Miracle-dz/UniFAR-FTUs huggingface dataset:
Choice of Mastectomy May Increase the Extent of Axillary Surgery in Women with Breast Cancer

Introduction Based on the ACOSOG Z0011 trial, women who undergo breast conservation therapy (BCT) and have limited disease in the axilla on sentinel lymph node (SLN) biopsy do not require axillary lymph node dissection (ALND). In this study we investigate the incidence of ALND in patients undergoing elective mastectomy with limited disease in the axilla to identify how many women may have been spared additional axillary surgery if they chose BCT. Methods All women with invasive breast cancer treated at a single tertiary care breast center from 2010-2018 who were candidates for BCT but elected mastectomy and underwent SLN biopsy were identified through retrospective review of a prospectively maintained database. The primary outcome of interest was the incidence of ALND in women found to have a limited burden of disease in the axilla (1-2 positive SLNs). Results The study population comprised 151 patients with invasive breast cancer eligible for BCT who chose mastectomy. On final pathology, 34 patients had 1-2 positive SLNs, and 16 of these patients underwent completion ALND. These 16 patients out of 151 overall lumpectomy candidates electing mastectomy (10.6%) could have been spared ALND if they did not elect mastectomy. Discussion BCT candidates electing mastectomy have a 10.6% chance of undergoing more extensive axillary surgery than would have been recommended with BCT alone. The increased risk of undergoing additional axillary surgery should be incorporated into the preoperative discussion for patients choosing between BCT and mastectomy.
Trained Integrated Postexercise Myofibrillar Protein Synthesis Rates Correlate with Hypertrophy in Young Males and Females

ABSTRACT Purpose Resistance training induces skeletal muscle hypertrophy via the summated effects of postexercise elevations in myofibrillar protein synthesis (MyoPS) that persist for up to 48 h, although research in females is currently lacking. MyoPS is regulated by mTOR translocation and colocalization; however, the effects of resistance training on these intracellular processes are unknown. We hypothesized that MyoPS would correlate with hypertrophy only after training in both sexes and would be associated with intracellular redistribution of mTOR. Methods Recreationally active males and females (n = 10 each) underwent 8 wk of whole-body resistance exercise three times a week. Fasted muscle biopsies were obtained immediately before (REST) and 24 and 48 h after acute resistance exercise in the untrained (UT) and trained (T) states to determine integrated MyoPS over 48 h (D2O ingestion) and intracellular mTOR colocalization (immunofluorescence microscopy). Results Training increased (P < 0.01) muscle strength (~20%–126%), muscle thickness (~8%–11%), and average fiber cross-sectional area (~15%–20%). MyoPS increased above REST in UT (P = 0.032) and T (P < 0.01), but to a greater extent in males (~23%; P = 0.023), and was positively (P < 0.01) associated with muscle thickness and fiber cross-sectional area at T only in both males and females. mTOR colocalization with the cell periphery increased (P < 0.01) in T, irrespective of sex or acute exercise. Training increased (P ≤ 0.043) total mTOR, LAMP2 (lysosomal marker), and their colocalization (P < 0.01), although their colocalization was greater in males at 24 and 48 h independent of training status (P < 0.01). Conclusions MyoPS during prolonged recovery from exercise is greater in males but related to muscle hypertrophy regardless of sex only in the trained state, which may be underpinned by altered mTOR localization.
The Relationship Between Temperature and Temporal Patterns and Incidence of Abusive Head Trauma in a Midwest Region Hospital

Background: Abusive head trauma (AHT) is a leading cause of death and disability in children and one of the most lethal forms of child abuse. Most known risk factors for AHT pertain to the infant’s caregiver and limited research has assessed external influences beyond the familial or caregiver/infant dyad. Objective: Our primary objective was to determine if temperature patterns are associated with AHT events. Secondary outcomes included associations between AHT and specific days of the week, months, or seasons. Methods: This was a retrospective review of 198 patients under 24 months old who were diagnosed with AHT at Saint Louis Children’s Hospital. Demographic information was obtained from the medical record for each patient. For each AHT incident, the date and zip code of the incident were recorded. Temperature on the date of incident was identified using the Midwestern Regional Climate Center (MRCC). Chi square tests were utilized to calculate differences in cases per year as well as temperature and seasonal variation. Results: Temperature was not associated with a statistically significant increase in cases of AHT. There was an increase in cases as temperatures rose, but no statistically significant associations between incidence of AHT and day of the week, month, or season. Conclusion: Our study suggests no significant association between AHT incidence and temperature or temporal patterns in this Midwest hospital.
New resources for the Drosophila 4th chromosome: FRT101F enabled mitotic clones and Bloom syndrome helicase enabled meiotic recombination

Abstract Genes on the long arm of the Drosophila melanogaster 4th chromosome are difficult to study because the chromosome lacks mitotic and meiotic recombination. Without recombination numerous standard methods of genetic analysis are impossible. Here, we report new resources for the 4th. For mitotic recombination, we generated a chromosome with an FRT very near the centromere in 101F and a derivative that carries FRT101F with a distal ubiquitously expressed GAL80 transgene. This pair of chromosomes enables both unmarked and MARCM clones. For meiotic recombination, we demonstrate that a Bloom syndrome helicase and recombination defective double mutant genotype can create recombinant 4th chromosomes via female meiosis. All strains will be available to the community via the Bloomington Drosophila Stock Center. Additional resources for studies of the 4th are in preparation and will also be made available. The goal of the 4th Chromosome Resource Project is to accelerate the genetic analysis of protein-coding genes on the 4th, including the 44 genes with no demonstrated function. Studies of these previously inaccessible but largely conserved genes will close longstanding gaps in our knowledge of metazoan development and physiology.
Childhood focal compressive mononeuropathies during the COVID‐19 pandemic in Buenos Aires, Argentina

Focal peripheral neuropathies are infrequently seen in pediatric patients. The COVID‐19 pandemic has disrupted normal life for many people, including complete lockdowns and school closing for long periods of time in many countries, which prompted children to stay at home. Our aim is to assess whether there has been an increased incidence of focal compressive peripheral neuropathies in the pediatric population during COVID‐19–associated lockdown.
Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9

Cytochrome P450 2C9 (CYP2C9) is a major drug-metabolizing enzyme that represents 20% of the hepatic CYPs and is responsible for the metabolism of 15% of drugs. A general concern in drug discovery is to avoid the inhibition of CYP leading to toxic drug accumulation and adverse drug–drug interactions. However, the prediction of CYP inhibition remains challenging due to its complexity. We developed an original machine learning approach for the prediction of drug-like molecules inhibiting CYP2C9. We created new predictive models by integrating CYP2C9 protein structure and dynamics knowledge, an original selection of physicochemical properties of CYP2C9 inhibitors, and machine learning modeling. We tested the machine learning models on publicly available data and demonstrated that our models successfully predicted CYP2C9 inhibitors with an accuracy, sensitivity and specificity of approximately 80%. We experimentally validated the developed approach and provided the first identification of the drugs vatalanib, piriqualone, ticagrelor and cloperidone as strong inhibitors of CYP2C9 with IC values <18 μM and sertindole, asapiprant, duvelisib and dasatinib as moderate inhibitors with IC50 values between 40 and 85 μM. Vatalanib was identified as the strongest inhibitor with an IC50 value of 0.067 μM. Metabolism assays allowed the characterization of specific metabolites of abemaciclib, cloperidone, vatalanib and tarafenacin produced by CYP2C9. The obtained results demonstrate that such a strategy could improve the prediction of drug-drug interactions in clinical practice and could be utilized to prioritize drug candidates in drug discovery pipelines.
JRC Summer School on Non-animal Approaches in Science, May 2021

“The JRC Summer School on Non-animal Approaches in Science — a flair of holidays and fun. Learning and socialising, intellectual challenge and playful competition. ” That was our tempting vision, back in 2016, for installing such a training course at EURL ECVAM — and we decided to go for it. We already had some experience in this respect, as every year students from the Karolinska Toxicology Master course programme visited the EURL ECVAM laboratories to learn more about non-animal methods and regulatory toxicology, and to have a closer look on the life in an international research centre such as the Joint Research Centre (JRC). Our aim was to share knowledge and experience on the latest non-animal approaches in science with young scientists and professionals, to give them new insights and to enable networking and exchange among all participants — students as well as invited experts and ourselves at the JRC.We wanted the experience to be as interactive as possible for the students, hopefully eliciting input from every participant. With the approval of our hierarchy, a rather small group of brave people started to tackle the preparatory work for the inaugural summer school, which turned out to be quite extensive. Besides the elaboration of the programme itself, there was also a broad range of logistical challenges. Increasingly more people became involved, beyond the staff of our unit — for example, technical, catering, cleaning, transport and security services were all required. Many people had to be transported around (local public transport is, to put it mildly, suboptimal), accommodated and fed. In order to reach as many students as possible to inform them about the event, a range of different communication channels were explored. To limit the participation to our targeted audience, i.e. students or early-career scientists (maximum of four years post-masters or PhD) in relevant fields, and to ensure a good level of existing scientific education, we asked for a motivation letter, a CVand a poster abstract to be submitted along with the application. Based on these pre-defined criteria, these documents were used for the selection of participants.
Severely impaired CTL killing is a feature of the neurological disorder Niemann-Pick Syndrome type C1.

Niemann-Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder resulting from mutations in an endo-lysosomal cholesterol transporter, NPC1. Despite typically presenting with pronounced neurological manifestations, NP-C1 also resembles long-term congenital immunodeficiencies that arise due to impairment of cytotoxic T lymphocyte (CTL) effector function. CTLs kill their targets through exocytosis of the contents of lysosome-like secretory cytotoxic granules (CGs) that store, and ultimately release the essential pore-forming protein perforin and pro-apoptotic serine proteases, granzymes, into the synapse formed between the CTL and a target cell. We have discovered that NPC1 deficiency increases CG lipid burden, impairs autophagic flux due to stalled trafficking of the transcription factor EB (TFEB), and dramatically reduces CTL cytotoxicity. Using a variety of immunological and cell biology techniques, we show that the cytotoxic defect arises specifically due to impaired perforin pore-formation. We demonstrated defects of CTL function of varying severity in NP-C1 patients, with the greatest loss of function associated with the most florid and/or earliest disease presentations. Remarkably, perforin function and CTL cytotoxicity were restored in vitro by promoting lipid clearance with therapeutic 2-hydroxypropyl-b-cyclodextrin (HPbCD), whereas restoring autophagy through TFEB over-expression was ineffective. Overall, our study revealed that NPC1 deficiency has a deleterious impact on CTL (but not natural killer cell) cytotoxicity that, in the long term, may predispose NP-C1 patients to atypical infections and impaired immune surveillance more generally.
A Learning Experience? Enjoyment at Sexual Debut and the Gender Gap in Sexual Desire among Emerging Adults

ABSTRACT Gender differences in experience of first intercourse are among the largest in sexuality research, with women recalling less pleasure and satisfaction than men. This “enjoyment gap” has not been considered in explanations of gender differences in sexual desire. Yet, reinforcement and incentive learning feature prominently in recent models of women’s sexual desire, and nonhuman animal models demonstrate their impact at sexual debut. We examined whether women’s lower sexual desire is explained by their gender or by gendered experience of enjoyment at sexual debut. Emerging adults (N = 838) provided retrospective accounts of physical (orgasm) and affective (satisfaction) enjoyment at (hetero)sexual debut. We replicated gender differences across behavioral, general, and multidimensional measures of trait sexual desire; however, they were contingent on experience and measurement method. When its cognitive multidimensional properties were appreciated, women’s sexual desire varied with experience of orgasm at sexual debut and diverged from men’s only when orgasm did not occur. Such effects were not observed for satisfaction, nor for men. Nor did effects of a control event – masturbatory debut – extend beyond solitary sexual desire. Findings underscore the importance of orgasm equality, and suggest its absence at sexual debut may play an unacknowledged role in differentiating sexual desire.
Genome diversity of domesticated Acinetobacter baumannii ATCC 19606T strains

Acinetobacter baumannii has emerged as an important opportunistic pathogen worldwide, being responsible for large outbreaks for nosocomial infections, primarily in intensive care units. A. baumannii ATCC 19606T is the species type strain, and a reference organism in many laboratories due to its low virulence, amenability to genetic manipulation and extensive antibiotic susceptibility. We wondered if frequent propagation of A. baumannii ATCC 19606T in different laboratories may have driven micro- and macro-evolutionary events that could determine inter-laboratory differences of genome-based data. By combining Illumina MiSeq, MinION and Sanger technologies, we generated a high-quality whole-genome sequence of A. baumannii ATCC 19606T, then performed a comparative genome analysis between A. baumannii ATCC 19606T strains from several research laboratories and a reference collection. Differences between publicly available ATCC 19606T genome sequences were observed, including SNPs, macro- and micro-deletions, and the uneven presence of a 52 kb prophage belonging to genus Vieuvirus. Two plasmids, pMAC and p1ATCC19606, were invariably detected in all tested strains. The presence of a putative replicase, a replication origin containing four 22-mer direct repeats, and a toxin-antitoxin system implicated in plasmid stability were predicted by in silico analysis of p1ATCC19606, and experimentally confirmed. This work refines the sequence, structure and functional annotation of the A. baumannii ATCC 19606T genome, and highlights some remarkable differences between domesticated strains, likely resulting from genetic drift.
Endovascular treatment with versus without tirofiban for stroke patients with large vessel occlusion: The multicenter, randomized, placebo-controlled, double-blind RESCUE BT study protocol

Background: Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, has been shown to reduce the risk of thrombotic complications during percutaneous coronary intervention. However, it remains unknown whether tirofiban improves outcomes in large vessel occlusion stroke patients undergoing endovascular treatment. Objective: This trial aims to assess whether additional intravenous tirofiban therapy can improve the clinical outcomes in large vessel occlusion stroke patients who undergo endovascular treatment within 24 h of symptom onset. Methods and design: The Endovascular Treatment With versus Without Tirofiban for Stroke Patients With Large Vessel Occlusion (RESCUE BT) Trial is an investigator-initiated, randomized, placebo-controlled, double-blind, multicenter trial. Up to 930 eligible patients will be consecutively randomized to intravenous tirofiban or placebo in 1:1 ratio over 3 years across 50 endovascular-capable stroke centers in China. Outcomes: The primary end point is the disability level as measured by overall distribution of the 90-day modified Rankin Scale scores. Primary safety end points include symptomatic intracerebral hemorrhage at 48 h and mortality at 90 days. Trial registry number: ChiCTR-INR-17014167 (www.chictr.org.cn).
Humoral immune response of patients infected by earlier lineages of SARS-CoV-2 neutralizes wild types of the most prevalent variants in Brazil

In the present study, serum samples of 20 hospitalized COVID-19 patients from Brazil who were infected by the earlier SARS-CoV-2 lineages B.1. 1.28 and B.1. 1.33, and by the variant of concern (VOC) Gamma (P.1) were tested by plaque reduction neutralization test (PRNT90) with wild isolates of a panel of SARS-CoV-2 lineages, including B.1, Zeta, N.10, and the VOCs Gamma, Alpha, and Delta that emerged in different timeframes of the pandemic. The main objectives of the present study were to evaluate if serum of COVID-19 patients infected by earlier lineages of SARS-CoV-2 were capable to neutralize recently emerged VOCs, and if PRNT90 is a reliable serologic method to distinguish infections caused by different SARS-CoV-2 lineages. Overall, sera collected from the day of admittance to the hospital to 21 days after diagnostic of patients infected by the two earlier lineages B.1. 1.28 and B.1. 1.33 presented neutralizing capacity for all challenged VOCs, including Gamma and Delta, that were the most prevalent VOCs in Brazil. Among all variants tested, Delta and N.10 presented the lowest mean of neutralizing antibody titers, and B.1. 1.7, presented the highest titers. Four patients infected with Gamma, that emerged in December 2020, presented neutralizing antibodies for B.1, B.1. 1.33 and B.1. 1.28, its ancestor lineage. All of them had neutralizing antibodies under the level of detection for the VOC Delta. Interestingly, patients infected by B.1. 1.28 presented very similar mean of neutralizing antibody titers for both B.1. 1.33 and B.1. 1.28. Findings presented here indicate that most patients infected in early stages of COVID-19 pandemic presented neutralizing antibodies up to 21 days after diagnostic capable to neutralize wild types of all recently emerged VOCs in Brazil, and that the PRNT90 it is not a reliable serologic method to distinguish natural infections caused by different SARS-CoV-2 lineages.
Stigma against mental health disorders in Nepal conceptualised with a ‘what matters most’ framework: a scoping review

Abstract Aims Stigma related to mental disorders is a barrier to quality mental healthcare. This scoping review aimed to synthesise literature on stigma related to mental disorders in Nepal to understand stigma processes. The anthropological concept of ‘what matters most’ to understand culture and stigma was used to frame the literature on explanatory models, manifestations, consequences, structural facilitators and mitigators, and interventions. Methods We conducted a scoping review with screening guided by the Preferred Reporting Items for Systematic Review and Meta-analysis Extension for Scoping Reviews (PRISMA-ScR). A structured search was done using three international databases (PsycINFO, Medline and Web of Science), one Nepali database (NepJol) and cross-referencing for publications from 1 January 2000 through 24 June 2020. The search was repeated to include structural stigma-related terms. Quality of quantitative studies was assessed using the Systematic Assessment of Quality in Observational Research (SAQOR) tool. The review was registered through the Open Science Framework (OSF) (osf.io/u8jhn). Results The searches yielded 57 studies over a 20-year period: 19 quantitative, 19 qualitative, nine mixed methods, five review articles, two ethnographies and three other types of studies. The review identified nine stigma measures used in Nepal, one stigma intervention, and no studies focused on adolescent and child mental health stigma. The findings suggest that ‘what matters most’ in Nepali culture for service users, caregivers, community members and health workers include prestige, productivity, privacy, acceptance, marriage and resources. Cultural values related to ‘what matters most’ are reflected in structural barriers and facilitators including lack of policies, programme planning and resources. Most studies using quantitative tools to assess stigma did not describe cultural adaptation or validation processes, and 15 out of the 18 quantitative studies were ‘low-quality’ on the SAQOR quality rating. The review revealed clear gaps in implementation and evaluation of stigma interventions in Nepal with only one intervention reported, and most stigma measures not culturally adapted for use. Conclusion As stigma processes are complex and interlinked in their influence on ‘what matters most’ and structural barriers and facilitators, more studies are required to understand this complexity and establish effective interventions targeting multiple domains. We suggest that stigma researchers should clarify conceptual models to inform study design and interpretations. There is a need to develop procedures for the systematic cultural adaptation of stigma assessment tools. Research should be conducted to understand the forms and drivers of structural stigma and to expand intervention research to evaluate strategies for stigma reduction.
Reversing and Fuzzing the Google Titan M Chip

Google recently introduced a secure chip called Titan M in its Pixel smartphones, enabling the implementation of a Trusted Execution Environment (TEE) in Tamper Resistant Hardware. TEEs have been proven effective in reducing the attack surface exposed by smartphones, by protecting specific security-sensitive operations. However, studies have shown that TEE code and execution can also be targeted and exploited by attackers, therefore, studying their security lays the basis of the trust we have in their features. In this paper, we provide the first security analysis of Titan M. First, we reverse engineer the firmware and we review the open source code in the Android OS that is responsible for the communication with the chip. By exploiting a known vulnerability, we then dynamically examine the memory layout and the internals of the chip. Finally, leveraging the acquired knowledge, we design and implement a structure-aware black-box fuzzer. Using our fuzzer, we rediscover several known vulnerabilities after a few seconds of testing, proving the effectiveness of our solution. In addition, we identify and report a new vulnerability in the latest version of the firmware.