Miracle-dz/UniFAR-FTUs huggingface dataset:
Epidemiology, clinical profile, management, and outcome of COVID-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India – Collaborative OPAI-IJO Study on Mucormycosis in COVID-19 (COSMIC), Report 1

Purpose: COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM) has reached epidemic proportion during India's second wave of COVID-19 pandemic, with several risk factors being implicated in its pathogenesis. This study aimed to determine the patient demographics, risk factors including comorbidities, and medications used to treat COVID-19, presenting symptoms and signs, and the outcome of management. Methods: This was a retrospective, observational study of patients with COVID-19-associated ROCM managed or co-managed by ophthalmologists in India from January 1, 2020 to May 26, 2021. Results: Of the 2826 patients, the states of Gujarat (22%) and Maharashtra (21%) reported the highest number of ROCM. The mean age of patients was 51.9 years with a male preponderance (71%). While 57% of the patients needed oxygen support for COVID-19 infection, 87% of the patients were treated with corticosteroids, (21% for > 10 days). Diabetes mellitus (DM) was present in 78% of all patients. Most of the cases showed onset of symptoms of ROCM between day 10 and day 15 from the diagnosis of COVID-19, 56% developed within 14 days after COVID-19 diagnosis, while 44% had delayed onset beyond 14 days. Orbit was involved in 72% of patients, with stage 3c forming the bulk (27%). Overall treatment included intravenous amphotericin B in 73%, functional endoscopic sinus surgery (FESS)/paranasal sinus (PNS) debridement in 56%, orbital exenteration in 15%, and both FESS/PNS debridement and orbital exenteration in 17%. Intraorbital injection of amphotericin B was administered in 22%. At final follow-up, mortality was 14%. Disease stage >3b had poorer prognosis. Paranasal sinus debridement and orbital exenteration reduced the mortality rate from 52% to 39% in patients with stage 4 disease with intracranial extension (p < 0.05). Conclusion: Corticosteroids and DM are the most important predisposing factors in the development of COVID-19-associated ROCM. COVID-19 patients must be followed up beyond recovery. Awareness of red flag symptoms and signs, high index of clinical suspicion, prompt diagnosis, and early initiation of treatment with amphotericin B, aggressive surgical debridement of the PNS, and orbital exenteration, where indicated, are essential for successful outcome.
Intraoperative blood volume loss according to gestational age at delivery among pregnant women with placenta accreta spectrum (PAS): an 11-year experience in Songklanagarind Hospital

Abstract A retrospective study was conducted to evaluate the intraoperative blood volume loss in pregnant women with PAS according to gestational age at delivery. A total of 116 women were enrolled, 39 (33.6%) had an intraoperative massive blood loss (>5000 ml). The massive haemorrhage group had statistically significantly higher percentages of increta and percreta type than the non-massive haemorrhage group (94.9 vs. 67.5%, p < .001). Multiple linear regression analysis showed a decreasing trend of intraoperative blood loss after 34 weeks’ gestation with the nadir period between 35 and 36+6 weeks’ gestation, especially from 36–36+6 weeks’ gestation which was statistically significant, p <. 05. The perinatal morbidities from 36–36+6 weeks were not statistically significantly different from 37 weeks’ gestation. Therefore, we recommend that pregnant women with PAS and stable clinical symptoms should be scheduled for caesarean hysterectomy from 36–36+6 weeks’ gestation. Impact statement What is already known on this subject? Massive obstetric haemorrhage from PAS disorders is the main concern for caesarean hysterectomy among these patients as it leads to secondary complications including coagulopathy, multisystem organ failure, and death. What do the results of this study add? The amount of intraoperative blood loss in pregnant women who underwent caesarean hysterectomy due to PAS, was lowest from 36–36+6 weeks’ gestation. What are the implications of these findings for clinical practice and/or further research? We recommend that pregnant women with PAS and stable clinical symptoms should be scheduled for caesarean hysterectomy from 36–36+6 weeks’ gestation.
Nitric Oxide-Dependent Electron Transport Chain Inhibition by the Cytochrome bc1 Inhibitor and Pretomanid Combination Kills Mycobacterium tuberculosis

Mycobacterium tuberculosis, the causative agent of human tuberculosis, harbors a branched electron transport chain, preventing the bactericidal action of cytochrome bc1 inhibitors (e.g., TB47). Here, we investigated, using luminescent mycobacterial strains, the in vitro combination activity of cytochrome bc1 inhibitors and nitric oxide (NO) donors including pretomanid (PMD) and explored the mechanisms of combination activity. ABSTRACT Mycobacterium tuberculosis, the causative agent of human tuberculosis, harbors a branched electron transport chain, preventing the bactericidal action of cytochrome bc1 inhibitors (e.g., TB47). Here, we investigated, using luminescent mycobacterial strains, the in vitro combination activity of cytochrome bc1 inhibitors and nitric oxide (NO) donors including pretomanid (PMD) and explored the mechanisms of combination activity. The TB47 and PMD combination quickly abolished the light emission of luminescent bacilli, as was the case for the combination of TB47 and aurachin D, a putative cytochrome bd inhibitor. The TB47 and PMD combination inhibited M. tuberculosis oxygen consumption, decreased ATP levels, and had a delayed bactericidal effect. The NO scavenger carboxy-PTIO prevented the bactericidal activity of the drug combination, suggesting the requirement for NO. In addition, cytochrome bc1 inhibitors were largely bactericidal when administered with DETA NONOate, another NO donor. Proteomic analysis revealed that the cotreated bacilli had a compromised expression of the dormancy regulon proteins, PE/PPE proteins, and proteins required for the biosynthesis of several cofactors, including mycofactocin. Some of these proteomic changes, e.g., the impaired dormancy regulon induction, were attributed to PMD. In conclusion, combination of cytochrome bc1 inhibitors with PMD inhibited M. tuberculosis respiration and killed the bacilli. The activity of cytochrome bc1 inhibitors can be greatly enhanced by NO donors. Monitoring of luminescence may be further exploited to screen cytochrome bd inhibitors.
Is Food Addictive? A Review of the Science.

As ultraprocessed foods (i.e., foods composed of mostly cheap industrial sources of dietary energy and nutrients plus additives) have become more abundant in our food supply, rates of obesity and diet-related disease have increased simultaneously. Food addiction has emerged as a phenotype of significant empirical interest within the past decade, conceptualized most commonly as a substance-based addiction to ultraprocessed foods. We detail (a) how approaches used to understand substance-use disorders may be applicable for operationalizing food addiction, (b) evidence for the reinforcing potential of ingredients in ultraprocessed foods that may drive compulsive consumptions, (c) the utility of conceptualizing food addiction as a substance-use disorder versus a behavioral addiction, and (d) clinical and policy implications that may follow if ultraprocessed foods exhibit an addictive potential. Broadly, the existing literature suggests biological and behavioral parallels between food addiction and substance addictions, with ultraprocessed foods high in both added fat and refined carbohydrates being most implicated in addictive-like eating. Future research priorities are also discussed, including the need for longitudinal studies and the potential negative impact of addictive ultraprocessed foods on children. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Giant exciton-enhanced shift currents and direct current conduction with subbandgap photo excitations produced by many-electron interactions

Significance Shift current, a bulk photovoltaic effect, arises from nonlinear light–matter interaction in a noncentrosymmetric crystal under continuous wave illumination. Although it is a promising mechanism for photocurrent generation without p–n junctions, the short-circuit current (which is related to the power efficiency of a solar cell device) is usually low. It is therefore important to understand the physics of the phenomenon and find materials with strong shift current conductivity. We calculate the shift current conductivity including excitonic effects in a real material (monolayer GeS) from first principles. We show that electron–hole interactions can dramatically enhance and qualitatively change shift current in reduced-dimensional materials. Our results indicate low-dimensional materials are promising candidates for next-generation photovoltaic devices with high efficiencies. Shift current is a direct current generated from nonlinear light–matter interaction in a noncentrosymmetric crystal and is considered a promising candidate for next-generation photovoltaic devices. The mechanism for shift currents in real materials is, however, still not well understood, especially if electron–hole interactions are included. Here, we employ a first-principles interacting Green’s-function approach on the Keldysh contour with real-time propagation to study photocurrents generated by nonlinear optical processes under continuous wave illumination in real materials. We demonstrate a strong direct current shift current at subbandgap excitation frequencies in monolayer GeS due to strongly bound excitons, as well as a giant excitonic enhancement in the shift current coefficients at above bandgap photon frequencies. Our results suggest that atomically thin two-dimensional materials may be promising building blocks for next-generation shift current devices.
Model-Oriented Dose Optimization of Voriconazole in Critically Ill Children

This study aimed to employ a population pharmacokinetic (PK) model to optimize the dosing regimen of voriconazole (VRC) in children with a critical illness. A total of 99 children aged from 0.44 to 13.58 years were included in this study. ABSTRACT This study aimed to employ a population pharmacokinetic (PK) model to optimize the dosing regimen of voriconazole (VRC) in children with a critical illness. A total of 99 children aged from 0.44 to 13.58 years were included in this study. The stability and predictive performance of the final model were evaluated by statistical and graphical methods. The optimal dosing regimen was proposed for children with different body weights, CYP2C19 phenotypes, and coadministrations with omeprazole. The PK of VRC was described by a two-compartment model with nonlinear Michaelis-Menten elimination. Body weight, CYP2C19 phenotype, and omeprazole were significant covariates on the maximum velocity of elimination (Vmax), which had an estimated typical value of 18.13 mg · h−1. Bayesian estimation suggested that the dose-normalized concentration and total exposure (peak concentration [Cmax]/D, trough concentration [Cmin]/D, and area under the concentration-time curve over 24 h [AUC24]/D) were significantly different between extensive metabolizer (EM) patients and poor metabolizer (PM) patients. To achieve the target concentration early, two loading doses of 9 mg · kg−1 of body weight every 12 h (q12h) were reliable for most children, whereas three loading doses of 6 to 7.5 mg · kg−1 q8h were warranted for young children weighing ≤18 kg (except for PM patients). The maintenance doses decreased about 30 to 40% in PM patients compared to that in EM patients. For children aged <2 years, in EM patients, the maintenance dose could be as high as 9 mg · kg−1. The maintenance dose of VRC was supposed to decrease slightly when coadministered with omeprazole. A population PK model of intravenous VRC for critically ill children has been successfully developed. It is necessary to adjust dosing regimens according to the CYP2C19 genotype. Optimal dosing regimens have been recommended based on the final model.
Modeling the Life Cycle of the Intramitochondrial Bacterium “Candidatus Midichloria mitochondrii” Using Electron Microscopy Data

Our results suggest that Midichloria mitochondrii, the intramitochondrial bacterium, does not invade mitochondria like predatory bacteria do but instead moves from mitochondrion to mitochondrion within the oocytes of Ixodes ricinus. A better understanding of the lifestyle of M. mitochondrii will allow us to better define the role of this bacterial symbiont in the host physiology. ABSTRACT “Candidatus Midichloria mitochondrii” is a Gram-negative bacterium that lives in strict intracellular symbiosis with the hard tick Ixodes ricinus, forming one of the most intriguing endosymbiosis described to date. The bacterium is capable of durably colonizing the host mitochondria, a peculiar tropism that makes “Ca. Midichloria mitochondrii” a very interesting tool to study the physiology of these cellular organelles. The interaction between the symbiont and the organelle has, however, been difficult to characterize. A parallelism with the predatory bacterium Bdellovibrio bacteriovorus has been drawn, suggesting the hypothesis that “Ca. Midichloria mitochondrii” could prey on mitochondria and consume them to multiply. We studied the life cycle of the bacterium within the host oocytes using a multidisciplinary approach, including electron microscopy, molecular biology, statistics, and systems biology. Our results were not coherent with a predatory-like behavior by “Ca. Midichloria mitochondrii” leading us to propose a novel hypothesis for its life cycle. Based on our results, we here present a novel model called the “mitochondrion-to-mitochondrion hypothesis. ” Under this model, the bacterium would be able to move from mitochondrion to mitochondrion, possibly within a mitochondrial network. We show that this model presents a good fit with quantitative electron microscopy data. IMPORTANCE Our results suggest that “Candidatus Midichloria mitochondrii,” the intramitochondrial bacterium, does not invade mitochondria like predatory bacteria do but instead moves from mitochondrion to mitochondrion within the oocytes of Ixodes ricinus. A better understanding of the lifestyle of “Ca. Midichloria mitochondrii” will allow us to better define the role of this bacterial symbiont in the host physiology.
Ferredoxin 1 is downregulated by the accumulation of abscisic acid in an ABI5-dependent manner to facilitate rice stripe virus infection in Nicotiana benthamiana and rice.

Ferredoxin 1 (FD1) accepts and distributes electrons in the electron transfer chain of plants. Its expression is universally downregulated by viruses and its roles in plant immunity have been brought into focus over the past decade. However, the mechanism by which viruses regulate FD1 remains to be defined. In a previous report, we found that the expression of Nicotiana benthamiana FD1 (NbFD1) was downregulated following potato virus X (PVX) infection, and that NbFD1 regulates callose deposition at plasmodesmata to play a defense role against PVX infection. We now report that NbFD1 is downregulated by RSV infection and that silencing of NbFD1 also facilitates rice stripe virus (RSV) infection, while viral infection was inhibited in a transgenic line overexpressing NbFD1, indicating that NbFD1 also functions in defense against RSV infection. Next, an RSV-derived small interfering RNA was identified that contributes to the downregulation of FD1 transcripts. Further analysis showed that the abscisic acid (ABA) which accumulates in RSV-infected plants also repressed NbFD1 transcription. It does this by stimulating expression of ABA insensitive 5 (ABI5), which binds the ABA response element (ABRE) motifs in the NbFD1 promoter, resulting in negative regulation. Regulation of FD1 by ABA was also confirmed in RSV-infected plants of the natural host rice. The results therefore suggest a mechanism by which virus regulates ChRGs to suppress their defense roles.
Nucleophosmin1 and isocitrate dehydrogenase 1 and 2 as measurable residual disease markers in acute myeloid leukemia

Monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML) plays an important role in predicting relapse and outcome. The applicability of the leukemia-initiating nucleophosmin1 (NPM1) gene mutations in MRD detection is well-established, while that of isocitrate dehydrogenase1/2 (IDH1/2) mutations are matter of debate. The aim of this study was to investigate the stability of NPM1 and IDH1/2 mutations at diagnosis and relapse retrospectively in 916 adult AML patients. The prognostic value of MRD was evaluated by droplet digital PCR on the DNA level in a selected subgroup of patients in remission. NPM1 re-emerged at relapse in 91% (72/79), while IDH1/2 in 87% (20/23) of mutation-positive cases at diagnosis. NPM1 mutation did not develop at relapse, on the contrary novel IDH1/2 mutations occurred in 3% (3/93) of previously mutation-negative cases. NPM1 MRD-positivity after induction (n = 116) proved to be an independent, adverse risk factor (MRDpos 24-month OS: 39.3±6.2% versus MRDneg: 58.5±7.5%, p = 0.029; HR: 2.16; 95%CI: 1.25–3.74, p = 0.006). In the favorable subgroup of mutated NPM1 without fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) or with low allelic ratio, NPM1 MRD provides a valuable prognostic biomarker (NPM1 MRDpos versus MRDneg 24-month OS: 42.9±6.7% versus 66.7±8.6%; p = 0.01). IDH1/2 MRD-positivity after induction (n = 62) was also associated with poor survival (MRDpos 24-month OS: 41.3±9.2% versus MRDneg: 62.5±9.0%, p = 0.003; HR 2.81 95%CI 1.09–7.23, p = 0.032). While NPM1 variant allele frequency decreased below 2.5% in remission in all patients, IDH1/2 mutations (typically IDH2 R140Q) persisted in 24% of cases. Our results support that NPM1 MRD even at DNA level is a reliable prognostic factor, while IDH1/2 mutations may represent pre-leukemic, founder or subclonal drivers.
The efficacy and deficiency of contemporary treatment for spinal cord arteriovenous shunts.

Contemporary treatments for spinal cord arteriovenous shunts are only based on clinicians' treatment experiences and expertise due to its rarity. We reviewed the clinical course of the largest multi-cantered cohort to evaluate the efficacy and deficiency of contemporary interventional treatments for spinal cord arteriovenous shunts. The clinical features, treatment results and clinical outcomes of 463 spinal cord arteriovenous shunts patients were retrospectively assessed. The main outcome was the neurological deterioration that was evaluated based on the modified Aminoff and Logue scale. According to post-treatment DSA, complete obliteration was defined as disappearance of the intradural lesion, whereas partial obliteration was defined as any residual intradural lesion remaining visible and was further categorized as shunt-reduction obliteration (the nidus or shunt points was reduced) or palliative obliteration (only obliterated aneurysms or feeders). Cure rate was 40.6% for whole cohort, 58.5% after microsurgery, and 26.4% after embolization. The curative resection was associated with non-metameric lesions, lesions with a maximum diameter < 3 cm and lesions without anterior sulcal artery supply. The curative embolization was associated with fistula-type lesions, non-metameric lesions, and main drainage diameter < 1.5 mm. Permanent treatment-related neurological deficits rate was 11.2% for the whole cohort, 16.1% after microsurgery, and 5.6% after embolization. The pre-treatment clinical deterioration rate was 32.5%/year, which decreased to 9.3%/year after clinical interventions. After partial treatment, the long-term acute and gradual deterioration rate were 5.3%/year and 3.6%/year, respectively. The acute deteriorations were associated with metameric lesions, craniocervical lesions, lesions with a maximum diameter ≥2 cm and residual aneurysm. Residual aneurysm was the only predictor of acute deterioration for non-metameric spinal cord arteriovenous shunts. The gradual deteriorations were associated with palliative obliteration, absence of pre-treatment acute deterioration and intact main drainage. Although clinical risks of spinal cord arteriovenous shunts were reduced after clinical interventions, contemporary treatments for spinal cord arteriovenous shunt remains associated with considerable risks and incomplete efficacy. Individualized treatment plans should be adopted according to the angioarchitectural features and major clinical risks of specific lesions. There is a higher opportunity for complete obliteration for lesions with simple angioarchitecture. However, regarding most of spinal cord arteriovenous shunts with complex vascular anatomy, partial treatment is the only choice. For these patients, palliative obliteration targeting the aneurysms is recommended for reducing hemorrhagic risk, whereas shunt-reduction obliteration is necessary for non-haemorrhagic myelopathy. Contemporary treatment is ineffective in reducing hemorrhagic risk of incurable metameric spinal cord arteriovenous shunts.
Estimation of Lewis‐negative alleles by high‐resolution melting analysis of three tag SNPs of FUT3

The expression of type 1 chain Lewis blood group antigens is regulated by secretor‐type α(1,2)fucosyltransferase, encoded by FUT2, and Lewis α(1,3/1,4)fucosyltransferase, encoded by FUT3. Accumulating evidence has linked Lewis phenotypes or genotypes to various clinical conditions. Thus, in addition to FUT2, large‐scale FUT3 genotyping is important. Because FUT3 has two paralogous genes (FUT5 and FUT6) with high DNA sequence similarity, we should select the polymerase chain reaction (PCR) primers carefully for FUT3 genotyping. Previously, we suggested that 13G>A (rs28362458), 59T>G (rs28362459) and 202T>C (rs812936) could be selected as tag single nucleotide polymorphisms (SNPs) for detection of Lewis‐negative alleles (le).
Strategies for the diagnosis and management of meningitis in HIV-infected adults in resource limited settings

ABSTRACT Introduction The incidence of human immunodeficiency virus-1 (HIV-1) associated meningitis has been declining in the post-combination antiretroviral treatment (ART) era, although survival rates remain low for the common causes like tuberculosis and cryptococcal disease. Diagnosis and treatment of meningitis in HIV-1 is complicated by atypical clinical presentations, limited accuracy of diagnostic tests, access to diagnostic tests, and therapeutic agents in low- and middle-income countries (LMIC) and immune reconstitution inflammatory syndrome (IRIS). Areas covered We provide an overview of the common etiologies of meningitis in HIV-1-infected adults, suggest a diagnostic approach based on readily available tests, and review specific chemotherapeutic agents, host-directed therapies, supportive care, timing of ART initiation, and considerations in the management of IRIS with a focus on resource-limited settings. They identify key knowledge gaps and suggest areas for future research. Expert opinion Evidence-based management of HIV-1-associated meningitis is sparse for common etiologies. More readily available and sensitive diagnostic tests as well as standardized investigation strategies are required in LMIC. There is a lack of availability of recommended drugs in areas of high HIV-1 prevalence and a limited pipeline of novel chemotherapeutic agents. Host-directed therapies have been inadequately studied.