Miracle-dz/UniFAR-FTUs huggingface dataset:
Fontan operation at less than 3 years of age is not a risk factor for long-term failure.

OBJECTIVES The age at which the Fontan operation is performed varies globally. Over the last decade, the median age of patients having the Fontan in Australia and New Zealand has been 4.6 years, including 6% of patients younger than 3 years. Long-term outcomes of an early Fontan operation are unclear and are described in this study. METHODS Patients from the Australian and New Zealand Fontan Registry were grouped by age at Fontan. A Fontan before 3 years (early Fontan) was compared to the combined second and third quartiles by age at surgery in the Registry (3.6-6.1 years; control). Outcomes included Fontan failure (death, transplant, New York Heart Association functional group III/IV heart failure, Fontan takedown or conversion, protein losing enteropathy and plastic bronchitis), arrhythmias, thromboembolism and reinterventions. RESULTS A total of 191 patients who had early Fontan operations were compared to 781 controls. Profound or progressive cyanosis was noted more frequently in the early than in the control group (63% vs 23%; P < 0.001). The early group was followed up for a median 22.1 years. The incidence of long-term failure was similar between the 2 groups (early, 1.08 failures per 100 patient-years of follow-up vs control, 0.99; log-rank P = 0.79). Adjusted for risk factors, early age at Fontan was not a risk factor for long-term failure [hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.77-1.76; P = 0.48], new-onset arrhythmia (HR 0.93, 95% CI 0.63-1.39; P = 0.73), thromboembolism (HR 0.50, 95% CI 0.28-0.91; P = 0.024) or reintervention (HR 1.08, 95% CI 0.80-1.45; P = 0.62). CONCLUSIONS Having the Fontan operation at an early age was not a risk factor for short- or long-term adverse outcomes in our cohort.
Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D2 Dopamine Receptor

ONC201 is a first-in-class imipridone compound that is in clinical trials for the treatment of high-grade gliomas and other advanced cancers. Recent studies identified that ONC201 antagonizes D2-like dopamine receptors at therapeutically relevant concentrations. In the current study, characterization of ONC201 using radioligand binding and multiple functional assays revealed that it was a full antagonist of the D2 and D3 receptors (D2R and D3R) with low micromolar potencies, similar to its potency for antiproliferative effects. Curve-shift experiments using D2R-mediated β-arrestin recruitment and cAMP assays revealed that ONC201 exhibited a mixed form of antagonism. An operational model of allostery was used to analyze these data, which suggested that the predominant modulatory effect of ONC201 was on dopamine efficacy with little to no effect on dopamine affinity. To investigate how ONC201 binds to the D2R, we employed scanning mutagenesis coupled with a D2R-mediated calcium efflux assay. Eight residues were identified as being important for ONC201's functional antagonism of the D2R. Mutation of these residues followed by assessing ONC201 antagonism in multiple signaling assays highlighted specific residues involved in ONC201 binding. Together with computational modeling and simulation studies, our results suggest that ONC201 interacts with the D2R in a bitopic manner where the imipridone core of the molecule protrudes into the orthosteric binding site, but does not compete with dopamine, whereas a secondary phenyl ring engages an allosteric binding pocket that may be associated with negative modulation of receptor activity. SIGNIFICANCE STATEMENT ONC201 is a novel antagonist of the D2 dopamine receptor with demonstrated efficacy in the treatment of various cancers, especially high-grade glioma. This study demonstrates that ONC201 antagonizes the D2 receptor with novel bitopic and negative allosteric mechanisms of action, which may explain its high selectivity and some of its clinical anticancer properties that are distinct from other D2 receptor antagonists widely used for the treatment of schizophrenia and other neuropsychiatric disorders.
SupPoRtive Exercise Programmes for Accelerating REcovery after major ABdominal Cancer surgery trial (PREPARE‐ABC): Pilot phase of a multicentre randomised controlled trial

PREPARE‐ABC is a pragmatic multicentre randomised controlled trial including an internal pilot designed to assess the clinical and cost‐effectiveness of pre‐ and postoperative exercise in relation to short‐ and longer‐term postoperative recovery outcomes in colorectal cancer patients undergoing surgical resection. Here, we report on internal pilot phase data for the first 200 patients randomised to the trial, which included prespecified stop‐go criteria used to inform the decision to progress to the fully powered trial by the funder.
Phytase Production from a Novel Klebsiella sp. on Wheat Bran for Animal Feed Digestion

Background. The present study was aimed to isolate phytase producing bacteria and optimize the physicochemical parameters of their phytase production. Materials and methods. Four bacterial isolates (Phs4, Phs5, Phs6, and Phs8), based on clear zone formation on phytase screening medium, were selected and tested for finding out the highest phytase producing strain. The production of phytase was then optimized and its biochemical properties were determined to judge the applicability of phytase as a digestive aid in animal feed. Results. The 4 bacterial isolates (Phs4, Phs5, Phs6 and Phs8) were identified by morphological, cultural, biochemical and molecular characterization as Burkholderia cepacia, Escherichia coli, Klebsiella pneumoniae and Klebsiella sp. respectively. Of these isolates, Phs8 (Klebsiella sp.) was found to produce maximum phytase in shake culture in a basal medium containing Na-phytate at 37C and pH 5.5 after 72 hours of incubation. The omission of Na-phytate from the medium almost completely abolished the phytase production capacity of the isolate and thus signified its important role as an inducer. Among the different complex carbon sources, viz., glucose, wheat bran, rice bran and chickpea, maximum phytase production (94 unit/ ml) was obtained with wheat bran under comparable cultivation conditions. The phytase works best at a temperature of 37C and pH of 4.0 with a wide temperature stability (more than 80% activity up to 80C) and wide pH stability (more than 80% activity within a range of pH 3-8). Although Zn, Co, and Fe slightly increased the phytase activity Cu and Mg strongly inhibited the enzyme. Conclusion. The present findings will be very useful for the development of a bioprocess of the enzyme for its large-scale production at the pilot and finally at the commercial level.
Comparative efficacy of single-inhaler triple therapies for COPD: A protocol for systematic review and network meta-analysis

Introduction 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Reports recommends that patients with clinically significant symptoms and exacerbations of chronic obstructive pulmonary disease (COPD) should escalate to triple therapy, a combined use of inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA) and long-acting b2-agonists (LABA)(ICS/LAMA/LABA). Triple therapy in fixed-dose combinations (FDCs), i.e., combining ICS, LABA with LAMA and administrating by a single inhalation device, has appeared in recent years. This study aims to compare the efficacy of triple therapy in FDCs in treating patients with moderate to severe COPD. Methods and analyses Literature search will be conducted on PubMed, Embase and Web of science, according to pre-specified and corresponding search strategies, for relevant reports published since the inception dates of the databases. Randomised controlled trials (RCT) which compared the triple therapy in FDCs with other pharmacological therapies will be included. The Cochrane risk of bias assessment tool (RoB 2) will be used to assess the RCT quality. The outcomes will be analyzed as rate ratios and mean differences under a random-effects model in a frequentist network meta-analysis (NMA). Additional statistical analyses including subgroup analysis, sensitivity analysis, and publication bias analysis will be performed to assess the evidential heterogeneity and robustness. The strength of evidence from the NMA will be evaluated with the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) methods. Ethics and dissemination No ethics approval is required as this systematic review and network meta-analysis do not collect confidential personal data and do not carry out interventions in treating patients. Protocol registration number CRD42021240823.
Recent progress towards vaccines and antibody-based therapies against Alzheimer's disease.

Alzheimer's disease (AD), one of the progressive neurodegenerative disorders, is featured by clinical features such as memory loss, acquired skill loss, apraxia, and interpersonal and social communication disorders. The AD hallmarks at neuropathological level include intracellular neurofibrillary tangles constituted by the hyperphosphorylated tau protein as well as the senile extracellular plaques dominated by the amyloid-β (Aβ) deposits. At present, AD treatment is mainly targeted towards improving symptoms, and effective drugs to delay or stop disease progression are lacking. vaccines and antibody-based therapies are a type of natural, synthetic, and gene recombinant biological product that treat or prevent disease progression by stimulating specific or non-specific immune responses. Compared with traditional targeted drugs, vaccines and antibody-based therapies have better safety and effectiveness, and can even maintain the expression and stability of Aβ and Tau proteins in patients for a long time. Logically, vaccines and antibody-based therapies are somewhat different from traditional drugs because these drugs can achieve the therapeutic effect of AD by activating immune cells and regulating the immune system of patients themselves, thereby clearing disease-related proteins, and long-term survival or even complete cure is observed in some patients after receiving the immunotherapy. Currently available vaccines and antibody-based therapies mainly target Aβ and phosphorylated tau proteins. There are 44 vaccines and antibody-based therapies for AD, among which nine drugs are discontinued, three drugs are inactive, eleven drugs are in clinical phase 1, twelve drugs are in clinical phase 2, and seven drugs are in clinical phase 3. Currently, no vaccines and antibody-based therapies have been approved for AD treatment. In this paper, we review and analyse the research progress of vaccines and antibody-based therapies that are used to treat AD.
Neural correlates of affective stimulus evaluation: a case-by-case analysis

Abstract A recent study provided first evidence that neural correlates of affective stimulus evaluation, that is, the early posterior negativity (EPN) and late positive potential (LPP), can be assessed at the individual case level. Expanding the case-by-case approach, the main aim of the present study was to explore the process of affective stimulus evaluation within the individual participant with respect to multiple emotional stimulus classes. Toward this end, each participant viewed separate blocks of low- and high-arousing pictures from behavior systems of predator fear, disease avoidance and sexual reproduction. Thirteen out of 16 participants showed larger EPN and LPP amplitudes for higher- than lower-arousing stimuli for all three behavior systems. Furthermore, rather than indicating a general lack of emotional modulation, cases of non-significant EPN (N = 3) and LPP (N = 2) tests in individual participants appeared to be specific to a single emotion category. Overall, assessing the emotional modulation of the EPN and LPP across multiple behavior systems strengthens the case-by-case approach regarding an effect that is ‘common to all’ as well as by differentiating non-significant effects within individuals in terms of a content-specific or general phenomenon. Implications for revealing a general principle of emotion functioning and biomarker development are discussed.
Mind the gap: Contesting normal/abnormal constructs of human biology and behaviors

Training in anthropology and evolutionary science ideally prepares scholars to recognize and challenge culturally grounded views of human variation. But upon inspection we find that idealized, and thus perhaps biased, conceptualizations of what is “normal” continue to permeate evaluations of human biology and behaviors. Each of the 13 contributions in this special issue on biological normalcy tackles these concerns as they pertain to some universal, but also variable, human biological or behavioral phenotype. These papers consider the ways in which the term “normal” is used in everyday life, in biomedicine, and in scientific studies to characterize some portion of the variability in a human phenotype. The contributors to this special issue, some of whom present original research findings, discuss the ongoing debates and challenges in the study of human biology and behavior, and critically examine how “normal” is used in their specific research area, thereby exposing and countering biases in the discourse on human phenotypic variation.
Effects of chronic exposure to low levels of IR on Medaka (Oryzias latipes): a proteomic and bioinformatic approach

Abstract Purpose Chronic exposure to ionizing radiation (IR) at low doses (<100 mGy) has been insufficiently studied to understand fully the risk to health. Relatively little knowledge exists regarding how species and healthy tissues respond at the protein level to chronic exposure to low doses of IR, and mass spectrometric-based profiling of protein expression is a powerful tool for studying changes in protein abundance. Materials and methods SDS gel electrophoresis, LC-MS/MS mass spectrometry-based approaches and bioinformatic data analytics were used to detect proteomic changes following chronic exposure to moderate/low doses of radiation in adults and normally developed Medaka fish (Oryzias latipes). Results Significant variations in the abundance of proteins involved in thyroid hormone signaling and lipid metabolism were detected, which could be related to the gonadal regression phenotype observed after 21.04 mGy and 204.3 mGy/day exposure. The global proteomic change was towards overexpression of proteins in muscle and skin, while the opposite effect was observed in internal organs. Conclusion The present study provides information on the impacts of biologically relevant low doses of IR, which will be useful in future research for the identification of potential biomarkers of IR exposure and allow for a better assessment of radiation biosafety regulations.
In vitro DNA binding, pBR322 cleavage and molecular docking studies of 1,2-diaminobenzene, dichloro glycyl glycinate tin(IV) and zirconium(IV) complexes

Abstract De novo design and synthesis of complexes 1,2-diaminobenzene, dichloro glycyl glycinate tin(IV) and zirconium(IV), 1 and 2 as molecular drug entities were carried out. The structure elucidation of 1 and 2 was done by analytical techniques and spectroscopic methods viz. IR, UV–vis, 1H, 13C, 119Sn NMR, ESI–Mass and XRD techniques. In vitro DNA binding studies of 1 and 2 by various biophysical techniques viz electronic absorption, emission spectroscopy and circular dichroism measurements were carried out to evaluate their potential to act as chemotherapeutic candidates; furthermore, cleavage studies with pBR322plasmid DNA and computer-aided molecular docking studies were also done to study the mechanistic pathway and mode of binding at the molecular level. The observed results revealed that complex 1 exhibited greater DNA binding propensity in contrast to complex 2 primarily via electrostatic binding mode. The pBR322 DNA cleavage studies of both the complexes revealed the hydrolytic cleavage mechanism and DNA minor groove binding, which was ascertained by molecular docking studies of the drug candidate. Communicated by Ramaswamy H. Sarma
Evaluating the feasibility and acceptability of a community dialogue intervention in the prevention and control of schistosomiasis in Nampula province, Mozambique.

BACKGROUND Schistosomiasis is a parasitic neglected tropical disease that ranks second only to malaria in terms of human suffering in the tropics and subtropics. Biomedical disease control interventions need to be complemented with effective prevention and health education strategies, that address the social and environmental determinants of disease. Malaria Consortium conducted an implementation research study between May 2014 and February 2016, in four districts of Nampula province, Mozambique, to test a Community Dialogue (CD) intervention to enhance schistosomiasis prevention and control. The study aimed to evaluate the acceptability and feasibility of using CD to improve communities' level of knowledge, attitudes and practices, and engagement in wider schistosomiasis prevention and control efforts. METHODS The feasibility and acceptability of the CD intervention was evaluated using qualitative and process evaluation data collected throughout the development and implementation phases. Qualitative data sets included key informant interviews (N = 4) with health system personnel, focus group discussions (N = 22) with Community Dialogue facilitators and participants, field observation visits (N = 11), training reports (N = 7), feedback meeting reports (N = 5), CD monitoring sheets (N = 1,458) and CD planning sheets (N = 152). FINDINGS The CD intervention was found highly acceptable and feasible, particularly well-suited to resource poor settings. Non-specialist community volunteers were able to deliver participatory CDs which resulted in increased knowledge among participants and triggered individual and communal actions for improved disease prevention and control. The visual flipchart was a key aid for learning; the use of participatory communication techniques allowed the correction of misconceptions and positioned correct prevention and control practices as the community recommendations, through consensus building. CONCLUSION The Community Dialogue Approach should be embedded within neglected tropical disease control programmes and the health system to create long-lasting synergies between the community and health system for increased effectiveness. However, for behavioural change to be feasible, community engagement strategies need to be supported by improved access to treatment services, safer water and sanitation.
SARS-CoV-2 Variants in Immunocompromised Patient Given Antibody Monotherapy

A 72-year-old immunocompromised man infected with severe acute respiratory syndrome coronavirus 2 received bamlanivimab monotherapy. Viral evolution was monitored in nasopharyngeal and blood samples by melting curve analysis of single-nucleotide polymorphisms and whole-genome sequencing. Rapid emergence of spike receptor binding domain mutations was found, associated with a compartmentalization of viral populations.
Use of angiotensin-converting enzyme inhibitors or receptor blockers is associated with reduced mortality in patients with post-acute kidney injury: meta-analysis.

OBJECTIVE To investigate the association between the use of ACEis or ARBs and outcomes in patients recovering from AKI. MATERIALS AND METHODS We searched PubMed, MEDLINE, Cochrane Database, Web of Science and Embase databases from inception to May 2021 and performed a systematic review and meta-analysis using the "meta" package in R 4.0. 3. RESULTS Five cohort studies, published from 2018 to 2021 with 153174 participants and approximately 39081 mortalities, were included in our meta-analysis. The meta-analysis showed that the use of ACEis/ARBs in patients with post-AKI is associated with a significantly lower risk of death (HR 0.80; 95% CIs, 0.72-0.90) and subgroup analysis showed a significant result in ACEi/ARB users with over 1-year of follow-up (HR 0.86; 95% CIs, 0.77-0.95). CONCLUSIONS The use of ACEi/ARB in patients with post-AKI is associated with a significantly lower risk of death.
Level of adherence to option B plus PMTCT and associated factors among HIV positive pregnant and lactating women in public health facilities of Hawassa city, Southern Ethiopia

Background Adherence to antiretroviral therapy is very essential to achieve a great outcome of drugs via suppressing viral load, preventing multidrug resistance, and reducing mother to a child transmission rate of the Human Immune Virus. Objective This study aimed to assess the level of adherence to option B plus PMTCT and associated factors among HIV Positive pregnant and lactating women in public health facilities of Hawassa city, Southern Ethiopia, 2020 G.C. Methods Institution-based cross-sectional study was done on 254 HIV-positive pregnant and lactating women attending the prevention of mother-to-child transmission (PMTCT) follow-up. Participants were selected by simple random sampling. Data collected through a structured interviewer-administered questionnaire were cleaned and entered into Epi-data 3.1 and exported to SPSS 20 for statistical analysis. Descriptive analysis was done. Bivariable and multivariable logistic regressions were done to measure the strength of association between independent and dependent variables using the odds ratio and 95% of confidence interval. A p-value <0.05 was taken as statistically significant. Result The overall adherence level to option B+ was 224 (88.2%). Respondents in age group of ≤ 25 [AOR = 0.12, 95% CI (0.03, 0.42)], with no formal education [AOR = 0.12, 95% CI (0.03, 0.51)], experienced drug side effects [AOR = 0.11, 95% CI (0.04, 0.32)], have good knowledge of PMTCT [AOR = 3.6, 95% CI (1.16, 11.3)], and get support from partner/family [AOR = 4.5, 95% CI (1.62, 12.4)] were identified associated factors with adherence level. Conclusion The level of adherence to option B plus PMTCT was 88.2% which is suboptimal. Ages, educational level, knowledge on PMTCT, getting support from partner/family, and drug side effect were significantly associated with adherence. Therefore, educating and counseling on the service of PMTCT to improve their knowledge and encouraging partner/family involvement in care are mandatory to achieve the standard adherence level.
Stability of Halloysite, Imogolite, and Boron Nitride Nanotubes in Solvent Media

Inorganic nanotubes are attracting the interest of many scientists and researchers, due to their excellent application potential in different fields. Among them, halloysite and imogolite, two naturally-occurring aluminosilicate mineral clays, as well as boron nitride nanotubes have gained attention for their proper shapes and features. Above all, it is important to reach highly stable dispersion in water or organic media, in order to exploit the features of this kind of nanoparticles and to expand their applications. This review is focused on the structural and morphological features, performances, and ratios of inorganic nanotubes, considering the main strategies to prepare homogeneous colloidal suspensions in various solvent media as special focus and crucial point for their uses as nanomaterials.