Comparative proteomic analysis of sequential isolates of Mycobacterium tuberculosis sensitive and resistant Beijing type from a patient with pulmonary tuberculosis.

Abstract Aim & objective In India, tuberculosis (TB) is a foremost health problem, and the emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis ( M. tuberculosis ) has further complicated the situation. Although various mechanisms have been proposed to elucidate the emergence of resistance, our knowledge remains insufficient. The formation of a very complex network and drugs of proteins are countered by their efflux/modification or target over-expression/modification. The analysis of the over-expressed proteins and their qualitative and phenotypic evaluation before and after the development of drug-resistance may be the most appropriate tool to understand the mechanisms of the mechanism of development of drug-resistance. Most studies are performed on distinct strains. Therefore, the objective of this study was to compare the proteomic information of sequential isolates of M. tuberculosis Beijing type from a single patient who developed MDR-TB during the course of anti-tuberculosis therapy. Methods In this study, a clinical isolate of M. tuberculosis was grown in Middlebrook 7H9 broth medium for 2 weeks, and the cell lysate of isolates was prepared by sonication and centrifugation. We compared and analyzed the whole cell lysate proteins of M. tuberculosis sequential clinical isolate from a patient with pulmonary TB before and after the development of drug resistance using two-dimensional gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and bioinformatics tools. Results The genotypes of both isolates remained homologous, showing no re-infection. The first isolate (before treatment) was sensitive to all the first-line drugs, sequential isolate was found resistant to rifampicin (RIF) and isoniazid (INH) and developed mutations in r poB , katG and inhA . The concentrations of 17 protein spots were found to be consistently over-expressed in RIF- and INH-resistant isolates. The most prominent and over-expressed proteins found during the development of drug resistance were wag31, Rv2714, GarA, SSB, FabG4, Probable lipase, Rv3924c, Rv3204A, Rv2031c, Rv3418c and GroES. The InterProScan and homology searches generated insights into the possible functions and essential domains of the proteins. Rv1827, Rv2626c, Rv2714, Rv2970c, Rv3208A, and Rv3881c showed significant in silico interaction with RIF and INH; thus, the over-expression in the drug-resistant isolates could be compensating the inhibited/modulated molecules. Other proteins, which are over-expressed but do not unveil good binding with drug, might be indirectly associated with RIF and INH. Conclusions This proteomic study provides an understanding about the proteins that are over-expressed during the development of drug resistance. These over-expressed proteins, identified here, could prove useful as vaccine candidate, immunodiagnostic and possibly drug-resistant or chemotherapeutic markers in future

Pessaries (mechanical devices) for managing pelvic organ prolapse in women

Background Pelvic organ prolapse is a common problem in women. About 40% of women will experience prolapse in their lifetime, with the proportion expected to rise in line with an ageing population. Women experience a variety of troublesome symptoms as a consequence of prolapse, including a feeling of 'something coming down' into the vagina, pain, urinary symptoms, bowel symptoms and sexual difficulties. Treatment for prolapse includes surgery, pelvic floor muscle training (PFMT) and vaginal pessaries. Vaginal pessaries are passive mechanical devices designed to support the vagina and hold the prolapsed organs back in the anatomically correct position. The most commonly used pessaries are made from polyvinyl‐chloride, polythene, silicone or latex. Pessaries are frequently used by clinicians with high numbers of clinicians offering a pessary as first‐line treatment for prolapse. This is an update of a Cochrane Review first published in 2003 and last published in 2013. Objectives To assess the effects of pessaries (mechanical devices) for managing pelvic organ prolapse in women; and summarise the principal findings of relevant economic evaluations of this intervention. Search methods We searched the Cochrane Incontinence Specialised Register which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In‐Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 28 January 2020). We searched the reference lists of relevant articles and contacted the authors of included studies. Selection criteria We included randomised and quasi‐randomised controlled trials which included a pessary for pelvic organ prolapse in at least one arm of the study. Data collection and analysis Two review authors independently assessed abstracts, extracted data, assessed risk of bias and carried out GRADE assessments with arbitration from a third review author if necessary. Main results We included four studies involving a total of 478 women with various stages of prolapse, all of which took place in high‐income countries. In one trial, only six of the 113 recruited women consented to random assignment to an intervention and no data are available for those six women. We could not perform any meta‐analysis because each of the trials addressed a different comparison. None of the trials reported data about perceived resolution of prolapse symptoms or about psychological outcome measures. All studies reported data about perceived improvement of prolapse symptoms. Generally, the trials were at high risk of performance bias, due to lack of blinding, and low risk of selection bias. We downgraded the certainty of evidence for imprecision resulting from the low numbers of women participating in the trials. Pessary versus no treatment: at 12 months' follow‐up, we are uncertain about the effect of pessaries compared with no treatment on perceived improvement of prolapse symptoms (mean difference (MD) in questionnaire scores ‐0.03, 95% confidence interval (CI) ‐0.61 to 0.55; 27 women; 1 study; very low‐certainty evidence), and cure or improvement of sexual problems (MD ‐0.29, 95% CI ‐1.67 to 1.09; 27 women; 1 study; very low‐certainty evidence). In this comparison we did not find any evidence relating to prolapse‐specific quality of life or to the number of women experiencing adverse events (abnormal vaginal bleeding or de novo voiding difficulty). Pessary versus pelvic floor muscle training (PFMT): at 12 months' follow‐up, we are uncertain if there is a difference between pessaries and PFMT in terms of women's perceived improvement in prolapse symptoms (MD ‐9.60, 95% CI ‐22.53 to 3.33; 137 women; low‐certainty evidence), prolapse‐specific quality of life (MD ‐3.30, 95% CI ‐8.70 to 15.30; 1 study; 116 women; low‐certainty evidence), or cure or improvement of sexual problems (MD ‐2.30, 95% ‐5.20 to 0.60; 1 study; 48 women; low‐certainty evidence). Pessaries may result in a large increase in risk of adverse events compared with PFMT (RR 75.25, 95% CI 4.70 to 1205.45; 1 study; 97 women; low‐certainty evidence). Adverse events included increased vaginal discharge, and/or increased urinary incontinence and/or erosion or irritation of the vaginal walls. Pessary plus PFMT versus PFMT alone: at 12 months' follow‐up, pessary plus PFMT probably leads to more women perceiving improvement in their prolapse symptoms compared with PFMT alone (RR 2.15, 95% CI 1.58 to 2.94; 1 study; 260 women; moderate‐certainty evidence). At 12 months' follow‐up, pessary plus PFMT probably improves women's prolapse‐specific quality of life compared with PFMT alone (median (interquartile range (IQR)) POPIQ score: pessary plus PFMT 0.3 (0 to 22.2); 132 women; PFMT only 8.9 (0 to 64.9); 128 women; P = 0.02; moderate‐certainty evidence). Pessary plus PFMT may slightly increase the risk of abnormal vaginal bleeding compared with PFMT alone (RR 2.18, 95% CI 0.69 to 6.91; 1 study; 260 women; low‐certainty evidence). The evidence is uncertain if pessary plus PFMT has any effect on the risk of de novo voiding difficulty compared with PFMT alone (RR 1.32, 95% CI 0.54 to 3.19; 1 study; 189 women; low‐certainty evidence). Authors' conclusions We are uncertain if pessaries improve pelvic organ prolapse symptoms for women compared with no treatment or PFMT but pessaries in addition to PFMT probably improve women's pelvic organ prolapse symptoms and prolapse‐specific quality of life. However, there may be an increased risk of adverse events with pessaries compared to PFMT. Future trials should recruit adequate numbers of women and measure clinically important outcomes such as prolapse specific quality of life and resolution of prolapse symptoms. The review found two relevant economic evaluations. Of these, one assessed the cost‐effectiveness of pessary treatment, expectant management and surgical procedures, and the other compared pessary treatment to PFMT

Prolapse or incontinence: what affects sexual function the most?

Introduction and hypothesis Pelvic organ prolapse (POP) and stress urinary incontinence (SUI) adversely affect sexual function in women. Comparative studies of the two subgroups are few and results are conflicting. The aim of this study was to compare the effect of POP and SUI on the sexual function of women undergoing surgery for these conditions. Methods The study population comprised women with POP or SUI in a tertiary referral hospital in the UK. Women who underwent SUI surgery had no symptoms of POP and had urodynamically proven stress incontinence. Patients with POP had ≥ stage 2 prolapse, without bothersome urinary symptoms. Pre-operative data on sexual function were collected and compared using an electronic pelvic floor assessment questionnaire (ePAQ). The incidence of sexual dysfunction and comparison of symptoms in both groups were calculated using the Mann–Whitney U test. Results Three hundred and forty-three women undergoing surgery for either SUI or POP were included. Patients were age-matched, with 184 undergoing SUI surgery (age range 33–77 years) and 159 POP surgery (age range 27–78 years; p = 0.869). The overall impact of POP and SUI was not significantly different in the two subgroups (p = 0.703). However, both patients (73 % vs 36 %; p = 0.00) and partners (50 % vs 24 %; p = 0.00) avoid intercourse significantly more frequently in cases with POP compared with SUI. This did not have a significant impact on quality of life. Conclusions The impact of bothersome SUI or POP on sexual function was found to be similar, but patient and partner avoidance in women with POP was greater than those with SUI

Obstetric anal sphincter injuries

Obstetric anal sphincter injuries can be associated with significant short and long term consequences causing devastating impacts on the quality of lives of young, otherwise healthy women. The major consequence is anal incontinence which may be short or long term and vary in severity. The other consequences include pain, infection, dyspareunia and sexual dysfunction. This may in turn result in considerable economic burden to health care providers and patients. It also has an implication on future deliveries. Although it can never be eliminated, it can be reduced by improving practice, training and provision of high quality multidisciplinary care in order to reduce long-term morbidity. Obstetric anal sphincter injuries are also a source of litigation which can be distressing to both patients and clinicians. The aim of this review article is to explore the available evidence on epidemiology, strategies for preventions, prognosis and also how to deal with governance issues

Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives

The treatment of type 2 diabetes is a challenging problem. Most subjects with type 2 diabetes have progression of beta cell failure necessitating the addition of multiple antidiabetic agents and eventually use of insulin. Intensification of insulin leads to weight gain and increased risk of hypoglycemia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antihyperglycemic agents which act by blocking the SGLT2 in the proximal tubule of the kidney. They have potential benefits in terms of weight loss and reduction of blood pressure in addition to improvements in glycemic control. Further, one of the SGLT2 inhibitors, empagliflozin has proven benefits in reducing adverse cardiovascular (CV) outcomes in a CV outcome trial. Adding SGLT2 inhibitors to insulin in subjects with type 2 diabetes produced favorable effects on glycemic control without the weight gain and hypoglycemic risks associated with insulin therapy. The general risks of increased genital mycotic infections, urinary tract infections, volume, and osmosis-related adverse effects in these subjects were similar to the pooled data of individual SGLT2 inhibitors. There are subsets of subjects with type 2 diabetes who may have insulin deficiency, beta cell autoimmunity, or is prone to diabetic ketoacidosis. In these subjects, SGLT2 inhibitors should be used with caution to prevent the rare risks of ketoacidosis