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(1) Background: The purpose of this study was to evaluate the time toxicity, or time spent in health care, of immunotherapy- versus chemotherapy-based regimens for metastatic esophageal and gastric cancers. (2) Methods: A literature search was conducted, and 18 phase III clinical trials of immune checkpoint inhibitors were selected for analysis. Health care days were calculated based on the number of days associated with receiving therapy and the adverse events reported in the clinical trials. Both the number of health care days and the median overall survival were compared among chemotherapy-only, immunotherapy-only, and chemo-immunotherapy regimens across this cohort of drug registration trials. (3) Results: The estimated median number of health care days was 37 (range of 7-52) days, or 1.2 (range of 0.2-1.7) months, compared to a median survival of 10.2 months across these 18 studies. For the chemotherapy-only regimens, the median number of health care days was 39 (range of 21-51) days, and for chemo-immunotherapy, it was 39 (range of 30-52) days. The immunotherapy-only regimens had fewer days, a median of 28 (range of 24-41), p < 0.05, compared to the other two arms. (4) Conclusions: The chemo-immunotherapy regimens did not add time toxicity compared to chemotherapy alone. The immunotherapy-only regimens had lower time toxicity compared to chemotherapy alone. In the setting of decreased time toxicity and improved overall survival, further development of immunotherapy-based regimens could improve outcomes in advanced esophageal and gastric cancers.

New avenues for research have opened, which assess the influence of systemic disease on periodontium and vice versa. To find the correlation between polycystic ovary syndrome (PCOS) and periodontium by assessing clinical parameters [plaque index (PI), probing depth, periodontal disease index (PDI)] and the anthropological parameter [body mass index (BMI)] and to find the correlation between body mass index and periodontal disease index in subjects with and without PCOS. Sixty females comprising 30 with PCOS and 30 without PCOS were selected. Clinical, anthropological, and radiological assessment was done. Double blinding was incorporated. There was a statistically highly significant difference in mean age, mean PI, and mean PDI ( P < 0.001) in PCOS group when compared to those without PCOS group by unpaired t -test for inter-group analysis. A statistically significant difference was found in mean probing depth and mean BMI ( P < 0.05) in PCOS group when compared to those without PCOS group by unpaired t -test for inter-group analysis. No statistically significant correlation was found between mean PDI and mean BMI in PCOS and non-PCOS group subjects using Spearman's rank correlation. Women suffering from PCOS may be at a heightened risk for developing periodontal disease as our study re-establishes this association with respect to some periodontal parameters. With such a result, general practitioners/gynecologists can be encouraged to refer cases of PCOS to periodontists for early detection, prevention of periodontal disease, and maintenance of periodontal health., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Community Medicine.)

Background: Postoperative pain is a common concern in root canal treatment, and the choice of instrumentation technique can significantly impact patient comfort. This study aimed to evaluate the impact of different instrumentation techniques on the incidence of postoperative pain in patients undergoing root canal treatment., Methods: A randomized controlled trial was conducted on 208 patients randomly assigned to four groups: step-back preparation, crown-down preparation, hybrid technique, and conventional instrumentation. Pain intensity was assessed using a verbal rating scale (VRS) at six, 12, 24, 48, and 72 hours postoperatively. Data were analyzed using appropriate statistical methods., Results: The mean pain scores and standard deviations (SDs) were calculated for each instrumentation technique at different time intervals. At six hours, the step-back preparation group reported a mean pain score of 2.3 (SD = 0.8), the crown-down preparation group had a score of 2.8 (SD = 0.9), the hybrid technique group had a score of 2.5 (SD = 0.7), and the conventional instrumentation group had a score of 3.1 (SD = 0.1). The differences in pain scores between the groups were statistically significant at all time intervals (p < 0.05)., Conclusion: The choice of instrumentation technique significantly influenced the incidence of postoperative pain in root canal treatment. The step-back preparation technique was associated with lower pain intensity than the crown-down preparation, hybrid technique, and conventional instrumentation. These findings highlight the importance of considering the instrumentation technique to optimize patient comfort during and after root canal treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Agrawal et al.)

Diurnal rhythmicity of cellular function is key to survival for most organisms on Earth. Many circadian functions are driven by the brain, but regulation of a separate set of peripheral rhythms remains poorly understood. The gut microbiome is a potential candidate for regulation of host peripheral rhythms, and this study sought to specifically examine the process of microbial bile salt biotransformation. To enable this work, an assay for bile salt hydrolase (BSH) that could work with small quantities of stool samples was necessary. Using a turn-on fluorescence probe, we developed a rapid and inexpensive assay to detect BSH enzyme activity with concentrations as low as 6-25 μM, which is considerably more robust than prior approaches. We successfully applied this rhodamine-based assay to detect BSH activity in a wide range of biological samples such as recombinant protein, whole cells, fecal samples, and gut lumen content from mice. We were able to detect significant BSH activity in small amounts of mouse fecal/gut content (20-50 mg) within 2 h, which illustrates its potential for use in various biological/clinical applications. Using this assay, we investigated the diurnal fluctuations of BSH activity in the large intestine of mice. By using time restricted feeding conditions, we provided direct evidence of 24 h rhythmicity in microbiome BSH activity levels and showed that this rhythmicity is influenced by feeding patterns. Our novel function-centric approach has potential to aid in the discovery of therapeutic, diet, or lifestyle interventions for correction of circadian perturbations linked to bile metabolism.

Background: Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis. Oral miltefosine (MF) is the first-line treatment for PKDL patients in South Asia. This study assessed the safety and effectiveness of MF therapy after 12 months of follow-up to explore more precise data., Methods: In this observational study, 300 confirmed PKDL patients were enrolled. MF with the usual dose was administered to all patients for 12 weeks and followed up for 1 year. Clinical evolution was recorded systematically by photographs at screening and at 12 weeks, 6 months, and 12 months after treatment onset. Definitive cure consisted of disappearance of skin lesions with a negative PCR at 12 weeks or with >70% of lesions, disappearing or fading at 12-month follow-up. Patients with reappearing clinical features and any positive diagnostics of PKDL during the follow-up were considered as nonresponsive., Results: Among 300 patients, 286 (95.3%) completed 12 weeks of treatment. The per-protocol cure rate at 12 months was 97%, but 7 patients relapsed and 51 (17%) were lost to 12-month follow-up, resulting in a final cure rate of only 76%. Eye-related adverse events were noted in 11 (3.7%) patients and resolved in most (72.7%) within 12 months. Unfortunately, 3 patients had persistent partial vision loss. Mild to moderate gastrointestinal side effects were seen in 28% patients., Conclusions: Moderate effectiveness of MF was observed in the present study. A significant number of patients developed ocular complications, and thus MF for treatment for PKDL should be suspended and replaced with a safer alternative regimen., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: The study was conducted to determine the frequency of alloimmunization to various blood group antibodies in pregnant women, and the risk of hemolytic disease in the fetus and newborn., Methods: All antenatal women, irrespective of the period of gestation or obstetric history, were included, whereas those taking anti-D immune-prophylaxis or with a history of blood transfusion were excluded. Antibody screening and identification were performed using a Bio-Rad ID microtyping system., Results: Of 2,084 antenatal females, 1,765 were D-antigen positive and 319 D-antigen negative. Sixty-five (3.119%) women alloimmunized. Out of 54 (2.591%) who had sensitized to D-antigen, 11 (0.527%) also sensitized to other antibodies. These 11 alloantibodies identified included: anti-M (n=6; 9.23%), anti-C (n=1; 3.076%), anti-E (n=1; 1.538%), anti-e (n=1; 1.538%), anti-Lewis (a) (n=1; 1.538%), and unspecified antibodies (n=1; 1.538%). Multiple antibodies were seen in four patients that combined: anti-D and anti-C (n=2; 3.076%), anti-e and anti-c (n=1; 1.538%), and anti-D and anti-G (n=1; 1.538%)., Conclusion: The rate of alloimmunization in D-antigen-negative women was high. Apart from this, the alloimmunization rate in women with bad obstetric history was very high, at 8.1%. In developing countries such as India, universal antenatal antibody screening, though desirable, may not be justified at present, as the cost and infrastructure required would be immense because of the lower alloimmunization rates in RhD antigen-positive women. However, it is necessary to impose properly formulated protocols to screen pregnant women with bad obstetric history.

Background: Recent trials testing immune-checkpoint inhibitors in esophago-gastric malignancies have shown mixed results. We aim to assess key subgroups using the ASCO Net Health Benefit Score (NHBS) and ESMO Magnitude of Clinical Benefit Scale (MCBS)., Materials and Methods: A search for phase III trials of FDA-approved anti-PD-1 or anti-PD-L1 drugs in esophago-gastric cancer trials was identified using www.clinicaltrials.gov. These published studies were scored using the ASCO NHBS and ESMO MCBS. The ASCO NHBS scores were compared by primary site of cancer (esophageal vs gastric) and PD-L1 expression using the Mann-Whitney test and the ESMO-MCBS grading, by Fisher's Exact test., Results: Fifteen of 45 clinical trials were included. Of them, 6 were primarily esophageal cancer trials, and 9 were primarily gastric cancer trials. Ten stratified their analysis based on PD-L1 expression. The ASCO NHBS score was higher (mean 40, range 20 to 56.6 vs. mean 12, range -1.1 to 18.4, P < .01) for esophageal cancer than gastric cancer. No difference was observed in survival and response endpoints between the 2 groups. Similarly, the ESMO MCBS scored higher for esophageal cancer group than gastric cancer (P < .05). Additionally, the scores were higher in those with high PD-L1 expression vs. low PD-L1 (mean 36, range 11.2-66.6 vs. mean 14, range -19.5 to 43.6, P < .05)., Conclusion: The ASCO NHB and ESMO scores were consistently higher among esophageal cancer trials than gastric cancer trials and in those with high PD-L1 expression than low expression. Histology and PD-L1 expression should be considered when discussing value of immunotherapy to patients., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction: Lysosomal storage disorders (LSDs) are rare disorders and pose a diagnostic challenge for clinicians owing to their generalized symptomatology. In this study, we aim to classify LSDs into two broad categories, namely, Gaucher disease (GD) and Niemann-Pick/Niemann-Pick-like diseases (NP/NP-like diseases) based on the morphology of the storage cells in the bone marrow (BM) aspiration smears and trephine biopsy sections., Materials and Method: This retrospective study includes 32 BM specimens morphologically diagnosed as LSDs at our institute, in the last 10 years. Subsequently, they were subclassified into GD and NP/NP-like diseases. Further, we have compared and analyzed the clinical, hematological, and biochemical parameters for the two groups of LSDs., Results: Based on BM morphology, 59.4% (n = 19) cases were diagnosed as NP/NP-like diseases and 40.6% (n = 13) cases as GD. Abdominal distension and failure to thrive were the most common clinical manifestations in both groups of LSDs. Anemia and thrombocytopenia were frequently seen in either of the LSDs. On the assessment of metabolic profile, elevated total/direct bilirubin and liver enzymes were more commonly seen in NP/NP-like diseases when compared with GD., Conclusion: We have classified LSDs into GD and NP/NP-like diseases based on the morphology of the storage cells in the BM specimen. The hallmark findings on BM biopsy annexed with the comparative features of the two proposed categories can aid the clinician in clinching the diagnosis. Formulation of such a methodology will prove instrumental for patient care in an underresourced setting., Competing Interests: None

Background: Factor VIII (FVIII) replacement and emicizumab are effective at preventing bleeds in patients with hemophilia A (HA). Though benefits of emicizumab among inhibitor patients with HA (PwHA) are well established, more real-world evidence among non-inhibitor patients is needed., Methods: Using a United States healthcare claims database, we compared billed annualized bleed rates (ABR b ) and the total cost of care (TCC) before and after switching from FVIII prophylaxis to emicizumab among non-inhibitor male PwHA. Bayesian inferences were used to assess the difference in ABR b and TCC per patient per year (PPPY) pre- versus post-prophylaxis switch., Results: We included 101 non-inhibitor male PwHA aged between 3 and 63 years old who switched from FVIII prophylaxis to emicizumab prophylaxis in 2018 or 2019. The ABR b increased from 0.52 to 0.62 ( p  = 0.83) after switch. The posterior probability of the mean ABR b increasing after the switch was 75.54%. The TCC PPPY increased from $517,143 to $627,005 ( p  < 0.0001) after switch and the posterior probability of mean costs increasing after the switch was 99.80%., Conclusions: Personalization of care through the identification of the most appropriate therapy for each patient can optimize clinical and economic outcomes. Future real-world evidence research could help establish the value of prophylactic options in targeted populations such as the non-inhibitor male PwHA.

Background: The study aimed to compare the clinical efficacy, safety, and acceptability of buffered lidocaine (8.4% sodium bicarbonate and 2% lidocaine with 1:80,000 adrenaline) versus non-buffered lidocaine (2% lidocaine with 1:80,000 adrenaline) during inferior alveolar nerve block., Materials and Methods: Fifty patients who required bilateral extractions in a single arch were included in this study. One hundred extractions were carried out, and all of the patients had nerve blocks during the procedure. We also took note of the patient's pain level as measured on a visual analog scale, as well as the start of the action, duration of postoperative analgesia, and occurrence of any problems. The duration of anesthesia was assessed by the feeling of numbness and the first sign of pain., Result: All the patients in both study groups reported subjective numbness of the lips and tongue. The depth of anesthesia was evaluated by pain and comfort during the procedure with a visual analog scale and showed no significant difference between the two groups. The onset of action for the pterygomandibular nerve block was 1.240.31 minutes (buffered) and 1.710.51 minutes (non-buffered). When compared, the duration of anesthesia was 327.18102.98 minutes (buffered) and 129.0826.85 minutes (non-buffered)., Conclusion: This study concludes that the buffered solution has a faster onset of action than the non-buffered solution. Both solutions exhibit similar intraoperative efficacy. The duration of postoperative anesthesia was prolonged with buffering. Buffering also reduced pain scores during the early postoperative period., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Jain et al.)

Considering the exceptional growth of Cyber Physical Systems (CPSs), multiple and potentially grave security challenges have emerged in this field. Different vulnerabilities and attacks are present in front of new generation CPSs, such as Industrial CPS (I-CPS). The underlying non-uniform standards, device heterogeneity, network complexity, etc., make it difficult to offer a systematized coverage on CPS security in an industrial environment. This work considers the security perspective of I-CPSs, and offers a decade-wide survey including different vulnerabilities, attacks, CPS components, and various other aspects. The comparative year-wise analysis of the existing works w.r.t objective, approach referred, testbed used and derived inference, is also presented over a decade. Additionally, the work details different security issues and research challenges present in I-CPS. This work attempts to offer a concise and precise literature study focused on the state-of-the-art I-CPS security. This work also encourages the young researchers to explore the wide possibilities present in this emerging field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 ISA. Published by Elsevier Ltd. All rights reserved.)

Objective: Factor VIII (FVIII) replacement and emicizumab have demonstrated efficacy for prevention of bleeds among patients with hemophilia A (PwHA) compared to on-demand (OD) use. Evidence investigating clinical outcomes and healthcare costs of non-inhibitor PwHA switching from prophylaxis with FVIII concentrates to emicizumab has not been well-established within large real-world datasets. This study aimed to investigate billed annualized bleed rates (ABR b ) and total cost of care (TCC) among non-inhibitor PwHA switching from FVIII-prophylaxis to emicizumab-prophylaxis., Methods: This retrospective, observational study was conducted using IQVIA PharMetrics Plus, a US administrative claims database. The date of first claim for emicizumab was defined as the index date. OD patients and inhibitor patients were excluded. Bleeds were identified using a list of 535 diagnosis codes. Bayesian models were developed to estimate the probability ABR b worsens and TCC increases after switching to emicizumab. Wilcoxon rank-sum tests were used to test statistical significance of changes in ABR b and TCC after switch., Results: Among the 121 identified patients, the difference in mean ABR b between FVIII-prophylaxis (0.68 [SD = 1.28]) and emicizumab (0.55 [SD = 1.48]) was insignificant ( p  = .142). The mean annual TCC significantly increased for patients switching from FVIII-prophylaxis ($518,151 [SD = $289,934]) to emicizumab ($652,679 [SD = $340,126]; p  < .0001). The Bayesian models estimated a 21.0% probability of the ABR b worsening and a 99.9% probability of increasing TCC after switch., Conclusions: This study found that in male non-inhibitor PwHA, switching from FVIII prophylaxis to emicizumab incurs substantial cost increase with no significant benefit in ABR b . This evidence may help guide providers, payers, and patients in shared decision-making conversations around best treatment options.

Competing Interests: There are no conflicts of interest.

Aim of the Study: The objective of this in-vitro study was to assess the screening capabilities of three endodontic sealers, namely the BioRoot RCS, the MTA Fillapex, and Sealapex (a calcium hydroxide-based sealer), and the gutta-percha cone by using a scanning electron microscopy to the dentine walls. The results from the research are presented here., Results: ZOE exhibited more gaps in the sealing materials evaluated with the least dental sealing performance, followed by the cervical third by the MTA Fillapex, the Sealapex, and the BioRoot RCS. The ZOE, followed by Sealapex, MTA Fillapex, and BioRoot RCS, exhibited inadequate dental wall sealing capacity in the middle of the third. The third apical ZOE exhibited more deficiencies in the formation of dental walls, followed by Sealapex, MTA Fillapex, and BioRoot RCS., Conclusion: Under the constraints of the investigation, it can be stated that for the bioceramic sealer, a minimal gap was seen, with RCS of BioRoot superior to Fillapex of MTA. In the middle third, Sealapex was better adapted to the calcium hydroxide-based sealant than the MTA Fillapex sealer. MTA Filllapex had lower gap development than Sealapex in cervical or apical thirds., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Pharmacy and Bioallied Sciences.)

Objective: To measure the anatomical dimensions of the vulva in adult Indian women. To analyze their correlations with age, body mass index (BMI), parity, and mode of delivery., Methods: This cross-sectional study was conducted in a tertiary care university hospital in India, among 400 women aged 18 years and above. Various vulval measurements were taken, and Pearson's correction was applied to variables like age, BMI, parity, and mode of delivery., Results: Mean length of glans of clitoris was 5.2 ± 1.43 mm, the labia minora width was 2.6 ± 0.74 cm, length of introitus was 1.3 ± 0.59 cm, and perineal body length was 2.3 ± 0.60 cm. The range of some measurements was extensive, for example labia minora width ranged from 0.7 to 4.9 cm. Normal centile curves were constructed for vulval measurements according to age groups. Statistically significant positive correlations of age, BMI, and obstetrical history were seen with labia minora width (r = 0.165, P = 0.001; r = 0.284, P < 0.001; r = 0.246, P < 0.001, respectively)., Conclusion: The centile curves can be used as a reference for the Indian population of different ages. These can be used when counseling women coming for female genital cosmetic surgery., (© 2021 International Federation of Gynecology and Obstetrics.)

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016-2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Graphene quantum dots (GQDs) are a luminescent class of carbon nanomaterials with a graphene-like core structure, possessing quantum confinement and edge effects. They have gained importance in the biological world due to their inherent biocompatibility, good water dispersibility, excellent fluorescence and photostability. The improved properties of GQDs require the logical enactment of functional groups, which can be easily attained through post-synthetic non-covalent routes of modification. In this regard, the present work has for the first time employed a simple one-pot post-modification method utilizing the salt of amino caproic acid, an FDA approved reagent. The adsorption of the modifier on GQDs with varying weight ratios is characterized through DLS, zeta potential, Raman, absorption and fluorescence spectroscopy. A decrease of 20% in the fluorescence intensity with an increase in the modifier ratio from 1 to 1000 and an increased DLS size as well as zeta potential demonstrate the efficient modification as well as higher stability of the modified GQDs. The modified GQDs with a high weight ratio (1 : 100) of the modifier showed superior ability to sense dopamine, a neurotransmitter, as well as competent biofilm degradation ability. The modified GQDs could sense more efficiently than pristine GQDs, with a sensitivity as low as 0.06 μM (limit of detection) and 90% selectivity in the presence of other neurotransmitters. The linear relationship showed a decrease in the fluorescence intensity with increasing dopamine concentration from 0.0625 μM to 50 μM. Furthermore, the efficiency of the modified GQDs was also assessed in terms of their antibiofilm effect against Staphylococcus aureus . The unmodified GQDs showed only 10% disruption of the adhered bacterial colonies, while the modified GQDs (1 : 100) showed significantly more than 60% disruption of the biofilm, presenting the competency of the modified GQDs. The unique modifications of GQDs have thus proven to be an effective method for the proficient utilization of zero-dimensional carbon nanomaterials for biosensing, bioimaging, antibacterial and anti-biofilm applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

MPS II is an X linked recessive lysosomal storage disorder with multi-system involvement and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 144 Indian patients with MPS II from 130 unrelated families. Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the IDS gene. In cases where causative variation was not detected by Sanger sequencing, MLPA and RFLP were performed to identify large deletions/duplications and complex rearrangements. Cytogenetic microarray was done in one patient to see the breakpoints and extent of deletion. In one patient with no detectable likely pathogenic or pathogenic variation, whole-genome sequencing was also performed. Novel variants were systematically assessed by in silico prediction software and protein modelling. The pathogenicity of variants was established based on ACMG criteria. An attempt was also made to establish a genotype-phenotype correlation. Positive family history was present in 31% (41/130) of patients. Developmental delay and intellectual disability were the main reasons for referral. Macrocephaly, coarse facies and dysostosis were present in almost all patients. Hepatosplenomegaly, joint contractures and short stature were the characteristic features, seen in 87% (101/116), 67.8% (74/109) and 41.4% (41/99) patients respectively. Attenuated phenotype was seen in 32.6% (47/144) patients, while severe phenotype was seen in 63% (91/144) patients. The detection rate for likely pathogenic or pathogenic variants in our cohort is 95.5% (107/112) by Sanger sequencing, MLPA and RFLP. We also found two variants of unknown significance, one each by Sanger sequencing and WGS. Total of 71 variants were identified by Sanger sequencing and 29 of these variants were found to be novel. Amongst the novel variants, there was a considerable proportion (51%) of frameshift variants (15/29). Almost half of the causative variants were located in exon 3,8 and 9. A significant genotype-phenotype correlation was also noted for both known and novel variants. This information about the genotype spectrum and phenotype will be helpful for diagnostic and prognostic purposes., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Vitamin D deficiency is widespread globally and is associated with type 2 diabetes mellitus (T2DM). Studies suggest markedly lower prevalence of vitamin D deficiency in outdoor workers compared to indoor workers. However, data on the vitamin D status of outdoor workers with T2DM is lacking., Aims: We assessed the vitamin D status of outdoor workers with T2DM residing across several districts of Southern West Bengal, India., Design: The present study is a descriptive observational study., Material and Methods: A total of 128 outdoor workers with T2DM were assessed for serum 25-hydroxyvitamin D (25(OH)D) during December 2019 after excluding common confounders except sun exposure (which was detailed using a questionnaire). Hospital staff were indoor controls, and vitamin D status was classified as per the Institute of Medicine guidelines., Results: The mean serum 25(OH)D of outdoor workers with T2DM was 21.79 ± 6.31 ng/mL, with only 2.34% (n = 3) having vitamin D deficiency and 57.03% (n = 73) having sufficient serum 25(OH)D levels. The mean serum 25(OH)D of indoor controls was significantly lower at 16.67 ± 9.82 ng/mL (p = 0.003), with 33.33% being vitamin D deficient. Serum 25(OH)D in outdoor workers with T2DM did not have a significant correlation with indices of sun exposure., Conclusions: Vitamin D deficiency is practically absent in outdoor workers with T2DM residing in Southern West Bengal, India., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Goswami et al.)

Introduction: Hemophilia B is associated with molecular heterogeneity, with more than 1200 unique variants in the F9 gene. We hereby describe the mutational spectrum of severe hemophilia B patients presenting in a tertiary-care center in India., Method: DNA was extracted from peripheral blood samples of 35 diagnosed severe hemophilia B patients belonging to 32 families, and were subjected to Sanger sequencing. Determination of the effect of novel variants on the protein structure and correlation between genotype and phenotype was attempted using in-silico tools., Results: Twenty-seven different mutations were detected in 30 probands, including 20 known and 7 novel variants. Also, we found one suspected case of whole gene deletion. The serine peptidase domain harbored most of the variants (48.1%). Inhibitory antibodies were found in two patients., Conclusions: This study provides a comprehensive mutational spectrum and mutation screening strategy by Sanger sequencing of F9 gene in severe hemophilia B patients, in a resource-constraint setting., (© 2021 John Wiley & Sons Ltd.)

Background : Adolescents are at risk for mental health (MH) disorders but are unlikely to seek services and may be reluctant to talk about their MH. An anonymous, online MH-focused community could help reduce suffering. However, online forums can also promote negative behaviours such as cyberbullying. This study aimed to evaluate the safety and feasibility of an online community - LovesCompany - to improve MH outcomes for adolescents. Methods : American adolescents (14-17 years) were recruited through social media. Eligible participants were randomised to LovesCompany or a placebo MH resource site. Outcomes were assessed every other week for six months, and at twelve months. Multilevel models assessed group differences in depression, anxiety, and suicidal ideation. A subgroup of participants participated in qualitative interviews. Results : Participants ( N = 202) were mostly female (70%), White non-Hispanic (69%), and cisgender (80%). There were no instances of inappropriate behaviour such as bullying or posting explicit content. Symptoms for both groups improved over time. Participants appreciated hearing others' experiences and valued the opportunity to offer support. Conclusion : Although adolescents are often resistant to MH treatment, they appear to be interested in anonymous, online, MH-focused conversation, and can benefit from giving and seeking support. Finding a balance between an appealing user experience, ethical considerations, and resource needs is challenging.

Introduction: Renal dysfunction at presentation is uncommon in primary membranous nephropathy (PMN). The data on the outcome of PMN patients with renal dysfunction at outset are scarce. The objective of the current study was to report the clinical outcomes of PMN patients with renal dysfunction., Material and Methods: This prospective longitudinal observational study included PMN patients (both incident and treatment resistant) with an estimated glomerular filtration rate of <60 mL/min/1.73 m2. Immunosuppressive treatment was as per the unit's protocol. Patients were evaluated for proteinuria, creatinine, and serum albumin at monthly intervals for 6 months, then quarterly for a year, and then biannually. Both serum and tissue anti-PLA2R were performed at baseline., Outcome: Percentage of patients achieving clinical remission., Results: Sixty-four adults met study criteria and were analysed. The median (IQR) age of the patients was 48 (40, 56) years. PMN was PLA2R related in 52 (81.3%) patients. Twenty-eight (43.8%) and 30 (46.9%) patients were in remission at 12 months and at the end of the study [median (IQR) follow up: 24 months (12, 35)], respectively. Eight (12.5%) had progressed to end-stage renal disease at the last follow-up. Median (IQR) baseline anti-PLA2R titre was 150.1 RU/mL (38.5, 308). Nineteen (61.3%) and 18 (58.1%) patients with >90% reduction in anti-PLA2R titres at 12 months were in clinical remission at 12 months and at the end of the follow-up, respectively. Both cyclical cyclophosphamide/steroids (cCYC/GC) and rituximab were equally effective in inducing remission, but rituximab had a favourable adverse event profile compared to cCYC/GC., Conclusion: To conclude, both cCYC/GC and rituximab are equally effective in inducing remission of nephrotic state with compromised renal function due to PMN. Immunosuppression induces remission in up to 50% PMN patients with CKD-stage 3-4., (© 2021 S. Karger AG, Basel.)

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action., Competing Interests: The authors have declared that no competing interests exist.

Key Message: Heavy doses of gamma irradiation can reduce linkage drag by disrupting large sized alien translocations and promoting exchanges between crop and wild genomes. Resistance to mustard aphid (Lipaphis erysimi) infestation was significantly improved in Brassica juncea through B. juncea-B. fruticulosa introgression. However, linkage drag caused by introgressed chromatin fragments has so far prevented the deployment of this resistance source in commercial cultivars. We investigated the patterns of donor chromatin segment substitutions in the introgression lines (ILs) through genomic in situ hybridization (GISH) coupled with B. juncea chromosome-specific oligonucleotide probes. These allowed identification of large chromosome translocations from B. fruticulosa in the terminal regions of chromosomes A05, B02, B03 and B04 in three founder ILs (AD-64, 101 and 104). Only AD-101 carried an additional translocation at the sub-terminal to intercalary position in both homologues of chromosome A01. We validated these translocations with a reciprocal blast hit analysis using shotgun sequencing of three ILs and species-specific contigs/scaffolds (kb sized) from a de novo assembly of B. fruticulosa. Alien segment substitution on chromosome A05 could not be validated. Current studies also endeavoured to break linkage drag by exposing seeds to a heavy dose (200kR) of gamma radiation. Reduction in the size of introgressed chromatin fragments was observed in many M 3 plants. There was a complete loss of the alien chromosome fragment in one instance. A few M 3 plants with novel patterns of chromosome segment substitutions displayed improved agronomic performance coupled with resistance to mustard aphid. SNPs in such genomic spaces should aid the development of markers to track introgressed DNA and allow application in plant breeding., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The objectives of this study were to describe the characteristics and initial treatment patterns, healthcare resource use (HCRU), and costs of patients newly diagnosed with neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN)., Methods: This was a retrospective study of individuals enrolled in the IBM MarketScan Multi-State Medicaid database from 1 October 2014 to 31 December 2017. Patients aged ≤18 years at the index date (first diagnosis of NF1 or PN, whichever occurred later) with at least 1 ICD-10-CM diagnosis code for both NF1 and PN were included. All-cause HCRU and the associated direct costs during the follow-up period were calculated per patient per year (PPPY) in 2018 USD., Results: A total of 383 patients were included with a mean follow-up of 448 days. Most patients were diagnosed by a specialist (63.5%). During the follow-up period, pain medications were used by 58.5% of patients, 25.1% were treated with chemotherapy, 7.1% received surgery for PN, 1.6% received MEK inhibitors, and 0.8% received radiation. Mean PPPY inpatient, outpatient, ER, pharmacy, and other visits were 1.4, 17.3, 1.6, 13.6, and 25.8, respectively. Mean ± SD (median) total PPPY healthcare costs were $17,275 ± $61,903 ($2889), with total medical costs of $14,628 ± $56,203 ($2334) and pharmacy costs of $2646 ± $13,303 ($26)., Conclusions: This study showed that many pediatric patients newly diagnosed with NF1 and PN were initially treated with supportive care only, highlighting a substantial unmet medical need. This study also highlights the considerable economic burden among patients with NF1 and PN.

Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID., (© 2021 Wiley Periodicals LLC.)

Silver is commonly used in wound dressing, photography, health care products, laboratories, pharmacy, biomedical devices, and several industrial purposes. Silver (Ag + ) ions are more toxic pollutants widely scattered in the open environment by natural processes and dispersed in soil, air, and water bodies. Ag + binds with metallothionein, macroglobulins, and albumins, which may lead to the alteration of various enzymatic metabolic pathways. To analyze the uptake and metabolism of silver ions in vitro as well as in cells, a range of high-affinity fluorescence-based nanosensors has been constructed using a periplasmic protein CusF , a part of the CusCFBA efflux complex, which is involved in providing resistance against copper and silver ions in Escherichia coli . This nanosensor was constructed by combining of two fluorescent proteins (donor and acceptor) at the N- and C-terminus of the silver-binding protein ( CusF ), respectively. SenSil (WT) with a binding constant ( K d ) of 5.171 μM was more efficient than its mutant variants (H36D and F71W). This nanosensor allows monitoring the level of silver ions in real time in prokaryotes and eukaryotes without any disruption of cells or tissues., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Video 1EGD revealing 1 column of nonbleeding grade 2 varices in the middle third of the esophagus at the anterior wall; absent red wale sign and 3 columns of nonbleeding grade 3 varices in the upper third of the esophagus in the anterior and posterior wall. Stigmata of recent bleeding evident, red wale signs present, and 1 white nipple sign identified in the anterior wall, in the same column coming from the middle esophagus. Successful variceal banding ligation was performed, and there was no recurrence of bleeding., (© 2021 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Background: Unlike adults, primary membranous nephropathy (PMN) comprises only 1-2% of childhood nephrotic syndrome. The clinical behaviour of PMN in children is not explicit and we report upon clinical presentation and outcome., Methods: This prospective study includes children and adolescents (< 20 years) with biopsy-proven PMN without secondary causes. Anti-PLA2R assessment: before and after completing therapy., Outcome: percentage of patients achieving remission., Results: Study cohort included 48 (M:F ratio 1.1:1) patients and median age 17 (IQR 15-18) years, with 35 (72.9%) PLA2R related. Median interval from symptom onset to presentation was 5 months, where median proteinuria, serum albumin and creatinine were 4.9 g/day, 2.1 g/dL and 0.63 mg/dL, respectively. Forty-seven patients received immunosuppressive therapy, with various agents used as first-line therapy: cyclical CYC/GC (53.1%), CNI/GC (21.3%), rituximab (14.9%), prednisolone alone (4.3%), azathioprine (4.3%) and mycophenolate mofetil (2.1%). Median follow-up was 29 (14, 59) months. At 6 months, 11 (24.4%) and 17 (37.7%) had complete remission (CR) or partial remission (PR), while at last follow-up (median 29 months), 20 (45.4%) and 14 (31.8%) had CR and PR respectively. No significant differences in outcome were observed with different agents. A total of 60% patients treated with rituximab as first line/for relapsing disease, and all cases with resistant disease receiving rituximab had CR or PR at last follow-up. PLA2R antibody presence was associated with clinical outcome., Conclusions: Three-quarters of PMN in children and adolescents is PLA2R related and two-thirds respond to immunosuppressive therapy. Rituximab is a promising agent to manage PMN in children. Anti-PLA2R is associated with clinical outcomes.

Error-free progression through mitosis is critical for proper cell division and accurate distribution of the genetic material. The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase regulates the progression from metaphase to anaphase and its activation is controlled by the cofactors Cdc20 and Cdh1. Additionally, genome stability is maintained by the spindle assembly checkpoint (SAC), which monitors proper attachment of chromosomes to spindle microtubules prior to cell division. We had shown a role for Tank Binding Kinase 1 (TBK1) in microtubule dynamics and mitosis and here we describe a novel role of TBK1 in regulating SAC in breast and lung cancer cells. TBK1 interacts with and phosphorylates Cdc20 and Cdh1 and depletion of TBK1 elevates SAC components. TBK1 inhibition increases the association of Cdc20 with APC/C and BubR1 indicating inactivation of APC/C; similarly, interaction of Cdh1 with APC/C is also enhanced. TBK1 and TTK inhibition reduces cell viability and enhances centrosome amplification and micronucleation. These results indicate that alterations in TBK1 will impede mitotic progression and combining TBK1 inhibitors with other regulators of mitosis might be effective in eliminating cancer cells., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To assess the effects of the COVID-19 pandemic on obstetric care and outcomes., Methods: A prospective observational single-center study was performed, including all antenatal and parturient women admitted from April to August, 2020. Data were collected regarding number of admissions, deliveries, antenatal visits, reason for inaccessibility of health care, and complications during pregnancy, and compared with data from the pre-COVID period of October 2019 to February 2020., Results: There was a reduction of 45.1% in institutional deliveries (P < 0.001), a percentage point increase of 7.2 in high-risk pregnancy, and 2.5-fold rise in admission to the intensive care unit of pregnant women during the pandemic. One-third of women had inadequate antenatal visits. The main reason for delayed health-seeking was lockdown and fear of contracting infection, resulting in 44.7% of pregnancies with complications. Thirty-two symptomatic women who tested positive for COVID-19 were managed at the center with good maternal and fetal outcomes., Conclusion: Although COVID-19 does not directly affect pregnancy outcomes, it has indirect adverse effects on maternal and child health. Emergency obstetric and antenatal care are essential services to be continued with awareness of people while maintaining social distancing and personal hygiene., (© 2020 International Federation of Gynecology and Obstetrics.)

Introduction: IgA nephropathy (IgAN) is the most common form of glomerulonephritis across the world. Oxford classification defines criteria and effects of endocapillary hypercellularity on E score but the reproducibility of the same is debatable. Hence, there is a need for an objective marker that could establish a gold standard in assessing endocapillary hypercellularity., Methods: Forty biopsies of proven IgAN were taken and grouped into two groups based on the presence or absence of endocapillary hypercellularity ( n = 20 each). These biopsies were then stained by CD68 immune stain and the glomerular macrophages were quantified. Mean serum creatinine, presence of hypertension, degree of proteinuria and haematuria at the time of biopsy were also recorded and the correlation between these parameters and endocapillary hypercellularity was also studied., Results: Mean glomerular CD 68+ cell count was significantly higher in glomeruli showing endocapillary hypercellularity. Utilising the objective cutoff values of 0.6 CD68+ per glomerulus, more than 8 glomerular CD68+ cells in the entire biopsy and/or around 4 CD68+ cells in the most inflamed glomerulus, endocapillary hypercellularity can be predicted with a sensitivity of 70-80% and specificity of 70%. After regrouping the biopsies based on the cutoff values obtained from the receiver operating curve analysis the mean urine RBC count per high power field showed a significant correlation with endocapillary hypercellularity., Conclusion: Glomerular CD68+ macrophage count seems to be a promising approach in assessing endocapillary hypercellularity. Further studies with emphasis on correlation with the clinical outcome are needed to validate its utility as an objective tool., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Nephrology.)

Purpose: The model biological organism Drosophila melanogaster has been utilized to assess the effect of extremely low-frequency electromagnetic field (ELF-EMF) on locomotion, longevity, developmental dynamics, cell viability and oxidative stress., Materials and Method: Developmental stages of Drosophila melanogaster (Oregon R strain) individually exposed to ELF-EMF (75 Hz, 550 µ T) for 6 h once for acute exposure. For chronic exposure, complete life cycle of fly, that is, egg to adult fly was exposed to ELF-EMF for 6 h daily. The effect of exposure on their crawling and climbing ability, longevity, development dynamics, cellular damage and oxidative stress (generation of reactive oxygen species (ROS)) was evaluated., Results: The crawling ability of larvae was significantly ( p  < .05) reduced on acute (third stage instar larvae) as well as chronic exposure (F0 and F1 larvae). When locomotion of flies was tested using climbing assay, no alteration was observed in their climbing ability under both acute and chronic exposure; however, when their speed of climbing was compared, a significant decrease in speed of F1 flies was observed ( p = .0027) on chronic exposure. The survivability of flies was significantly affected under chronic and acute exposure (at third stage instar larvae). In case of acute exposure of the third stage instar larvae, although all the flies were eclosed by the 17th day, there was a significant decline in the number of flies ( p = .007) in comparison to control. While in case of chronic exposure apart from low number of flies eclosed in comparison to control, there was delay in eclosion by one day ( p = .0004). Using trypan blue assay, the internal gut damage of third stage instar larvae was observed. Under acute exposure condition at third stage instar larvae, 30% larvae has taken up trypan blue, while only 10% larvae from acute exposure at adult stage. On chronic exposure, 50% larvae of the F1 generation have taken up trypan blue. On evaluation of oxidative stress, there is a significant rise in ROS in case of acute exposure at third stage instar larvae ( p = .0004), adult fly stage ( p = .0004) and chronic exposure ( p = .0001)., Conclusion: ELF-EMF has maximum effects on acute exposure of third stage instar larvae and chronic exposure (egg to adult fly stage). These results suggest that electromagnetic radiations, though, have become indispensible part of our lives but they plausibly affect our health.

Introduction: Breast cancer is rapidly emerging as the leading cause of cancer in Indian women. Robust cytopathology and histopathology services are required to tackle this growing burden. The use of rapid on-site evaluation (ROSE) and the International Academy of Cytology (IAC) Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytopathology, which offers structured protocols, are expected to improve breast cytopathology reporting., Methods: We retrieved the cytopathology slides, categorized them by the IAC Yokohama System and histopathology data of all the patients who had been investigated for breast lesions from September 2016 to December 2018, and compared the cytopathology and histopathology. Risk of malignancy (ROM) and performance metrics, like sensitivity, specificity, predictive values, accuracy, and area under the curve were computed., Results: A total of 1,147 FNABs were evaluated, of which 442 (38.5%) underwent ROSE and 624 (54.4%) histopathology. Reported using IAC categories, our cohort recorded 4.9% inadequate, 65.3% benign, 7.8% atypical, 3.3% suspicious for malignancy, and 18.7% malignant lesions. The overall sensitivity and specificity for identifying in situ and malignant lesions were 99.1% and 99.3%, respectively, and were substantially improved by ROSE. ROSE improved the concordance between cytopathology and histopathology from 76.9% to 90.2%, by reducing inadequate (p < 0.001) cases. The ROM increased along a gradient from inadequate to malignant categories, with the gradient being sharpened by ROSE. The false negativity rate was 0.7% and false positivity rate 0%., Conclusion: Incorporating ROSE and the IAC Yokohama System for breast cytopathology reporting improves accurate diagnosis of breast lesions, prevents missed diagnoses, and provides reliable estimates of ROM. These protocols also aid in standardizing a reproducible system for monitoring and auditing of breast pathology services, identify areas that need strengthening, and improve training at pathology centers., (© 2021 S. Karger AG, Basel.)

Crop brassicas include three diploid [ Brassica rapa (AA; 2 n = 2 x = 16), B. nigra (BB; 2 n = 2 x = 18), and B. oleracea (CC; 2 n = 2 x = 20)] and three derived allotetraploid species. It is difficult to distinguish Brassica chromosomes as they are small and morphologically similar. We aimed to develop a genome-sequence based cytogenetic toolkit for reproducible identification of Brassica chromosomes and their structural variations. A bioinformatic pipeline was used to extract repeat-free sequences from the whole genome assembly of B. rapa . Identified sequences were subsequently used to develop four c. 47-mer oligonucleotide libraries comprising 27,100, 11,084, 9,291, and 16,312 oligonucleotides. We selected these oligonucleotides after removing repeats from 18 identified sites (500-1,000 kb) with 1,997-5,420 oligonucleotides localized at each site in B. rapa . For one set of probes, a new method for amplification or immortalization of the library is described. oligonucleotide probes produced specific and reproducible in situ hybridization patterns for all chromosomes belonging to A, B, C, and R ( Raphanus sativu s) genomes. The probes were able to identify structural changes between the genomes, including translocations, fusions, and deletions. Furthermore, the probes were able to identify a structural translocation between a pak choi and turnip cultivar of B. rapa. Overall, the comparative chromosomal mapping helps understand the role of chromosome structural changes during genome evolution and speciation in the family Brassicaceae. The probes can also be used to identify chromosomes in aneuploids such as addition lines used for gene mapping, and to track transfer of chromosomes in hybridization and breeding programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Agrawal, Gupta, Banga and Heslop-Harrison.)

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition which predisposes individuals to tumors of the nervous system, skin, bones, and eyes. Plexiform neurofibromas (PNs) occur in 20-50% of NF1 cases, causing multiple morbidities and conferring a risk of malignancy. NF1 with PN is poorly characterized in the literature with regard to treatment patterns, healthcare resource utilization, and costs in the real world., Methods: This was a retrospective analysis of data from a commercial claims database in the US between October 2014 and March 2018. Persons with at least 1 diagnostic code for both NF1 and PN, aged ≤18 years on the index date, and continuously enrolled for ≥12 months before the index date were included. The index date was defined as the date of the first diagnosis of NF1 or PN during the study period, whichever occurred later. Healthcare resource utilization during follow-up included outpatient, inpatient, emergency room (ER), and pharmacy encounters; corresponding costs were calculated as the mean per patient per year (PPPY) in 2018 US dollars. Treatments were classified as PN surgery, pain medication, chemotherapy, radiotherapy, and targeted therapies. All analyses were descriptive., Results: A total of 301 patients were included. In the follow-up period, nearly all patients (99.7%) had outpatient visits, while 81.1% had pharmacy visits, 25.2% had ER visits, and 13.0% had inpatient visits. Mean ± SD [median] total healthcare costs PPPY were $38,292 ± $80,556 [$16,037]. During follow-up, 44.2% of patients used pain medications, 23.9% received chemotherapy, 5.0% underwent surgery for PN, 1.3% received radiotherapy, and 1.0% received targeted therapies., Conclusion: Commercially insured pediatric patients diagnosed with NF1 and PN were treated primarily with supportive care, highlighting a substantial unmet need in the United States., Competing Interests: Xiaoqin Yang, Kaushal Desai, Eric Sarpong, and Shuvayu Sen are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may be stockholders of Merck & Co., Inc., Kenilworth, NJ, USA. Kaushal Desai is a stockholder of AstraZeneca. Neha Agrawal, Kirti Mirchandani, and Sagnik Chatterjee, are employees of Complete HEOR Solutions, North Wales, PA, USA which has received financial compensation for conducting the study analysis. The authors report no other conflicts of interest in this work., (© 2020 Yang et al.)

Transverse vaginal septum is one of the variants of Mullerian duct anomaly, caused as a result of defective fusion or recanalisation of vaginal and Mullerian organs. At an early age, it commonly presents as primary amenorrhea along with cyclical abdominal pain while later on usually it presents as dyspareunia and infertility. Our 22-year-old patient presented with secondary amenorrhea. It is very unusual for a transverse vaginal septum to cause secondary amenorrhea. MRI and clinical examination raised the suspicion of transverse vaginal septum causing secondary amenorrhea. She attained regular menstrual cycle after septum excision. The proposed theory behind it is obliteration of microperforated transverse vaginal septum because of menstrual blood and cell debris. Thus, a rare possibility of transverse vaginal septum should also be considered as a differential diagnosis of secondary amenorrhea., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Even as the field of microbiome research has made huge strides in mapping microbial community composition in a variety of environments and organisms, explaining the phenotypic influences on the host by microbial taxa-both known and unknown-and their specific functions still remain major challenges. A pressing need is the ability to assign specific functions in terms of enzymes and small molecules to specific taxa or groups of taxa in the community. This knowledge will be crucial for advancing personalized therapies based on the targeted modulation of microbes or metabolites that have predictable outcomes to benefit the human host. This perspective article advocates for the combined use of standards-free metabolomics and activity-based protein profiling strategies to address this gap in functional knowledge in microbiome research via the identification of novel biomolecules and the attribution of their production to specific microbial taxa., (Copyright © 2020 Couvillion, Agrawal, Colby, Brandvold and Metz.)

Objectives: Lead is one of the most toxic heavy metal prevalent in the environment, which affects almost all major organs including heart, brain, intestines, kidneys as well as reproductive organs. It has been known that serum iron deficiency is associated with increased serum lead levels as lead is a particularly pernicious element to iron metabolism. Lead is also known to freely cross the placenta too; hence, this study was planned to determine any association between antenatal iron deficiency anemia (IDA), raised blood lead levels (BPb), and adverse pregnancy outcomes., Materials and Methods: This was an observational study done on 99 antenatal women with IDA and 41 nonanemic antenatal women. Lead levels were assessed in these 140 antenatal women and they were followed for adverse pregnancy outcomes. Chi-square test was used to find a difference in quantitative variables and Pearson's correlation test was used to assess association between BPb and hemoglobin levels., Results: We found that in 11 out of 99 (11.11%) women with IDA, BPb levels were high as compared to high BPb levels in only 1 out of 41 (2.4%) women without IDA and the high BPb levels ranged from 4 μg/dl-16.9 μg/dl with a mean BPb of 8.1 μg/dl. The difference in BPb among anemic and nonanemic antenatal women was significant ( P < 0.05) and there was a negative dose effect relationship between BPb levels and hemoglobin levels. This difference in antenatal outcomes among women with and without high BPb levels was also significant with increased incidence of pre-eclampsia, FGR, and preterm deliveries in women with raised BPb levels. The incidence of NICU admission was also higher in the neonates of mothers with high BPb levels., Conclusions: We propose screening of high-risk women based on their social, occupational, environmental, and personal factors, with serum lead levels in the preconception period itself. All public and personal measures must be taken to reduce lead consumption and exposure in the preconception and antenatal period., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Family Medicine and Primary Care.)