could be further improved with regression-based bias correction.
Investigation ofRFC1tandem nucleotide repeat locus in diverse neurodegenerative outcomes in an Indian cohort
Authors: Tyagi Nishu , Uppili Bharathram , Sharma Pooja , Parveen Shaista , Saifi Sheeba , Jain Abhinav , Sonakar Akhilesh , Ahmed Istaq , Sahni Shweta , Shamim Uzma , Anand Avni , Suroliya Varun , Asokachandran Vivekanand , Srivastava Achal , Sivasubbu Sridhar , Scaria Vinod , Faruq Mohammed 
Published: June 2023

AbstractBackground and ObjectivesAn intronic bi-allelic pentanucleotide repeat expansion mutation, (AAGGG)400-2000at AAAAG repeat locus inRFC1gene is known as underlying genetic cause in cases with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) and late onset sporadic ataxia. Biallelic positive cases carry a common recessive risk haplotype, ‘AAGA’ spanningRFC1gene. In this study our aim is to find prevalence of bi-allelic (AAGGG)expin Indian ataxia and other neurological disorders and investigate the complexity ofRFC1repeat locus and its potential association with neurodegenerative diseases in Indian population-based cohorts.MethodsWe carried out repeat number and repeat type estimation using flanking PCR and repeat primed PCR (AAAAG/AAAGG/AAGGG) in three Indian disease cohorts and healthy controls. Haplotype assessment of suspected cases was done by genotyping and confirmed by sanger sequencing. Blood samples and consent of all the cases and detailed clinical details of positive cases were collected in collaboration with AIIMS. Further, comprehension ofRFC1repeat locus and risk haplotype analysis in Indian background was performed on the NGS data of Indian healthy controls by ExpansionHunter, ExpansionHunter de novo and PHASE analysis respectively.ResultsGenetic screening ofRFC1-TNR locus in 1998 uncharacterised cases (SCA12: 87; Uncharacterised ataxia: 1818, CMT: 93) and 564 heterogenous controls showed that the frequency of subjects with bi-allelic (AAGGG)expare 1.15%, <0.05%, 2.15% and 0% respectively. TwoRFC1positive sporadic late onset ataxia cases, one bi-allelic (AAGGG)expand another, (AAAGG)exp/(AAGGG)exphad recessive risk haplotype and CANVAS symptoms. Long normal alleles, 15-27, are significantly rare in ataxia cohort. In IndiGen control population (IndiGen; N=1029), long normal repeat range, 15-27, is significantly associated with A3G3and some rare repeat motifs, AGAGG, AACGG, AAGAG, and AAGGC. Risk-associated ‘AAGA’ haplotype of the original pathogenic expansion of A2G3was found associated with the A3G3representing alleles in background population.DiscussionApart from bi-allelic (AAGGG)exp, we report cases with a new pathogenic expansion of (AAAGG)exp/(AAGGG)expinRFC1and recessive risk haplotype, ‘AAGA’. We found different repeat motifs atRFC1TNR locus, like, AAAAG, AAAGG, AAAGGG, AAAAGG, AAGAG, AACGG, AAGGC, AGAGG, AAGGG, in Indian background population except ACAGG and (AAAGG)n/(AAGGG)n. Our findings will help in further understanding the role of long normal repeat size and different repeat motifs specifically, AAAGG, AAAGGG and other rare repeat motifs, atRFC1locus.Abstract FigureGraphical Abstract:Genetic heterogenicity atRFC1-TNR locus.
Transfer Learning Enhanced Graph Neural Network for Aldehyde Oxidase Metabolism Prediction and Its Experimental Application
Authors: Xiong Jiacheng , Cui Rongrong , Li Zhaojun , Zhang Wei , Zhang Runze , Fu Zunyun , Liu Xiaohong , Li Zhenghao , Chen Kaixian , Zheng Mingyue 
Published: June 2023

AbstractAldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available athttps://aomp.alphama.com.cn.
Soluble CTLA-4 raises the threshold for T-cell activation and modulates anti-tumour immunity
Authors: Kennedy Paul T. , Saulters Emma L. , Duckworth Andrew D. , Lim Yeong Jer , Woolley John F. , Slupsky Joseph R. , Cragg Mark S. , Ward Frank J. , Dahal Lekh N. 
Published: June 2023

AbstractCTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumour control. Antibodies targeting CTLA-4 have been promising treatment for numerous cancers, but the mechanistic basis of their anti-tumoral immune boosting effects are poorly understood. Although thectla4gene also encodes an alternatively-spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in murine cancer model. We show that expression of sCTLA-4 in tumour cells suppresses CD8+T-cellsin vitro, and accelerates growth and experimental metastasis of murine tumoursin vivo. These effects were accompanied by modification of the immune infiltrate, notably restraining CD8+T-cells in a non-effector state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoural CD8+T-cell activation and cytolytic potential, correlating with therapeutic efficacy and tumour control. This previously unappreciated role of sCTLA-4 suggests that better understanding of the biology and function of multi-gene products of immune checkpoint receptors needs to be fully elucidated for improved cancer immunotherapy.
Imaging the pharmacokinetics and therapeutic availability of the bispecific CD3xTRP1 antibody in syngeneic mouse tumor models
Authors: Sandker Gerwin G.W. , Middelburg Jim , Wilbrink Evienne , Molkenboer-Kuenen Janneke , Aarntzen Erik H.J.G. , van Hall Thorbald , Heskamp Sandra 
Published: June 2023

AbstractBackgroundCD3 bispecific antibodies (CD3-bsAbs) require binding of both a tumor-associated surface antigen and CD3 for their immunotherapeutic effect. Their efficacy is, therefore, influenced by the absolute tumor uptake and the extracellular dose. To optimize their currently limited efficacy in solid tumors, increased understanding of their pharmacokinetics andin vivointernalization is needed.MethodsHere were studied the pharmacokinetics andin vivointernalization of CD3xTRP1, a fully murine Fc-inert bsAb, in endogenous TRP1-expressing immunocompetent male C57BL/6J mice bearing TRP1-positive and negative tumors over time. Matching bsAbs lacking TRP1- or CD3-binding capacity served as controls. BsAbs were radiolabeled with111In to investigate their pharmacokinetics, target binding, and biodistribution through SPECT/CT imaging andex vivobiodistribution analyses. Co-injection of111In- and125I-labeled bsAb was performed to investigate thein vivointernalization by comparing tissue concentrations of cellular residing111In versus effluxing125I. Anti-tumor therapy effects were evaluated by monitoring tumor growth and immunohistochemistry.ResultsSPECT/CT and biodistribution analyses showed that CD3xTRP1 specifically targeted TRP1-positive tumors and CD3-rich lymphoid organ and uptake peaked 24 hours pi (KPC3-TRP1: 37.7±5.3 %ID/g, spleen: 29.0±3.9 %ID/g). Studies with control bsAbs demonstrated that uptake of CD3xTRP1 in TRP1-positive tumors and CD3-rich tissues was primarily receptor-mediated. Together with CD3xTRP1 in the circulation being mainly unattached, this indicates that CD3+T cells are generally not traffickers of CD3-bsAbs to the tumor. Additionally, “antigen-sink” effects by TRP1-expressing melanocytes were not observed. We further demonstrated rapid internalization of CD3xTRP1 in KPC3-TRP1 tumors (24h pi: 54.9±2.3% internalized) and CD3-rich tissues (spleen, 24h pi: 79.7±0.9% internalized). Therapeutic effects by CD3xTRP1 were observed for TRP1-positive tumors and consisted of high tumor influx of CD8+T cells and neutrophils, which corresponded with increased necrosis and growth delay.ConclusionsWe show that CD3xTRP1 efficiently targets TRP1-positive tumors and CD3-rich tissues primarily through receptor-mediated targeting. We further demonstrate rapid receptor-mediated internalization of CD3xTRP1 in TRP1-positive tumors and CD3-rich tissues. Even though this significantly decreases the therapeutical available dose, CD3xTRP1 still induced effective anti-tumor T-cell responses and inhibited tumor growth. Together, our data on the pharmacokinetics and mechanism of action of CD3xTRP1 pave the way for further optimization of CD3-bsAb therapies.Graphical abstractImaging the pharmacokinetics and therapeutic availability of the bispecific CD3xTRPl antibody in syngeneic mouse tumor models
Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy
Authors: Siricilla Shajila , Hansen Christopher J. , Rogers Jackson H. , De Debasmita , Simpson Carolyn L. , Waterson Alex G. , Sulikowski Gary A. , Crockett Stacey L. , Boatwright Naoko , Reese Jeff , Paria Bibhash C. , Newton J , Herington Jennifer L. 
Published: June 2023

AbstractCurrently, there is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and its analog mundulone acetate (MA) as inhibitors ofin vitrointracellular Ca2+-regulated myometrial contractility. In this study, we probed the tocolytic and therapeutic potential of these small molecules using myometrial cells and tissues obtained from patients receiving cesarean deliveries, as well as a mouse model of PL resulting in preterm birth. In a phenotypic assay, mundulone displayed greater efficacy in the inhibition of intracellular-Ca2+from myometrial cells; however, MA showed greater potency and uterine-selectivity, based IC50and Emaxvalues between myometrial cells compared to aorta vascular smooth muscle cells, a major maternal off-target site of current tocolytics. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted concentration-dependent inhibition ofex vivomyometrial contractions and that neither mundulone or MA affected vasoreactivity of ductus arteriosus, a major fetal off-target of current tocolytics. A high-throughput combination screen ofin vitrointracellular Ca2+-mobilization identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these synergistic combinations, mundulone + atosiban demonstrated a favorablein vitrotherapeutic index (TI)=10, a substantial improvement compared to TI=0.8 for mundulone alone. Theex vivoandin vivosynergism of mundulone and atosiban was substantiated, yielding greater tocolytic efficacy and potency on isolated mouse and human myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone 5hrs after mifepristone administration (and PL induction) dose-dependently delayed the timing of delivery. Importantly, mundulone in combination with atosiban (FR 3.7:1, 6.5mg/kg + 1.75mg/kg) permitted long-term management of PL after induction with 30 μg mifepristone, allowing 71% dams to deliver viable pups at term (> day 19, 4-5 days post-mifepristone exposure) without any visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the future development of mundulone as a stand-alone single- and/or combination-tocolytic therapy for management of PL.