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Novel therapeutics are required for improving the management of chronic inflammatory diseases. Aptamers are single-stranded RNA or DNA molecules that have recently shown utility in a clinical setting, as they can specifically neutralize biomedically relevant proteins, particularly cell surface and extracellular proteins. The nuclear chromatin protein DEK is a secreted chemoattractant that is abundant in the synovia of patients with juvenile idiopathic arthritis (JIA). Here, we show that DEK is crucial to the development of arthritis in mouse models, thus making it an appropriate target for aptamer-based therapy. Genetic depletion of DEK or treatment with DEK-targeted aptamers significantly reduces joint inflammation in vivo and greatly impairs the ability of neutrophils to form neutrophil extracellular traps (NETs). DEK is detected in spontaneously forming NETs from JIA patient synovial neutrophils, and DEK-targeted aptamers reduce NET formation. DEK is thus key to joint inflammation, and anti-DEK aptamers hold promise for the treatment of JIA and other types of arthritis. DEK is a secreted protein abundant in the synovia of patients with juvenile idiopathic arthritis. Here the authors show DEK is important for neutrophil extracellular trap formation and joint inflammation, and demonstrate therapeutic efficacy of DEK-targeting aptamers in a mouse model of arthritis.

Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare, and the persistence of cutaneous disease can prevent complete disease remission. The noninvasive study of cutaneous expression signatures through tape stripping (TS) holds the potential to reveal mechanisms underlying disease heterogeneity and organ-specific inflammation. The objectives of this study were to (a) define TS expression signatures in lesional and nonlesional JDM skin, (b) analyze TS signatures to identify JDM disease endotypes, and (c) compare TS and blood signatures. Although JDM lesional skin demonstrated interferon signaling as the top upregulated pathway, nonlesional skin uniquely highlighted pathways involved in metabolism, angiogenesis, and calcium signaling. Both lesional and nonlesional skin shared inflammasome pathway dysregulation. Using unsupervised clustering of skin expression data, we identified a treatment-refractory JDM subgroup distinguished by upregulation of genes associated with mitochondrial dysfunction. The treatment-refractory JDM subgroup also demonstrated higher interferon, angiogenesis, and innate immune expression scores in skin and blood, though scores were more pronounced in skin as compared with blood. TS expression signatures in JDM provided insight into disease mechanisms and molecular subgroups. Skin, as compared with blood, transcriptional profiles served as more sensitive markers to classify disease subgroups and identify candidate treatment targets.

Background. We studied the impact of the multicomponent interventions on body weight and cardiometabolic risk factors in overweight individuals working in corporate worksites. Methods. Overweight (BMI ≥ 23 kg/m2) subjects were recruited from four randomised worksites [two active intervention (n, recruited, 180, completed 156) and two control (n, recruited 130, completed 111)]. Intensive intervention was given at intervention worksite. Results. High prevalence (%) of obesity (90.9, 80.2), abdominal obesity (93.5, 84.3), excess skinfold thickness (70.3, 75.9), and low high-density lipoprotein cholesterol (HDL-c) levels (56.8, 63.7) were seen in the intervention and the control group, respectively. At the end of intervention, the following significant changes were observed in the intervention group: decrease in weight, BMI, waist circumference, serum triglycerides, and increase in HDL-c. Weight loss of more than 5% was seen in 12% and 4% individuals in the intervention and control groups, respectively. Most importantly, the sum of all the skinfold measurements (mm) in the intervention group decreased significantly more than the control group (12.51 ± 10.38 versus 3.50 ± 8.18, resp.). Conclusion. This multicomponent worksite trial showed a reduction in weight, excess subcutaneous fat, and cardiometabolic risk factors after 6 months of active intervention in overweight Asian Indians. Trial Registration. This trial is registered with NCT03249610.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient’s peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

PurposeThe Million Farmers School (MFS) program—also known as Kisan Pathshala was launched to impart training to the farmers by the government of the state of Uttar Pradesh (India) in December 2017. This study estimates the impact of training on agricultural knowledge of the farmers.Design/methodology/approachThe study is based on household survey conducted in Uttar Pradesh (UP), India, during March–May 2019. The authors employed matching methods, the two-stage least square (2SLS)-residual and endogenous switching regression approaches to control for selection bias and endogeneity.FindingsThe results suggest that knowledge outcomes are significantly better among participants vis-à-vis non-participants. The results are robust to different model specifications. Further, the benefits are observed across different regions and social groups.Research limitations/implicationsThe MFS program can go a long way in enhancing agricultural know-how and the farmers' economic well-being, bringing a transformative change in the agricultural landscape of UP.Originality/valueThis study is based on a field survey data and analyzes various aspects of the program's impact, design and implementation, and offers implementation advice for greater efficacy in future.

Background: Extensive ongoing research is aimed at enhancing the efficacy of inferior alveolar nerve block (IANB). Even though magnesium itself is not a primary analgesic, it has been shown to increase the effects of analgesics when used as an adjuvant or a supplement. Magnesium sulphate (MgSO 4 ) has reportedly been used to supplement regional blocks and spinal anaesthesia in various surgical procedures. Building on the concept of MgSO 4 as an analgesic adjuvant, our study aimed to assess its efficacy in increasing IANB success and controlling postsurgical pain. The split‐mouth study evaluated the effectiveness of adding MgSO 4 to 2% lignocaine in improving block success and offering postsurgical pain relief after the transalveolar extraction of impacted mandibular third molars (MTMs). Methodology: We carried out a double‐blinded, randomized, split‐mouth study in 26 patients having bilateral impacted MTM. Patients presenting with impacted MTM bilaterally with a Pederson’s score of ≤ 6 were included. The primary outcomes evaluated were the onset time, duration of anaesthesia, need for additional injections, and burning sensation during injection. The secondary outcomes assessed included postoperative pain relief and the quantity of rescue analgesics required. Results: The test side showed a significantly longer duration of analgesia than the control side ( p < 0.001). The MgSO 4 group showed a lesser requirement for additional injections; however, it was not found to be statistically significant (0.289). No significant differences were seen in postoperative pain and the number of rescue analgesics. Conclusion: The addition of MgSO 4 to 2% lidocaine resulted in a significantly longer duration of analgesia. Trial Registration: CTRI identifier: CTRI/2018/05/013842

Lymphangioma circumscriptum (LC) is a rare benign lymphatic malformation of deep dermis and subcutaneous layer. Although it commonly affects the trunk, axilla, thighs, and oral cavity, its appearance in the scrotum is extremely rare and can lead to considerable psychological distress, often due to concerns regarding sexually transmitted infections. We present a case of a 42‐year‐old married Nepali male who presented with multiple slow‐growing, fluid‐filled, grouped vesicular lesions on the scrotum that had gradually increased over 12 years. The diagnosis of LC was confirmed through clinical evaluation and histopathological findings. The patient was counseled regarding the condition and was referred for surgical management.

Behcet's disease is a rare multisystem vasculitis that demands early diagnosis and prompt treatment. Clinicians must maintain a high index of suspicion, especially in patients presenting with recurrent oral and genital ulcers with systemic symptoms and adopt a multidisciplinary approach for the optimal management.

The corticosteroids have been used for preemptive management of surgical sequelae after mandibular third molar extraction. The aim of this article was to review the efficacy of methylprednisolone versus dexamethasone in the management of postsurgical pain, swelling, and trismus after mandibular third molar surgery. Randomized, double-blinded studies from PubMed, CINAHL, Scopus, DOSS, Cochrane central, and Web of Science were identified by using a search strategy. Randomized controlled trials evaluating the efficacy of use of dexamethasone versus methylprednisolone for mandibular third molar extraction were only considered. The studies involving the use of any other corticosteroid agent were excluded. Outcomes assessed were postoperative pain, the number of rescue analgesics required, swelling, trismus, and adverse events. The search strategy yielded 1046 articles for title and abstract screening, out of which only seven studies were included in the systematic review after full text screening. There was considerable heterogeneity between the studies with regards to the method as well as the parameters assessed. Risk of bias was low in three studies and unclear in other four studies. On pooled analyses, there was no significant difference with respect to pain, rescue analgesics, and swelling in the test and the control group. Forest plot analysis showed that dexamethasone had lesser trismus in early postoperative period (postoperative day 2) as compared to methylprednisolone. None of the included studies reported any adverse effects. Both the corticosteroids have similar efficacy in reducing the postoperative pain and swelling; however, dexamethasone showed statistically significant difference from methylprednisolone in reducing trismus (estimated standardized mean difference of −0.69 mm; 95% CI: −1.01 to −0.38; p<0.0001) in the early postoperative period. However, due to statistical heterogeneity, quality of the evidence for the review was low to moderate. Hence, more studies with larger study sample and low risk of bias are needed to confirm these results.

Substrate efflux by ATP-binding cassette (ABC) transporters, which play a major role in multidrug resistance, entails the ATP-powered interconversion between transporter intermediates. Despite recent progress in structure elucidation, a number of intermediates have yet to be visualized and mechanistically interpreted. Here, we combine cryogenic-electron microscopy (cryo-EM), double electron–electron resonance spectroscopy and molecular dynamics simulations to profile a previously unobserved intermediate of BmrCD, a heterodimeric multidrug ABC exporter from Bacillus subtilis. In our cryo-EM structure, ATP-bound BmrCD adopts an inward-facing architecture featuring two molecules of the substrate Hoechst-33342 in a striking asymmetric head-to-tail arrangement. Deletion of the extracellular domain capping the substrate-binding chamber or mutation of Hoechst-coordinating residues abrogates cooperative stimulation of ATP hydrolysis. Together, our findings support a mechanistic role for symmetry mismatch between the nucleotide binding and the transmembrane domains in the conformational cycle of ABC transporters and is of notable importance for rational design of molecules for targeted ABC transporter inhibition.Cryo-EM analysis with DEER spectroscopy and molecular dynamics simulations of the ABC exporter BmrCD reveal dual-mode substrate binding in an ATP- and substrate-bound state.