Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparative pharmacokinetics of valproic acid among Pakistani and South Korean patients: A population pharmacokinetic study

Purpose The pharmacokinetics of valproic acid have been evaluated in a variety of populations however, the comparison in two different populations was yet to be reported. This study is aimed to compare the pharmacokinetics of valproic acid in Pakistani and South Korean patients. Method The therapeutic drug monitoring (TDM) data of valproic acid from 92 Pakistani patients with 218 samples was combined with the data of 99 South Korean patients with 335 samples in order to form a pooled dataset of 191 patients with 553 samples. Population pharmacokinetic model was developed on NONMEM® software by using first order conditional estimation method for estimation of pharmacokinetic parameters. The influence of different covariates including ethnicity was evaluated the stepwise covariate modelling. The final model was evaluated for predictive performance and robustness by using goodness of fit plots and bootstrap analysis respectively. Results The data was better described by one compartment model with first order elimination. The value for clearance (CL) of valproic in pooled data was 0.931 L/h with 43.4% interindividual variability (IIV) while volume of distribution (Vd) was 16.6 L with 22.3% IIV. In covariate analysis, ethnicity and body weight were significant covariates for CL while body weight was also significant for Vd. Conclusion A significant difference in CL of valproic acid among Pakistani and South Korean patients was observed. The model can be used for the dose tailoring of valproic acid based on ethnicity and body weight of Pakistani and South Korean patients.
Clinical characteristics and outcomes of patients with COVID‐19 and psoriasis

To summarize the clinical characteristics and explore the role of treatment types in outcomes among psoriasis patients with coronavirus disease 2019 (COVID‐19). The principal summary measures were pooled prevalence and risk ratio (RR) with 95% confidential interval (CI). R statistic software was used for all the analysis. A total of 19 studies including 4073 psoriasis patients with COVID‐19 were eligible for the meta‐analysis. The overall hospitalization rate is about 20.2% (95% CI: 12.7%–28.7%), and changed to be 18.0% (95% CI: 9.9%–27.6%) or 14.1% (95% CI: 5.9%–24.6%) after systemic or biologic treatment. Moreover, the overall fatality rate is 1.5% (95% CI: 0.4%–3.0%), and turned to be 0.7% (95% CI: 0%–2.0%) or 0.5% (95% CI: 0%–2.2%) after systemic or biologic therapy. Notably, a lower hospitalization RR was found in patients receiving biologic therapy than those receiving other treatments (RR = 0.62, 95% CI: 0.42–0.94). The results were consistent after sensitivity analysis and trim‐and‐fill analysis. Systemic, especially biologic therapy could lessen the clinical severity in psoriasis patients with COVID‐19. Our finding will help to guide current recommendations and provide a reference for clinical decision‐making.
Structural insights into thermostable direct hemolysin of Vibrio parahaemolyticus using single‐particle cryo‐EM

Thermostable direct hemolysin (TDH) is a ~19 kDa, hemolytic pore‐forming toxin from the gram‐negative marine bacterium Vibrio parahaemolyticus, one of the causative agents of seafood‐borne acute gastroenteritis and septicemia. Previous studies have established that TDH exists as a tetrameric assembly in physiological state; however, there is limited knowledge regarding the molecular arrangement of its disordered N‐terminal region (NTR)—the absence of which has been shown to compromise TDH's hemolytic and cytotoxic abilities. In our current study, we have employed single‐particle cryo‐electron microscopy to resolve the solution‐state structures of wild‐type TDH and a TDH construct with deletion of the NTR (NTD), in order to investigate structural aspects of NTR on the overall tetrameric architecture. We observed that both TDH and NTD electron density maps, resolved at global resolutions of 4.5 and 4.2 Å, respectively, showed good correlation in their respective oligomeric architecture. Additionally, we were able to locate extra densities near the pore opening of TDH which might correspond to the disordered NTR. Surprisingly, under cryogenic conditions, we were also able to observe novel supramolecular assemblies of TDH tetramers, which we were able to resolve to 4.3 Å. We further investigated the tetrameric and inter‐tetrameric interaction interfaces to elaborate upon the key residues involved in both TDH tetramers and TDH super assemblies. Our current structural study will aid in understanding the mechanistic aspects of this pore‐forming toxin and the role of its disordered NTR in membrane interaction.
Molecular prevalence and zoonotic potential of trichomonads from oral cavities in household dogs

This study investigated the molecular prevalence of oral trichomonads in household dogs. Of the 144 dogs, 21 (14.6%, 21/144) tested positive for oral trichomonads. The prevalence was significantly higher in dogs with severe gingivitis (gingival index 3: 30.0%, 8/26) than that in normal dogs (gingival index 0: 2.7%, 1/37). Therefore, an interaction between oral trichomonads and the development of periodontal disease is suggested. Of the 21 positive samples, 16 isolates were T. brixi, four isolates were T. tenax, and one was Tetratrichomonas sp. Considering T. tenax is recognized as a zoonotic agent, transmission between dogs and humans cannot be neglected.
Treatment outcomes in Polish COVID-19 patients requiring hospitalisation in the intensive care unit: a single-centre retrospective study

Background COVID-19 has disturbed the functioning of Polish healthcare for the past two years. Due to the high proportion of patients requiring admission to the intensive care unit (ICU), these wards are particularly overwhelmed and are considered the bottleneck of the healthcare system. The aim of this study was to describe clinical outcomes of critically ill patients treated in a single tertiary ICU in Poland, assess factors associated with mortality and compare outcomes of patients treated during the 2nd and 3rd waves of the pandemic. Methods This is a retrospective single-centre study including patients admitted to the ICU between October 2020 and May 2021 (the 3rd wave) with confirmed SARS-CoV-2 infection. Patients were followed up until death or 90 days after ICU admission. The co-primary endpoints of this study included ICU, 30-day and 90-day mortality. Results We enrolled 108 patients at a mean age of 64.3 (SD = 12) years, the majority of whom were male (63.9%). Mortality in the ICU, after 30 days and 90 days was 44.4% (48/108), 50.0% (54/108), and 57.9% (62/108), respectively. Mortality at 90 days was associated with increasing age (OR = 3.97, 95% CI: 1.87–8.41) and was significantly higher during the 2nd wave (65.6 vs. 46.5%, log-rank P = 0.043) compared to the 3rd wave of the pandemic. Conclusions This retrospective single-centre study confirms the high mortality rate among critically ill patients with COVID-19. Moreover, it suggests a significant association between 90-day mortality and increasing age as well as differences in mortality between the 2nd and 3rd waves of the pandemic in Poland.
Sexual dysfunction in the third trimester of pregnancy and postpartum period: a prospective longitudinal study

Abstract The purpose of this prospective longitudinal study was to determine the prevalence of sexual dysfunction (SD) in women in the third trimester of pregnancy and at 8 week and 6 months in the postpartum period, as well as to identify the factors affecting sexual function in the postpartum period. 110 pregnant women were included in the study. The results showed significant differences in the scores between pregnancy and 6 months after delivery and between 8 weeks and 6 months after delivery. The scores in desire, sexual arousal, lubrication, orgasm, and satisfaction subdimensions were significantly higher and the score in pain subdimension was significantly lower at 6 months than during pregnancy and at eight weeks after delivery. Sexual dysfunction is a common problem in women in the last trimester of pregnancy and at eight weeks after delivery. However, this problem substantially resolves at postpartum 6 months. IMPACT STATEMENT What is already known on this subject? Physiological, psychological, and hormonal changes, especially during pregnancy and postpartum period, have a considerable impact on sexual function. Therefore, identifying various aspects of sexual problems during pregnancy and postpartum period and improving the body of knowledge about sexual function would contribute to the health of women and couples. What the results of this study add? Sexual dysfunction is a common problem in women in the last trimester of pregnancy and at 8 weeks after delivery. However, this problem substantially resolves at postpartum 6 months. What the implications are of these findings for clinical practice and/or further research? A striking finding in the study is the increase of SD risk in the sixth month of postpartum with women’s starting to work. This problem, which has been addressed sparsely in the current literature, can be considered a condition requiring an in-depth research.
A phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia

A phase 1b/2, three‐month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300‐mg loading dose with subsequent 150‐mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment‐emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on‐demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose‐related manner, with steady‐state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment‐related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).
Association of Upper Gastrointestinal Surgery of Great Britain and Ireland (AUGIS)/Perioperative Quality Initiative (POQI) consensus statement on intraoperative and postoperative interventions to reduce pulmonary complications after oesophagectomy

Abstract Background Pulmonary complications are the most common morbidity after oesophagectomy, contributing to mortality and prolonged postoperative recovery, and have a negative impact on health-related quality of life. A variety of single or bundled interventions in the perioperative setting have been developed to reduce the incidence of pulmonary complications. Significant variation in practice exists across the UK. The aim of this modified Delphi consensus was to deliver clear evidence-based consensus recommendations regarding intraoperative and postoperative care that may reduce pulmonary complications after oesophagectomy. Methods With input from a multidisciplinary group of 23 experts in the perioperative management of patients undergoing surgery for oesophageal cancer, a modified Delphi method was employed. Following an initial systematic review of relevant literature, a range of anaesthetic, surgical, and postoperative care interventions were identified. These were then discussed during a two-part virtual conference. Recommendation statements were drafted, refined, and agreed by all attendees. The level of evidence supporting each statement was considered. Results Consensus was reached on 12 statements on topics including operative approach, pyloric drainage strategies, intraoperative fluid and ventilation strategies, perioperative analgesia, postoperative feeding plans, and physiotherapy interventions. Seven additional questions concerning the perioperative management of patients undergoing oesophagectomy were highlighted to guide future research. Conclusion Clear consensus recommendations regarding intraoperative and postoperative interventions that may reduce pulmonary complications after oesophagectomy are presented.
Gauge Theory and the Geometric Langlands Program

The Langlands program of number theory, or what we might call Langlands duality, was proposed in more or less its present form by Robert Langlands, in the late 1960s. It is a kind of unified scheme for many results in number theory ranging from quadratic reciprocity, which is hundreds of years old, to modern results such as Andrew Wiles’ proof of Fermat’s last theorem, which involved a sort of special case of the Langlands program. For today, however, I will not assume any prior knowledge of the Langlands program.
Conducting caregiver focus groups on autism in the context of an international research collaboration: Logistical and methodological lessons learned in South Africa

Most autism research has been conducted in high-income countries, with participants typically from White, upper-middle-income families. Given the disparities experienced by autistic individuals living in underserved communities globally, there is a critical need for research to include individuals from culturally, linguistically, socioeconomically, and geographically diverse backgrounds to understand their unique needs. Qualitative research has the potential to describe the “lived experience” of families historically underrepresented in the autism literature. Here we describe the logistical and methodological challenges of conducting focus group discussions with 22 caregivers of young autistic children living in Cape Town, South Africa. Logistical challenges included (1) recruitment, (2) response rate, and (3) resource access. Methodological challenges included (1) participant background and experiences, (2) interpersonal dynamics, and (3) research ethics. We present recommendations based on lessons learned to reduce these challenges and improve rigorous qualitative research practices in similar low-resource contexts. Lay abstract Most of the autism research to date has been conducted in high-income countries, with children and families typically from White, upper-middle-income backgrounds. However, we know there are significant inequalities that exist which influence how autistic individuals from diverse, underserved communities can access services they need. As many of these individuals have not been included in the majority of autism research to date, there is much we do not know about these individuals’ life experiences, which are critically needed to better inform the development and implementation of care for families from historically underrepresented groups. In this article, we describe the research process we took to conduct focus group discussions with 22 caregivers of young autistic children living in Cape Town, South Africa. We specifically describe the lessons we learned in implementing these focus groups and provide recommendations aimed at how to best reduce logistical and methodological challenges moving forward to improve research conducted in similar low-resource contexts.
Incidence of Stroke in Randomized Trials of COVID-19 Therapeutics: A Systematic Review and Meta-Analysis

Background: COVID-19 has been frequently associated with an increased risk of thrombotic complications. There have also been reports of an increased likelihood of stroke, although its true incidence in patients with COVID-19 is currently unknown. Methods: Electronic databases PubMed and Scopus were searched from inception up to July 30, 2021 to identify randomized controlled studies in patients with confirmed COVID-19 undergoing one or more interventions. Studies were screened for eligibility using a predefined inclusion criterion and selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A random-effects model meta-analysis was conducted, and heterogeneity was assessed using I-squared test. Results: Out of 3960 potentially eligible articles, 77 randomized studies (38 732 patients) were included. Mean age of the study population was 55±9.3 years. Females constituted 38% of the study population and mean duration of follow-up after study enrollment was 23±12.9 days. Cumulative incidence of stroke in the overall study population was 0.001 (95% CI, 0.001–0.002) with a total of 65 events in 38 732 patients, corresponding to an absolute incidence of 0.168%. Incidence of stroke in the inpatient population was 0.001 (95% CI, 0.001–0.002; 65 events in 37 069 patients), corresponding to an absolute incidence of 0.175%. No strokes were observed in the outpatient setting. Conclusions: The overall incidence of stroke in patients with COVID-19 appears to be lower than that reported in previous observational reports.
Offset Responses in the Auditory Cortex Show Unique History Dependence

Sensory responses typically vary depending on the recent history of sensory experience. This is essential for processes, including adaptation, efficient coding, and change detection. In the auditory cortex (AC), the short-term history dependence of sound-evoked (onset) responses has been well characterized. Yet many AC neurons also respond to sound terminations, and little is known about the history dependence of these “offset” responses, whether the short-term dynamics of onset and offset responses are correlated, or how these properties are distributed among cell types. Here we presented awake male and female mice with repeating noise burst stimuli while recording single-unit activity from primary AC. We identified parvalbumin and somatostatin interneurons through optotagging, and also separated narrow-spiking from broad-spiking units. We found that offset responses are typically less depressive than onset responses, and this result was robust to a variety of stimulus parameters, controls, measurement types, and selection criteria. Whether a cell's onset response facilitates or depresses does not predict whether its offset response facilitates or depresses. Cell types differed in the dynamics of their onset responses, and in the prevalence, but not the dynamics, of their offset responses. Finally, we clustered cells according to spiking responses and found that response clusters were associated with cell type. Each cluster contained cells of several types, but even within a cluster, cells often showed cell type-specific response dynamics. We conclude that onset and offset responses are differentially influenced by recent sound history, and discuss the implications of this for the encoding of ongoing sound stimuli. SIGNIFICANCE STATEMENT Sensory neuron responses depend on stimulus history. This history dependence is crucial for sensory processing, is precisely controlled at individual synapses and circuits, and is adaptive to the specific requirements of different sensory systems. In the auditory cortex, neurons respond to sound cessation as well as to sound itself, but how history dependence is used along this separate, “offset” information stream is unknown. We show that offset responses are more facilitatory than sound responses, even in neurons where sound responses depress. In contrast to sound onset responses, offset responses are absent in many cells, are relatively homogeneous, and show no cell type-specific differences in history dependence. Offset responses thus show unique response dynamics, suggesting their unique functions.
Defining compassion: A Delphi study of compassion therapists’ experiences when introducing patients to the term ‘compassion’

Abstract Objectives Compassion‐focused therapy (CFT) is shown to be an effective psychological intervention; however, patients can experience resistance to CFT due to preconceptions regarding the term ‘compassion’. This study aims to obtain guidance from therapists in how to overcome these resistances Design This is the first study using the Delphi methodology to ask CFT therapists about how their patients understanding of the term compassion might act as a barrier to engaging with an otherwise beneficial therapy. Methods Two rounds of interview questions were posed to 15 expert CFT therapists. Results The results provide verification that there is resistance to CFT due to preconceptions around ‘compassion’, specifically its association with ‘pity’, ‘weakness’ and low‐rank social positions. Further, this appears to be pronounced in patients who value competitiveness. Conclusions The results have practical implications such as the need for therapists to acknowledge the potential for resistance and the need for experiential strategies and illustrative examples of compassion to facilitate successful engagement with CFT.
First trimester sex hormone-binding globulin predicts gestational diabetes mellitus in a population of Nigerian women

Abstract There has been a steady rise in the disease burden of Gestational Diabetes Mellitus (GDM) in the sub-Saharan African region over time. Diagnostic testing for GDM is currently recommended at 24 − 28 weeks of gestation, leaving a narrow window for intervention before delivery. Hence the need for early prediction and preventive intervention. The performance of first trimester serum sex hormone-binding globulin (SHBG) assay as a predictor of GDM was determined by binary logistic regression. Women with GDM (n = 49) had a significantly lower mean first trimester SHBG level (104.7 ± 61.6 nmol/L) than did those without GDM (n = 180; 265.2 ± 141.5 nmol/L; p < .001). First trimester SHBG was significantly negatively correlated (r pb = −0.460, p value = <.001) with subsequent development of GDM and an area under receiver operator characteristics (ROC) curve of 0.874 (p < .001). A cut-off value of 158.0 nmol/L predictive of GDM had a diagnostic sensitivity of 81.5%, a specificity of 80.1%, and an overall diagnostic efficiency of 80.3%. IMPACT STATEMENT What is already known on this subject? GDM is associated with high risk of various complications and is commonly diagnosed at 24–28 weeks of gestation, leaving a narrow window for intervention. The performance of current maternal clinical and demographic risk factor-based prediction approaches is unreliable. Thus, more favourable prediction approaches need to be developed. Previous studies have suggested that SHBG, a readily assessable marker, has potential to predict GDM; however, these studies have mostly involved Caucasian and other non-African populations. What the results of this study add? SHBG may serve as a reliable first trimester screening tool for GDM development in Nigerian women with singleton pregnancies. This study demonstrates that first trimester SHBG can predict GDM development in sub-Saharan African women despite racial, ethnic and geographical differences. What are the implications of these findings for clinical practice and/or further research? Effective first trimester prediction of GDM using SHBG may enable preventive interventions, thereby mitigating the high burden of the disease in the sub-Saharan African region. It may also provide relevant information that may guide adaptation of current management guidelines to ensure effective management of GDM in the region.