Independent and joint effects of neighborhood-level environmental and socioeconomic exposures on body mass index in early childhood: The environmental influences on child health outcomes (ECHO) cohort.

Past studies support the hypothesis that the prenatal period influences childhood growth. However, few studies explore the joint effects of exposures that occur simultaneously during pregnancy. To explore the feasibility of using mixtures methods with neighborhood-level environmental exposures, we assessed the effects of multiple prenatal exposures on body mass index (BMI) from birth to age 24 months. We used data from two cohorts: Healthy Start (n = 977) and Maternal and Developmental Risks from Environmental and Social Stressors (MADRES; n = 303). BMI was measured at delivery and 6, 12, and 24 months and standardized as z-scores. We included variables for air pollutants, built and natural environments, food access, and neighborhood socioeconomic status (SES). We used two complementary statistical approaches: single-exposure linear regression and quantile-based g-computation. Models were fit separately for each cohort and time point and were adjusted for relevant covariates. Single-exposure models identified negative associations between NO2 and distance to parks and positive associations between low neighborhood SES and BMI z-scores for Healthy Start participants; for MADRES participants, we observed negative associations between O3 and distance to parks and BMI z-scores. G-computations models produced comparable results for each cohort: higher exposures were generally associated with lower BMI, although results were not significant. Results from the g-computation models, which do not require a priori knowledge of the direction of associations, indicated that the direction of associations between mixture components and BMI varied by cohort and time point. Our study highlights challenges in assessing mixtures effects at the neighborhood level and in harmonizing exposure data across cohorts. For example, geospatial data of neighborhood-level exposures may not fully capture the qualities that might influence health behavior. Studies aiming to harmonize geospatial data from different geographical regions should consider contextual factors when operationalizing exposure variables.

Application of co-processed excipients for developing fast disintegrating tablets: A review.

The introduction of tablet dosage forms has brought a revolution in the pharmaceutical drug delivery system. Different forms of tablets have been developed based on the target site, the onset of action, and therapeutic drug delivery methods. Fast-disintegrating tablets (FDTs) are the most promising pharmaceutical dosage form, especially for pediatric and geriatric patients having difficulty swallowing. The key feature of FDTs is quick drug release soon after their administration through the oral cavity. With innovations in the formulation of FDTs, the demand for excipients with better functionalities, particularly in terms of flow and compression characteristics, has increased. Co-processed excipients are a mixture of 2 or more conventional excipients that provides significant benefits over the individual excipients while minimizing their shortcomings. Such multifunctional co-processed excipients minimize the number of excipients that are to be incorporated into tablets during the manufacturing process. The present review discusses FTDs formulated from co-processed excipients, their manufacturing techniques, and the latest research, patents and commercially available co-processed FDTs.

Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Colorectal Carcinoma: A Potential Area of Focus for Future Diagnostics.

Objective In this study, we aimed to explore the potential diagnostic utility of human epidermal growth factor receptor 2 (HER2) expression in colorectal carcinoma. We investigated the association of HER2 expression with the type and grade of the tumor along with the pattern, staining intensity, and the percentage of cells stained. Methods This was an observational study involving 50 cases of colorectal carcinoma that underwent immunohistochemistry to analyze the HER2 expression. Results The positive expression of HER2 was seen in 16 (32%) cases. The majority of the study population was between the fifth-seventh decades of life. The most commonly diagnosed tumor was conventional adenocarcinoma with grade II, cytoplasmic pattern, +2 positivity, and moderate intensity. The maximum positivity for HER2 was seen in tumors of the rectum in eight (16%) cases. Conclusion A substantial rate of HER2 overexpression paves the way for it to become a potential future target in cancer therapeutics.

Upregulation of cytokine signalling in platelets increases risk of thrombophilia in severe COVID-19 patients.

Abnormal coagulation dynamics, including disseminated intravascular coagulopathy, pulmonary embolism, venous thromboembolism and risk of thrombosis are often associated with the severity of COVID-19. However, very little is known about the contribution of platelets in above pathogenesis. In order to decipher the pathophysiology of thrombophilia in COVID-19, we recruited severely ill patients from ICU, based on the above symptoms and higher D-dimer levels, and compared these parameters with their asymptomatic counterparts. Elevated levels of platelet-derived microparticles and platelet-leukocyte aggregates suggested the hyperactivation of platelets in ICU patients. Strikingly, platelet transcriptome analysis showed a greater association of IL-6 and TNF signalling pathways in ICU patients along with higher plasma levels of IL-6 and TNFα. In addition, upregulation of pathways like blood coagulation and hemostasis, as well as inflammation coexisted in platelets of these patients. Further, the increment of necrotic pathway and ROS-metabolic processes in platelets was suggestive of its procoagulant phenotype in ICU patients. This study suggests that higher plasma IL-6 and TNFα may trigger platelet activation and coagulation, and in turn aggravate thrombosis and hypercoagulation in severe COVID-19 patients. Therefore, the elevated IL-6 and TNFα, may serve as potential risk factors for platelet activation and thrombophilia in these patients.

α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt.

BACKGROUND: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. METHODS: We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. FINDINGS: Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. INTERPRETATION: Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. FUNDING: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).

Food Safety in Eating Establishments: Assessing Conformance of Eating Establishments to Food Safety and Standards Regulations.

INTRODUCTION: In view of the rising burden of the foodborne illnesses and the rise of eating out culture in India, food safety has assumed greater significance. The Food Safety and Standards Authority of India has prescribed food safety and standards regulations (FSSRs) for commercial eating establishments (EEs). The present study was carried out to ascertain conformance of the EEs to these regulations. METHODOLOGY: It was a cross-sectional study conducted on 74 EEs in a metro city in western Maharashtra from May to October 2019 using an interviewer-administered study tool based on FSSR 2011. The study tool covered critical domains such as food hygiene, equipments, health and personal cleanliness, training of food handlers, and product information. RESULTS: Seventy-four EEs included 29 restaurants, 21 bakeries, and 24 snack bars. The score ranged between 42.3% and 73.3%. Of 74, 20 (27%) EEs were placed in poor category (score <50%), Only 3 EE scored >70% and were rated as very good. Only 13 (17.6%) EEs were cleaning the food contact surfaces adequately, i.e. before and after each use, whereas 38 (51.4%) were not cleaning food contact surfaces at least daily. The knowledge regarding food handlers as potential carriers of disease was poor with 60.81% of the respondents having no knowledge about it. CONCLUSION: The study found significant gaps in EEs with respect to studied food safety domains of FSSR 2011.

Window of Implantation is Significantly Displaced in Patients with Adenomyosis with Previous Implantation Failure as Determined by Endometrial Receptivity Assay.

BACKGROUND: Adenomyosis is associated with implantation failure and poor reproductive performance in IVF/ICSI cycles. AIMS: To compare if window of implantation (WOI) is displaced in patients having adenomyosis compared to controls using endometrial receptivity array (ERA) test. SETTINGS AND DESIGN: Retrospective Case control study. 374 patients with previous one or more IVF failures who underwent ERA test between 2013-2016 at our centre were enrolled. Patients were divided into two groups; Group A-36 patients with adenomyosis (study group) and Group B- 338 patients without adenomyosis (controls). STATISTICAL ANALYSIS: Normality assumptions for continuous variables were tested using Kolmogorov Smirnov test. Mean values of two groups were compared using Student's t-independent test. Frequency data by categories were compared using Chi-square/Fisher's exact test. Risk ratio and 95% confidence limits were calculated. P < 0.05 was considered for statistical significance. RESULTS: WOI was displaced (Non Receptive ERA) significantly in adenomyosis 47.2% (17/36) compared to controls 21.6% (73/338) (P < 0.001, CI-8.7%-42.5%) making risk ratio of displaced WOI in adenomyosis versus controls to be 2:1. The incidence of RIF was 66.6% in adenomyosis compared to 34.9% in controls (P < 0.001, CI- 15.5%-47.9%). Pregnancy rate after personalized embryo transfer in adenomyosis group was 62.5%, signifying displaced WOI as a cause of implantation failure in adenomyosis patients with previous implantation failure. CONCLUSIONS: Our study suggests it is prudent to evaluate Endometrial receptivity before embryo transfer in patients with adenomyosis to avoid wastage of good embryos.

The role of Indian gynecologists in oncofertility care and counselling.

Oncofertility is gaining importance because of increasing cancer incidence, high survivorship, the need to provide a good quality of life to survivors and the desire of patients to preserve their fertility. Disseminating information about the effect of cancer and cancer treatment on fertility and the availability and effectiveness of fertility preservation techniques is critical. Gynaecologists in India act as family physicians and are in a unique position to guide cancer patients on issues of fertility and fertility preservation. Their contribution in oncofertility is vital to improve the quality of life of many young survivors. This paper presents the result of a survey done with Indian gynaecologists. The aim of this survey was to ascertain awareness and knowledge of reproductive damage by cancer therapy, knowledge of fertility preservation techniques and an understanding of the barriers to fertility preservation. This information would assist in planning programs to improve oncofertility care and counselling.

Genetic Variability in Probe Binding Regions Explains False Negative Results of a Molecular Assay for the Detection of Dengue Virus.

Dengue fever is currently the most prevalent disease caused by mosquito-borne flaviviruses. Despite being potentially fatal, there are no specific antiviral therapies for Dengue virus (DENV) infections. Therefore, early, accurate, and rapid diagnosis plays an important role in proper patient management. In this study, we evaluated the performance of a probe-based real-time RT-PCR (rRT-PCR) assay against that of a conventional RT-PCR assay in three sample cohorts from Pakistan (n = 94) and Singapore (first cohort; n = 559, second cohort; n = 123). The Pakistan cohort also included a comparison with virus isolation. The rRT-PCR assay showed relatively lower overall sensitivity (20.2%) in the Pakistan cohort than that in first (90.8%) and second (80.5%) Singapore cohorts. Surprisingly, the overall sensitivity of rRT-PCR assay was lower compared with the virus isolation (26.6%) among Pakistan samples, indicating a high percentage (79.8%) of false negatives due to rRT-PCR assay. The analysis of sequences of failed and successful DENV isolates indicated mismatches in probe binding regions as the likely cause of rRT-PCR assay failure. Our observations testify the importance of utilizing a combination of methods for dengue diagnostics and surveillance. We emphasize that a thorough understanding of the genetic composition of local DENV populations as well as regular monitoring of the performance and reviewing of probe/primer sequences are essential to maintain a consistently high diagnostic accuracy of PCR-based assays.

Sero-prevalence and cross-reactivity of chikungunya virus specific anti-E2EP3 antibodies in arbovirus-infected patients.

Chikungunya virus (CHIKV) and clinically-related arboviruses cause large epidemics with serious economic and social impact. As clinical symptoms of CHIKV infections are similar to several flavivirus infections, good detection methods to identify CHIKV infection are desired for improved treatment and clinical management. The strength of anti-E2EP3 antibody responses was explored in a longitudinal study on 38 CHIKV-infected patients. We compared their anti-E2EP3 responses with those of patients infected with non-CHIKV alphaviruses, or flaviviruses. E2EP3 cross-reactive samples from patients infected with non-CHIKV viruses were further analyzed with an in vitro CHIKV neutralization assay. CHIKV-specific anti-E2EP3 antibody responses were detected in 72% to 100% of patients. Serum samples from patients infected with other non-CHIKV alphaviruses were cross-reactive to E2EP3. Interestingly, some of these antibodies demonstrated clearly in vitro CHIKV neutralizing activity. Contrastingly, serum samples from flaviviruses-infected patients showed a low level of cross-reactivity against E2EP3. Using CHIKV E2EP3 as a serology marker not only allows early detection of CHIKV specific antibodies, but would also allow the differentiation between CHIKV infections and flavivirus infections with 93% accuracy, thereby allowing precise acute febrile diagnosis and improving clinical management in regions newly suffering from CHIKV outbreaks including the Americas.

Subcutaneous Axillary and Scalp Metastases from Non-Gynecological Retroperitoneal Leiomyosarcoma: An Unusual Presentation After Surgical Resection.

Retroperitoneal leiomyosarcomas are rare sarcomas, with an incidence of less than 2 per million population. Cutaneous metastases from sarcoma account for only 1-2.6% of metastatic skin lesions. Cutaneous and subcutaneous metastasis from retroperitoneal leiomyosarcoma is a very rare entity. We present a case of 72-year-old male with scalp nodule and subcutaneous swelling in left posterior axillary fold. Fine needle aspiration cytology from both these sites revealed a sarcoma, which was positive for Smooth Muscle Actin and negative for S100 on cell block immuno-histochemistry (IHC). The past history revealed surgical resection of a retroperitoneal mass in 2010 which was diagnosed on histopathology and IHC as leiomyosarcoma. A final diagnosis of metastatic deposits from leiomyosarcoma was made. Retroperitoneal leiomyosarcoma presenting as scalp and subcutaneous metastasis is an unusual presentation. Adequate clinical history and a high index of clinical suspicion is required to detect cutaneous and subcutaneous metastatic deposits occurring five years after surgical resection.