Contextualising gender intersectionality with the COVID-19 pandemic.

OBJECTIVES: To explore the association of gender inequality index (GII) with healthcare access and quality index (HAQI) for the male to female ratio of confirmed COVID-19 cases. STUDY DESIGN: Secondary analysis of COVID-19 cases with GII and HAQI datasets. METHODS: Data for sex-disaggregated COVID-19 cases were collected from Global Health 50/50, for GII from the United Nations Development Programme (UNDP) and for HAQI from the Institute for Health Metrics and Evaluation (IHME). We used Spearman's correlation in SPSS version 23 to evaluate the association between the variables. RESULTS: Cambodia had the highest male to female ratio (M:F) of 4.08:1, followed by Pakistan (M:F = 2.85:1) and Nepal (M:F = 2.69:1). We observed a positive correlation between GII and M:F ratio (Spearman's rho = 0.681, P-value <0.001) and a negative correlation between HAQI and M:F ratio (Spearman's rho = -0.676, P-value <0.001). CONCLUSIONS: Countries with institutionalised gender disparities and poor healthcare access and quality tend to have higher M:F ratios of confirmed COVID-19 cases; thus, highlighting underutilisation of testing services, influenced by multiple individuals, social and policy factors. Robust gender-based data are required to understand disparities throughout the continuum of care and to devise gender-responsive pandemic strategies.

Identification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer.

BACKGROUND: Over the past years, some members of the family of suppressor of cytokine signalling (SOCS) proteins have emerged as potential tumour suppressors. This study aimed at investigating the clinical significance of SOCS proteins in colorectal carcinoma (CRC). METHODS: We integrated publicly available microarray expression data on CRC in humans, analysed the expression pattern of SOCSs and assessed the predictive power of SOCS2 and SOCS6 for diagnostic purposes by generating receiver operating characteristic curves. Using laser microdissected patient material we assessed SOCS expression on RNA and protein levels as well as their methylation status in an independent CRC patient cohort. Finally, we investigated the prognostic value of SOCS2 and SOCS6. RESULTS: The meta-analysis as well as the independent patient cohort analysis reveal a stage-independent downregulation of SOCS2 and SOCS6 and identify both molecules as diagnostic biomarkers for CRC. We demonstrate a different methylation pattern within the SOCS2 promoter between tumour tissue and normal control tissue in 25% of CRC patients. Furthermore, early CRC stage patients with low expression of SOCS2 display significantly shorter disease-free survival. CONCLUSIONS: Our data offers evidence that SOCS2 and SOCS6 levels are reduced in CRC and may serve as diagnostic biomarkers for CRC patients.

Anchoring of self-expanding metal stents using the over-the-scope clip, and a technique for subsequent removal.

BACKGROUND AND STUDY AIMS: Standard clips do not consistently prevent the migration of covered self-expanding metal stents (SEMS). The aims of this study were to assess the efficacy and safety of the over-the-scope clip (OTSC) system for anchoring SEMS to the esophagus, and to evaluate a novel OTSC removal technique. METHODS: This was a single-center, retrospective, cohort study of consecutive patients undergoing SEMS anchoring with OTSC. Removal of the OTSC was accomplished using an inject-and-resect technique. RESULTS: A total of 12 patients were included. The indications for endoscopic stenting were: tracheo-esophageal fistula (n = 7), postoperative leak or fistula (n = 4), perforation (n = 1). Successful application of the OTSC system was accomplished in all patients (100 %). Stent migration during follow-up (mean 3 weeks, range 2 - 4 weeks) occurred in two patients (16.7 %). After healing of the underlying condition, the stent was removed in six patients (50.0 %). In four patients (33.3 %), the anchored stent was left indefinitely in order to treat the underlying condition. There were no complications associated with deployment of the OTSC or SEMS removal. CONCLUSIONS: Although endoscopic anchoring of fully covered SEMS with the OTSC was feasible, easy to accomplish, safe, and prevented stent migration in most cases, larger studies are needed to confirm these encouraging early findings. The inject-and-resect technique was safe and efficient for OTSC and stent removal in all cases in which it was attempted.

A zwitterionic probe for ratiometric fluorescent detection of aluminium(III) ion in aqueous medium and its application in bioimaging.

In the present study, we have synthesized an aminobenzoic acid containing Schiff base (compound 1) and its structure was confirmed through single crystal X-ray study. Importantly, the compound 1 crystallizes in the zwitterionic form, with an anionic carboxylate group (-COO-) and a cationic iminium group (-C = NH+-). The compound 1 is highly soluble in water due to its zwitterionic feature in the solid state. Interestingly, compound 1 acts as a ratiometric fluorescent probe for the selective detection of Al3+ ion in aqueous solution without organic cosolvent. It can also detect Al3+ ion by visual colour change to bluish-green fluorescence under 365 nm UV light. The association constant between compound 1 with Al3+ ion was estimated to be 1.67 × 104 M-1. The lowest detection limit for Al3+ ion was calculated to be 7.05 × 10-8 M in water. Compound 1 in combination with Al3+ ion demonstrated fluorescent imaging potential of the nucleus of in RAW 264.7 murine macrophage cell line. In addition, the sensing model is developed as paper based sensor ''Test Kit' 'for its practical applicability.

Mice deficient in AKAP13 (BRX) develop compulsive-like behavior and increased body weight.

OBJECTIVE: Hormonal contributions to the sex-dependent development of both obsessive-compulsive disorder (OCD) and obesity have been described, but the underlying mechanisms are incompletely understood. A-kinase anchoring protein 13 (AKAP13) significantly augments ligand-dependent activation of estrogen receptors alpha and beta. The hypothalamus and pituitary gland are implicated in the development and exacerbation of OCD and obesity and have strong AKAP13 expression. The AKAP13 localization pattern observed in these key brain regions together with its effects on sex steroid action suggest a potential role for AKAP13 in compulsive-like behaviors. Here we tested the role of AKAP13 in compulsive-like behavior and body weight using an Akap13 haploinsufficient murine model. MATERIALS AND METHODS: Targeted deletion of the Akap13 gene generated haploinsufficient (Akap13+/-) mice in a C57BL6/J genetic background. Established behavioral assays were conducted, video recorded, and scored blindly to assess compulsive-like behavior based on genotype and gender. Tests included: marble-burying, grooming, open- field and elevated plus-maze. Brain and body weights were also obtained. Mean levels of test outcomes were compared using multi-way ANOVA to test for genotype, sex, genotype*sex, and genotype*sex*age interaction effects with Bonferroni adjustment for multiple comparisons, to further explain any significant interactions. RESULTS: The marble-burying and grooming assays revealed significant sex-dependent increases in perseverative, compulsive-like behaviors in female Akap13 haploinsufficient mice compared to female wild type (WT) mice by demonstrating increased marble-burying activity (p = .0025) and a trend towards increased grooming behavior (p = .06). Male Akap13 haploinsufficient mice exhibited no behavioral changes (p > 0.05). Elevated plus-maze and open-field test results showed no overt anxiety-like behavior in Akap13 haploinsufficient mice irrespective of sex (p > 0.05, both). No differences in brain weight were found in Akap13 haploinsufficient mice compared to WT mice (p > 0.05). However, female Akap13 haploinsufficient mice weighed more than female WT mice in the 4 to <7 months age range (p = .0051). Male Akap13 haploinsufficient mice showed no differences in weight compared to male WT mice (p = >0.05) at any age range examined. CONCLUSION: Akap13 haploinsufficiency led to sex-dependent, compulsive-like behavioral changes in a murine model. Interestingly, Akap13 haploinsufficiency also led to a sex-dependent increase in body weight. These results revealed a requirement for AKAP13 in murine behavior, particularly in female mice, and is the first report of AKAP13 involvement in murine behavior. Future studies may examine the involvement of AKAP13 in the pathophysiology of OCD in female humans and may contribute to a better understanding of the role of AKAP13 and sex hormones in the development and exacerbation of OCD.

Progesterone-Mediated Non-Classical Signaling.

Progesterone is essential for pregnancy maintenance and menstrual cycle regulation. Hormone action has been primarily ascribed to the well-characterized classical signaling pathway involving ligand binding, activation of nuclear progesterone receptors (PRs), and subsequent activation of genes containing progesterone response elements (PREs). Recent studies have revealed progesterone actions via non-classical signaling pathways, often mediated by non-genomic signaling. Progesterone signaling, in conjunction with growth factor signaling, impacts on the function of growth factors and regulates important physiological actions such as cell growth and remodeling, as well as apoptosis. This review focuses on non-classical progesterone signaling pathways, both including and excluding PR, and highlights how research in this area will provide a better understanding of progesterone actions and may inform novel therapeutic strategies.

Helicobacter pylori infection is associated with an altered gastric microbiota in children.

The intestinal microbiome in early life influences development of the mucosal immune system and predisposition to certain diseases. Because less is known about the microbiome in the stomach and its relationship to disease, we characterized the microbiota in the stomachs of 86 children and adults and the impact of Helicobacter pylori infection on the bacterial communities. The overall composition of the gastric microbiota in children and adults without H. pylori infection was similar, with minor differences in only low abundance taxa. However, the gastric microbiota in H. pylori-infected children, but not infected adults, differed significantly in the proportions of multiple high abundance taxa compared with their non-infected peers. The stomachs of H. pylori-infected children also harbored more diverse microbiota, smaller abundance of Firmicutes, and larger abundance of non-Helicobacter Proteobacteria and several lower taxonomic groups than stomachs of H. pylori-infected adults. Children with restructured gastric microbiota had higher levels of FOXP3, IL10, and TGFß expression, consistent with increased T-regulatory cell responses, compared with non-infected children and H. pylori-infected adults. The gastric commensal bacteria in children are altered during H. pylori infection in parallel with more tolerogenic gastric mucosae, potentially contributing to the reduced gastric disease characteristic of H. pylori-infected children.

Comparison of the functional significance of left ventricular hypertrophy in hypertrophic cardiomyopathy and glycogenosis type III.

A comparison of blood pressure response with exercise stress, thallium scintigraphy, and 24-hour electrocardiographic monitoring between 5 patients with left ventricular hypertrophy associated with glycogen storage disease type III and 10 matched patients with hypertrophic cardiomyopathy revealed normal results in the former group. These data highlight the importance of the etiology of left ventricular hypertrophy before the application of risk stratification.

The failing Fontan circulation: successful conversion of atriopulmonary connections.

OBJECTIVES: Symptoms from low cardiac output or refractory atrial arrhythmias are complicating atriopulmonary (classical) Fontan connections. We present our experience of converting such patients to total cavopulmonary connections with and without arrhythmia surgery. METHODS: Between 1997 and 2002, 15 patients (mean age, 19.7 +/- 7.0 years) underwent conversion operations 12.7 +/- 3.5 years after atriopulmonary Fontan operations. Preoperative New York Heart Association functional class was I in 2 patients, II in 2 patients, III in 6 patients, and IV in 5 patients. Four patients underwent intracardiac lateral tunnel conversion alone, and 11 received extracardiac total cavopulmonary connection, right atrial reduction, and cryoablation. RESULTS: No mortality occurred. One patient had conduit obstruction in the immediate postoperative period requiring replacement, and another required a redo operation for endocarditis. Average hospitalization was 17.9 +/- 9.38 days; chest drains were removed on median day 4 (range, 1-29; mean, 7.4 +/- 7.58 days). At follow-up (mean, 42.6 +/- 22.1 months), late atrial arrhythmias had recurred in 3 of 4 patients with intracardiac total cavopulmonary connections (without ablation) and 1 of 11 patients with extracardiac total cavopulmonary connections with ablation. All patients are in New York Heart Association class I or II. Exercise ability (Bruce protocol) improved 69% from a mean of 6.18 +/- 4.01 minutes to 10.45 +/- 2.11 minutes (P <.05). Need for antiarrhythmic agents decreased postoperatively (patients receiving < or =1 antiarrhythmic: 9 preoperatively vs 15 at long-term follow-up, P <.05). No patient has required transplantation. Protein-losing enteropathy, which was present in 1 patient, improved transiently with conversion. There was 1 late death from gastrointestinal hemorrhage. CONCLUSIONS: Fontan conversion can be achieved with low mortality and improvement in New York Heart Association class and exercise ability. Concomitant arrhythmia surgery reduces the incidence of late arrhythmias.

Evidence for autoimmunity to myosin and other heart-specific autoantigens in patients with dilated cardiomyopathy and their relatives.

Autoimmune disease is characterised by the presence of circulating autoantibodies in the affected patients and in a proportion of their relatives. These antibodies are generally not pathogenic but are reliable markers of immune-mediated tissue damage. In organ-specific autoimmune disease, the destruction process is largely restricted to one organ within the body and the autoantibodies react with autoantigens which are unique to the diseased target organ. At least in a patient subset, myocarditis and dilated cardiomyopathy (DCM) may represent the acute and chronic stages of a progressive organ-specific autoimmune disease of the myocardium. Autoimmune features in patients with myocarditis/DCM include: familial aggregation, a weak association with HLA-DR4, abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy, and detection of organ- and disease-specific cardiac autoantibodies, by immunofluorescence and absorption techniques, in the affected patients and in a proportion of their symptom-free relatives from both familial and non-familial DCM pedigrees. The organ-specific cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. One of these, first identified using immunoblotting and confirmed by ELISA, is the cardiac-specific alpha-myosin isoform. Myosin fulfils the expected criteria for organ-specific autoimmunity, in that immunisation with cardiac but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of DCM; in addition, alpha-myosin is entirely cardiac-specific and is only expressed in the myocardium. Using ELISA, high titer organ- and disease-specific anti alpha-myosin antibodies have been found in 16% of the symptom-free relatives of DCM patients and in 38% of the pedigrees of the same cohort of relatives studied by immunofluorescence. The ELISA results provide additional evidence for autoimmunity in a subset of DCM families, and emphasise the importance of alpha-myosin as a target antigen.

Creatine kinase isoforms as circulating markers of deterioration in idiopathic dilated cardiomyopathy.

BACKGROUND: A proportion of patients with dilated cardiomyopathy (DCM) may have ongoing myocardial damage secondary to viral or immune mediated myocardial inflammation. HYPOTHESIS: The prognostic determinants identify patients with decreased survival but do not provide a measure of myocardial damage. To obtain an objective assessment of myocardial damage in DCM, we measured plasma levels of creatine kinase (CK), its isoenzymes (CK-MM and CK-MB), and separated the isoforms of CK-MM and CK-MB. METHODS: The cohort consisted of 77 consecutive patients (61 men, 16 women) with DCM (World Health Organization criteria), aged 49 +/- 14 years (range 19-60). Patients had been symptomatic for 29 +/- 38 months (range 0.5-200 months) with 48 in New York Heart Association class I/II and 29 in class III/IV at the time of diagnosis. During median follow-up of 27 months from diagnosis (range 0.6-165), 50 patients remained clinically stable and 27 had deteriorated. RESULTS: A significantly higher proportion of patients with DCM had abnormal MB2/MB1 ratio compared with normal volunteers (11, 14% vs. 1,1%, p = 0.003). Patients who deteriorated had higher MB2/MB1 ratio, (1.22 +/- 0.62 vs. 0.85 +/- 0.56; p = 0.01), and more frequently had abnormal MB2/ MB1 ratio (8, 30% vs. 3, 6%; p = 0.004) and CK and CK-MM activities (5, 19% vs. 2, 4%; p = 0.03) than those who remained stable. Patients with DCM with high CK-MB activity had 3.13-fold increased odds of sudden death or need for cardiac transplantation (95% confidence interval 1.53-6.40, p = 0.008). Thus, CK measurements, in particular CK-MB isoforms, are markers of myocardial damage in a subset of patients with DCM and could be useful in investigating the possibility of persistent myocardial damage in these patients.

Annual profiles of sex steroids in blood plasma and ovarian tissue of wild female musk shrew, Suncus murinus.

Relative ovarian weights with bursa and annual profiles of sex steroids have been described in the female musk shrew, Suncus murinus, collected in the vicinity of Rawalpindi, Pakistan. The relative gonadal weight was basal (23.20 +/- 1.20 mg/100 g) during anoestrus but enhanced (39.93 +/- 2.73 mg/100 g) abruptly at the onset of the breeding season. Plasma progesterone concentrations, measured during different parts of the year, indicated elevated levels during the late pregnant stage (p less than 0.01). The ovarian progesterone was also comparatively higher in late pregnant animals. No significant difference was observed in plasma and ovarian oestradiol.

A porcine model of intimal-medial hyperplasia in polytetrafluoroethylene arteriovenous grafts.

PURPOSE: Vascular access polytetrafluoroethylene (PTFE) graft failure is a major cause of morbidity in the hemodialysis population. The most common cause of graft failure is thrombosis secondary to stenosis at the venous outflow tract. Venous outflow stenosis is characterized by intimal-medial hyperplasia. We have developed a porcine arteriovenous (AV) graft model that may be used to investigate this proliferative response and aid in the development of new therapies to prevent intimal-medial hyperplasia and improve graft patency. METHODS: Left carotid to right external jugular vein PTFE (6 mm) grafts were implanted in the necks of swine. Immediately following anatomosis, flow rates were recorded. In one group of animals (n = 4) the venous outflow tract was harvested after 7 days and morphometric analysis of intimal and medial area was performed. In a second group (n = 8) the graft patency was monitored until 28 days. RESULTS: All porcine PTFE fistula grafts were patent at 7 days and 100% patency was maintained until 14 days. After 28 days, 75% of the grafts failed due to thrombosis. The venous outflow tract developed a significant proliferative response. After 7 days the intimal and medial areas were 469 +/- 9 microm2 and 875 +/- 26 microm2 respectively. At 28 days the intimal and medial areas were 913 +/- 55 microm2 and 1437 +/- 182 microm2 respectively. Luminal flow rate of the venous outflow tract was reduced significantly (344 +/- 11 ml/min at Day 0 to 129 +/- 14 ml/min at Day 7, p < 0.05). CONCLUSIONS: This porcine model rapidly, reliably and robustly reproduces the flow reducing stenosis and intimal-medial hyperplasia at the venous outflow tract of PTFE arteriovenous fistula. It represents a promising tool for investigating the mechanisms of intimal-medial hyperplasia, evaluating therapeutic interventions and new graft materials.

Family-based analysis of candidate genes for polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families. OBJECTIVE: The aims of the study are: 1) to genotype single nucleotide polymorphisms (SNPs) in the region of D19S884; and 2) to follow up with an independent data set, published results reporting evidence for PCOS candidate gene associations. DESIGN: The transmission disequilibrium test (TDT) was used to analyze linkage and association between PCOS and SNPs in candidate genes previously reported by us and by others as significantly associated with PCOS. SETTING: The study was conducted at academic medical centers. PATIENTS OR OTHER PARTICIPANTS: A total of 453 families having a proband with PCOS participated in the study. Sisters with PCOS were also included. There was a total of 502 probands and sisters with PCOS. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): The outcome measure was transmission frequency of SNP alleles. RESULTS: We identified a six-SNP haplotype block spanning a 6.7-kb region on chromosome 19p13.2 that includes D19S884. SNP haplotype allele-C alone and in combination with D19S884-allele 8 is significantly associated with PCOS: haplotype-C TDT chi(2) = 10.0 (P = 0.0016) and haplotype-C/A8 TDT chi(2) = 7.6 (P = 0.006). SNPs in four of the other 26 putative candidate genes that were tested using the TDT were nominally significant (ACVR2A, POMC, FEM1B, and SGTA). One SNP in POMC (rs12473543, chi(2) = 9.1; P(corrected) = 0.042) is significant after correction for multiple testing. CONCLUSIONS: A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest.

Does rectus sheath infusion of bupivacaine reduce postoperative opioid requirement?

INTRODUCTION: The aim of this work was to assess the effect of intermittent bupivacaine infusion into rectus sheath space on postoperative opioid requirement, postoperative pain score and peak expiratory flow rate. PATIENTS AND METHODS: A prospective, randomised study involving patients undergoing midline laparotomy. Patients were randomised to receive either intermittent infusion of bupivacaine 0.25% or normal saline via catheters placed in the rectus sheath for 48 h after operation. All patients received intravenous morphine infusion on demand with a patient-controlled analgesic device (PCAD). RESULTS: Forty ASA I-III patients were studied. Nineteen were randomised to receive bupivacaine and 21 patients received normal saline. Patient characteristics and surgical variables were comparable in the two groups. The mean wound lengths were similar. There was no statistically significant difference in postoperative opioid requirement, postoperative pain score and peak expiratory flow rate between the two groups. CONCLUSIONS: Intermittent bupivacaine infusion into the rectus sheath space after midline laparotomy does not reduce postoperative opioid requirement nor does it affect postoperative pain score or peak expiratory flow rate.