Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3.

Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.

Rho-dependent termination enables cellular pH homeostasis.

The termination factor Rho, an ATP-dependent RNA translocase, preempts pervasive transcription processes, thereby rendering genome integrity in bacteria. Here, we show that the loss of Rho function raised the intracellular pH to >8.0 in Escherichia coli. The loss of Rho function upregulates tryptophanase-A (TnaA), an enzyme that catabolizes tryptophan to produce indole, pyruvate, and ammonia. We demonstrate that the enhanced TnaA function had produced the conjugate base ammonia, raising the cellular pH in the Rho-dependent termination defective strains. On the other hand, the constitutively overexpressed Rho lowered the cellular pH to about 6.2, independent of cellular ammonia levels. Since Rho overexpression may increase termination activities, the decrease in cellular pH could result from an excess H+ ion production during ATP hydrolysis by overproduced Rho. Furthermore, we performed in vivo termination assays to show that the efficiency of Rho-dependent termination was increased at both acidic and basic pH ranges. Given that the Rho level remained unchanged, the alkaline pH increases the termination efficiency by stimulating Rho's catalytic activity. We conducted the Rho-mediated RNA release assay from a stalled elongation complex to show an efficient RNA release at alkaline pH, compared to the neutral or acidic pH, that supports our in vivo observation. Whereas acidic pH appeared to increase the termination function by elevating the cellular level of Rho. This study is the first to link Rho function to the cellular pH homeostasis in bacteria. IMPORTANCE The current study shows that the loss or gain of Rho-dependent termination alkalizes or acidifies the cytoplasm, respectively. In the case of loss of Rho function, the tryptophanase-A enzyme is upregulated, and degrades tryptophan, producing ammonia to alkalize cytoplasm. We hypothesize that Rho overproduction by deleting its autoregulatory DNA portion increases termination function, causing excessive ATP hydrolysis to produce H+ ions and cytoplasmic acidification. Therefore, this study is the first to unravel a relationship between Rho function and intrinsic cellular pH homeostasis. Furthermore, the Rho level increases in the absence of autoregulation, causing cytoplasmic acidification. As intracellular pH plays a critical role in enzyme function, such a connection between Rho function and alkalization will have far-reaching implications for bacterial physiology.

Updates in the Management of Paraneoplastic Syndrome.

Paraneoplastic neurological syndromes (PNS) are defined as remote neurologic immune-mediated effects triggered by underlying systemic tumors. While recognizing specific syndromes can aid early cancer detection, overutilization of paraneoplastic assays in the absence of a classic syndrome can precipitate overdiagnosis and overtreatment. PNS involve autoantibodies targeting intracellular or extracellular antigens, with variable immunotherapy responses based on antigen type. Diagnosing PNS is challenging, requiring exclusion of other differential diagnoses. New diagnostic criteria classify PNS into high-risk and intermediate-risk phenotypes based on clinical phenotype, neuronal antibodies, and cancer presence. Patients with cell surface antibodies respond better to immunotherapies compared to those with intracellular antigen targets. Understanding PNS syndromes, serological markers, and oncological features guides management, which facilitates initiation of immunosuppression for PNS alongside treatment of the underlying neoplasm, thereby improving neurologic and oncologic outcomes. Initial treatments often include intravenous methylprednisolone, plasma exchange, or intravenous immunoglobulins. Second-line immunosuppressants like rituximab or cyclophosphamide may be necessary if initial treatments fail. Specific therapies vary based on antibody target. Here, we summarize the current approach to the investigation, diagnosis, and treatment of patients with suspected PNS.

Comparative genomics and characterization of a multidrug-resistant Acinetobacter baumannii VRL-M19 isolated from a crowded setting in India.

A crowded vegetable market serves as a mass gathering, posing a potential risk for infection transmission. In this study, we isolated a multidrug-resistant Acinetobacter baumannii strain, VRL-M19, from the air of such a market and conducted comparative genomics and phenotypic characterization. Antimicrobial susceptibility testing, genome sequencing using Illumina HiSeq X10, and pan-genome analysis with 788 clinical isolates identified core, accessory, and unique drug-resistant determinants. Mutational analysis of drug-resistance genes, virulence factor annotation, in vitro pathogenicity assessment, subsystem analysis, Multilocus sequence typing, and whole genome phylogenetic analysis were performed. VRL-M19 exhibited multidrug resistance with 69 determinants, and analysis across 788 clinical isolates and 350 Indian isolates revealed more accessory genes (52 out of 69) in the Indian isolates. Multiple mutations were observed in drug target modification genes, and the strain was identified as a moderate biofilm-former with 55 virulence factors. Whole genome phylogenetics indicated a close relationship between VRL-M19 and clinical A. baumannii strains. In conclusion, our comprehensive study suggests that VRL-M19 is a multidrug-resistant, potential pathogen with biofilm-forming capabilities, closely associated with clinical A. baumannii strains.

Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating JMJD3.

Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.

In Vitro and In Silico Studies on 4-Nitroacetophenone Thiosemicarbazone Potential Cytotoxicity Against A549 Cell Lines.

Lung malignancy is a major worldwide issue that occurs due to the dysregulation of various growth factors. Lung cancer has no apparent signs in the early stages, which makes it harder to catch it in time and leads to a higher fatality rate. So, the goal of this work was to create and analyze a novel chemical molecule called 4-nitro acetophenone thiosemicarbazone (4-NAPTSc) against the lung cancer cell line A549 and human non-tumorigenic lung epithelial cell line BAES-2B. The ligand was synthesized by refluxing the reaction mixture of 4-nitro acetophenone and thiosemicarbazide and was further characterized by UV, FTIR, and 1H and 13C NMR and Differential Scanning Calorimetry (DSC) study. Cytotoxicity assay/MTT (3-(4,5-dimethylthiazol-2-yl))2,5-diphenyltetrazolium bromide) was used to evaluate the cytotoxicity of the compound. Epidermal growth factor receptors (EGFR), polo-like kinase-1 (PLK1), and vascular endothelial growth factor receptors (VEGFR) were chosen as the target proteins for molecular docking to find potential ligand binding sites and inhibit their function. A novel yellow-colored crystalline solid has been synthesized. 4-NAPTSc had an IC50 of 2.93 µg/mL against the A549 lung cancer cells. When the dosage is increased from 5 to 15 µg/mL along with time, the cell viability falls. Docking results showed that the compound binds with the targeted proteins' amino acid residues, and the likeness profile of the compound is also favorable. This study reveals that the compound has the potential for further investigation and can be used in multitargeted cancer therapies.

Assessment of interleukin 1 receptor antagonist (IL-1RA) levels in children with and without community acquired pneumonia: a hospital based case-control study.

The primary objective was to compare serum interleukin-1 receptor antagonist (IL-1RA) levels in cases of community acquired pneumonia (CAP) and healthy age-gender-matched controls. The secondary objective was to compare serum IL-1RA levels in cases which were positive or negative for Streptococcus pneumoniae in the blood by real-time-polymerase chain reaction (RT-PCR). Hospitalized children with World Health Organization defined CAP, aged 2-59 months, were included as cases. Healthy controls were recruited from the immunization clinic of the hospital. Enzyme-linked immunosorbent assay (ELISA) test was used to detect serum IL-1RA levels. Identification of S.pneumoniae in blood was done by RT-PCR. From October 2019 to October 2021, 330 cases (123, 37.27% female) and 330 controls (151, 45.75% females) were recruited. Mean serum IL-1RA levels (ng/ml) were 1.36 ± 0.95 in cases and 0.25 ± 0.25 in controls (p < 0.001). Within cases, serum IL-1RA levels were significantly higher in those whose RT-PCR was positive for S.pneumoniae. Thus serum IL-1RA levels may be evaluated as a surrogate marker of S.pneumoniae in future studies.

The main purpose of the study was to compare the levels of a protein in the blood that is part of the immune system, called interleukin-1 receptor antagonist (IL-1RA) which binds to the same site in the body as an antibody does when it is fighting certain diseases, like pneumonia. We then compared the levels of this protein, IL-1RA, in hospitalized cases of community acquired pneumonia (CAP), caused from exposure to germs in the community, rather than obtained or contracted in a hospital, to that found in healthy people or 'controls' recruited from an immunization clinic. Cases and controls were matched for age and gender. The secondary objective of our study was to compare the level of IL-1RA protein in the blood in cases that were positive for the bacteria Streptococcus pneumoniae measured in the blood by a molecular test called real-time-polymerase chain reaction which can detect a very small amounts of a protein that is uniquely found in the S.pneumoniae bacteria that causes CAP. This case­control study was conducted in a large teaching institution that receives referrals from the other hospitals in northern India. It was found that serum IL-1RA levels were raised in cases of CAP, especially those which were possibly due to S.pneumoniae.

Unmasking the Hidden Threat of Cardiac Involvement in Dengue Fever: A Critical Longitudinal Study.

INTRODUCTION: Dengue fever (DF) arises from the dengue virus (DENV), a common viral illness transmitted by arthropods. This medical condition has the potential to result in severe complications, including but not limited to liver failure, disseminated intravascular coagulation, dengue encephalopathy, myocarditis, acute renal failure, and hemolytic uremic syndrome. Evaluating cardiac manifestations in dengue is crucial for timely intervention and intensive care to save patients' lives. MATERIALS AND METHODS: A longitudinal study involved 104 dengue fever patients admitted to the Department of Medicine at New Civil Hospital, Surat, between May 2021 and October 2021, to identify potential cardiac involvement. RESULTS: The study found that out of the 104 patients, 28 (26.92%) showed cardiac involvement based on clinical manifestations. Among these patients, 28 (26.92%) exhibited abnormal ECG results, and 39 (37.50%) showed elevated creatine kinase-MB (CK-MB) levels. Of the 28 patients who showed ECG changes, 14 (50%) displayed abnormal 2D-echocardiography (ECHO) results. The most common electrocardiographic anomaly was a T-wave inversion in V1-V4. The predominant 2D-ECHO finding was mild pericardial effusion. CONCLUSION: Cardiac involvement in dengue presents atypically and can lead to conditions like myocarditis, arrhythmias, cardiac failure, or shock. Assessing cardiac manifestations in dengue patients is pivotal for appropriate management.

A review on therapeutic mechanism of medicinal plants against osteoporosis: effects of phytoconstituents.

Osteoporosis is a metabolic bone disorder that over time results in bone loss and raises the risk of fracture. The condition is frequently silent and only becomes apparent when fractures develop. Osteoporosis is treated with pharmacotherapy as well as non-pharmacological therapies such as mineral supplements, lifestyle changes, and exercise routines. Herbal medicine is frequently used in clinical procedures because of its low risk of adverse effects and cost-effective therapeutic results. In the current review, we have used a thorough strategy to identify some known medicinal plants with anti-osteoporosis capabilities, their origin, active ingredients, and pharmacological information. Furthermore, several signaling pathways, such as the apoptotic pathway, transcription factors, the Wnt/-catenin signaling pathway, and others, are regulated by bioactive components and help to improve bone homeostasis. This review will provide a better understanding of the anti-osteoporotic effects of bioactive components and the concomitant modulations of signaling pathways.

Comparison of single and multiple file rotary endodontic instruments for debris and irrigant extrusion: An in vitro study.

Aim: The aim of this study was to assess and compare the quantity of apically debris which was extruded apically by TruNatomy (TN), ProTaper Next (PTN), HyFlex electric discharge machining (EDM), and HyFlex controlled memory (CM), following root canal preparation. Materials and Methods: Sixty extracted single-canal mandibular premolars were used. The root canal preparation was done with TN, HyFlex EDM, PTN, or HyFlex CM files. The preweight debris, which was extruded apically, was collected in the Eppendorf tube and later on incubated at 670°C for 3 days and weighed again to record the extruded debris. Results: The result showed that there was a significant reduction in debris extrusion by TN system, followed by PTN system, HyFlex EDM, and maximum extrusion in HyFlex CM (P < 0.05). Between the PTN and TN groups as well as between the HyFlex EDM and HyFlex CM groups, statistically significant difference was not observed (P > 0.05). Conclusion: Apical debris extrusion is the inherent nature of the all file systems. Nevertheless, the TN file system produced substantially minimum debris extrusion among other systems compared in the study.

Managing Multiple Schwannomatosis of Vagus and Hypoglossal Nerves: The Unanticipated Complications.

Schwannomas are rare benign tumours of the nerve sheath. Extracranial schwannomas are usually found solitary, in the absence of other features of neurofibromatosis. The non NF1/2 multiple schwannomas are collectively described as the clinical scenario called schwannomatosis. We present a rare case of two extracranial schwannomas involving vagus and hypoglossal nerves in a 22-year-old female along with an unusual surgical complication of CSF leak presenting as post-op neck mass and a review of previously reported similar cases. A thorough literature search using the MeSH terms-'schwannomatosis' or 'Multiple Schwannoma' and 'Vagal Schwannoma' and 'Hypoglossal Schwannoma', was conducted using online databases and augmentated by hand search. A total of 13 reported cases were found and reviewed. Of the 14 cases described from review of literature and our case, 50% had involvement of vagus nerve as one of the components. 12.5% had hypoglossal and cervical sympathetic plexus involvement each. All patients underwent surgical excision. Half of the patients suffered intraoperative nerve sacrifice with resultant severe functional deficits like vocal cord paralysis, Horners syndrome, hypoglossal palsy, facial palsy and eleventh nerve palsy. In our case, there was un-unusual complication of CSF leak presenting as a cervical neck mass. Multiple extracranial head and neck schwannomas are rare and their management is fraught with several complications. Decision to operate is often perplexing. However, early planned surgical excision and preservation of nerve of origin minimizes the impact on quality of life postoperatively.

Hearing outcomes in pediatric tympanoplasty and factors affecting surgical outcomes in the current era.

OBJECTIVES: Type-1 tympanoplasty continues to be the treatment of choice for tympanic membrane perforations resulting from chronic suppurative otitis media (CSOM) in children, which is a principal cause of correctable hearing loss in the pediatric population. There is an ongoing debate about the surgical success rate, the factors affecting success as well as the best intervention time for this population group. This study assessed the outcome of Type-1 tympanoplasty in children in terms of 1) graft uptake and 2) hearing improvement as assessed by audiology. METHODS: The study involved 40 patients aged 6 to ≤14 years suffering from tubotympanic chronic suppurative otitis media. The patients in the study had a central perforation of the pars tensa of the tympanic membrane. Pre-op investigations included Pure tone audiometry, Eustachian tube function test and nasopharyngeal x-ray. Type-1 tympanoplasty was performed on all patients. They were followed up at end of two months, six months, and one year postoperatively to assess surgical success and hearing outcomes. RESULTS: Overall graft uptake and the surgical success rate was 80%. Postoperatively air-bone gap closure up to 5 dB was achieved in 62.5% of patients at the end of one year. A normal type A tympanometry curve was achieved in 75% of patients. There was a significant reduction in hearing handicap. The best results were obtained in the 9-10 years age group. CONCLUSION: Tympanoplasty has a high success rate in children. There is a significant improvement in hearing post-surgery. There is a minimal impact of traditionally believed confounding factors. Considering the positive impact of improved hearing and reduced hearing disability, the authors suggest that surgeons should take young children up for tympanoplasty.

Association of Interleukin-1 Receptor Antagonist ( IL-1RA ) Gene Polymorphism with Community-Acquired Pneumonia in North Indian Children: A Case-Control Study.

Background Community-acquired pneumonia (CAP) is the leading cause of death in children < 5 years of age. The primary objective of the study was to assess the association of IL-1RA gene polymorphism in children aged 2 to 59 months with CAP and the secondary objective was to assess the association of gene polymorphism with mortality among hospitalized CAP cases. Study Design This case-control study was conducted in a tertiary teaching institute in Northern India. Hospitalized children aged 2 to 59 months with World Health Organization-defined CAP were included as cases after parental consent. Age-matched healthy controls were recruited from the immunization clinic of the hospital. Genotyping was done using polymerase chain reaction to analyze the variable number of tandem repeats of IL-1RA gene polymorphism. Result From October 2019 to October 2021, 330 cases (123, 37.27% female), and 330 controls (151, 45.75% female) were recruited. Genotype A2/A2 of the IL-1RA gene was found to be associated with the increased risk for CAP children with adjusted odds ratio (AOR) of 12.24 (95% confidence interval [CI] 5.21-28.7, p < 0.001). A2 and A4 alleles were also found to be at risk for CAP. A1/A2 genotype was found to be protective for CAP with an AOR of 0.29 (95% CI 0.19-19.0.45). The genotype A2/A2 and A2 allele of IL-1RA gene was associated with child mortality with CAP cases. Conclusion In IL1RA gene, A2/A2 genotype and A2 allele were associated with increased risk of CAP and A1/A2 were found to be protective for CAP. The genotype A2/A2 and A2 was associated with CAP mortality.

Identification of a Major-Effect Quantitative Trait Loci Associated with Begomovirus Resistance in Cucurbita moschata.

Begomoviruses, viz. squash leaf curl China virus and tomato leaf curl New Delhi virus causative diseases are major concerns of quantitative and qualitative losses in pumpkin (Cucurbita moschata) worldwide. Punjab Agricultural University (PAU) in India has identified a resistant source (PVR-1343) against mixed infection (MI-Sq/To) of these begomoviruses. Introgression of resistance in diverse genetic backgrounds requires the identification of quantitative trait loci (QTLs) associated with MI-Sq/To resistance. Phenotyping of 229 F2:3 progenies derived from the PVR-1343 × P-135 cross revealed digenic recessive inheritance against MI-Sq/To resistance in PVR-1343. To identify the genomic region, resistant and susceptible bulks were subjected to whole-genome resequencing along with their parents. The whole-genome resequence analysis of parents and bulks using QTLseq/QTLseqr approaches identified an overlapping 1.52 Mb region on chromosome 7 (qMI-Sq/To7.1), while chromosomal region spanning 0.87 Mb on chromosome17 (qMI-Sq/To17.1) was additionally identified by QTLseqr. However, the highest peak value on chromosome 7 with three algorithms {G', ∆(SNP-index) and -log10 (P value)} highlighted the major contribution of qMI-Sq/To7.1 in MI-Sq/To resistance. Nine polymorphic SNPs identified within the highly significant qMI-Sq/To7.1 region were converted into KASP markers. KASP genotyping of F2 individuals narrowed down the qMI-Sq/To7.1 interval to 103 kb region flanked by two markers, Cmo3914729 and Cmo4018182, which contained 16 annotated genes and accounted for 59.84% of phenotypic variation. The Cmo4018182 KASP marker accurately predicted disease reaction in 91% of diverse Cucurbita genotypes and showed nonsynonym substitutions in the coding region of putative candidate SYNTAXIN-121 gene. These findings pave the way for marker-assisted breeding and elucidating the underlying mechanism of begomovirus resistance in C. moschata.

Diagnostic Concordance of Telemedicine as Compared With Face-to-Face Care in Primary Health Care Clinics in Rural India: Randomized Crossover Trial.

BACKGROUND: With the COVID-19 pandemic, there was an increase and scaling up of provider-to-provider telemedicine programs that connect frontline health providers such as nurses and community health workers at primary care clinics with remote doctors at tertiary facilities to facilitate consultations for rural patients. Considering this new trend of increasing use of telemedicine, this study was conducted to generate evidence for patients, health providers, and policymakers to compare if provider-to-provider telemedicine-based care is equivalent to in-person care and is safe and acceptable in terms of diagnostic and treatment standards. OBJECTIVE: This study aims to compare the diagnosis and treatment decisions from teleconsultations to those of in-person care in teleclinics in rural Gujarat. METHODS: We conducted a diagnostic concordance study using a randomized crossover study design with 104 patients at 10 telemedicine primary care clinics. Patients reporting to 10 telemedicine primary care clinics were randomly assigned to first receive an in-person doctor consultation (59/104, 56.7%) or to first receive a health worker-assisted telemedicine consultation (45/104, 43.3%). The 2 groups were then switched, with the first group undergoing a telemedicine consultation following the in-person consultation and the second group receiving an in-person consultation after the teleconsultation. The in-person doctor and remote doctor were blinded to the diagnosis and management plan of the other. The diagnosis and treatment plan of in-person doctors was considered the gold standard. RESULTS: We enrolled 104 patients reporting a range of primary health care issues into the study. We observed 74% (77/104) diagnostic concordance and 79.8% (83/104) concordance in the treatment plan between the in-person and remote doctors. No significant association was found between the diagnostic and treatment concordance and the order of the consultation (P=.65 and P=.81, respectively), the frontline health worker-doctor pair (both P=.93), the gender of the patient (both P>.99), or the mode of teleconsultation (synchronous vs asynchronous; P=.32 and P=.29, respectively), as evaluated using Fisher exact tests. A significant association was seen between the diagnostic and treatment concordance and the type of case (P=.004 and P=.03, respectively). The highest diagnostic concordance was seen in the management of hypertension (20/21, 95% concordance; Cohen kappa=0.93) and diabetes (14/15, 93% concordance; Cohen kappa=0.89). The lowest values were seen in cardiology (1/3, 33%) and patients presenting with nonspecific symptoms (3/10, 30%). The use of a digital assistant to facilitate the consultation resulted in increased adherence to evidence-based care protocols. CONCLUSIONS: The findings reflect that telemedicine can be a safe and acceptable alternative mode of care especially in remote rural settings when in-person care is not accessible. Telemedicine has advantages. for the potential gains for improved health care-seeking behavior for patients, reduced costs for the patient, and improved health system efficiency by reducing overcrowding at tertiary health facilities.

Resolution of Maximum Entropy Method-Derived Posterior Conformational Ensembles of a Flexible System Probed by FRET and Molecular Dynamics Simulations.

Maximum entropy methods (MEMs) determine posterior distributions by combining experimental data with prior information. MEMs are frequently used to reconstruct conformational ensembles of molecular systems for experimental information and initial molecular ensembles. We performed time-resolved Förster resonance energy transfer (FRET) experiments to probe the interdye distance distributions of the lipase-specific foldase Lif in the apo state, which likely has highly flexible, disordered, and/or ordered structural elements. Distance distributions estimated from ensembles of molecular dynamics (MD) simulations serve as prior information, and FRET experiments, analyzed within a Bayesian framework to recover distance distributions, are used for optimization. We tested priors obtained by MD with different force fields (FFs) tailored to ordered (FF99SB, FF14SB, and FF19SB) and disordered proteins (IDPSFF and FF99SBdisp). We obtained five substantially different posterior ensembles. As in our FRET experiments the noise is characterized by photon counting statistics, for a validated dye model, MEM can quantify consistencies between experiment and prior or posterior ensembles. However, posterior populations of conformations are uncorrelated to structural similarities for individual structures selected from different prior ensembles. Therefore, we assessed MEM simulating varying priors in synthetic experiments with known target ensembles. We found that (i) the prior and experimental information must be carefully balanced for optimal posterior ensembles to minimize perturbations of populations by overfitting and (ii) only ensemble-integrated quantities like inter-residue distance distributions or density maps can be reliably obtained but not ensembles of atomistic structures. This is because MEM optimizes ensembles but not individual structures. This result for a highly flexible system suggests that structurally varying priors calculated from varying prior ensembles, e.g., generated with different FFs, may serve as an ad hoc estimate for MEM reconstruction robustness.

Development of a Digital Assistant to Support Teleconsultations Between Remote Physicians and Frontline Health Workers in India: User-Centered Design Approach.

BACKGROUND: Many low- and middle-income countries have adopted telemedicine programs that connect frontline health workers (FHWs) such as nurses, midwives, or community health workers in rural and remote areas with physicians in urban areas to deliver care to patients. By leveraging technology to reduce temporal, financial, and geographical barriers, these health worker-to-physician telemedicine programs have the potential to increase health care quality, expand the specialties available to patients, and reduce the time and cost required to deliver care. OBJECTIVE: We aimed to identify, validate, and prioritize unmet needs in the health care space of health worker-to-physician telemedicine programs and develop and refine a solution that addresses those needs. METHODS: We collected information regarding user needs through ethnographic research, direct observation, and semistructured interviews with 37 stakeholders (n=5, 14% physicians; n=1, 3% public health program manager; n=12, 32% community health workers; and n=19, 51% patients) at 2 telemedicine clinics in rural West Bengal, India. We used the Spiral-Iterative Innovation Model to design and develop a prototype solution to meet these needs. RESULTS: We identified 74 unmet needs through our immersion in health worker-to-physician telemedicine programs. We identified a critical unmet need that achieving optimal teleconsultations in low- and middle-income countries often requires shifting tasks such as history taking and physical examination from high-skilled remote physicians to FHWs. To meet this need, we developed a prototype digital assistant that would allow FHWs to assume some of the tasks carried out by remote clinicians. The user needs of multiple stakeholder groups (patients, FHWs, physicians, and health organizations) were incorporated into the design and features of the task-shifting tool. The final prototype was shared with the health workers, physicians, and public health program managers who expressed that the tool would be useful and valuable. CONCLUSIONS: The final prototype that was developed was released as an open-source digital public good and may improve the quality and efficiency of care delivery in health worker-to-physician telemedicine programs.

Biochemical aspects of effects of mesenchymal stem cell treatment in chronic wounds progressive healing.

Chronic wounds are a persistent burden for medical professionals. Despite developments and advancements in treatment, these wounds do not heal completely. Mesenchymal stem cells (MSCs) are the epicenter of regenerative medicine that have shown promising results in chronic wound regeneration. Autologous peripheral blood-derived MSCs (PB-MSCs) are comparatively new in wound healing treatment, bone-marrow-derived MSCs (BM-MSCs), and adipose-derived stem cells (ADSCs) are commonly being practiced. In the present study, PB-MSCs treatment was given to chronic wound patients. Various biochemical parameters like random blood glucose, serum urea, serum creatinine, bilirubin (total and direct), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), total protein, albumin levels, and association of other factors/conditions such as age, sex, addiction of drug/alcohol were also evaluated/compared with complete and without complete healing. The wound area of the ulcer was found to be significantly reduced and the wound was healthier after the treatment. These biochemical parameters could be certainly utilized as biomarkers to anticipate the risk of chronic wounds. These findings may contribute to the development of better wound care treatment strategies and drug discovery in the field of regenerative medicine.

Gracin's Syndrome, a Rare Clinical Challenge in the Setting of Invasive Mucormycosis: A Systematic Review.

Garcin's Syndrome is a rare pathology involving multiple cranial nerves in the setting of invasive mucormycosis, usually in immunocompromised patients. Owing to its extremely high mortality rate, clinician should have a high suspicion for diagnosis. This article presents a rare case of Rhino-Orbito-Cerebral Mucormycosis with Garcin's syndrome in a 33-years old male along with a discussion of previously reported cases. The case is discussed in light of scant contemporary literature on the cited subject. A thorough search using the keywords Garcin's Syndrome, Invasive Mucormycosis, Rhino-orbital, Rhino-cerebral mucormycosis, was conducted on Pubmed/MEDLINE, Google scholar, LILACS, medRxiv and Google. A total of six reported cases found in international literature published between 2000 and 2020 were reviewed and analyzed. Garcin's Syndrome is associated with a high mortality rate. In our review, of the total seven patients, only three survived, bringing the collective mortality to 42.85%. Patients had multiple cranial nerve involvement leading to long term sequelae. Our case showed the unique finding of VIII nerve involvement. Early intervention helped in patient survival and better functional outcome. This literature review highlights the distinct clinical nature of the presentation of disease and the importance of prompt diagnosis and early management in the reversal of complications in an otherwise potentially fatal disease.