DHFS-ECM: Design of a Dual Heuristic Feature Selection-based Ensemble Classification Model for the Identification of Bamboo Species from Genomic Sequences.

Background: Analyzing genomic sequences plays a crucial role in understanding biological diversity and classifying Bamboo species. Existing methods for genomic sequence analysis suffer from limitations such as complexity, low accuracy, and the need for constant reconfiguration in response to evolving genomic datasets. Aim: This study addresses these limitations by introducing a novel Dual Heuristic Feature Selection-based Ensemble Classification Model (DHFS-ECM) for the precise identification of Bamboo species from genomic sequences. Methods: The proposed DHFS-ECM method employs a Genetic Algorithm to perform dual heuristic feature selection. This process maximizes inter-class variance, leading to the selection of informative N-gram feature sets. Subsequently, intra-class variance levels are used to create optimal training and validation sets, ensuring comprehensive coverage of class-specific features. The selected features are then processed through an ensemble classification layer, combining multiple stratification models for species-specific categorization. Results: Comparative analysis with state-of-the-art methods demonstrate that DHFS-ECM achieves remarkable improvements in accuracy (9.5%), precision (5.9%), recall (8.5%), and AUC performance (4.5%). Importantly, the model maintains its performance even with an increased number of species classes due to the continuous learning facilitated by the Dual Heuristic Genetic Algorithm Model. Conclusion: DHFS-ECM offers several key advantages, including efficient feature extraction, reduced model complexity, enhanced interpretability, and increased robustness and accuracy through the ensemble classification layer. These attributes make DHFS-ECM a promising tool for real-time clinical applications and a valuable contribution to the field of genomic sequence analysis.

Once-daily oral small-molecule glucagon-like peptide-1 receptor agonist lotiglipron (PF-07081532) for type 2 diabetes and obesity: Two randomized, placebo-controlled, multiple-ascending-dose Phase 1 studies.

AIM: To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity. MATERIALS AND METHODS: Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron. RESULTS: Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose-dependent reductions in mean daily glucose. The 180-mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (-1.61% [90% confidence interval {CI} -2.08, -1.14] vs. -0.61% [-1.56, 0.34] for placebo) and body weight (-5.10 kg [90% CI -6.62, -3.58] vs. -2.06 kg [90% CI -4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once-daily dosing. CONCLUSIONS: The profile of once-daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose-dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses. CLINICALTRIALS: gov identifier: NCT04305587, NCT05158244.

Quality of Life and Its Association With Time in Range Among People With Type 2 Diabetes Mellitus Following Different Dietary Interventions: A Crossover Clinical Trial.

Background Quality of Life (QoL) is an essential consideration in healthcare. Numerous studies have examined QoL in India; however, data on QoL following different dietary interventions are lacking. Similarly, the use of technology such as continuous glucose monitoring (CGM) for diabetes care has independently demonstrated improvements in glycemic control; however, its association with QoL remains limited. Purpose The purpose was to study the role of different dietary interventions on QoL and its association with Time in Range (TIR), Time Above Range (TAR), and Time Below Range (TBR) among the Type 2 Diabetes Mellitus (T2DM) population. Methodology A crossover interventional clinical trial (CTRI/2022/07/044356) was conducted among participants with T2DM of less than 5 years' duration, aged between 25 and 55 years, with an HbA1c level of less than 8%, and who were on Metformin only. Their QoL was assessed after following two diet patterns: the Continuous Calorie Restricted Diet (CCRD) - calorie reduction with small frequent meals, and Time Restricted Intermittent Fasting (TRIF) - calorie reduction with only two meals a day, using the Modified QoL (MDQOL-17) questionnaire. The association between post-dietary interventions QoL and TIR was studied using a 14-day CGM device. Results The overall QoL of 51 participants at the end of the dietary interventions was significantly better compared to their QoL before any dietary intervention (85.6±19.0% and 63.1±13.0%, respectively, p = 0.000). Decreased TIR correlated with increased role limitations due to physical functioning (p = 0.002) and decreased energy levels (p = 0.00). As TBR increased, role limitation due to emotional well-being increased, and energy levels decreased significantly (p = 0.01). As TAR increased, energy levels decreased (p = 0.01). A simple linear regression model was statistically significant for role limitations due to physical functioning (p = 0.003) and energy fatigue (p = 0.000), suggesting that higher TIR is associated with higher scores in these domains. Conclusion Dietary interventions that improve the TIR and reduce the TAR and TBR can enhance the QoL of individuals with T2DM.

Exploring the Impact of Optimized Probiotic Supplementation Techniques on Diabetic Nephropathy: Mechanisms and Therapeutic Potential.

Worldwide, diabetic nephropathy (DN) is a significant contributor to end-stage renal failure and chronic kidney disease. Probiotic supplementation has recently gained popularity as a potential nutritional therapy in several clinical trials aimed at improving renal function, inflammation, oxidative stress, dyslipidemia, glycemic control, and inflammation. However, they still need to undergo a thorough assessment of DN. It is crucial that the optimal dosage, duration, and combination of probiotic strains administered for the purpose of slowing down the advancement of DN be assessed. Based on the available publications, including relevant randomized controlled trials, systematic reviews, and meta-analysis from 2013-2023 from search engines like MEDLINE (PubMed), Scopus, and Web of Science, a literature review was generated using the keywords "gut microbiota," "gut microbiome," "diabetic kidney disease," "diabetic nephropathy," "probiotic," and "prebiotic." Multiple clinical trials focusing on probiotic administration techniques revealed changes in renal, glucose, and lipid biomarkers. Probiotic supplementation using Bifidobacterium bifidum, Lactobacillus acidophilus, and Streptococcus thermophilus for 12 weeks indicated a reduction in glycosylated hemoglobin, fasting blood glucose, and the microalbuminuria/creatinine ratio. Multispecies as well as single-species probiotic administration containing Lactobacillus, Bifidobacterium, and Streptococcus thermophilus spp. greater than 4*109 colony forming units (CFU)/day for 8-12 weeks in DN patients improves renal metabolic markers and reduces the progression of disease patterns. Optimal supplementation techniques of probiotics in conjunction with prebiotics and synbiotics in DN benefit glycaemic control, renal function, blood lipid profile, inflammation, and oxidative stress. Future randomized controlled trials supplementing specific probiotics coupled with prebiotics and synbiotics, with larger sample sizes and longer follow-up times, will generate more reliable findings for the impact of probiotic supplementation on DN.

Dietary composition and time in range in population with type 2 diabetes mellitus-exploring the association using continuous glucose monitoring device.

AIM: To understand the association between macronutrient composition of a diet with Time in Range (TIR), Time above Range (TAR) and Time below Range (TBR) derived using a Continuous Glucose Monitoring (CGM) device for 14 days. METHODOLOGY: An exploratory analysis on the baseline data of 50 Type 2 Diabetes Mellitus participants with age 25-55 years, HbA1c upto 8% and on Metformin only) enrolled for an interventional clinical trial was performed. RESULTS: Participants consuming adequate carbohydrates (CHO) of 55 to 60% of total calories had better Average Blood Glucose of 142.0 ± 24.0 mg/dL with a significance of p = 0.03 and Glucose Management Indicator (GMI) of 6.6 ± 0.7% significant at p = 0.01, than those with high CHO intake >60% of the total calories, with Average Blood Glucose - 155.0 ± 13.4 mg/dL and GMI - 7.06 ± 0.4%. Similarly, TIR - 68.2 ± 5.1% and TAR - 23.0 ± 10.8% was significantly better (p = 0.00) among those consuming adequate protein (12-15%) as compared to low protein (≤ 10%) with TIR- 61.0 ± 5.1% & TAR- 32.9 ± 10.3%. A correlation (r = -0.482 & p = 0.00) and simple linear regression analysis (R² = 0.33, F = 7.72, p = 0.000) revealed that when CHO intake increases the TIR decreases whereas TAR increases (r = 0.380 & p = 0.006). We did not find any significant relation between fat intake and TIR, TAR or TBR. CONCLUSION: Our results suggest that lowering CHO, while increasing protein in the diet may help improve TIR. Further in-depth studies are needed to confirm these findings.

Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.

BACKGROUND: Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. METHODS: Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. PERSPECTIVE: Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05546476.

Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Danuglipron in Participants With Type 2 Diabetes.

Danuglipron (PF-06882961) is an oral, small-molecule glucagon-like peptide-1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is prevalent in patients with T2D. This Phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate [eGFR] unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log-linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function.

Structure-function relationship and diagnostic value of macular ganglion cell complex measurement using Fourier-domain OCT in glaucoma.

PURPOSE: To evaluate the relationship between visual function and macular ganglion cell complex (GCC) thickness measured by Fourier-domain optical coherence tomography (OCT) and evaluate the diagnostic value of GCC measurement compared to retinal nerve fiber layer (RNFL) thickness and macular thickness in detecting early, moderate, and severe glaucomas. METHODS: Subjects underwent standard automated perimetry (SAP), OCT imaging with optic nerve head mode and GCC mode. The relationship between OCT parameters (mean GCC thickness, mean RNFL thickness, and macular thickness) and perimetry global indices (mean deviation [MD] and pattern standard deviation [PSD]) was evaluated by regression analysis. Diagnostic values of mean RNFL thickness, GCC parameters, and macular thickness were compared with the area under the receiver operating characteristic curves (AUC). RESULTS: A total of 84 eyes, 42 of each normal and primary open-angle glaucoma patients were included in the study. Compared with linear models, second-order polynomial models better described relationships between GCC thickness and MD ( P < 0.001), and between GCC thickness and PSD ( P = 0.00). RNFL parameter, inferior RNFL thickness had the highest AUC for detecting early glaucoma. The AUC of mean GCC thickness for early glaucoma was higher than that of mean RNFL; however, the difference was not significant ( P = 0.09), which was higher than that of macular thickness. CONCLUSION: The relationship between visual field (VF) sensitivity and GCC thickness is best expressed by the curvilinear function. Macular GCC thickness and RNFL thickness showed similar diagnostic values but were better than macular thickness for detecting early glaucoma but inferior to macular thickness and RNFL thickness for detecting moderate glaucoma.

Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: A 12-week, randomized, placebo-controlled, Phase 2 study comparing different dose-escalation schemes.

AIM: To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron. MATERIALS AND METHODS: This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID. RESULTS: Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m2 ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05). CONCLUSIONS: Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses. CLINICALTRIALS: gov identifier: NCT04617275.

Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Currently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration. Objective: To investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks. Design, Setting, and Participants: A phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions. Interventions: Participants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily. Main Outcomes and Measures: Change from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period. Results: Of 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of -1.16% (90% CI, -1.47% to -0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of -33.24 mg/dL (90% CI, -45.63 to -20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of -2.04 kg (90% CI, -3.01 to -1.07 kg) for the 80-mg twice daily group and -4.17 kg (90% CI, -5.15 to -3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting. Conclusions and Relevance: In adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action. Trial Registration: ClinicalTrials.gov Identifier: NCT03985293.

Inhibition of Diacylglycerol Acyltransferase 2 Versus Diacylglycerol Acyltransferase 1: Potential Therapeutic Implications of Pharmacology.

PURPOSE: Hepatic steatosis due to altered lipid metabolism and accumulation of hepatic triglycerides is a hallmark of nonalcoholic fatty liver disease (NAFLD). Diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, catalyze the terminal reaction in triglyceride synthesis, making them attractive targets for pharmacologic intervention. There is a common misconception that these enzymes are related; however, despite their similar names, DGAT1 and DGAT2 differ significantly on multiple levels. As we look ahead to future clinical studies of DGAT2 inhibitors in patients with NAFLD and nonalcoholic steatohepatitis (NASH), we review key differences and include evidence to highlight and support DGAT2 inhibitor (DGAT2i) pharmacology. METHODS: Three Phase I, randomized, double-blind, placebo-controlled trials assessed the safety, tolerability, and pharmacokinetic properties of the DGAT2i ervogastat (PF-06865571) in healthy adult participants (Single Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of PF-06865571 [study C2541001] and Study to Assess the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of PF-06865571 in Healthy, Including Overweight and Obese, Adult Subjects [study C2541002]) or participants with NAFLD (2-Week Study in People With Nonalcoholic Fatty Liver Disease [study C2541005]). Data from 2 Phase I, randomized, double-blind, placebo-controlled trials of the DGAT1i PF-04620110 in healthy participants (A Single Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961001] and A Multiple Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961002]) were included for comparison. Safety outcomes were the primary end point in all studies, except in study C2541005, in which safety was the secondary end point, with relative change from baseline in whole liver fat at day 15 assessed as the primary end point. Safety data were analyzed across studies by total daily dose of ervogastat (5, 15, 50, 100, 150, 500, 600, 1000, and 1500 mg) or PF-04620110 (0.3, 1, 3, 5, 7, 10, 14, and 21 mg), with placebo data pooled separately across ervogastat and PF-04620110 studies. FINDINGS: Published data indicate that DGAT1 and DGAT2 differ in multiple dimensions, including gene family, subcellular localization, substrate preference, and specificity, with unrelated pharmacologic inhibition properties and differing safety profiles. Although initial nonclinical studies suggested a potentially attractive therapeutic profile with DGAT1 inhibition, genetic and pharmacologic data suggest otherwise, with common gastrointestinal adverse events, including nausea, vomiting, and diarrhea, limiting further clinical development. Conversely, DGAT2 inhibition, although initially not pursued as aggressively as a potential target for pharmacologic intervention, has consistent efficacy in nonclinical studies, with reduced triglyceride synthesis accompanied by reduced expression of genes essential for de novo lipogenesis. In addition, early clinical data indicate antisteatotic effects with DGAT2i ervogastat, in participants with NAFLD, accompanied by a well-tolerated safety profile. IMPLICATIONS: Although pharmacologic DGAT1is are limited by an adverse safety profile, data support use of DGAT2i as an effective and well-tolerated therapeutic strategy for patients with NAFLD, NASH, and NASH with liver fibrosis. CLINICALTRIALS: gov identifiers: NCT03092232, NCT03230383, NCT03513588, NCT00799006, and NCT00959426.

A phase 2a, randomized, double-blind, placebo-controlled, three-arm, parallel-group study to assess the efficacy, safety, tolerability and pharmacodynamics of PF-06835919 in patients with non-alcoholic fatty liver disease and type 2 diabetes.

AIM: To assess the safety, tolerability and pharmacodynamics (PD) of the ketohexokinase inhibitor PF-06835919 in participants with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). MATERIALS AND METHODS: This double-blind, placebo-controlled, parallel-group study enrolled adults with NAFLD (≥ 8% whole liver fat [WLF] using MRI proton density fat fraction [MRI-PDFF]) and T2D on stable doses of metformin (≥ 500 mg/day). Participants received once-daily placebo, PF-06835919 150 or 300 mg for 16 weeks. Randomization (1:1:1) was via an interactive response technology system. Endpoints included percentage change from baseline (CFB) in WLF using MRI-PDFF (primary endpoint) and CFB in HbA1c (co-primary endpoint) at 16 weeks, PD, safety and tolerability. RESULTS: Among 164 participants randomized and treated, 145 completed the treatment (placebo, n = 50; PF-06835919 150 mg, n = 46; PF-06835919 300 mg, n = 49). At week 16, least squares mean (90% confidence interval) percentage CFB in WLF was -5.26% (-12.86%, 2.99%), -17.05% (-24.01%, -9.46%) and -19.13% (-25.51%, -12.20%) in the placebo, PF-06835919 150-mg and 300-mg groups, respectively (PF-06835919 300-mg group vs. placebo, P = .0288). Modest numerical reductions in HbA1c were observed in all groups that did not reach statistical significance. Treatment-emergent adverse event incidence was similar across groups (40.7%, 45.5% and 32.7% in the placebo, PF-06835919 150-mg and 300-mg groups, respectively), with no apparent dose-related trend. CONCLUSIONS: PF-06835919 administration over 16 weeks was generally safe and well tolerated and resulted in reductions in WLF in participants with NAFLD and T2D.

A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese adults with type 2 diabetes mellitus.

AIMS: This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), which is a novel, oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice-daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight. RESULTS: In the 37 participants randomized, the most common treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse events were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady state (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo-adjusted difference of up to -67.89 (-88.98, -46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to -40.87 (-53.77, -27.98) mg/dl], glycated haemoglobin [up to -1.41% (-2.01%, -0.82%)] and body weight [up to -1.87 (-3.58, -0.17) kg]. CONCLUSIONS: In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady state and robustly reduced glycaemic parameters and body weight after 8 weeks of dosing, with a safety profile consistent with the mechanism of action.

A Study and Analysis of Disease Identification using Genomic Sequence Processing Models: An Empirical Review.

Human gene sequences are considered a primary source of comprehensive information about different body conditions. A wide variety of diseases including cancer, heart issues, brain issues, genetic issues, etc. can be pre-empted via efficient analysis of genomic sequences. Researchers have proposed different configurations of machine learning models for processing genomic sequences, and each of these models varies in terms of their performance & applicability characteristics. Models that use bioinspired optimizations are generally slower, but have superior incremental-performance, while models that use one-shot learning achieve higher instantaneous accuracy but cannot be scaled for larger disease-sets. Due to such variations, it is difficult for genomic system designers to identify optimum models for their application-specific & performance-specific use cases. To overcome this issue, a detailed survey of different genomic processing models in terms of their functional nuances, application-specific advantages, deployment-specific limitations, and contextual future scopes is discussed in this text. Based on this discussion, researchers will be able to identify optimal models for their functional use cases. This text also compares the reviewed models in terms of their quantitative parameter sets, which include, the accuracy of classification, delay needed to classify large-length sequences, precision levels, scalability levels, and deployment cost, which will assist readers in selecting deployment-specific models for their contextual clinical scenarios. This text also evaluates a novel Genome Processing Efficiency Rank (GPER) for each of these models, which will allow readers to identify models with higher performance and low overheads under real-time scenarios.

A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

Role of Placental Glucose Transporters in Determining Fetal Growth.

Maternal nutrient availability and its transport through the placenta are crucial for fetal development. Nutrients are transported to the fetus via specific transporters present on the microvillous (MVM) and basal membrane (BM) of the placenta. Glucose is the most abundant nutrient transferred to the fetus and plays a key role in the fetal growth and development. The transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations, and is mediated by glucose transporter family proteins (GLUTs). Maternal glucose concentration influences expression and activity of GLUTs in the MVM (glucose uptake) and BM (glucose delivery). Alteration in the number and function of these transporters may affect the growth and body composition of the fetus. The thin-fat phenotype of the Indian baby (low ponderal index, high adiposity) is proposed as a harbinger of future metabolic risk. We propose that placental function mediated through nutrient transporters contributes to the phenotype of the baby, specifically that glucose transporters will influence neonatal fat. This review discusses the role of various glucose transporters in the placenta in determining fetal growth and body composition, in light of the above hypothesis.

Heuristic Analysis of Genomic Sequence Processing Models for High Efficiency Prediction: A Statistical Perspective.

Genome sequences indicate a wide variety of characteristics, which include species and sub-species type, genotype, diseases, growth indicators, yield quality, etc. To analyze and study the characteristics of the genome sequences across different species, various deep learning models have been proposed by researchers, such as Convolutional Neural Networks (CNNs), Deep Belief Networks (DBNs), Multilayer Perceptrons (MLPs), etc., which vary in terms of evaluation performance, area of application and species that are processed. Due to a wide differentiation between the algorithmic implementations, it becomes difficult for research programmers to select the best possible genome processing model for their application. In order to facilitate this selection, the paper reviews a wide variety of such models and compares their performance in terms of accuracy, area of application, computational complexity, processing delay, precision and recall. Thus, in the present review, various deep learning and machine learning models have been presented that possess different accuracies for different applications. For multiple genomic data, Repeated Incremental Pruning to Produce Error Reduction with Support Vector Machine (Ripper SVM) outputs 99.7% of accuracy, and for cancer genomic data, it exhibits 99.27% of accuracy using the CNN Bayesian method. Whereas for Covid genome analysis, Bidirectional Long Short-Term Memory with CNN (BiLSTM CNN) exhibits the highest accuracy of 99.95%. A similar analysis of precision and recall of different models has been reviewed. Finally, this paper concludes with some interesting observations related to the genomic processing models and recommends applications for their efficient use.

Printed microfluidic sweat sensing platform for cortisol and glucose detection.

Wearable sweat biosensors offer compelling opportunities for improved personal health monitoring and non-invasive measurements of key biomarkers. Inexpensive device fabrication methods are necessary for scalable manufacturing of portable, disposable, and flexible sweat sensors. Furthermore, real-time sweat assessment must be analyzed to validate measurement reliability at various sweating rates. Here, we demonstrate a "smart bandage" microfluidic platform for cortisol detection and continuous glucose monitoring integrated with a synthetic skin. The low-cost, laser-cut microfluidic device is composed of an adhesive-based microchannel and solution-processed electrochemical sensors fabricated from inkjet-printed graphene and silver solutions. An antibody-derived cortisol sensor achieved a limit of detection of 10 pM and included a low-voltage electrowetting valve, validating the microfluidic sensor design under typical physiological conditions. To understand effects of perspiration rate on sensor performance, a synthetic skin was developed using soft lithography to mimic human sweat pores and sweating rates. The enzymatic glucose sensor exhibited a range of 0.2 to 1.0 mM, a limit of detection of 10 µM, and reproducible response curves at flow rates of 2.0 µL min-1 and higher when integrated with the synthetic skin, validating its relevance for human health monitoring. These results demonstrate the potential of using printed microfluidic sweat sensors as a low-cost, real-time, multi-diagnostic device for human health monitoring.

Oral Curcumin With Piperine as Adjuvant Therapy for the Treatment of COVID-19: A Randomized Clinical Trial.

Background: Coronavirus disease-2019 (COVID-19) has a wide range of pathophysiological effects. Curcumin, an active constituent of Curcuma longa (turmeric), has several properties, including anti-inflammatory, antioxidant, antiviral, anti-thrombotic, and anti-proliferative effects, which make it a promising candidate for the symptomatic treatment of COVID-19. Objective: We aimed to determine the effects of curcumin administered with piperine (to optimize absorption) on symptoms in patients with COVID-19 in a double-blind, randomized, controlled trial at a 30-bed dedicated COVID Health Center (DCHC) in Maharashtra, India. Methods: In addition to conventional COVID-19 treatment, patients in the control group received a dose of probiotics twice a day, and patients in the study group received curcumin (525 mg) with piperine (2.5 mg) in tablet form twice a day. The effects of curcumin/piperine treatment on primary and secondary outcomes were assessed for the duration of hospitalization. Results: Patients with mild, moderate, and severe symptoms who received curcumin/piperine treatment showed early symptomatic recovery (fever, cough, sore throat, and breathlessness), less deterioration, fewer red flag signs, better ability to maintain oxygen saturation above 94% on room air, and better clinical outcomes compared to patients of the control group. Furthermore, curcumin/piperine treatment appeared to reduce the duration of hospitalization in patients with moderate to severe symptoms, and fewer deaths were observed in the curcumin/piperine treatment group. Conclusions: Administration of oral curcumin with piperine as an adjuvant symptomatic therapy in COVID-19 treatment could substantially reduce morbidity and mortality, and ease the logistical and supply-related burdens on the healthcare system. Curcumin could be a safe and natural therapeutic option to prevent Post-Covid thromboembolic events. Clinicaltrials.gov identifier: CTRI/2020/05/025482.

Energy intake as a short-term biomarker for weight loss in adults with obesity receiving liraglutide: A randomized trial.

BACKGROUND AND OBJECTIVE: Obesity is a chronic disease associated with many serious comorbidities. Pharmacologic therapies are approved for the treatment of obesity; however, short-term biomarkers to predict weight loss are not well understood. This study aimed to determine the ability of single-meal energy intake (EI) to predict weight loss in participants with obesity treated with liraglutide. METHODS: In this randomized, double-blind, placebo-controlled study, participants received subcutaneous liraglutide (titrated to 3.0 mg/day) or placebo once daily, with inpatient assessments at baseline and weeks 3 and 6. The primary endpoint was change from baseline (CFB) in EI during consecutive ad libitum lunch meals at weeks 3 and 6. Secondary endpoints included CFB in 24- and 48-h EI, weight, appetite scores, and gastric emptying measures. RESULTS: Sixty-one participants were randomized (n = 32, liraglutide; n = 29, placebo). The least squares mean (LSM) difference (95% CI; p-value) in CFB in EI during ad libitum lunch meals between the liraglutide and placebo groups was -236 (-322, -149; p < 0.0001) kcal at week 3 and -244 (-339, -148, p < 0.0001) kcal at week 6. The liraglutide group experienced significant weight loss at weeks 3 and 6, compared with placebo. Weight loss was significantly correlated with EI, but not with appetite score or gastric emptying. CONCLUSIONS: EI during a single meal is a robust clinical predictor of weight changes in participants with obesity. Future clinical trials can utilize EI at a single meal as a predictor of weight loss.