Miracle-dz/UniFAR-FTUs huggingface dataset:
Voriconazole versus Itraconazole for the Initial and Step-Down Treatment of Histoplasmosis: A Retrospective Cohort.

BACKGROUND Itraconazole is the preferred azole for histoplasmosis in the current Infectious Diseases Society of America guidelines. Voriconazole is increasingly used as treatment for histoplasmosis; it has in-vitro activity against Histoplasma capsulatum and has shown success in case reports and small case series but may have a lower barrier to resistance. No comparative studies have been published. METHODS We constructed a single-center retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Individual charts were reviewed to gather clinical information including demographics, clinical features, immune status, treatments, and mortality. Patients were categorized based on initial choice of azole, either as initial treatment or as step-down therapy from amphotericin B. Initial therapies with other azoles were excluded. Mortality was compared using a multivariable Cox proportional hazards with Heaviside function at 42 days. RESULTS We identified 261 cases of histoplasmosis from 2002 to 2017. After excluding patients not treated with itraconazole or voriconazole, 194 patients remained. 175 (90%) patients received itraconazole and 19 (10%) received voriconazole. There were no significant demographic differences between patient populations receiving either azole as their initial azole treatment. Death at 180 days occurred in 41 patients (23.4%) in the itraconazole group and 6 patients (31.6%) in the voriconazole group. Patients on voriconazole had a statistically significant increase in mortality during the first 42 days after initiation of treatment when compared to patients receiving itraconazole (HR 4.30 [95% CI 1.3-13.9, p 0.015]) when controlled for other risk factors. CONCLUSION Voriconazole in histoplasmosis was associated with increased mortality in the first 42 days compared to itraconazole.
Virtual reality exposure therapy for social anxiety disorder: a systematic review and meta-analysis

Abstract Background Virtual reality exposure therapy (VRET) is currently being used to treat social anxiety disorder (SAD); however, VRET's magnitude of efficacy, duration of efficacy, and impact on treatment discontinuation are still unclear. Methods We conducted a meta-analysis of studies that investigated the efficacy of VRET for SAD. The search strategy and analysis method are registered at PROSPERO (#CRD42019121097). Inclusion criteria were: (1) studies that targeted patients with SAD or related phobias; (2) studies where VRET was conducted for at least three sessions; (3) studies that included at least 10 participants. The primary outcome was social anxiety evaluation score change. Hedges' g and its 95% confidence intervals were calculated using random-effect models. The secondary outcome was the risk ratio for treatment discontinuation. Results Twenty-two studies (n = 703) met the inclusion criteria and were analyzed. The efficacy of VRET for SAD was significant and continued over a long-term follow-up period: Hedges' g for effect size at post-intervention, −0.86 (−1.04 to −0.68); three months post-intervention, −1.03 (−1.35 to −0.72); 6 months post-intervention, −1.14 (−1.39 to −0.89); and 12 months post-intervention, −0.74 (−1.05 to −0.43). When compared to in vivo exposure, the efficacy of VRET was similar at post-intervention but became inferior at later follow-up points. Participant dropout rates showed no significant difference compared to in vivo exposure. Conclusion VRET is an acceptable treatment for SAD patients that has significant, long-lasting efficacy, although it is possible that during long-term follow-up, VRET efficacy lessens as compared to in vivo exposure.
De novo variants in MPP5 cause global developmental delay and behavioral changes.

MPP5 is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD), and compared their phenotypes and MRIs to ascertain how MPP5 DNV lead to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRIs ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on developing brain was assessed by creating a heterozygous (het) murine model with CNS-specific nestin-Cre drivers (het CKO). In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared to wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.
Missing heritability in Bloom syndrome: First report of a deep intronic variant leading to pseudo‐exon activation in the BLM gene

Pathogenic biallelic variants in the BLM/RECQL3 gene cause a rare autosomal recessive disorder called Bloom syndrome (BS). This syndrome is characterized by severe growth delay, immunodeficiency, dermatological manifestations and a predisposition to a wide variety of cancers, often multiple and very early in life. Literature shows that the main mode of BLM inactivation is protein translation termination. We expanded the molecular spectrum of BS by reporting the first deep intronic variant causing intron exonisation. We describe a patient with a clinical phenotype of BS and a strong increase in sister chromatid exchanges (SCE), who was found to be compound heterozygous for a novel nonsense variant c.3379C>T, p.(Gln1127Ter) in exon 18 and a deep intronic variant c.3020‐258A>G in intron 15 of the BLM gene. The deep intronic variant creates a high‐quality de novo donor splice site, which leads to retention of two intron segments. Both pseudo‐exons introduce a premature stop codon into the reading frame and abolish BLM protein expression, confirmed by Western Blot analysis. These findings illustrate the role of non‐coding variation in Mendelian disorders and herewith highlight an unmet need in routine testing of Mendelian disorders, being the added value of RNA‐based approaches to provide a complete molecular diagnosis.
Association of crossing capillaries in the finger nailfold with diabetic retinopathy in type 2 diabetes mellitus

Crossing capillaries in the finger nailfold might potentially be a novel diabetic retinopathy (DR) biomarker that could be assessed non‐invasively in the clinical setting. However, the association between crossing capillaries and DR is controversial. This study aimed to investigate the association between the percentage of crossing capillaries in the finger nailfold and DR in patients with type 2 diabetes mellitus.
Fishery Appraisal of Portunus spp. (Family Portunidae) using Different Surplus Production Models from Pakistani Waters, Northern Arabian Sea

Muhsan Ali Kalhoro1,2, Danling Tang1,*, Ye Hai Jun1, Morozov Evgeny1, Sufen Wang1 and Muhammad Aslam Buzdar2 1Research Center for Remote Sensing of Marine Ecology and Environment, State Key Laboratory of Tropical Oceanography, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510075, China 2Faculty of Marine Sciences, Lasbela University of Agriculture, Water and Marine Sciences, Uthal, Balochistan, Pakistan Article Information Received 16 November 2016 Revised 03 March 2017 Accepted 24 April 2017 Available online 02 January 2018
Biotic Interactions, Structure, and Long-term Changes in Marine Benthic Assemblages

Predicting spatial distribution of organisms still remains a challenge of ecology. Small-scale variation is high in most marine benthic communities. Our long-term observations on soft -sediment intertidal assemblages revealed high level of small-scale spatial variation, and most temporal variation was also associated with this scale. As biotic interactions oft en drive small-scale patterns, we focused on the communities with multiple foundation species where they are understudied. We assessed overgrowth and feeding interference between co-dominating foundation species, long-term recruitment variation in their populations, and their eff ect on on the rest of assemblage. Our observations and experiments indicated that large suspension-feeders develop a facilitation cascade in the White Sea shallow subtidal, boosting species diversity and driving patch dynamics on mixed sediments. Supervisors Dr. Eugene L. Yakovis Department of Invertebrate Zoology Faculty of Biology and Soil Sciences St. Petersburg State University, Russia Opponents Professor Kirill V. Galaktionov (Chairman) Department of Invertebrate Zoology Faculty of Biology and Soil Sciences St. Petersburg State University, Russia Professor Andrey I. Azovsky Department of Hydrobiology Biological Faculty Moscow State University, Russia Professor Th omas Brey Department of Functional Ecology Alfred-Wegener-Institute for Polar and Marine Research Bremerhaven, Germany Dr. Stanislav G. Denisenko Head of Department of Marine Research Zoological Institute of Russian Academy of Science St. Petersburg, Russia. Professor Andrei I. Granovitch Head of Department of Invertebrate Zoology Faculty of Biology and Soil Sciences St. Petersburg State University, Russia Dr. Paul E. Renaud Akvaplan-niva Fram High North Research Centre for Climate and the Environment, Tromso, University Center in Svalbard, Norway Dr. Alexey A. Sukhotin Department of Invertebrate Zoology Faculty of Biology and Soil Sciences St. Petersburg State University, Russia
Characterization of the synoptic‐scale diversity, biogeography, and size distribution of diatoms in the North Pacific

The diversity, biogeography, and size distribution of diatoms in the North Pacific and underlying mechanisms shaping those patterns have little been characterized despite their importance in marine ecosystems. Here, we examined the community structure of diatoms in the surface and subsurface chlorophyll a maximum (SCM) layers of the North Pacific using light and scanning electron microscopy. Diatom carbon biomass in both the subarctic and temperate coastal regions was higher than that in the open subtropical and tropical waters. Species density was high in the temperate coastal region and certain open ocean stations where coastal water could be intruded. Diversity was generally higher in the SCM layer than that in the surface layer without a clear latitudinal trend. All diatom species in the open subtropical waters were observed in the temperate coastal waters, suggesting that the coastal regions act as a species bank. Certain indigenous species in the subarctic waters were considered as cryophilic species. We found that the general patterns of the size spectrum were nearly identical among different geographical regions of the North Pacific, irrespective of the species composition, environmental conditions, and seasonality. Our results provide mechanistic insights indicating that the diatom biodiversity in the species bank around the coastal region and the following current systems from the coastal to oceanic regions could principally determine biodiversity patterns in the North Pacific. The species‐specific ecophysiological traits of diatoms and environmental conditions may further modify the biodiversity patterns and size distribution of diatoms.
p67: a cryptic lysosomal hydrolase in Trypanosoma brucei?

Abstract p67 is a type I transmembrane glycoprotein of the terminal lysosome of African trypanosomes. Its biosynthesis involves transport of an initial gp100 ER precursor to the lysosome, followed by cleavage to N-terminal (gp32) and C-terminal (gp42) subunits that remain non-covalently associated. p67 knockdown is lethal, but the only overt phenotype is an enlarged lysosome (~250 to >1000 nm). Orthologues have been characterized in Dictyostelium and mammals. These have processing pathways similar to p67, and are thought to have phospholipase B-like (PLBL) activity. The mouse PLBD2 crystal structure revealed that the PLBLs represent a subgroup of the larger N-terminal nucleophile (NTN) superfamily, all of which are hydrolases. NTNs activate by internal autocleavage mediated by a nucleophilic residue, i.e. Cys, Ser or Thr, on the upstream peptide bond to form N-terminal α (gp32) and C-terminal β (gp42) subunits that remain non-covalently associated. The N-terminal residue of the β subunit is then catalytic in subsequent hydrolysis reactions. All PLBLs have a conserved Cys/Ser dipeptide at the α/β junction (Cys241/Ser242 in p67), mutation of which renders p67 non-functional in RNAi rescue assays. p67 orthologues are found in many clades of parasitic protozoa, thus p67 is the founding member of a group of hydrolases that likely play a role broadly in the pathogenesis of parasitic infections.
Mutant IDH1 Enhances Temozolomide Sensitivity via Regulation of the ATM/CHK2 Pathway in Glioma

Purpose Isocitrate dehydrogenase 1 (IDH1) mutations are the most common genetic abnormalities in low-grade gliomas and secondary glioblastomas. Glioma patients with these mutations had better clinical outcomes. However, the effect of IDH1 mutation on drug sensitivity is still under debate. Materials and Methods IDH1-R132H mutant cells were established by lentivirus. IDH1-R132H protein expression was confirmed by western blot. The expression of ataxia telangiectasia mutated (ATM) signaling pathway and apoptosis-related proteins were detected by immunofluorescence and western blot. Temozolomide (TMZ) induced cell apoptosis was detected by flow cytometry. Tumor cell proliferation was detected by Cell Counting Kit-8. In vivo nude mice were used to confirm the in vitro roles of IDH1 mutation. Results We established glioma cell lines that expressed IDH1-R132H mutation stably. We found that TMZ inhibited glioma cells proliferation more significantly in IDH1 mutant cells compared to wild type. The IC50 of TMZ in IDH1-R132H mutant group was less than half that of wild-type group (p < 0.01). TMZ significantly induced more DNA damage (quantification of γH2AX expression in IDH1 mutation vs. wild type, p < 0.05) and apoptosis (quantification of AnnexinV+propidium iodide− cells in IDH1 mutation versus wild type, p < 0.01) in IDH1 mutant gliomas compared to wild-type gliomas. The ATM-associated DNA repair signal was impaired in IDH1 mutant cells. Inhibiting the ATM/checkpoint kinase 2DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy. We found that IDH1 mutation significantly inhibited tumor growth in vivo (the tumor size was analyzed statistically, p < 0.05). Moreover, we confirmed that gliomas with IDH1 mutation were more sensitive to TMZ in vivo compared to wild type significantly and the results were consistent with the in vitro experiment. Conclusion These results provide evidence that combination of TMZ and ATM inhibitor enhances the antitumor effect in IDH1 mutant gliomas.
Fighting an Infodemic in the Time of the COVID-19 Pandemic in India: Leveraging Technology and Social Media

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Dear Editor, We read with interest the article titled “Impact of rumors and misinformation on COVID-19 in social media” published in your esteemed journal [1]. As a continuation of the points made in that article, in this letter, we would like to discuss how technology and social media are being or should be leveraged to fight the coronavirus disease 2019 (COVID-19) “infodemic” and COVID-19-related misinformation in India. These strategies can further be replicated in the rest of the world. Misinformation is spreading through the use of technology (smartphones, Internet/mobile applications [e.g., WhatsApp]), social media platforms (e.g., Facebook, Twitter, YouTube, TikTok), and traditional mass media, and thus needs better regulation. This situation is exacerbated by the particularly low levels of health literacy in India [2], and it may not be possible for the majority of people in India to identify correct information from the vast ocean of available media, in which there are massive amounts of misinformation. To fight this infodemic—or, in other words, this menace of misinformation—the government of India is promoting the use of official websites such as the Ministry of Health and FampISSN 1975-8375 eISSN 2233-4521
Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.
Aerobic Bacterial Flora of Chimpanzees – A Four‐Year Study 1

The aerobic bacterial flora of a chimpanzee colony maintained in captivity has been followed over a 4‐year period. In many respects, this flora is similar to that of man. E. coli is the most commonly isolated bacteria from the intestinal tract. Alpha streptococci predominate in the mouth. Both Shigella and Salmonella were recovered in routine samplings and did not appear to be (with one exception) associated with sick animals. Enteropathogenic E. coli group B appears to be involved in illness – 56% of the isolates were from sick animals. The value of obtaining bacteriology specimens from the oral cavity or vagina of these animals, sick or healthy, is questioned.
Predicting antibiotic resistance in hospitalized patients by applying machine learning to electronic medical records

Background: Computerized decision support systems are becoming increasingly prevalent with advances in data collection and machine learning algorithms. However, they are scarcely used for empiric antibiotic therapy. Here we accurately predict the antibiotic resistance profiles of bacterial infections of hospitalized patients using machine learning algorithms applied to patients' electronic medical records. Methods: The data included antibiotic resistance results of bacterial cultures from hospitalized patients, alongside their electronic medical records. Five antibiotics were examined: Ceftazidime (n=2942), Gentamicin (n=4360), Imipenem (n=2235), Ofloxacin (n=3117) and Sulfamethoxazole-Trimethoprim (n=3544). We applied lasso logistic regression, neural networks, gradient boosted trees, and an ensemble combining all three algorithms, to predict antibiotic resistance. Variable influence was gauged by permutation tests and Shapely Additive Explanations analysis. Results: The ensemble model outperformed the separate models and produced accurate predictions on a test set data. When no knowledge regarding the infecting bacterial species was assumed, the ensemble model yielded area under the receiver-operating-characteristic (auROC) scores of 0.73-0.79, for different antibiotics. Including information regarding the bacterial species improved the auROCs to 0.8-0.88. The effects of different variables on the predictions were assessed and found consistent with previously identified risk factors for antibiotic resistance. Conclusions: Our study demonstrates the potential of machine learning models to accurately predict antibiotic resistance of bacterial infections of hospitalized patients. Moreover, we show that rapid information regarding the infecting bacterial species can improve predictions substantially. The implementation of such systems should be seriously considered by clinicians to aid correct empiric therapy and to potentially reduce antibiotic misuse.
Value of Neuropsychological Tests to Identify Patients with Depressive Symptoms on the Alzheimer’s Disease Continuum

Background: Depressive symptoms often co-occur with Alzheimer’s disease (AD) and can impact neuropsychological test results. In early stages of AD, disentangling cognitive impairments due to depression from those due to neurodegeneration often poses a challenge. Objective: We aimed to identify neuropsychological tests able to detect AD-typical pathology while taking into account varying degrees of depressive symptoms. Methods: A battery of neuropsychological tests (CERAD-NP) and the Geriatric Depression Scale (GDS) were assessed, and cerebrospinal fluid (CSF) biomarkers were obtained. After stratifying patients into CSF positive or negative and into low, moderate, or high GDS score groups, sensitivity and specificity and area under the curve (AUC) were calculated for each subtest. Results: 497 participants were included in the analyses. In patients with low GDS scores (≤10), the highest AUC (0.72) was achieved by Mini-Mental State Examination, followed by Constructional Praxis Recall and Wordlist Total Recall (AUC = 0.714, both). In patients with moderate (11–20) and high (≥21) GDS scores, Trail Making Test-B (TMT-B) revealed the highest AUCs with 0.77 and 0.82, respectively. Conclusion: Neuropsychological tests showing AD-typical pathology in participants with low GDS scores are in-line with previous results. In patients with higher GDS scores, TMT-B showed the best discrimination. This indicates the need to focus on executive function rather than on memory task results in depressed patients to explore a risk for AD.