Objective To compare the effects of Metformin with N-acetyl cysteine in polycystic ovarian syndrome (PCOS). Methods A prospective, randomised controlled study was conducted in the Department of Obstetrics and Gynaecology in a Medical College and General Hospital. Total 115 cases of polycystic ovarian syndrome presenting with different complaints were selected for the study. Fifty nine cases were treated with Metformin (Group-M) and other 56 with N-acetyl cysteine (Group-N). Primary outcome measures are improvement in clinical features and biochemical profile, where as secondary outcome measures are improvement in hormonal profile and ultrasonographic findings. Statistical analysis was done by Z test and Chi square test. Results From each group, 50 patients were ultimately evaluated. There was significant improvement in some of the clinical features like weight gain, acne and hirsutism in group-N (P < 0.05), but there was no significant change in other features like oligomenorrhea, amenorrhoea and infertility. The biochemical markers of insulin resistance like fasting insulin, fasting glucose/insulin ratio and HOMA-IR were significantly reduced in group-N. Hormone levels like serum LH, FSH, TT and LH/FSH ratio was significantly decreased in group-N, but FT, FT/TT ratio and SHBG were similar in both the groups. Ultrasonographic findings were similar in both the groups. Conclusion N-acetyl Cysteine had better improvement in clinical, biochemical and hormonal profile than Metformin in PCOS patients. It can be used as a substitute for insulin reducing medications in treatment of PCOS patients, considering its limited adverse effects.

General anaesthesia for obstetric surgery has distinct characteristics that may contribute towards a higher risk of accidental awareness during general anaesthesia. The primary aim of this study was to investigate the incidence, experience and psychological implications of unintended conscious awareness during general anaesthesia in obstetric patients. From May 2017 to August 2018, 3115 consenting patients receiving general anaesthesia for obstetric surgery in 72 hospitals in England were recruited to the study. Patients received three repetitions of standardised questioning over 30 days, with responses indicating memories during general anaesthesia that were verified using interviews and record interrogation. A total of 12 patients had certain/ probable or possible awareness, an incidence of 1 in 256 (95%CI 149-500) for all obstetric surgery. The incidence was 1 in 212 (95%CI 122-417) for caesarean section surgery. Distressing experiences were reported by seven (58.3%) patients, paralysis by five (41.7%) and paralysis with pain by two (16.7%). Accidental awareness occurred during induction and emergence in nine (75%) of the patients who reported awareness. Factors associated with accidental awareness during general anaesthesia were: high BMI (25-30 kg.m -2 ); low BMI (<18.5 kg.m -2 ); out-of-hours surgery; and use of ketamine or thiopental for induction. Standardised psychological impact scores at 30 days were significantly higher in awareness patients (median (IQR [range]) 15 (2.7-52.0 [2-56]) than in patients without awareness 3 (1-9 [0-64]), p = 0.010. Four patients had a provisional diagnosis of post-traumatic stress disorder. We conclude that direct postoperative questioning reveals high rates of accidental awareness during general anaesthesia for obstetric surgery, which has implications for anaesthetic practice, consent and follow-up.

SummaryThe IRE1a-XBP1 pathway, a conserved adaptive mediator of the unfolded protein response, is indispensable for the development of secretory cells. It maintains endoplasmic reticulum homeostasis by facilitating protein folding and enhancing secretory capacity of the cells. Its role in immune cells is emerging. It is involved in dendritic cell, plasma cell and eosinophil development and differentiation. Using genome-wide approaches, integrating ChIPmentation and mRNA-sequencing data, we have elucidated the regulatory circuitry governed by the IRE1a-XBP1 pathway in type-2 T helper cells (Th2). We show that the XBP1 transcription factor is activated by splicing in vivo in T helper cell lineages. We report a comprehensive repertoire of XBP1 target genes in Th2 lymphocytes. We found that the pathway is conserved across cell types in terms of resolving secretory stress, and has T helper cell-specific functions in controlling activation-dependent Th2 cell proliferation and regulating cytokine expression in addition to secretion. These results provide a detailed picture of the regulatory map governed by the XBP1 transcription factor during Th2 lymphocyte activation.

Non-cancerous stromal cells represent a highly diverse compartment of the tumour, yet their role across tumour evolution remains unclear. We employed single-cell RNA sequencing to determine stromal adaptations in murine melanoma at different points of tumour development. Naive lymphocytes recruited from lymph nodes underwent activation and clonal expansion within the tumour, prior to PD1 and Lag3 expression, while tumourassociated myeloid cells promoted the formation of a suppressive niche through cytokine secretion and inhibitory T cell interactions. We identified three temporally distinct cancerassociated fibroblast (CAF) populations displaying unique signatures, and verified these in human datasets. In early tumours, immune CXCL12/CSF1 and complement -expressing CAFs supported recruitment of macrophages, whereas contractile CAFs became more prevalent in later tumours. This study highlights the complex interplay and increasing diversity among cells that co-evolve with the tumour, indicating that from early stages of development, stromal cells acquire the capacity to modulate the immune landscape towards suppression.In particular, extensive heterogeneity has been reported within tumour fibroblast populations.Cancer associated fibroblasts (CAFs) are the most abundant non-immune stromal component, secreting growth factors, promoting angiogenesis, facilitating metastasis and regulating immune infiltrates 9-15 . Although they express typical fibroblast markers, such as fibroblast activation protein (FAP), platelet derived growth factor receptors α (PDGFRα) and β (PDGFRβ), podoplanin (PDPN), Thy-1 and α-smooth muscle actin (αSMA), no single marker universally identifies all CAFs within the tumour stroma 16-18 . To date, many studies rely on positive selection approaches, in which one or two markers are used to isolate CAFs for functional characterisation. Consequently, these findings likely reflect a sub-population of cells and may bias our perceptions of CAF function. It remains unclear whether fibroblast subpopulations with distinct roles are present in the tumour microenvironment.Current approaches lack the resolution to visualise the true extent of stromal heterogeneity and may mask rare populations, or cellular phenotypes, that could be critical for tumour survival. Therefore, we have employed single-cell RNA sequencing (scRNAseq) to profile both immune and non-immune stromal populations from the B16-F10 murine model of melanoma. Furthermore, cells were isolated from both primary tumours and draining lymph nodes, at different stages of tumour development, enabling a systems level interrogation of the melanoma microenvironment in real-time. Here, we identified the presence of a diverse immune landscape, in which the composition and phenotype of leukocytes change as the tumour evolves. In particular, effector T cells displaying signs of dysfunction, were detected predominantly in late stage tumours. This work also highlighted significant heterogeneity within the CAF compartment of the primary tumour. Three distinc...

SummaryAcute Physiology and Chronic Health Evaluation (APACHE) II scoring is widely used as an index of illness severity, for outcome prediction, in research protocols and to assess intensive care unit performance and quality of care. Despite its widespread use, little is known about the reliability and validity of APACHE II scores generated in everyday clinical practice. We retrospectively re-assessed APACHE II scores from the charts of 186 randomly selected patients admitted to our medical and surgical intensive care units. These`new' scores were compared with the original scores calculated by the attending physician. We found that most scores calculated retrospectively were lower than the original scores; 51% of our patients would have received a lower score, 26% a higher score and only 23% would have remained unchanged. Overall, the original scores changed by an average of 6.4 points. We identified various sources of error and concluded that wide variability exists in APACHE II scoring in everyday clinical practice, with the score being generally overestimated. Accurate use of the APACHE II scoring system requires adherence to strict guidelines and regular training of medical staff using the system. [4] are used widely in most intensive care units (ICUs). They are used not only as an index of illness severity and outcome prediction, but also to assess clinical performance and quality of care [5, 6]. The APACHE II score is the most frequently used scoring system and has become an important tool in efforts to improve effective use of intensive care [7±11]. In addition, it is often used in research protocols to ascertain that different treatment groups are comparable.Despite its widespread use in ICUs, little is known about the reliability and validity of the APACHE II scoring system in everyday medical practice. We reported that there was wide interobserver variation in the application of the APACHE II score when a group of doctors (residents and intensivists) assessed the same patient [12]. Chen et al.[13] studied interobserver variability and variability in data collection in a number of community and teaching hospitals; they reported that revised mortality predictions were similar to the original [13]. However, their study did not discuss in detail the specific sources of error and problems in APACHE II scoring.This study was designed to: (i) assess the accuracy of APACHE II scoring in a medical and surgical ICU; (ii) assess the influence of the method of data collection, manual or via a patient data management system (PDMS), on accuracy and overall variability in scoring; (iii) specifically identify and discuss sources of error and q 2001 Blackwell Science Ltd 47 confusion; and (iv) provide suggestions on how to decrease variability. MethodsThe charts of 64 patients admitted to the medical ICU and 122 patients admitted to the surgical ICU over a 6-month period were randomly selected. APACHE II scores are assessed routinely in all patients admitted to the ICU within 2 days of admission. In the medical ICU...

The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment.

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