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The IFIH1 gene, encoding melanoma differentiation‐associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain‐of‐function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi–Goutieres and Singleton–Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID‐19 or multisystem inflammatory syndrome in children (MIS‐C) were identified with putative loss‐of‐function IFIH1 variants by whole‐exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL‐6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID‐19 or MIS‐C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS‐C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss‐of‐function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS‐CoV‐2‐related disorders. [ABSTRACT FROM AUTHOR]

Missense variants in the RNF13 gene have been previously known to cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive through a gain‐of‐function disease mechanism. Here, we identify a nonsense variant, expected to result in protein truncation, in a similarly affected patient. We show that this nonsense variant, residing in the terminal exon, is likely to escape nonsense‐mediated decay while removing a critical region for protein function, thus resulting in a gain‐of‐function effect. We review the literature and disease databases and identify several other affected individuals with overlapping phenotypes carrying distinct truncating variants in the terminal exon upstream of the putative critical region. Furthermore, we analyze truncating variants from the general population, namely, the Genome Aggregation Database (gnomAD), and provide additional evidence supporting our hypothesis, and ruling out haploinsufficiency as an alternative disease mechanism. In summary, our case report, literature review, and analysis of disease and population databases strongly support the hypothesis that heterozygous gain‐of‐function variants in a critical region of RNF13 cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive. [ABSTRACT FROM AUTHOR]

Objective: Oral submucous fibrosis (OSF) is a debilitating potentially malignant condition of the buccal cavity characterized by extensive extracellular matrix deposition resulting in stiffness and trismus. As OSF is a progressive disease, we hypothesized that there would be extensive epigenetic changes in OSF tissues. Materials and Methods: Using the Infinium HumanMethylation450 BeadChip Array, we analyzed gross DNA methylation changes in seven OSF tissues compared to five controls. Comparison with transcriptomic data and pathway analyses was conducted to find commonly regulated genes. Results: A total of 3,294 differentially methylated regions mapping to 857 genes were identified. Comparison with transcriptome data revealed 38 downregulated‐hypermethylated genes and 55 hypomethylated‐upregulated genes. Using methylation‐specific and qRT‐PCR, aberrant hypomethylation and increased expression of FGF13, RPS6KA3, and ACSL4 genes were confirmed. Pathways involved in insulin signaling, ubiquitin‐mediated proteolysis, nicotine addiction, and RAS/MAPK pathways were dysregulated, among others. Intriguingly, numerous genes located on the X chromosome were dysregulated in OSF tissues as the transcript for XIST gene was downregulated due to hypermethylation of the XIST promoter. Conclusions: This study highlights global epigenetic dysregulation of tissues of the oral cavity in OSF patients and hints at possible X chromosomal dysregulation, previously not implicated in the pathogenesis of OSF. [ABSTRACT FROM AUTHOR]

Purpose: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long‐term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR). Methods: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932–1933) and the WWII (1941–1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942–1945. Results: During the Holodomor and WWII, perinatal famine was associated with a 1.76‐fold (p = 0.019) and 3.02‐fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66‐fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05). Conclusion: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications. [ABSTRACT FROM AUTHOR]

Objective: Electronic consultation (eConsult) communications between primary care physicians (PCPs) and rheumatologists may reveal common knowledge gaps and educational opportunities. The aim of our study was to identify content themes in PCP questions and rheumatology recommendations through analysis of eConsult and the need for rheumatology appointments and facilitated urgent visits post‐eConsult. Methods: A descriptive cross‐sectional study involving qualitative and quantitative analysis of rheumatology eConsults in a single center was performed from May 1, 2019, to January 9, 2020. Conventional content analysis was used to derive content themes in PCP questions and rheumatology recommendations. We evaluated the proportion of eConsults, which included a need for rheumatology appointments and expedited visits through frequency counts. Results: Among 120 rheumatology eConsults, six PCP questions and five rheumatology recommendation content themes were identified. The most common PCP question themes were the following: 1) joint pain, 2) suspected rheumatic disease differential, and 3) abnormal laboratory tests. The most common rheumatology recommendation or teaching themes were the following: 1) education on differential diagnoses of rheumatic diseases, 2) education on the specific rheumatic disease, and 3) laboratory test interpretation. The majority of eConsults (82%) recommended a subsequent rheumatology appointment, and 27% facilitated an expedited appointment. Conclusion: In this analysis of eConsults, we identified common knowledge gaps in PCPs and rheumatology educational topics, including differentiating inflammatory from noninflammatory arthritis, using caution in interpreting abnormal laboratory tests without clinical manifestations, managing chronic gout, evaluating elevated creatine phosphokinase levels, and differentiating C‐reactive protein (CRP) from high‐sensitivity CRP. Timely feedback through eConsult recommendations may allow for focused educational opportunities. [ABSTRACT FROM AUTHOR]

Objective: Patients with coronavirus disease 2019 (COVID‐19) can progress to a state of unregulated inflammation called cytokine storm syndrome (CSS). We describe formation and operation of a COVID‐19 multidisciplinary consultation service that was allowed to individualize treatment for critically ill patients with COVID‐19 during the pandemic. Methods: Institutional experts from different subspecialties formed a COVID‐19 CSS task force at Montefiore Medical Center, Bronx, NY. They agreed on a set of four clinical and six laboratory parameters that can help early identify COVID‐19 CSS. We describe the formation and implementation of the COVID‐19 task force. The case series description of the COVID‐19 CSS consultation cohort highlights consultation volume, baseline characteristics, clinical and laboratory parameters, and how biologic treatments were allocated to these patients. Results: Between April 4,2020, and May 7,2020, the COVID‐19 CSS task force was formed, consisting of adult and pediatric rheumatologists and allergy and immunology physicians. The task force evaluated a total of 288 patients, of whom 197 (68%) were male, the median (interquartile range [IQR]) age was 62 (51‐70) years, 122 (42%) were Hispanic, and 88 (31%) were Black or African American. The common presenting symptoms in all referred patients were dyspnea (85%) and diarrhea (80%). Thirty‐one patients who received biologic therapy were younger, with a median (IQR) age of 53 (32‐63) years, as opposed to 62.5 (52‐70) years in the nonbiologic group (P = 0.008). A higher proportion receiving biologics was in the critical care setting (26 [84%] vs 151 [59%]; P = 0.006). Conclusion: To the best of our knowledge, this is the first multidisciplinary collaborative effort to provide individualized patient recommendations for evaluation and treatment of patients with COVID‐19 who may have CSS. This working model helped to devise an approach that may have identified patients who were most likely to benefit from biologic therapy in the absence of evidence‐based guidelines. [ABSTRACT FROM AUTHOR]

Herein, we present the surface electronic structure and morphological evolution under reduction and oxidation conditions for Pd@Co (PC) core‐shell nanoparticles with different Pd : Co ratio (PC=2 : 1, 1 : 1 and 1 : 2). Extensive measurements have been made with NAPXPS (near ambient pressure x‐ray photoelectron spectroscopy) under oxidising and reducing conditions, and ex‐situ HRTEM. It has been demonstrated that PC catalysts are thermally stable towards morphological changes, at least up to 575 K. Nonetheless, it shows a significant surface electronic structure changes under reaction environments, which are highly relevant to heterogeneous catalysis. As expected, high (low) population of metallic (oxidised) Co was observed, while retaining core shell structure under reduction (H2 and vacuum annealing) environment. Interestingly, the Pd−Co metallic interface helps to overcome the pyrophoric nature of cobalt and stabilised a significant amount of metallic Co at Pd−Co interface even in the presence of 0.1 mbar O2 up to 575 K. The presence of Pd−Co and Pd−Co@Co3O4 interfaces in reaction environment makes the catalyst dual functional. The proof of concept has been explored in terms of oxidation of CO in the presence of H2 or O2. [ABSTRACT FROM AUTHOR]

Mumps, a vaccine‐preventable disease, cause inflammation of salivary glands and may cause severe complications, such as encephalitis, meningitis, deafness, and orchitis/oophoritis. In India, mumps vaccine is not included in the universal immunization program and during 2009 to 2014, 72 outbreaks with greater than 1500 cases were reported. In August 2016, a suspected mumps outbreak was reported in Jaisalmer block, Rajasthan. We investigated to confirm the etiology, describe the epidemiology, and recommend prevention and control measures. We defined a case as swelling in the parotid region in a Jaisalmer block resident between 23 June 2016 and 10 September 2016. We searched for cases in health facilities and house‐to‐house in affected villages and hamlets. We tested blood samples of cases for mumps immunoglobulin M (IgM) enzyme‐linked immunosorbent assay (ELISA). We found 162 cases (60% males) with a median age of 9.4 years (range: 7 month‐38 years) and 65 (40%) were females. Symptoms included fever (70%) and bilateral swelling in neck (65%). None of them were vaccinated against mumps. Most (84%) cases were school‐going children (3‐16 years old). The overall attack rate was 2%. Village A, with two hamlets, had the highest attack rate (hamlet 1 = 13% and hamlet 2 = 12%). School A of village A, hamlet 1, which accommodated 200 children in two classrooms, had an attack rate of 55%. Of 18 blood samples from cases, 11 tested positive for mumps IgM ELISA. This was a confirmed mumps outbreak in Jaisalmer block that disproportionately affected school‐going children. We recommended continued surveillance, 5‐day absence from school, and vaccination. Dr Pramod Goel: co‐investigator of the outbreak Dr Jalam Singh: assisted with data collection and laboratory investigation Dr Naina Ram Nayak: assisted with data collection and public health action Dr Meera Dhuria: guided the outbreak investigation Dr Ruchi Jain: facilitated and supported the outbreak investigation Dr Rajesh Yadav: guided the outbreak investigation and reviewed manuscript drafts Dr Ekta Saroha: guided data analysis and manuscript preparation Dr Samir V Sodha: reviewed manuscript drafts Dr CS Aggarwal: provided national level support for the investigation Dr Srinivas Venkatesh: provided national level support for the investigation [ABSTRACT FROM AUTHOR]

Cancer is a class of diseases that is characterized by the uncontrollable or unstoppable growth of abnormal cells with the potential to invade or spread to other normal body parts. According to WHO estimates, globally 10 million new cancer cases are diagnosed each year. Its 100% prevention becomes a major challenge for the scientific fraternity. Therefore, there is an urgent need to discover new drugs that could overcome the present issue. In order to meet the challenges, a library of 22 novel 1H‐1,2,3‐triazol‐4‐yl‐methyl tethered 3‐pyrrolyl isatin derivatives have been synthesized and well characterized by using different spectral techniques. The newly synthesized conjugates were screened for their anti‐proliferative activity against breast cancer MCF‐7 and MDA‐MB‐231, as well as human embryonic HEK 293 cell lines by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Cytotoxicity studies revealed that six of the compounds among entire series are three‐fold more potent than the commercially available reference drug tamoxifen against MDA‐MB‐231 and relatively safe towards HEK‐293 cells. In order to validate experimental results, the possible binding interaction of the most potent conjugate and tamoxifen with Topoisomerase II has been scrutinized by molecular docking studies. [ABSTRACT FROM AUTHOR]

Objective By 2030, the number of permanently homebound individuals in the US will increase by 50% to reach 2 million. However, no medicine subspecialty consult services exist for this rising subset of the population. This pilot program establishes a rheumatology consult service for the Mount Sinai Visiting Doctors, the largest primary care academic home visit program in the nation serving more than 1,000 patients in New York City. Our service addresses the unmet need for homebound patients with rheumatic diseases, and secondarily provides an educational opportunity for trainees in community-based rheumatology. Methods Using an electronic medical record, home-based primary care physicians sent consult requests to the Rheumatology Division. Initial assessments were made using the Routine Assessment of Patient Index Data 3 (RAPID3) questionnaire. Results Over 12 months, 57 home visits were made: 31 new consults and 26 followup visits. Reasons for referral included medical management of a known connective tissue disease, question of inflammatory arthritis, and procedures. The demographics for new consults were as follows: 94% women, 45% Hispanic, and 80% between ages 60 and 101 years. Thirty-nine percent of patients had rheumatoid arthritis. Treatment interventions included addition of a disease-modifying antirheumatic drug in 11 patients, 11 procedures, nonpharmacologic management in 8 patients, and a change in the dose of the existing medication in 5 patients. At the initial evaluation, the average RAPID3 scores for patients reflected high severity of disease. Conclusion The number of consults and the severity of disease seen highlight the importance of a rheumatologist's role in the community, especially because the number of homebound patients will dramatically increase in the future. [ABSTRACT FROM AUTHOR]

Entamoeba histolytica, the causative agent of human amoebiasis, is essentially anaerobic, requiring a small amount of oxygen for growth. It cannot tolerate the higher concentration of oxygen present in human tissues or blood. However, during tissue invasion it is exposed to a higher level of oxygen, leading to oxygen stress. Cysteine, which is a vital thiol in E. histolytica, plays an essential role in its oxygen-defence mechanisms. The major route of cysteine biosynthesis in this parasite is the condensation of O-acetylserine with sulfide by the de novo cysteine-biosynthetic pathway, which involves cysteine synthase (EhCS) as a key enzyme. In this study, EhCS was cloned, expressed in Escherichia coli and purified by affinity and size-exclusion chromatography. The purified protein was crystallized in space group P41 with two molecules per asymmetric unit and a complete data set was collected to a resolution of 1.86 Å. A molecular-replacement solution was obtained using the Salmonella typhimurium O-acetylserine sulfhydrylase structure as a probe and had a correlation coefficient of 37.7% and an R factor of 48.8%. [ABSTRACT FROM AUTHOR]

This study integrates production and financing to examine the impacts of financial structure change on the production, profitability, and productivity growth in the U.S. food manufacturing industry. Empirical results show that during the period covered by this study, agency cost associated with increased debt use by this industry negatively affected its output growth, input demand, profitability, and overall productivity growth. Dividend payment positively contributed to the production and performance of this industry via signaling benefit. However, the negative effects of increased debt use by this industry far outweighed the positive contribution of dividend payment. The U.S. food industry achieved a 0.9% average annual productivity growth, which came primarily from technological progress and capital adjustment. The rapid increase in debt use by this industry was responsible for slowing down the pace of productivity growth via its negative contribution to the total factor productivity growth. Capital expansion was the principal driver of output growth and profitability in this industry. [ABSTRACT FROM AUTHOR]