bluuebunny/crossref_metadata_2025_split huggingface dataset:
fastDFE: Fast and Flexible Inference of the Distribution of Fitness Effects
Authors: Sendrowski Janek , Bataillon Thomas 
Published: April 2024

Abstract
Estimating the distribution of fitness effects (DFE) of new mutations is of fundamental importance in evolutionary biology, ecology, and conservation. However, existing methods for DFE estimation suffer from limitations, such as slow computation speed and limited scalability. To address these issues, we introduce fastDFE, a Python-based software package, offering fast, and flexible DFE inference from site-frequency spectrum (SFS) data. Apart from providing efficient joint inference of multiple DFEs that share parameters, it offers the feature of introducing genomic covariates that influence the DFEs and testing their significance. To further simplify usage, fastDFE is equipped with comprehensive VCF-to-SFS parsing utilities. These include options for site filtering and stratification, as well as site-degeneracy annotation and probabilistic ancestral-allele inference. fastDFE thereby covers the entire workflow of DFE inference from the moment of acquiring a raw VCF file. Despite its Python foundation, fastDFE incorporates a full R interface, including native R visualization capabilities. The package is comprehensively tested and documented at fastdfe.readthedocs.io.
Optimal Sequential Strategies for Antibody-Drug Conjugate in Metastatic Breast Cancer: Evaluating Efficacy and Cross-Resistance
Authors: Chen Meiting , Huang Riqing , Chen Rishang , Pan Fei , Shen Xiujiao , Li Haifeng , Rong Qixiang , An Xin , Xue Cong , Shi Yanxia 
Published: April 2024

Abstract

Background
The optimal sequential strategy for antibody-drug conjugates (ADCs) in breast cancer remains uncertain. This study aimed to evaluate the efficacy and potential resistance of second ADC (ADC2) following the first ADC (ADC1) in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low MBC.

Methods
This retrospective, multicenter, real-world study enrolled patients with MBC who received at least 2 different types of ADCs in 3 hospitals in China between July 1, 2017 and May 1, 2023. Outcomes included the objective response rate (ORR) for ADC1 and ADC2, progression free survival 2 (PFS2), defined as the time from initiation of ADC2 to progression, and overall survival (OS).

Results
Seventy-nine female patients were included, 64 of whom had HER2-positive disease. The ORR for ADC2 with similar payload of ADC1 was found to be 5.3%. When switching to a different payload, the ORR of ADC2 increased to 22.6%. The PFS2 for ADC2 remained similar regardless of whether the payload was similar or different. Switching to different payload showed a higher ORR in patients with rapid progression and a durable response longer than 6 months (41.2% vs 15.0%). Specifically, significantly longer PFS2 and OS were seen in patients treated with trastuzumab deruxtecan (T-Dxd) compared to those treated with disitamab vedotin (RC48) after progression from trastuzumab emtansine (T-DM1; median PFS2 5.37 months vs 3.30 months, HR = 0.40, 95% CI 0.17-0.93, P = .034; median OS 50.6 months vs 20.2 months, HR = 0.27, 95% CI 0.08-0.91, P = .034). For patients who progressed after T-Dxd, the median PFS2 was 6.05 months for those treated with RC48 versus 0.93 months for those treated with T-DM1 (HR = 0.03, 95% CI 0.002-0.353, P = .0093). Genomic analysis revealed that alternation of retinoblastoma1 was significantly associated with superior PFS.

Conclusion
The alternation of payload achieves different responses in different settings. T-Dxd followed by RC48 may be a potentially beneficial strategy in HER2-positive disease. Further research is needed to elucidate the mechanism of cross-resistance.
Perioperative pain optimization in the age of the opioid epidemic
Authors: Patel Janki , Snyder Kyle , Brooks Amber K. 
Published: April 2024

Purpose of review
The opioid epidemic remains a constant and increasing threat to our society with overdoses and overdose deaths rising significantly during the COVID-19 pandemic. Growing evidence suggests a link between perioperative opioid use, postoperative opioid prescribing, and the development of opioid use disorder (OUD). As a result, strategies to better optimize pain management during the perioperative period are urgently needed. The purpose of this review is to summarize the most recent multimodal analgesia (MMA) recommendations, summarize evidence for efficacy surrounding the increased utilization of Enhanced Recovery After Surgery (ERAS) protocols, and discuss the implications for rising use of buprenorphine for OUD patients who present for surgery. In addition, this review will explore opportunities to expand our treatment of complex patients via transitional pain services.

Recent findings
There is ample evidence to support the benefits of MMA. However, optimal drug combinations remain understudied, presenting a target area for future research. ERAS protocols provide a more systematic and targeted approach for implementing MMA. ERAS protocols also allow for a more comprehensive approach to perioperative pain management by necessitating the involvement of surgical specialists. Increasingly, OUD patients taking buprenorphine are presenting for surgery. Recent guidance from a multisociety OUD working group recommends that buprenorphine not be routinely discontinued or tapered perioperatively. Lastly, there is emerging evidence to justify the use of transitional pain services for more comprehensive treatment of complex patients, like those with chronic pain, preoperative opioid tolerance, or substance use disorder.

Summary
Perioperative physicians must be aware of the impact of the opioid epidemic and explore methods like MMA techniques, ERAS protocols, and transitional pain services to improve the perioperative pain experience and decrease the risks of opioid-related harm.
A Case of CD4+ T-Cell Lymphoma With Gamma–Delta Phenotype, Incidentally Manifesting in a Wound Debridement Sample
Authors: Adams Paige E. , Ehyayee Vida , Ahmed Aadil 
Published: April 2024

Abstract:
We report an 85-year-old male patient with a medical history significant for psoriasis who presented with a thigh wound that expanded slowly over the course of 9 months. The patient was previously treated with amputation of hand digits for osteomyelitis. Histologic examination of the tissue sample revealed a broad ulceration with large areas of necrosis extending into the subcutis. The edge of the specimen also revealed a nodular lymphoid infiltrate in the subcutaneous adipose tissue composed of atypical cells. These cells were only positive for CD3, CD4, and T-cell receptor (TCR) delta stains . The Ki-67 proliferation index of tumor cells was about 70%. The tumor cells were negative for CD30, CD8, CD56, TCR BF1, granzyme, TIA1, CD123, and Epstein-Barr encoding region (EBER)-ish stains. A diagnosis of gamma–delta T-cell lymphoma was made. Further imaging showed regional lymphadenopathy. The patient was started on mini-CHOP and filgrastim; however, the patient died within 1 month after the diagnosis. This is an interesting case of gamma–delta T-cell lymphoma that was incidentally diagnosed on a chronic wound. In addition, it showed a CD4+, CD8− phenotype that is exceedingly rare for T-cell lymphomas with gamma–delta phenotype.
Nail Telocytes: Identification, Potential Physiological Function, and Role in Pathology: A Reappraisal of the So-Called Onychofibroblasts/Onychodermis
Authors: Perrin Christophe 
Published: April 2024

Abstract:
Some authors have suggested that the fibroblasts of the nail mesenchyme (onychofibroblasts) can be distinguished from skin fibroblasts by their high expression of CD10. My 2015 study documented the presence of a relatively sparse CD34+/CD10+ dendritic subpopulation in the dermis and hypodermis of the matrix. For some time now, my hypothesis has been that these interstitial dendritic mesenchymal cells of the matrix correspond to telocytes. Telocytes have been described as peculiar interstitial dendritic cells present in the mesenchymal tissue of numerous organs, including the skin, but their presence and characteristics in the nail unit have not been explored. This study was undertaken to more comprehensively investigate the existence and characteristics of nail telocytes. A series of 20 normal adult nail units were examined with a combination of morphological and immunohistochemical analyses. The matrix dermis contained a sparse subpopulation of CD34+/CD10+ elongated telocytes with a higher density in the lunular region and, at this distal level, a change in their immunohistochemical profile, resulting in a progressive loss of CD34 expression. The matrix hypodermis showed CD34+/CD10+ telocytes in their classical elongated aspect, which acquired, especially in the distal fibromyxoid area of the thumb, an oval to round morphology with multiple intracytoplasmic vacuoles. The characteristic dynamic immunophenotypic profile of the dermal telocytes with a progressive distal loss of the defining molecule CD34 was equally observed in the distal hypodermis. The nail bed dermis was thick with a dense fibrous connective tissue. A reticular network of CD34−/CD10+ telocytes was present in the superficial dermis of the proximal nail bed. The mesenchymal cells of the deep part of the proximal nail bed dermis and the entire distal nail bed dermis were CD34−/CD10−. The adult nail mesenchyme is composed of 3 microanatomically distinct regions. Only the thumb has a distal hypodermis rich in mucinous material. The population of telocytes is relatively sparse compared with the fibroblastic population of the entire nail mesenchyme. The concept of onychodermis/onychofibroblasts is not valid. Nail telocytes have a dynamic immunohistochemical profile depending on whether they are located proximally or distally. The CD34+/CD10+ profile correlates with the onychogenic epithelial region, while the CD34−/CD10+ profile correlates with a spatial rearrangement of the nail epidermal bed.
Fosfomycin Susceptibility Among Multidrug-Resistant Extended-Spectrum β-Lactamase and Metallo-β-Lactamase–Producing Uropathogens in a Tertiary Care Hospital
Authors: Kothari Aditi , Chaturvedi Parul , Bhumbla Upasana 
Published: April 2024

Background
Urinary tract infections (UTIs) affect an estimated 150 million people each year worldwide involving women more than men. Because of unrestricted use of antimicrobials and accelerating antimicrobial resistance, therapeutic options for treatment of UTIs are becoming limited. Fosfomycin, a broad-spectrum, rapidly absorbable, antimicrobial agent with good bioavailability and substantial activity against multidrug-resistant (MDR) isolates has antimicrobial activity against a substantial percentage of these MDR isolates.

Methods
A cross-sectional study over a period of 20 months on urine samples of all patients of all age groups clinically suspected of UTI was conducted in a tertiary care center of southern Rajasthan. Samples were processed immediately as per standard microbiological techniques, followed by culture by a semiquantitative method and antimicrobial susceptibility testing using the Kirby-Bauer disk diffusion method. All gram-negative pathogens were screened for extended-spectrum β-lactamase and further metallo-β-lactamase production using standard disk diffusion tests.

Results
Of the 1858 positive samples isolated, the most common uropathogen was Escherichia coli (59.96%), with 8.97% confirmed extended-spectrum β-lactamase–producing isolates. Fosfomycin had susceptibility of 96.69%, with its sensitivity and specificity being 98.15% and 6.98% more than nitrofurantoin, respectively. Among the metallo-β-lactamase producers, fosfomycin had susceptibility of 78.58%, with sensitivity and specificity being 91.67% and 25% more than nitrofurantoin, respectively.

Conclusion
With an increasing threat due to MDR uropathogens in both hospitals and in the community, fosfomycin, with its unique mechanism of action, appears to be a better oral, effective, and safe therapeutic option and a viable potential alternative over other drugs for treatment of UTIs.
On the Difficulty Predicting Word Recognition Performance After Cochlear Implantation
Authors: Bartholomew Ryan A. , Hoffman Samantha E. , Juliano Amy F. , Wu Pei-zhe , Zhao Yan , de Gruttola Victor , Liberman M. Charles , Maison Stéphane F. 
Published: April 2024

Hypothesis
Preimplantation word scores cannot reliably predict postimplantation outcomes.

Background
To date, there is no model based on preoperative data that can reliably predict the postoperative outcomes of cochlear implantation in the postlingually deafened adult patient.

Methods
In a group of 228 patients who received a cochlear implant between 2002 and 2021, we tested the predictive power of nine variables (age, etiology, sex, laterality of implantation, preimplantation thresholds and word scores, as well as the design, insertion approach, and angular insertion depth of the electrode array) on postimplantation outcomes. Results of multivariable linear regression analyses were then interpreted in light of data obtained from histopathological analyses of human temporal bones.

Results
Age and etiology were the only significant predictors of postimplantation outcomes. In agreement with many investigations, preimplantation word scores failed to significantly predict postimplantation outcomes. Analysis of temporal bone histopathology suggests that neuronal survival must fall below 40% before word scores in quiet begin to drop. Scores fall steeply with further neurodegeneration, such that only 20% survival can support acoustically driven word scores of 50%. Because almost all cochlear implant implantees have at least 20% of their spiral ganglion neurons (SGNs) surviving, it is expected that most cochlear implant users on average should improve to at least 50% word recognition score, as we observed, even if their preimplantation score was near zero as a result of widespread hair cell damage and the fact that ~50% of their SGNs have likely lost their peripheral axons. These “disconnected” SGNs would not contribute to acoustic hearing but likely remain electrically excitable.

Conclusion
The relationship between preimplantation word scores and data describing the survival of SGNs in humans can explain why preimplantation word scores obtained in unaided conditions fail to predict postimplantation outcomes.
Temporal Swelling Following Cochlear Implantation: Frequency, Treatment, and Outcomes
Authors: Kasuga Mariko , Yoshimura Hidekane , Takumi Yutaka 
Published: April 2024

Objective
To investigate the frequency, treatment, and outcomes of postoperative delayed-onset swelling around cochlear implants.

Study Design
Retrospective, observational, nonrandomized group study.

Setting
Academic medical center.

Patients/Interventions
Among 354 patients (516 ears) who underwent cochlear implantation (CI) at our hospital between May 2009 and October 2022, 329 (472 ears: 138 children [246 ears] and 191 adults [226 ears]) with a follow-up period of >3 months were included.

Main Outcome Measures
Physical examination and computed tomography of the head were performed.

Results
In total, 5.5% (26/472 ears) had a history of delayed-onset swelling around the implant. This complication occurred in 9.8% (24/246 ears) of children and 0.9% (2/226 ears) of adults. The mean time to onset of swelling was 50 (range, 5.5–147) months following CI. In 60% (21/35) of the cases, the cause was unknown, whereas in 25.7% (9/35) and 11.5% (4/35) of cases, it was head trauma and acute inflammation, respectively. Conservative treatment (observation, antibiotics, and/or strong magnetic compression) was adapted in 91.4% (32/35) of cases. After conservative treatment, revision CI surgery was performed in one ear. Additionally, recurrent swelling was observed in 23.1% (6/26 ears) of swelling cases.

Conclusions
The results suggest that delayed-onset swelling around implants occurs more frequently in children than in adults because of the higher incidence rates of head trauma and acute otitis media in children. In most cases, conservative treatment was adequate; however, careful follow-up is necessary. Our findings can serve as a reference for optimizing care and intervention options after CI.
FDG PET/CT in the Diagnosis and After Sunitinib Follow-up of Synchronous Base of Tongue and Thyroid Metastases From Renal Cell Carcinoma
Authors: Kumar Srinivas Ananth , Mittal Bhagwant Rai , Kumar Suraj , Singh Harmandeep , Kumar Rajender , Bal Amanjit 
Published: April 2024

Abstract
Renal cell carcinoma (RCC) is a leading cause of mortality among genitourinary malignancies with limited therapeutic options. The hematogenous route, lymphatic spread, and direct invasion have been documented in RCC. Usually, metastases are regional lymph nodes, lungs, bone, liver, adrenal glands, contralateral kidney, and brain. Metastases to the rare sites such as skin, breast, head and neck were documented in the literature. In the present case, we describe the synchronous metastases to the base of the tongue and thyroid gland in RCC and the response to sunitinib therapy on 18F-FDG PET/CT.
Bacterial etiologies, antimicrobial susceptibility profiles and associated factors among patients with otitis media referred to Nekemte Public Health Research and Referral Laboratory Center, Western Ethiopia: A prospective cross-sectional study
Authors: Guteta Endalu Tesfaye , Abdi Fedassan Alemu , Feyisa Seifu Gizaw , Zewudie Belay Merkeb , Kinfu Betrearon Sileshi , Geleta Hunduma Feyisa , Tafesse Tadesse Bekele 
Published: April 2024

AbstractBackgroundOtitis media is among the leading causes of illnesses responsible for causing hearing problems and adding significant costs to the public health system. Bacteria are the most common causative agents for otitis media. Currently, there is little information on the prevalence and antimicrobial susceptibility patterns of pathogenic bacterial isolates from patients with otitis media in Ethiopia.MethodologyA laboratory – based cross-sectional study was conducted from June to September 2023 among 242 patients with otitis media referred to Nekemte Public Health Research and Referral Laboratory Center. Sociodemographic and clinical data were obtained by trained nurses and/or health officers in face-to-face interviews using structured questionnaires. Middle ear discharge samples were collected by trained clinical microbiology experts following all aseptic techniques. Conventional culture, different biochemical tests and antimicrobial susceptibility testing were performed for all the isolated bacteria. Reference strains were used as a positive and negative controls. The data were checked for completeness and consistency, entered into EpiData version 4.6.06 and analyzed by SPSS version 25. Logistic regression analysis was performed to determine the associated factors of otitis media. Adjusted odds ratio was used to determine strength of association. Statistical significance was obtained at p-value of below 0.05. The data were interpreted using graphs, tables, and results statements.ResultsA total of 242 middle ear discharge samples were collected and cultured from which 212 (87.6%) were culture positive. A total of 228 pathogenic bacterial isolates were recovered. The predominant bacterial isolates wereS. aureus92 (40.4%) followed byP. aeruginosa33 (14.5%) andE. coli24 (10.5%). One hundred fifty-one (66.2%) bacterial pathogens were multidrug resistant. Piperacillin-tazobactam and tobramycin are relatively common drugs to which most of the isolates were susceptible while ampicillin and tetracycline were the most resistant. Purulent discharge (p-value = 0.001), middle ear discharge ≥14 days (P-value = 0.000) and a history of active/passive smoking (P-value = 0.043) were significantly associated with otitis media.ConclusionThe prevalence of bacterial pathogens, most of which were multidrug-resistant, was high among patients with otitis media. A significant association was observed with purulent ear discharge, chronic otitis media, and passive or active smoking. Choosing the proper antibiotic for the treatment of bacterial infection is crucial.
Cryo-EM Structures Reveal Tau Filaments from Down Syndrome Adopt Alzheimer’s Disease Fold
Authors: Ghosh Ujjayini , Tse Eric , Yang Hyunjun , Shi Marie , Caro Christoffer D. , Wang Feng , Merz Gregory E. , Prusiner Stanley B. , Southworth Daniel R. , Condello Carlo 
Published: April 2024

ABSTRACTDown syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer’s disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36 to 63 years of age by spectral confocal imaging with conformation-specific dyes and cryo–electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of twoC-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II–like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.