The inclusion of adults with intellectual disabilities in health research - challenges, barriers and opportunities: a mixed-method study among stakeholders in England.

BACKGROUND: The study aims to understand system barriers to research participation for people with intellectual disabilities. METHODS: A mixed-methods approach examined the inclusivity of people with intellectual disabilities (IDs) in a random sample of National Institute for Health and Care Research (NIHR) studies conducted in 2019-2020. An online questionnaire (stage 1) was sent to the selected studies lead investigators. An expert by experience panel of 25 people with intellectual disabilities (IDs, stage 2), discussed the stage 1 feedback. Descriptive statistics for quantitative data and thematic analysis for qualitative data was conducted. RESULTS: Of 180 studies reviewed, 131 studies (78%) excluded people with IDs. Of these, 45 (34.3%) study researchers provided feedback. Seven (20%) of the 34 studies which included people with IDs gave feedback. Of all respondents over half felt their study had some relevance to people with IDs. A minority (7.6%) stated their study had no relevance. For a quarter of respondents (23.5%), resource issues were a challenge. Qualitative analysis of both stages produced four overarching themes of Research design and delivery, Informed consent, Resource allocation, and Knowledge and skills. CONCLUSION: Health research continues to exclude people with IDs. Researchers and experts by experience identified non-accessible research design, lack of confidence with capacity and consent processes, limited resources such as time and a need for training as barriers. Ethics committees appear reluctant to include people with cognitive deficits to 'protect' them. People with IDs want to be included in research, not only as participants but also through coproduction.

Clinical characteristics of people with intellectual disability admitted to hospital with constipation: identifying possible specific high-risk factors.

BACKGROUND: People with intellectual disabilities (ID) die on an average 20 years earlier to the general population. They have higher rates of multimorbidity and polypharmacy. Around 25% of people with ID report chronic constipation. The England Learning Disabilities Mortality Review found that nearly 25% of deaths identified constipation as a long-term health problem. However, the likely risk factors for constipation related harm are poorly enumerated. We sought to identify possible specific high-risk factors by examining the clinical characteristics of people with ID admitted to hospital with constipation. METHODS: Data of people with ID admitted with constipation in two general hospitals covering a population of 1.3 million from 2017 to 2022 were reported using the STROBE guideline for cohort studies. Collected data included age, gender, intellectual disability severity, recorded medication, presenting complaint and co-morbidities. The medication anticholinergic burden was calculated using the anticholinergic burden scale. Continuous variables were summarised by mean and standard deviation if normally distributed, with categorical variables summarised by the number and percentage in each category. RESULTS: Of 46 admissions (males 52%), 57% had moderate to profound ID, 37% had epilepsy, 41% prescribed antiseizure medication (ASM) and 45% were on laxatives. Average age was 46 years. The anticholinergic burden score mean was 2.3 and median, one. CONCLUSIONS: We can hypothesise that people with more severe ID, suffering from epilepsy and on ASM may be more at risk of developing severe constipation. Some admissions may be avoided with earlier use of laxatives in the community.

Theoretical aspects of the adsorption of normal and modified base pairs of DNA on graphene models toward DNA sequencing.

A theoretical understanding of the adsorption of DNA base pairs (GC, AT, CAF-T and CAF-C) on the graphene models (Gr, SiGr and SiGr-COOH) is investigated. Among the complexes, SiGr-COOH_AT is found to have the highest adsorption energies of -202.83 kcal/mol. The strong adsorption between DNA base pairs and the SiGr-COOH model leads to concomitant charge transfer responsible for the stability of the corresponding models and is verified with NBO analysis. AIM analysis discloses the high orbital overlap that signifies the strong interaction. Closed-shell interactions are observed through the positive values of total electron density, and it is also observed that Si-O(N) interaction has both covalent and electrostatic characteristics. This is the first theoretical attempt to investigate the adsorption of DNA base pairs on SiGr-COOH, which is more favourable than other models and may call for further experimental studies, which is crucial in developing new bio-sensors.Communicated by Ramaswamy H. Sarma.

Quality of Life with the Rehabilitation After Partial Mandibulectomy: a Systematic Review.

To evaluate the QoL before and after prosthetic rehabilitation of partial mandibulectomy patients based on the type of surgery, effects of radiation, the type of prosthesis, and to enlist their outcome on the rehabilitation. Literature search as per PICO format was carried out within a time range from January 2000 to June 2021. The review followed PRISMA guidelines and registered with the PROSPERO(CRD42021258472). The focus question was established as per the PICO format (Population, Intervention, Comparison, Outcome). The population involved partial mandibulectomy individuals with prosthetic rehabilitation as an intervention. The outcome, quality of life (QoL), was compared with the pre and post partial mandibulectomy patients rehabilitated with a prosthesis. The search yielded 367 articles and based on the search criteria only 7 articles were suitable for qualitative analysis. Marginal resection of the mandible is less aggressive than segmental resection which provided function, phonation, and esthetics at acceptable levels but the food mixing ability was reduced when resection is accompanied by glossectomy. However, the perceived chewing ability and OHRQoL were not accountable to the extent of surgical excision. An overall increase in the QoL on rehabilitation with acrylic prosthesis depicting satisfactory functionality with a considerable improvement in mastication, speech, and social life. QoL and Denture Satisfaction Index did not differ based on the number of implants in an implant overdenture prosthesis, but the chewing ability was improved. An increase in the number of remaining occlusal units improved the overall QoL. Restoration of the function, psychological comfort, and improvement in esthetics was significant in patients who underwent prosthetic rehabilitation. The QoL between conventional and implant prostheses was observed to be more similar, and the effect of remaining hard and soft tissue structures has a major influence on patient comfort signifying the influence of the extent of surgical excision. Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-022-01664-x.

Awareness of social care needs in people with epilepsy and intellectual disability.

BACKGROUND: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. PURPOSE: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. METHOD: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher's exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. RESULTS: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. CONCLUSIONS: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways.

A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: This study assessed the effects of the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to efinopegdutide 10 mg or semaglutide 1 mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment. RESULTS: Among 145 randomized participants (efinopegdutide n = 72, semaglutide n = 73), 33.1% had T2DM. At baseline, mean BMI was 34.3 kg/m2 and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8-78.7]) than with semaglutide (42.3% [90% CI 36.5-48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p = 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events. CONCLUSIONS: In patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly. CLINICAL TRIAL NUMBER: EudraCT: 2020-005136-30; NCT: 04944992. IMPACT AND IMPLICATIONS: Currently, there are no approved therapies for non-alcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10 mg weekly) led to a significantly greater reduction in LFC compared to treatment with the GLP-1 receptor agonist semaglutide (1 mg weekly), suggesting that efinopegdutide may be an effective treatment for NASH.

An evidence-based approach to provide essential and desirable components to develop surveys on Sudden Unexpected Death in Epilepsy (SUDEP) for doctors: A focused review.

Sudden Unexpected Death in Epilepsy (SUDEP) is a major concern for people with epilepsy, their families, their care givers, and medical professionals. There is inconsistency in the SUDEP counselling doctors provide, compared to what is recommended in clinical guidelines. Numerous national and international surveys have highlighted how epilepsy professionals, usually doctors, deliver SUDEP risk counselling, particularly, when they deliver it and to whom. These surveys help understand the unmet need, develop suitable strategies, and raise awareness among clinicians with the eventual goal to reduce SUDEPs. However, there is no standardised survey or essential set of questions identified that can be used to evaluate SUDEP counselling practice globally. This focused review analyses the content of all published SUDEP counselling surveys for medical professionals (n=16) to date covering over 4000 doctors across over 30 countries and five continents. It identifies 36 question themes across three topics. The questions are then reviewed by an expert focus group of SUDEP communication experts including three doctors, an expert statistician and SUDEP Action, an UK based charity specialising in epilepsy deaths with a pre-set criterion. The review and focus group provide ten essential questions that should be included in all future surveys inquiring on SUDEP counselling. They could be used to evaluate current practice and compare findings over time, between services, across countries and between professional groups. They are provided as a template to download and use. The review also explores if there is a continued need in future for similar surveys to justify this activity.

Detection and genetic diversity of porcine rotavirus A, B and C in eastern Australian piggeries.

Rotaviruses (RV) have a high prevalence in piggeries worldwide and are one of the major pathogens causing severe diarrhoea in young pigs. RV species A, B, and C have been linked to piglet diarrhoea in Australian pig herds, but their genetic diversity has not been studied in detail. Based on sequencing of the structural viral protein 7 (VP7) RVA G genotypes G3, G4 and G5, and RVC types G1, G3, G5, and G6 have been identified in Australian piggeries in previous studies. Although occurrence of RVB was reported in Australia in 1988, no further genetic analysis has been conducted. To improve health management decisions in Australian pig herds, more information on RV prevalence and genetic diversity is needed. Here, 243 enteric samples collected from 20 pig farms within Eastern Australia were analysed for the presence of RV in different age groups using a novel PCR-based multiplex assay (Pork MultiPath™ enteric panel). RVA, RVB, and RVC were detected in 10, 14, and 14 farms, respectively. Further sequencing of VP7 in selected RV-positive samples revealed G genotypes G2, G5, G9 (RVA), G6, G8, G14, G16, G20 (RVB), and G1, G3, G5, G6 (RVC) present. RVA was only detected in young (<10 weeks old) pigs whereas RVB and RVC were also detected in older animals (>11 weeks old). Interestingly, RVB and RVC G-type occurrence differed between age groups. In conclusion, this study provides new insights on the prevalence and diversity of different RV species in pig herds of Eastern Australia whilst demonstrating the ability of the Pork MultiPath™ technology to accurately differentiate between these RV species.

Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions.

Here in, we report the design, synthesis and in vitro anticancer activity of a novel series of 24 quinoline analogues of substituted amide and sulphonamide derivatives. The anticancer activity of the synthesised compounds was evaluated against the HCC827, H1975 (L858R/T790 M), A549 (WT EGFR), A-549 and BEAS-2B cell lines. The majority of quinoline compounds demonstrated a significant cytotoxic effect. Compound 21 was found to be the most potent, with IC50 values of 0.010 µM, 0.21 µM, 0.99 µM and 2.99 µM as compared to Osimertinib with IC50 values with of 0.0042 µM, 0.04 µM, 0.92 µM and 2.67 µM. Compound 21 exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790 M with IC50 value of 138 nM, comparable to Osimertinib's 110 nM. Employing a Western blot assay on the phosphorylation of EGFR and the signalling pathways transmission in HCC827 cells, the anticancer activity of the synthesised compounds 18 and 21 was evaluated in terms of its mechanism of action. All the compounds were subjected to a comparative molecular docking study against various EGFR enzyme types, including the wild-type (PDB: 4I23) and T790 M mutant (PDB: 2JIV) enzymes. Furthermore, compounds were examined at the allosteric binding site of the EGFR enzyme with the L858R/T790 M/C797S mutation (PDB ID: 5D41). The MD simulation study was also performed for EGFR-compound 21 complex which indicates the stability compound 21 in both ATP and allosteric site of enzyme. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties.

HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis.

The chromatin-associated high mobility group protein N2 (HMGN2) cofactor regulates transcription factor activity through both chromatin and protein interactions. Hmgn2 expression is known to be developmentally regulated, but the post-transcriptional mechanisms that regulate Hmgn2 expression and its precise roles in tooth development remain unclear. Here, we demonstrate that HMGN2 inhibits the activity of multiple transcription factors as a general mechanism to regulate early development. Bimolecular fluorescence complementation, pull-down, and coimmunoprecipitation assays show that HMGN2 interacts with the transcription factor Lef-1 through its HMG-box domain as well as with other early development transcription factors, Dlx2, FoxJ1, and Pitx2. Furthermore, EMSAs demonstrate that HMGN2 binding to Lef-1 inhibits its DNA-binding activity. We found that Pitx2 and Hmgn2 associate with H4K5ac and H3K4me2 chromatin marks in the proximal Dlx2 promoter, demonstrating Hmgn2 association with open chromatin. In addition, we demonstrate that microRNAs (miRs) mir-23a and miR-23b directly target Hmgn2, promoting transcriptional activation at several gene promoters, including the amelogenin promoter. In vivo, we found that decreased Hmgn2 expression correlates with increased miR-23 expression in craniofacial tissues as the murine embryo develops. Finally, we show that ablation of Hmgn2 in mice results in increased amelogenin expression because of increased Pitx2, Dlx2, Lef-1, and FoxJ1 transcriptional activity. Taken together, our results demonstrate both post-transcriptional regulation of Hmgn2 by miR-23a/b and post-translational regulation of gene expression by Hmgn2-transcription factor interactions. We conclude that HMGN2 regulates tooth development through its interaction with multiple transcription factors.

Tackling increased risks in older adults with intellectual disability and epilepsy: Data from a national multicentre cohort study.

PURPOSE: People with intellectual disabilities (ID) suffer multimorbidity, polypharmacy and excess mortality at a younger age than general population. Those with ID and epilepsy are at higher risk of worse clinical outcomes than their peers without epilepsy. In the ID population the health profile of those aged ≥40 years can be compared to those aged over 65 in the general population. To date there is limited data available to identify clinical characteristics and risk factors in older adults (≥40 years) with ID and epilepsy. METHODS: The Epilepsy in ID National Audit (Epi-IDNA) identified 904 patients with ID and epilepsy from 10 sites in England and Wales. This subsequent analysis of the Epi-IDNA cohort compared the 405 adults over 40 years with 499 adults ≥18 years aged under 40 years. Comparison was made between clinical characteristics and established risk factors using the Sudden Unexpected Death in Epilepsy (SUDEP) and Seizure Safety Checklist. RESULTS: The older adults' cohort had significantly higher levels of co-morbid physical health conditions, mental health conditions, anti-seizure medications (median 5), and antipsychotics compared to the younger cohort. The older group were significantly less likely to be diagnosed with a co-morbid neurodevelopmental disorder, and to have an epilepsy care plan. CONCLUSION: This is the largest study to date focused on adults with ID and epilepsy over 40 years. The ≥40 years cohort compared to the younger group has higher levels of clinical risk factors associated with multi-morbidity, potential iatrogenic harm and premature mortality with worse clinical oversight mechanisms.

Glycine max Homologs of DOESN'T MAKE INFECTIONS 1, 2, and 3 Function to Impair Heterodera glycines Parasitism While Also Regulating Mitogen Activated Protein Kinase Expression.

Glycine max root cells developing into syncytia through the parasitic activities of the pathogenic nematode Heterodera glycines underwent isolation by laser microdissection (LM). Microarray analyses have identified the expression of a G. max DOESN'T MAKE INFECTIONS3 (DMI3) homolog in syncytia undergoing parasitism but during a defense response. DMI3 encodes part of the common symbiosis pathway (CSP) involving DMI1, DMI2, and other CSP genes. The identified DMI gene expression, and symbiosis role, suggests the possible existence of commonalities between symbiosis and defense. G. max has 3 DMI1, 12 DMI2, and 2 DMI3 paralogs. LM-assisted gene expression experiments of isolated syncytia under further examination here show G. max DMI1-3, DMI2-7, and DMI3-2 expression occurring during the defense response in the H. glycines-resistant genotypes G.max [Peking/PI548402] and G.max [PI88788] indicating a broad and consistent level of expression of the genes. Transgenic overexpression (OE) of G. max DMI1-3, DMI2-7, and DMI3-2 impairs H. glycines parasitism. RNA interference (RNAi) of G. max DMI1-3, DMI2-7, and DMI3-2 increases H. glycines parasitism. The combined opposite outcomes reveal a defense function for these genes. Prior functional transgenic analyses of the 32-member G. max mitogen activated protein kinase (MAPK) gene family has determined that 9 of them act in the defense response to H. glycines parasitism, referred to as defense MAPKs. RNA-seq analyses of root RNA isolated from the 9 G. max defense MAPKs undergoing OE or RNAi reveal they alter the relative transcript abundances (RTAs) of specific DMI1, DMI2, and DMI3 paralogs. In contrast, transgenically-manipulated DMI1-3, DMI2-7, and DMI3-2 expression influences MAPK3-1 and MAPK3-2 RTAs under certain circumstances. The results show G. max homologs of the CSP, and defense pathway are linked, apparently involving co-regulated gene expression.

Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism.

CONTEXT: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. OBJECTIVE: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. METHODS: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 µg if weight ≤ 60 kg, or 150 µg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. RESULTS: After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. CONCLUSION: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Black carbon over a high altitude Central Himalayan Glacier: Variability, transport, and radiative impacts.

Ambient equivalent black carbon (BC) measurements spanning from June to October have been carried out over an adjoining location of Satopanth and Bhagirath-Kharak Glaciers (3858m, amsl) of Central Himalaya during the year 2019. Hourly BC varied from 12 ng m-3 to 439 ng m-3 during the entire period of observation. Monthly averaged BC values showed the highest concentration during June (230.96 ± 85.46 ng m-3) and the lowest in August (118.02 ± 71.63 ng m-3). The decrease in BC during monsoon months is attributed to limited long-range transport and rapid wet scavenging processes. Transport model studies indicate a higher retention time of tracer in Uttarakhand, Punjab, Haryana, and adjacent polluted valley regions with increased biomass burning (BB) incidences. The high rate of BC influx during June, September, and October was attributed to transport from the polluted Indo-Gangetic Plain (IGP) region, wildfires, and vehicular emissions in the valley region. Higher equivalent brown carbon (BrC) influx is linked to BB, especially wood-burning, during intense forest fires at slopes of mountains. Data obtained from limited BC observations during the 2011-19 period showed no significant BC influx change during post-monsoon. The strong correlation between BC mass and BB affirms the dominant role of BB in contributing BC to the Glacier region. Increased TOA forcing induced by surface darkening and BC atmospheric radiative heating indicate an additional warming and possible changes of the natural snow cycle over the glacier depending on the characteristics and extent of debris cover.

Design and synthesis of novel conformationally constrained 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives as topoisomerase I inhibitors: In vitro screening, molecular docking and ADME predictions.

Novel non-camptothecin (non-CPT) class of conformationally constrained, hitherto unknown 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives have been designed, synthesized and evaluated for anti-cancer activity. In vitro anti-proliferation evaluation against human cancer cell lines (A549 and MCF-7) exhibited significant cytotoxicity. Among the derivatives (8-24), 8 (IC50 0.44 µM and IC50 0.62 µM) and 12 (IC50 0.69 µM and IC50 0.54 µM) were identified as the most promising candidate against A-549 and MCF-7 cancer cell lines respectively. Topo I inhibitory activity of 8 and 12 suggested that, they may be developed as potential anti-cancer molecules in future and rationalized by docking analysis with effective binding modes. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties. In precise, the present investigation displays a new strategy to synthesize and emphasis on anticancer activities of conformationally constrained dibenzo[b,h][1,6] naphthyridine derivatives and Chromeno[3,2-c] quinoline derivatives in the context of cancer drug development and refinement.