Determinants of polycystic ovary syndrome: A matched case-control study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a multifaceted endocrine disorder of women of reproductive age with a multifactorial aetiology. Despite much research, there is still inconclusive data on the impact of dietary, lifestyle and socio-economic factors on PCOS aetiology. Thus, the present study explored the association of PCOS with diet, eating behaviour, other lifestyle and socio-economic factors. METHODS: A matched-pair case-control study was conducted on 150 women with PCOS and 150 healthy controls. Information on diet, eating behaviour and physical activity, and also anthropometric and socio-economic data were collected through standard questionnaires. The adjusted odds ratios (AmOR) were calculated and reported using conditional multivariable logistic regression. RESULTS: The results showed low education level (AmOR = 8.44; 95% confidence interval [CI] = 1.63-43.68), high sugar consumption (AmOR = 11.61; 95% CI = 2.05-65.72) along with higher body mass index (BMI) and inactivity to be significantly associated with PCOS. Also, a significant protective effect was found for cognitive dietary restraint (AmOR = 0.79; 95% CI = 0.66-0.93), crude fibre (AmOR = 0.61; 95% CI = 0.45-0.82) and protein intake. CONCLUSIONS: Low education status may contribute to higher receptiveness to choosing unhealthy diets and lifestyles, resulting in adiposity and an increased risk of PCOS.

Transcutaneous Hitching Sutures in Paediatric Minimally Invasive Surgery: A Novel Technique of "Assistant Without Port".

BACKGROUND: Transcutaneous hitching sutures in paediatric minimally invasive surgery (MIS) is a unique and rare technique. This technique has been used previously in adult patients undergoing gastric resections and laparoscopic cholecystectomy; however, its use in paediatric population has never been reported in the world literature. The primary objective of this study was to bring out the advantages and feasibility of this technique in minimally invasive gastrointestinal, hepatobiliary, urological and thoracoscopic surgeries on paediatric patients. MATERIALS AND METHODS: This retrospective observational study was conducted on 167 paediatric patients who underwent MIS surgery for different indications between April 2016 and March 2020 at two paediatric surgery tertiary care centres. RESULTS: A total of 167 patients, including 91 boys and 76 girl patients between the age group of new-born period to 12 years were operated. The mean hospital stay was 4 days. Five out of 167 cases (3%) had post-operative surgical emphysema, which resolved spontaneously. At 6-month follow-up, parental satisfaction was 100%, and in 99% of patients, scars were imperceptible. CONCLUSION: This versatile technique is of exemplary utility, especially in paediatric patients where there is a paucity of working space at low intra-abdominal pressure, and eases the dissection even in narrow and closed spaces with a better functional and cosmetic outcome.

Ten Years Analysis of Parental Counselling-in-Continuum in Paediatric Surgery: Psychosocial and Medico-legal Outcome.

BACKGROUND: Parents are anxious and apprehensive about the health of their children. A standardised, reproducible and meticulous parental counselling is helpful to both the parents and the treating doctors, as well as markedly reduces instances of scrimmage and medico-legal litigations. The aim of this study is to assess the psychosocial and medico-legal outcomes of parental counselling-in-continuum (PCiC) in paediatric surgery. MATERIALS AND METHODS: The study was conducted at two government-run Tertiary Healthcare Centres in North India. The study design involves prospective feedback-based study. It included all the admitted paediatric surgery patients. Periodic multisession PCiC was done for each patient by three paediatric surgery teams from 2011 to 2021. At the time of discharge, feedback was taken to assess the psychosocial outcome of PCiC, and the medico-legal outcome was calculated based on the number of litigations. RESULTS: A total of 22,353 admissions were done in paediatric wards at these institutes. 1574 cases were managed conservatively and 20,779 patients who underwent surgeries were included in the study. 4758 (22.89%) were emergency procedures and 16,021 (77.11%) were elective procedures. Parents rated the counselling efforts excellent in 18,285 (81.80%), good in 3162 (14.14%), satisfactory in 876 (3.91%) and poor in 30 (0.13%) cases with zero medico-legal litigations and 12 incidents of scrimmage. CONCLUSIONS: PCiC, being a novel concept, should form a centerpiece of paediatric surgical management as it maximally enhances the patient satisfaction level and protects the treating paediatric surgical team from scrimmage and medico-legal litigations.

Comparable outcomes with low-dose and standard-dose horse anti-thymocyte globulin in the treatment of severe aplastic anemia.

BACKGROUND: The standard dose (SD) of horse anti-thymocyte globulin (hATG) ATGAM (Pfizer, USA) or its biosimilar thymogam (Bharat Serum, India) for the treatment of Aplastic Anemia (AA) is 40 mg/kg/day for 4 days in combination with cyclosporine. Data on the impact of hATG dose on long-term outcomes are limited. Here, we describe our comparative experience using 25 mg/kg/day (low-dose [LD]) hATG for 4 days with SD for the treatment of AA. METHODS: We retrospectively studied patients with AA (age > 12 years) who received two doses of hATG combined with cyclosporine. Among 93 AA patients who received hATG, 62 (66.7%) and 31 (33.3%) patients received LD and SD hATG with cyclosporine, respectively. Among these,seventeen(18.2%) patients also received eltrombopag with hATG and cyclosporine. Overall response rates [complete response (CR) and partial response (PR)] of LD and SD hATG groups at 3 months (50% vs. 48.4%; p = 0.88), 6 months (63.8% vs. 71.4%; p = 0.67), and 12 months (69.6% vs. 79.2%; p = 0.167) were comparable. The mean (Standard Deviation) 5-year Kaplan-Meier estimate of overall survival and event-free survival was 82.1 (4.6)% and 70.9 (5.5)% for the study population. The mean (standard deviation) 5-year Kaplan-Meier estimate of overall survival and event-free survival of those who received LD hATG versus SD hATG dose was 82.9 (5·3)% versus 74.8 (10·3)% (P = 0·439), and 75.2 (6.2)% versus 61.4(11.2)% (P = 0·441). CONCLUSION: Our study revealed that the response rates of patients with AA and LD were similar to those of patients with SD to hATG combined with cyclosporine in a real-world setting.

ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer.

The estrogen receptor-α (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1-2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 h. Gene set enrichment analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1-ER-E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumour cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance.

Treatment challenges in the management of difficult-to-treat gram-positive infections: A consensus view apropos therapeutic role of novel anti-MRSA antibiotics, levonadifloxacin (IV) and alalevonadifloxacin (oral).

PURPOSE: Treatment of antibiotic-resistant Gram-positive infections (GPIs), including methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult, particularly in patients with multiple co-morbidities who require antibiotics with greater safety and a consistent pharmacokinetic/pharmacodynamic (PK/PD) profile. Such difficult-to-treat GPIs are often associated with poor outcomes, extended hospital stay and increased expenditure. This can be partly attributed to the limited safety and aberrant PK/PD profile of existing anti-MRSA antibiotics. In this context, intravenous levonadifloxacin and its oral prodrug alalevonadifloxacin are novel anti-MRSA antibiotics that have significant advantages over conventional anti-Gram-positive antibiotics. The purpose of this paper was to generate a consensus on the optimal use of levonadifloxacin and alalevonadifloxacin for tackling resistant Gram-positive infections in patients with multiple co-morbidities. METHOD: Using a modified Delphi approach that combines critical appraisal of evidence and expert opinion, therapeutic use of levonadifloxacin and alalevonadifloxacin in various clinical scenarios and specific unmet conditions was deliberated. Fifteen expert members from medicine, critical-care, emergency, microbiology, and intensive-care disciplines participated and voted on 11 pre-conceived statements. When there was at least 70 % agreement, a consensus was reached. RESULTS: Following the voting, agreements were reached on 10 out of the 11 statements. Broadly, a consensus was reached in defining the therapeutic role of levonadifloxacin and alalevonadifloxacin in the treatment of various clinical indications involving resistant Gram-positive pathogens, including MRSA, in patients with co-morbidities, such as co-existing or increased risk for kidney dysfunction or hepatic disease and/or immunosuppression; also, in therapeutically challenging conditions caused by Gram-positive bacteria such as bacteraemia, bone and joint infection, diabetic foot infection, febrile neutropenia, and hospital-acquired pneumonia. CONCLUSIONS: This consensus supports the therapeutic use of levonadifloxacin and alalevonadifloxacin in the treatment of antibiotic-resistant GPIs, including those caused by MRSA and certain polymicrobial infections, in patients with multiple co-morbidities requiring drug with adequate safety and consistent efficacy.

EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer.

Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.

Molecular Determinants of Sensitivity to Polatuzumab Vedotin in Diffuse Large B Cell Lymphoma.

Polatuzumab Vedotin (Pola-V) is an antibody-drug conjugate directed to the CD79B subunit of the B cell receptor (BCR). When combined with conventional immunochemotherapy, Pola-V improves outcomes in DLBCL. To identify determinants of Pola-V sensitivity, we used CRISPR-Cas9 screening for genes that modulated Pola-V toxicity for lymphomas or the surface expression of its target, CD79B. Our results reveal the striking impact of CD79B glycosylation on Pola-V epitope availability on the lymphoma cell surface and on Pola-V toxicity. Genetic, pharmacological, and enzymatic approaches that remove sialic acid from N-linked glycans enhanced lymphoma killing by Pola-V. Pola-V toxicity was also modulated by KLHL6, an E3 ubiquitin ligase that is recurrently inactivated in germinal center derived lymphomas. We reveal how KLHL6 targets CD79B for degradation in normal and malignant germinal center B cells, thereby determining expression of the surface BCR complex. Our findings suggest precision medicine strategies to optimize Pola-V as a lymphoma therapeutic.

Differences among Indian and European pemphigus patients based on demographics, clinical parameters and propensity for relapse: results of a prospective bicontinental cohort study.

Limited studies have explored pemphigus variations among different ethnic groups residing in their respective geographical locations. This bicontinental study aimed to compare clinical and immunological parameters in Indian and European pemphigus patients in complete remission, off therapy, or on minimal therapy. 105 patients (India, n= 75; Bulgaria, n=15; Greece, n=15) with pemphigus vulgaris (PV) or pemphigus foliaceous (PF) in complete remission on minimal therapy (n=64) or complete remission off therapy (n=41) were recruited. Demographic, clinical, and immunological parameters were compared. Indian patients were significantly younger, the maximal disease severity during the preceding active disease phase was significantly lower, and treatment duration until complete remission was significantly shorter, compared to European patients. European patients had significantly higher anti-Dsg3 serum levels and higher IgG positivity rate based on direct immunofluorescence microscopy at baseline. Furthermore, European patients revealed higher CD19, CD19+ CD27+ cell counts, compared with patients from India. Of note, none of the European patients (n=30) relapsed within the study period, in contrast to 29/75 (38.6%) Indian patients. Treatment strategies differed significantly between the two cohorts, with more frequent utilization of rituximab to achieve remission in the Indian cohort, while prednisolone was more widely used for maintaining remission in the European cohort. The observed heterogeneity of pemphigus among patients of different ethnicities in terms of demographics, clinical parameters, and propensity for relapse may be due to genetic background or different treatment strategies.