Miracle-dz/UniFAR-FTUs huggingface dataset:
Rare mutations in the autophagy‐regulating gene AMBRA1 contribute to human neural tube defects

Neural tube defects (NTDs) are severe congenital malformations caused by failed neural tube closure. Recently, autophagy is revealed to play a vital role in neuroepithelium development and neurulation. Autophagy and beclin 1 regulator 1 (Ambra1) is a crucial regulator of autophagy initiation, and its deficiency in mice leads to exencephaly and/or spina bifida. However, the genetic contribution of AMBRA1 to the etiology of human NTDs remains unknown. In this study, we identified five rare missense mutations of AMBRA1 in 352 NTDs cases, which were absent in 224 matched controls. Western blotting and fluorescence puncta counting for MAP1LC3A/LC3 in HEK293T cells suggested that four of the mutations (AMBRA1 p.Thr80Met, p.Leu274Phe, p.Ser743Phe, and p.Met884Val) affected autophagy initiation to various extents. Furthermore, these four mutations also displayed loss‐of‐function effects compared with wild‐type AMBRA1 when we injected messenger RNA (mRNA) to overexpress or rescue ambra1a‐morpholino oligos (MO) knockdown in zebrafish. It is intriguing that trehalose, a natural disaccharide, could rescue ambra1a‐MO knockdown in a dose‐dependent manner independently or together with AMBRA1 mRNA. Taken together, our findings suggest that rare mutations of the autophagy regulator gene AMBRA1 may contribute to the etiology of human neural tube defects, and trehalose is a promising treatment for a subset of NTDs caused by autophagy impairment.
Hepatic portal venous gas with pneumatosis intestinalis secondary to mesenteric ischemia in elderly patients

Abstract Introduction: Hepatic portal venous gas (HPVG) is a rare imaging finding. When HPVG is accompanied with pneumatosis intestinalis (PI), the underlying cause is usually mesenteric ischemia with consequent intestinal necrosis. This combination of clinical conditions is associated with a poor prognosis. In this study, we present the cases of 2 elderly patients with HPVG and PI secondary to mesenteric ischemia. Patient concerns: In case 1, a 89-year-old male patient was admitted to intensive care unit with respiratory failure, On the fifth day of admission, he developed a high fever (39.5°C) and abdominal distension. In case 2, a 92-year-old male patient admitted to our intensive care unit and received mechanical ventilation due to acute respiratory failure. During the treatment, the patient developed gastrointestinal bleeding. On physical examination, abdominal bulging and tense abdominal walls were detected. Both patients underwent abdominal contrast-enhanced computed tomography, showed abundant HPVG with PI. Diagnoses: The patients were diagnosed as acute mesenteric ischemia, bowel necrosis, septic shock, multiple organ dysfunction syndrome based on computed tomography scan, abdominal signs, and laboratory tests. Interventions: Fluid resuscitation, high-dose vasopressors, and intravenous antibiotic therapy were given. Outcomes: Despite prompt treatment, the condition of both patients rapidly deteriorated, and the patients died shortly thereafter. Conclusion: Mesenteric ischemia is a clinical emergency. In patients with risk factors and abdominal signs, the clinical suspicion for this condition should be high. Although rare, both HPVG and PI are important radiological clues that usually indicate the presence of mesenteric ischemia with consequent intestinal necrosis.
Parameters of fluid responsiveness.

PURPOSE OF REVIEW On the basis of recent literature, we summarized the new advances on the use of available dynamic indices of fluid responsiveness. RECENT FINDINGS Reliability of passive leg raising to assess fluid responsiveness is well established provided that a real-time haemodynamic assessment is available. Recent studies have focused on totally noninvasive techniques to assess its haemodynamic effects with promising results. Presence of intra-abdominal hypertension is associated with false-negative cases of passive leg raising. Use of pulse pressure and stroke volume variations is limited and other heart-lung interaction tests have been developed. The tidal volume challenge may overcome the limitation of low tidal volume ventilation. Preliminary data suggest that changes in pulse pressure variation during this test well predict fluid responsiveness. Growing evidence confirms the good predictive performance of the end-expiratory occlusion test. All these dynamic tests allow selecting appropriate fluid responders and preventing excessive fluid administration. Performance of a mini-fluid challenge may help for the decision-making process of fluid management if other tests are not available. SUMMARY Several new dynamic variables and monitoring techniques to predict fluid responsiveness were investigated in the past years. Nevertheless, further research investigating their reliability and feasibility in larger cohorts is warranted. VIDEO ABSTRACT.
Association of Dickkopf-1 Polymorphisms With Radiological Damage and Periodontal Disease in Patients With Early Rheumatoid Arthritis: A Cross-Sectional Study.

BACKGROUND Rheumatoid arthritis (RA) is a systemic autoimmune disease that increased bone resorption. Periodontal disease (PD) is an associated risk factor of RA. Studies suggest an association between bone markers such as the dickkopf-related protein 1 (DKK-1) and progression of radiological damage. We aimed to evaluate the marker DKK-1, its polymorphisms in patients with early rheumatoid arthritis (eRA), and its association with rheumatic, radiological, and periodontal variables. METHODS This article is a cross-sectional study. Samples were obtained from 63 patients with eRA. Radiographs of hands and feet were evaluated by Sharp-van der Heijde score (SHS) and Simple Erosion Narrowing Score (SENS). Serum DKK-1 levels and high-resolution fusion analysis was used for polymorphisms (rs1896368, rs1896367, rs1528873). Bivariate analyses were performed. RESULTS Individuals heterozygous for rs1896367 had more frequent erosions (p = 0.026) and joint space narrowing (p = 0.005) in the feet, higher SHS (p = 0.016), and higher SENS (p ≤ 0.001). Patients homozygous for rs1896368 had less frequent joint space narrowing in hands and feet as assessed by SHS and less presence of erosions by SENS (odds ratio, 0.04; 95% confidence interval, 0.00-0.93; p < 0.05). The presence of PD was associated with the homozygous of rs1896367 (p = 0.009) and the heterozygous of rs1896368 (p = 0.033). CONCLUSIONS Polymorphism rs1896367 seems to be associated with greater radiological compromise; rs1896368 confers protection against bone damage in Colombian eRA patients.
SARS‐CoV‐2 can be detected in urine, blood, anal swabs, and oropharyngeal swabs specimens

Abstract Purpose The purpose of this study was to detect severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) ribonucleic acid (RNA) in urine and blood specimens, and anal and oropharyngeal swabs from patients with confirmed SARS‐CoV‐2 infection, and correlated positive results with clinical findings. Methods Patients with confirmed SARS‐CoV‐2 infections were included in this study. Patients' demographic and clinical data were recorded. Quantitative real‐time polymerase chain reaction was used to detect SARS‐CoV‐2 RNA in urine and blood specimens, and anal and oropharyngeal swabs. The study is registered at ClinicalTrials.gov (No. NCT04279782, 19 February, 2020). Results SARS‐CoV‐2 RNA was present in all four specimen types, though not all specimen types were positive simultaneously. The presence of viral RNA was not necessarily predictive of clinical symptoms, for example, the presence of viral RNA in the urine did not necessarily predict urinary tract symptoms. Conclusions SARS‐CoV‐2 can infect multiple systems, including the urinary tract. Testing different specimen types may be useful for monitoring disease changes and progression, and for establishing a prognosis.
A STAT3 of Addiction: Adipose Tissue, Adipocytokine Signalling and STAT3 as Mediators of Metabolic Remodelling in the Tumour Microenvironment

Metabolic remodelling of the tumour microenvironment is a major mechanism by which cancer cells survive and resist treatment. The pro-oncogenic inflammatory cascade released by adipose tissue promotes oncogenic transformation, proliferation, angiogenesis, metastasis and evasion of apoptosis. STAT3 has emerged as an important mediator of metabolic remodelling. As a downstream effector of adipocytokines and cytokines, its canonical and non-canonical activities affect mitochondrial functioning and cancer metabolism. In this review, we examine the central role played by the crosstalk between the transcriptional and mitochondrial roles of STAT3 to promote survival and further oncogenesis within the tumour microenvironment with a particular focus on adipose-breast cancer interactions.
Management of hospital-acquired infections among patients hospitalized at Zewditu memorial hospital, Addis Ababa, Ethiopia: A prospective cross-sectional study

Background Hospital-Acquired Infections (HAIs) are acquired when the patient is hospitalized for more than 48 hours. In Ethiopia data are scarce in management appropriateness of HAIs. Hence, this study was aimed to assess the prevalence and management of HAIs among patients admitted at Zewditu Memorial Hospital. Method A facility based prospective cross sectional study was conducted from March 1, 2017 to August 30, 2017. The sample was proportionally allocated among (medical, pediatrics, gynecology and obstetrics and surgical) wards, based on patient flow. Data were collected using data abstraction format and supplemented by key informant interview. Interview was made on eight physicians and four microbiologists who have been working in the wards during study period. Management appropriateness was assessed using Infectious Disease Society of America guideline and experts opinion (Infectious disease specialist). A multivariate logistic regression was used to identify factors associated with HAIs. Result The prevalence of HAIs was 19.8%. Surgical Site Infection (SSI) and pneumonia accounted for 20 (24.7%) of the infections. Culture and sensitivity was done for 24 (29.6%) patients. Of the 81 patients who developed HAIs, 54 (66.67%) of them were treated inappropriately. Physicians’ response for this variation was information gap, forgetfulness, affordability and availability issue of first line medications. Younger age (AOR (Adjusted odds ratio) = 8.53, 95% CI: 2.67–27.30); male gender (AOR = 2.06, 95% CI: 1.01–4.22); longer hospital stay (AOR = 0.17, 95% CI: 0.06–0.51); and previous hospital admission (AOR = 3.22, 95% CI: 1.76–5.89); were independent predictors of HAIs. Conclusion Prevalence of HAIs and inappropriate management were substantially high in this study. Pneumonia and SSI were the common types of HAIs. Locally conformable guidelines could help to correct such problems.
Leveraging open hardware to alleviate the burden of COVID-19 on global health systems

With the current rapid spread of COVID-19, global health systems are increasingly overburdened by the sheer number of people that need diagnosis, isolation and treatment. Shortcomings are evident across the board, from staffing, facilities for rapid and reliable testing to availability of hospital beds and key medical-grade equipment. The scale and breadth of the problem calls for an equally substantive response not only from frontline workers such as medical staff and scientists, but from skilled members of the public who have the time, facilities and knowledge to meaningfully contribute to a consolidated global response. Here, we summarise community-driven approaches based on Free and Open Source scientific and medical Hardware (FOSH) as well as personal protective equipment (PPE) currently being developed and deployed to support the global response for COVID-19 prevention, patient treatment and diagnostics.
Financial toxicity of childhood cancer and changes to parents’ employment after treatment completion

Childhood cancer can have short‐ and long‐term impacts on parents’ finances and employment. It is important to understand how families adjust to the financial and employment changes caused by childhood cancer, the ongoing impacts after treatment completion, and which families need more targeted support. Qualitative research is necessary to facilitate an in‐depth understanding of the employment and financial impacts on families and to capture parents’ complex and nuanced experiences and perspectives.
Manipulations of sensory experiences during development reveal mechanisms underlying vocal learning biases in zebra finches

Biological predispositions in learning can bias and constrain the cultural evolution of social and communicative behaviors (e.g., speech and birdsong), and lead to the emergence of behavioral and cultural “universals. ” For example, surveys of laboratory and wild populations of zebra finches (Taeniopygia guttata) document consistent patterning of vocal elements (“syllables”) with respect to their acoustic properties (e.g., duration, mean frequency). Furthermore, such universal patterns are also produced by birds that are experimentally tutored with songs containing randomly sequenced syllables (“tutored birds”). Despite extensive demonstrations of learning biases, much remains to be uncovered about the nature of biological predispositions that bias song learning and production in songbirds. Here, we examined the degree to which “innate” auditory templates and/or biases in vocal motor production contribute to vocal learning biases and production in zebra finches. Such contributions can be revealed by examining acoustic patterns in the songs of birds raised without sensory exposure to song (“untutored birds”) or of birds that are unable to hear from early in development (“early‐deafened birds”). We observed that untutored zebra finches and early‐deafened zebra finches produce songs with positional variation in some acoustic features (e.g., mean frequency) that resemble universal patterns observed in tutored birds. Similar to tutored birds, early‐deafened birds also produced song motifs with alternation in acoustic features across adjacent syllables. That universal acoustic patterns are observed in the songs of both untutored and early‐deafened birds highlights the contribution motor production biases to the emergence of universals in culturally transmitted behaviors.
Structural white matter alterations as compensatory mechanisms in Parkinson's disease: A systematic review of diffusion tensor imaging studies

Compensation is described as normal or near to normal performance in Parkinson's disease (PD), despite the ongoing neural loss. Functional compensation typically proceeds in an inverse U‐shaped manner: compensation initiates in the prodromal phase, followed by an increasing episode until plateauing and diminishes in the advanced stages of the disease. The first evidence of the structural compensation was reported by functional magnetic resonance imaging studies. Recent studies, which have used diffusion tensor imaging (DTI) as the basis for their investigation, have shown improved white matter diffusional properties both in motor‐ and non‐motor‐related structures in association with improved clinical scores in patients with PD. The majority of DTI studies have demonstrated microstructural compensation in the prodromal/early stages of PD at the regional scale. However, there have been reports of compensation in later stages of the disease and the whole‐brain/network scale that are probably due to the heterogeneous nature of PD. Although serving as a promising beginning to characterize compensation, lots remain to be clarified in understanding the underlying mechanisms of compensation and its structural pattern in PD. The existing knowledge gap necessitates studies that their main research questions are focused on structural compensation. This requirement becomes more apparent because structural compensation evidence has mostly emerged from the post hoc analysis of data and incidental findings of studies. Thus, future studies are required to investigate compensatory microstructural changes in PD to clarify the exact underlying mechanisms. These studies would also provide a basis to develop clinical improvements in the early diagnosis and management of PD.
Acute Ingestion of a Novel Nitrate-Rich Dietary Supplement Significantly Increases Plasma Nitrate/Nitrite in Physically Active Men and Women

Background: Dietary supplements purported to increase circulating nitric oxide are very popular among consumers. We determined the acute impact of two novel dietary supplements on plasma nitrate/nitrite (NOx) and nitrite alone. Methods: 20 men and women (age: 24 ± 5 years) ingested two different nitrate-rich supplements (Resync Recovery Blend at 7.5 g and 15 g; Resync Collagen Blend at 21 g), or placebo, on four different days. Fasting blood samples were obtained before and 75 min following ingestion and analyzed for NOx and nitrite. Results: Nitrite was not differently impacted by treatment (p > 0.05). The NOx response for men and women was very similar, with no sex interactions noted (p > 0.05). Condition (p < 0.0001), time (p < 0.0001), and condition x time (p < 0.0001) effects were noted for NOx. Values increased from baseline to post-ingestion for the Resync Recovery Blend at 7.5 g (11 ± 9 to 101 ± 48 µM) and at 15 g (9 ± 5 to 176 ± 91 µM), as well as for the Resync Collagen Blend (9 ± 9 to 46 ± 21 µM), while values for placebo remained stable (9 ± 7 to 8 ± 5 µM). Conclusion: While nitrite alone was not impacted by treatment, both Resync products result in an increase in plasma NOx, with the increase proportionate to the quantity of “nitric oxide blend” ingredients contained within each product. Future studies are needed to determine the physiological implications of the increased NOx, as pertaining to exercise performance and recovery, in addition to other aspects of human health.
Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies in non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain-null (NSG) mice and established humanized mouse NPC-patient-derived xenograft (NPC-PDX) model successfully. Epstein–Barr virus was detected in the NPC in both NSG and humanized mice as revealed by Epstein–Barr virus-encoded small RNA (EBER) in situ hybridization (ISH) and immunohistochemical (IHC) staining. In the NPC-bearing humanized mice, the percentage of tumor-infiltrating CD8+ cytotoxic T cells was lowered, and the T cells expressed higher levels of various inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) than those in blood. The mice were then treated with nivolumab and ipilimumab, and the anti-tumor efficacy of combination immunotherapy was examined. In line with paired clinical data, the NPC-PDX did not respond to the treatment in terms of tumor burden, whilst an immunomodulatory response was elicited in the humanized mice. From our results, human proinflammatory cytokines, such as interferon-gamma (IFN-γ) and interleukin-6 (IL-6) were significantly upregulated in plasma. After treatment, there was a decrease in CD4/CD8 ratio in the NPC-PDX, which also simulated the modulation of intratumoral CD4/CD8 profile from the corresponding donor. In addition, tumor-infiltrating T cells were re-activated and secreted more IFN-γ towards ex vivo stimulation, suggesting that other factors, including soluble mediators and metabolic milieu in tumor microenvironment may counteract the effect of ICB treatment and contribute to the tumor progression in the mice. Taken together, we have established and characterized a novel humanized mouse NPC-PDX model, which plausibly serves as a robust platform to test for the efficacy of immunotherapy and may predict clinical outcomes in NPC patients.
Does pandemic justify the use of hydroxychloroquine for treatment and prevention of COVID‐19 in India?

The Indian Council of Medical Research (ICMR), recommended the use of hydroxychloroquine (HCQ) as a prophylactic against COVID-19 among health care workers and asymptomatic contacts of laboratory confirmed cases of COVID. This is widely criticised as a hastily taken step with political inclination and minimal evidence backing. In the current scenario, where there is mass fear against COVID-19, this recommendation has made the people to believe that it will kill the viruses. This has important public health implications which are discussed below. Better communication should have been planned to ensure everyone does not go out and buy it. However, as a nation of 1.3 billion, we need to capitalize on this opportunity to generate data and valuable evidence on the use of HCQ to beat this pandemic. All health care workers taking this drug should volunteer themselves to be part of a trial/observational study and get registered online to generate useful data related to its safety and efficacy and guide future recommendations. The other risk group which includes asymptomatic contacts of laboratory confirmed COVID-19 patients are under surveillance by the state and local health authorities and could also be roped into this study to generate robust evidence. Of course, pandemic does not just justify the use of HCQ, but pandemic is the time to innovate, think out of box and generate evidence to prove the same so that we can lives. This article is protected by copyright. All rights reserved.
Changes in inner retinal layer thickness in patients with exudative age-related macular degeneration during treatment with anti-vascular endothelial growth factor

Abstract The aim of this study was to identify any changes that occur in the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) in patients with exudative age-related macular degeneration (AMD) during treatment with anti-vascular endothelial growth factor (VEGF) injections. Patients were enrolled in this retrospective study if they had exudative AMD, had received at least 3 injections of ranibizumab or aflibercept, and had a minimum of 12 months of follow-up. We analyzed the changes in the RNFL and GC-IPL using spectral-domain optical coherence tomography in rescan mode. Fifty-two eyes of 52 patients who had been treated with repeated anti-VEGF injections for exudative AMD were included. At the final visit, there was no significant between-group difference in best-corrected visual acuity or intraocular pressure. There was a significant decrease in central macular thickness in all groups (P < .05). There was a decrease in RNFL thickness that was only statistically significant in the ranibizumab group and when the ranibizumab or aflibercept groups were combined (P = .036 and .044, respectively). The thickness of the GC-IPL layer was significantly decreased in the aflibercept and total group (P = .035 and P = .048, respectively). The thicknesses of the RNFL and GC-IPL decreased in patients with exudative AMD who underwent repeated anti-VEGF injections.