Fixed-Dose Combination of Canagliflozin and Metformin as an Adjunct to Diet and Exercise in Indian Adults with Type 2 Diabetes Mellitus: Results from a Multicentric, Open-Label, Single-Arm, Phase IV Study.

BACKGROUND: Canagliflozin and metformin fixed-dose combination (CANA/MET FDC), an approved treatment for type 2 diabetes mellitus (T2DM) in India, effectively lowers glycated hemoglobin (HbA1c), promotes weight loss, and improves patient adherence. As a regulatory requirement, we aimed to evaluate the safety and efficacy of CANA/MET FDC in Indian patients with T2DM. RESEARCH DESIGN AND METHODS: This prospective, multicenter, open-label, single-arm, phase IV study included Indian patients with T2DM (aged 18-65 years) inadequately controlled on diet and exercise. Patients received CANA/MET (50/500 and 50/1000 mg) immediate-release (IR) FDC twice daily for 24 weeks. The primary endpoint was safety assessment, including adverse events (AEs) and serious AEs (SAEs). The secondary endpoint included a change in HbA1c from baseline to weeks 12 and 24. Descriptive statistics were used for all continuous safety variables and efficacy parameters. RESULTS: Of the 310 patients screened, 276 were enrolled. 114/274 (41.6%) patients had ≥1 treatment-emergent AE [treatment-emergent AEs (TEAEs), among which 29 (10.6%) were related to study intervention]. The most common TEAEs were dyslipidemia (4.7%), pyrexia (4.7%), genital infections (3.3%), hypoglycemia (3.3%), and urinary tract infections (2.6%). Three (1.1%) patients had serious TEAEs, and all cases were resolved. No deaths were reported. The mean change in HbA1c from baseline was -0.92 and -0.93% at weeks 12 and 24, respectively. CONCLUSION: The study demonstrates the safety and efficacy of CANA/MET FDC in Indian patients with T2DM, presenting a safe therapeutic option for diabetes management in India.

Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.

Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.

GeneXpert Ultra in Urine Samples for Diagnosis of Extra-Pulmonary Tuberculosis.

Extra-pulmonary tuberculosis (EPTB) continues to be difficult to diagnose. Novel biomarkers in biological specimens offer promise. Detection of Mycobacterium tuberculosis (Mtb) DNA in urine could prove useful in diagnosis of EPTB, possibly due to disseminated disease or micro-abscesses reported in kidneys. The current study was designed to detect Mtb DNA in stored urine samples from patients with EPTB. Diagnosis of EPTB was reached using Microbiological Reference Standards (MRS) on samples from the disease site using WHO Recommended Diagnostics (WRD), [smear microscopy, liquid culture (MGIT-960)] and GX (molecular WRD, mWRD) and Comprehensive reference standards [CRS, clinical presentation, microbiological reference standards, radiology, histopathology]. GX-Ultra was performed on urine samples stored in -80oC deep freezer, retrospectively. Of 70 patients, 51 (72.9%) were classified as confirmed TB, 11 (15.7%) unconfirmed TB, and 8 (11.4%) unlikely TB. GX-Ultra in urine samples demonstrated sensitivity of 52.9% and specificity of 57.9% against MRS, and higher sensitivity of 56.5% and specificity of 100% against CRS. The sensitivity and specificity of GX-Ultra in urine was 53.6% and 75% for pus sample subset and 52.2% and 53.3% for fluid sample subset. Urine being non-invasive and easy to collect, detection of Mtb DNA using mWRD in urine samples is promising for diagnosis of EPTB.

Novel Pyrazole-Based Transition Metal Complexes: Spectral, Photophysical, Thermal and Biological Studies.

A novel bioactive Schiff base (HL) named 3-methyl-1-phenyl-5-((5-nitrosalicylidene)amino)pyrazole was prepared by condensing 5-amino-3-methyl-1-phenylpyrazole with 5-nitrosalicyldehyde in methanol on a heating mantle in refluxing condition for 1 h. Some transition metal complexes of the ligand in (1 : 1) and (1 : 2) have also been prepared by condensing the metal acetate salt with the synthesized Schiff base. The Schiff base and metal complexes were characterized by different physiochemical techniques, i. e., 1 H-NMR, InfraRed, mass spectroscopy, elemental analysis, Ultraviolet-Visible, Cyclic voltammetry, electronic spectra and Electron spin resonance. The presence of water molecules in the complexes have been calculated with the help of thermogravimetric analysis. Kinetic parameters such that entropy change, enthalpy change and activation energy have been calculated with the help of Coats-Redfern equations. Fluorescence spectra showed enhancement in the fluorescence signal of the metal complexes. Square planar geometry for the copper complexes and octahedral geometry for the other metal complexes have been proposed with help of various methods. Biological activities of all the compounds have been carried out and the results disclosed that the metal complexes have high biological activity than the Schiff base having MIC value in the range 25-3.12 µg/mL and mycelial growth inhibition 60.82-96.98 %.

Impact of socio-demographic variables on antenatal services in eastern Uttar Pradesh, India.

We investigated the impact of socio-demographic variables on antenatal care (ANC) utilization and the low birth weight of a child. Data were collected from 300 pregnant females. Only 22.5% of females received full antenatal care (≥4 visits). Our results showed that female's age at marriage and education plays a significant role in improving ANC. We observed an overall decrease in the utilization of services provided during each antenatal visit. ANC visits from the first trimester decrease the risk of having a baby with low birth weight. Awareness programs and educating families about pregnancy care are recommended to improve ANC utilization.

Leishmania donovani Infection with Atypical Cutaneous Manifestations, Himachal Pradesh, India, 2014-2018.

We conducted a molecular study of parasite sequences from a cohort of cutaneous leishmaniasis patients in Himachal Pradesh, India. Results revealed atypical cutaneous disease caused by Leishmania donovani parasites. L. donovani variants causing cutaneous manifestations in this region are different from those causing visceral leishmaniasis in northeastern India.

AZF deletions in Indian populations: original study and meta-analyses.

PURPOSE: To identify the frequency of Y chromosome microdeletions in Indian populations and to quantitatively estimate the significance of association between these deletions and male infertility. METHODS: A total of 379 infertile males (302 azoospermic and 77 oligozoospermic infertile males) and 265 normozoospermic fertile males were evaluated for Y chromosome microdeletions (YCD) using PCR amplification and gel electrophoresis. Meta-analyses were performed on AZFa (2079 cases and 1217 controls), AZFb (2212 cases and 1267 controls), AZFc (4131 cases and 2008 controls), and AZFb+c (1573 cases and 942 controls) deletions data to quantitatively estimate the significance of association between these deletions and male infertility in Indian populations. RESULTS: The results revealed that out of 379 infertile azoospermic and oligozoospermic males, 38 (10.02%) had AZF deletions. No deletion was found in control samples. The highest percentage of deletions was observed in the AZFc region, followed by AZFa and AZFb. Qualitative analysis showed that AZF deletions were present in 0.59 to 32.62% (average 13.48%) of infertile cases in Indian populations. Meta-analysis revealed a significant association of AZFa (OR = 6.74, p value = 0.001), AZFb (OR = 4.694, p value = 0.004), AZFc (OR = 13.575, p value = 0.000), and AZFb+c (OR = 5.946, p value = 0.018) deletions with male infertility. CONCLUSION: AZF deletions were seen in 10.02% of azoospermic and oligozoospermic cases with the highest frequency of AZFc deletions. Pooled analysis for all studies showed deletion frequency from 0.59 to 32.62% (average = 13.48%). Meta-analysis showed significant association of AZFa, AZFb, and AZFb+c deletions with male infertility. Analysis of Y chromosome microdeletions should be reckoned as an essential testing for diagnostic and therapeutic purposes.

Duplications in 19p13.3 are associated with male infertility.

PURPOSE: To identify genomic imbalances and candidate loci in idiopathic male infertility. METHODS: Affymetrix CytoScan 750K Array was used to analyze genomic imbalances and candidate loci in 34 idiopathic infertile cases of different phenotypes (hypo-spermatogenesis, n = 8; maturation arrest, n = 7; and Sertoli cell-only syndrome, n = 13, severe oligozoospermia, n = 6, and 10 normozoospermic fertile men). Ten ethnically matched controls were screened for comparison. RESULTS: The cytogenetic array analysis detected a genomic gain at the 19p13.3 region in 9 (26.47%) cases, with the highest frequency in patients with Sertoli cell-only syndrome (SCOS) (38%). Its complete absence in the control group suggests its likely pathogenic nature. In addition to Y-classical, micro, and partial deletions, the duplication in 19p13.3 could serve as a unique biomarker for evaluation of infertility risk. The common region across the individuals harboring the duplication identified STK11, ATP5D, MIDN, CIRBP, and EFNA2 genes which make them strong candidates for further investigations. The largest duplicated region identified in this study displayed a major network of 7 genes, viz., CIRBP, FSTL3, GPX4, GAMT, KISS1R, STK11, and PCSK4, associated with reproductive system development and function. The role of chance was ruled out by screening of ethnically matched controls. CONCLUSION: The result clearly indicates the significance of 19p13.3 duplication in infertile men with severe testicular phenotypes. The present study underlines the utility and significance of whole genomic analysis in the cases of male infertility which goes undiagnosed due to limitations in the conventional cytogenetic techniques and for identifying genes that are essential for spermatogenesis.

SNPs in ERCC1, ERCC2, and XRCC1 genes of the DNA repair pathway and risk of male infertility in the Asian populations: association study, meta-analysis, and trial sequential analysis.

PURPOSE: We investigated if substitutions in the ERCC1, ERCC2, and XRCC1 genes of the DNA repair pathway correlate with non-obstructive azoospermia and male infertility. METHODS: A total of 548 azoospermic infertile males and 410 fertile controls were genotyped for XRCC1 399A > G, 280G > A, and ERCC1 C > A 3' UTR and 541 azoospermic infertile males and 416 fertile controls were genotyped for ERCC2 751A > C using iPLEX Gold Assay. Meta-analyses were performed on XRCC1 399A > G (1022 cases and 1004 controls), ERCC1 C > A 3' UTR (879 cases and 1059 controls), and ERCC2 751A > C (914 cases and 850 controls) polymorphisms to quantitatively estimate the significance of the association between these polymorphisms and the risk of infertility. RESULTS: Statistically significant association between ERCC2 751A > C SNP and male infertility was found using the codominant model (p = 0.03). Results of meta-analysis suggested a lack of correlation with male infertility risk, which could be due to pooling of studies from different ethnic populations. Due to limited the number of studies, a stratified analysis for different ethnic groups could not be performed. CONCLUSION (S): In conclusion, AA genotype of 751A > C SNP in ERCC2 correlated with a higher risk of male infertility and may contribute to an increased risk of azoospermia and male infertility in Indian men.

Genome-wide differential methylation analyses identifies methylation signatures of male infertility.

STUDY QUESTION: Do methylation changes in sperm DNA correlate with infertility? STUDY ANSWER: Loss of spermatogenesis and fertility was correlated with 1680 differentially-methylated CpGs (DMCs) across 1052 genes. WHAT IS KNOWN ALREADY: Methylation changes in a number of genes have been correlated with reduced sperm count and motility. STUDY DESIGN, SIZE, DURATION: This case-control study used spermatozoal DNA from 38 oligo-/oligoastheno-zoospermic infertile patients and 26 normozoospermic fertile men. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Genome-wide methylation analysis was undertaken using 450 K BeadChip on spermatozoal DNA from six infertile and six fertile men to identify DMCs. This was followed by deep sequencing of spermatozoal DNA from 32 infertile patients and 20 fertile controls. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1680 DMCs were identified, out of which 1436 were hypermethylated and 244 were hypomethylated. Classification of DMCs according to the genes identified BCAN, CTNNA3, DLGAP2, GATA3, MAGI2 and TP73 among imprinted genes, SPATA5, SPATA7, SPATA16 and SPATA22 among spermatogenesis-associated genes, KDM4C and JMJD1C, EZH2 and HDAC4 among genes which regulate methylation and gene expression, HLA-C, HLA-DRB6 and HLA-DQA1 among complementation and immune response genes, and CRISPLD1, LPHN3 and CPEB2 among other genes. Genes showing significant differential methylation in deep sequencing, i.e. HOXB1, GATA3, EBF3, BCAN and TCERG1L, are strong candidates for further investigations. The role of chance was ruled out by deep sequencing of select genes. LARGE-SCALE DATA: N/A. LIMITATIONS, REASON FOR CAUTION: Genome-wide analyses are fairly accurate, but may not be exactly validated in replication studies across all DMCs. We used the 't' test in the genome-wide methylation analysis, whereas other tests could provide a more robust and powerful analysis. WIDER IMPLICATIONS OF THE FINDINGS: DMCs can serve as markers for inclusion in infertility screening panels, particularly those in the genes showing differential methylation consistent with previous studies. The genes validated by deep sequencing are strong candidates for investigations of their roles in spermatogenesis. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Council of Scientific and Industrial Research (CSIR), Govt. of India with grant number BSC0101 awarded to Rajender Singh. None of the authors has any competing interest to declare.

Decline in seminal quality in Indian men over the last 37 years.

BACKGROUND: Since the first report of a decline in semen quality in 1974, there have been several reports of similar declines across populations. Despite some scattered reports of declining semen quality in the Indian sub-continent, comprehensive studies analyzing semen quality over the last few decades have not been undertaken. We undertook the present study to investigate the temporal trend in semen parameters in Indian populations over a period of 37 years (1979-2016). METHODS: Publications providing semen analysis details for fertile and infertile men from the Indian sub-continent were collected by a thorough literature search. Semen quality data for 6466 normal fertile or presumptive normal men (from 119 studies/data sets) and 7020 infertile men (from 63 studies/data sets) published between 1979 and 2016 were retrieved. We undertook systematic review and quantitative analysis of mean sperm count, motility, normal morphology and other available parameters. Data were analyzed to estimate semen parameters reference values for Indian men and to assess temporal trends in infertile, fertile and all subjects. RESULTS: Seminal quality shows a decreasing temporal trend and the decrease is higher in infertile than fertile males. In pooled analysis for all individuals, significant (p < 0.05 or < 0.001) declines in sperm concentration and normal morphology are observed; however, isolated analysis for each group shows declines without statistical significance. The mean (± SD) semen volume, sperm concentration, total motility, rapid linear progressive motility, normal sperm morphology and sperm viability for Indian fertile men are 2.88 ± 0.77 ml, 81.08 ± 29.21 million/ml, 66.37 ± 10.95%, 52.64 ± 15.78%, 56.68 ± 20.23% and 72.63 ± 8.31%, respectively, whereas in infertile these are 3.07 ± 1.27 ml, 37.94 ± 26.41 million/ml, 40.22 ± 13.76%, 26.79 ± 15.47%, 36.41 ± 21.66% and 55.25 ± 11.99%, respectively. The mean seminal parameter values were significantly lower (p < 0.001) in infertile as compared to fertile men, except semen volume. CONCLUSIONS: Semen parameters in Indian men have declined with time and the deterioration is quantitatively higher in the infertile group. The study also provides reference values for semen parameters in Indian men.

S100 proteins: An emerging cynosure in pregnancy & adverse reproductive outcome.

S100 proteins are calcium (Ca2+)-binding proteins and these have an important function in progression, manifestation and therapeutic aspects of various inflammatory, metabolic and neurodegenerative disorders. Based on their involvement in intracellular or extracellular regulatory effects, S100 proteins are classified into three subgroups: one subgroup is specialized in exerting only intracellular effects, other performs both intracellular and extracellular functions and the third subgroup members only display extracellular regulatory effects. S100 proteins are expressed particularly in vertebrates and have cell-specific expression. Functionally, S100 proteins act through their surface receptors and regulate cell functions in autocrine or paracrine mode. Receptor for advanced glycation end products (RAGEs) and toll-like receptor 4 are the main surface receptors. S100 proteins participate in the regulation of cellular differentiation, proliferation, apoptosis and inflammation along with Ca2+ homeostasis, energy metabolism and cellular migration, and perform the respective functions through their interaction with transcription factors, nucleic acids, enzymes, receptors, cytoskeleton system, etc. Currently, their role in adverse pregnancy outcomes and compromised reproductive health is being explored. These proteins are present in amniotic fluid, endometrium tissue and foetal brain; therefore, it is quite likely that alterations in the expression levels of S100 family members will be affecting the particular function they are involved in and ultimately affecting the pregnancy in adverse manner. The current review discusses about an association of S100 proteins in pregnancy disorders such as endometriosis, intrauterine growth retardation and miscarriage.

Urban green space availability in Bathinda City, India.

This paper aims to investigate and map the spatial distribution of urban green spaces (UGSs) in Bathinda City, India. Since urban green spaces affect the quality of life and provide various ecological, socio-cultural and economic benefits to a city, the spatial distribution of UGSs and per capita availability deserve greater consideration in urban planning and research. The UGSs are extracted from freely available Sentinel 2 image with spatial resolutions of 10 m (blue, green, red, and near infrared bands). The result indicates that the planned urban setups have higher area under UGSs as compared to the rest of the city. Analysis and intra-city comparison (ward wise) of distribution of green spaces and per capita availability indicate that there is an inequitable distribution of UGSs in Bathinda City. The study also attempts to accentuate the scope of green initiatives in the various wards of the city to ensure the well-being of people.

Heterogeneous pattern of DNA methylation in developmentally important genes correlates with its chromatin conformation.

BACKGROUND: DNA methylation is a major epigenetic modification, playing a crucial role in the development and differentiation of higher organisms. DNA methylation is also known to regulate transcription by gene repression. Various developmental genes such as c-mos, HoxB5, Sox11, and Sry show tissue-specific gene expression that was shown to be regulated by promoter DNA methylation. The aim of the present study is to investigate the establishment of chromatin marks (active or repressive) in relation to heterogeneous methylation in the promoter regions of these developmentally important genes. RESULTS: Chromatin-immunoprecipitation (ChIP) assays were performed to immuno-precipitate chromatin by antibodies against both active (H3K4me3) and repressive (H3K9me3) chromatin regions. The analysis of ChIP results showed that both the percentage input and fold enrichment of activated chromatin was higher in tissues expressing the respective genes as compared to the tissues not expressing the same set of genes. This was true for all the genes selected for the study (c-mos, HoxB5, Sox11, and Sry). These findings illustrate that inconsistent DNA methylation patterns (sporadic, mosaic and heterogeneous) may also influence gene regulation, thereby resulting in the modulation of chromatin conformation. CONCLUSIONS: These findings illustrate that various patterns of DNA methylation (asynchronous, mosaic and heterogeneous) correlates with chromatin modification, resulting in the gene regulation.

Immune-endocrine crosstalk during pregnancy.

The success of pregnancy depends mostly on a synchronized immune-endocrine crosstalk at the maternal-fetal interface. Hormones are important in terms of maintaining the suitable environment and sufficient nutrition for the developing fetus. They also play a major role during the process of parturition and lactation. Maternal immunomodulation is important for the tolerance of semiallogeneic fetus. This is achieved in concert with a variety of endocrine stimulation. Estrogen, progesterone, and Human Chorionic Gonadotropin play a major role in immune modulation during pregnancy. Hormones modulate B cells, dendritic cells, uterine natural killer cells, macrophages, neutrophils to adopt fetal friendly immune phenotypes. Recently the use of hormones in assisted reproductive technology has been found to improve the pregnancy outcome. The present review focuses on the pregnancy-related hormones, their role in immunomodulation for successful pregnancy outcome. This also shed light on the immune-endocrine crosstalk at maternal-fetal interface during pregnancy.

Increased expression of endosomal members of toll-like receptor family abrogates wound healing in patients with type 2 diabetes mellitus.

The inflammatory phase of wound healing cascade is an important determinant of the fate of the wound. Acute inflammation is necessary to initiate proper wound healing, while chronic inflammation abrogates wound healing. Different endosomal members of toll-like receptor (TLR) family initiate inflammatory signalling via a range of different inflammatory mediators such as interferons, internal tissue damaged-associated molecular patterns (DAMPs) and hyperactive effector T cells. Sustained signalling of TLR9 and TLR7 contributes to chronic inflammation by activating the plasmacytoid dendritic cells. Diabetic wounds are also characterised by sustained inflammatory phase. The objective of this study was to analyse the differential expression of endosomal TLRs in human diabetic wounds compared with control wounds. We analysed the differential expression of TLR7 and TLR9 both at transcriptional and translational levels in wounds of 84 patients with type 2 diabetes mellitus (T2DM) and 6 control subjects without diabetes using quantitative real-time polymerase chain reaction (RT-PCR), western blot and immunohistochemistry. TLR7 and TLR9 were significantly up-regulated in wounds of the patients with T2DM compared with the controls and were dependent on the infection status of the diabetic wounds, and wounds with microbial infection exhibited lower expression levels of endosomal TLRs. Altered endosomal TLR expression in T2DM subjects might be associated with wound healing impairment.

Fe-P: a new class of electroactive catalyst for oxygen reduction reaction.

It has been long thought that Fe-N-C structure, where Fe is bonded with an electronegative heteroatom N, plays a key role as nonprecious metal catalyst for oxygen reduction reaction (ORR) in fuel cells. However, electrocatalytic activity of Fe bonded with electropositive heteroatom P has never been considered for ORR. Herein we report the electrocatalytic activity for ORR of new Fe-P-C.

Work-Family Conflict and Oral and General Health-Related Quality of Life.

BACKGROUND: The characteristics of the work environment and relationships with family roles may impact on health and be of public health significance. PURPOSE: The aims were to investigate the cross-sectional association of work-family conflict with oral- and general health-related quality of life, and well-being. METHOD: A random sample of 45-54-year olds from Adelaide, South Australia, was surveyed by self-complete questionnaire in 2004-2005 (n = 879, response rate = 43.8%). Health-related quality of life was measured with the OHIP-14 and EQ-VAS instruments, and well-being by the Satisfaction With Life Scale. RESULTS: In adjusted analyses controlling for sex, income, education, tooth brushing frequency and social support, the higher Family Interferes with Work (FIW) tertile and the middle tertile of Work Interferes with Family (WIF) were associated with more oral health-related impacts as measured by OHIP-14 in relation to problems with teeth, mouth or dentures (Beta = 1.64, P < 0.05 and Beta = 2.85, P < 0.01). Both middle and higher tertiles of WIF were associated with lower general health (Beta = -4.20 and -5.71, P < 0.01) and well-being (Beta = -1.17 and -1.56, P < 0.01). CONCLUSION: Work-family conflict was associated with more oral health impacts and lower general health and well-being among employed middle-aged adults. This supports the view of work-family conflict as a psychosocial risk factor for health outcomes spanning function, health perceptions and well-being, and encompassing both oral health and general health.