A multi-centric, single-blinded, randomized, parallel-group study to evaluate the effectiveness of nasoalveolar moulding treatment in non-syndromic patients with complete unilateral cleft lip, alveolus and palate (NAMUC study): a study protocol for a randomized controlled trial.

BACKGROUND: Cleft lip and palate (CLP) are among the most common congenital anomaly that affects up to 33,000 newborns in India every year. Nasoalveolar moulding (NAM) is a non-surgical treatment performed between 0 and 6 months of age to reduce the cleft and improve nasal aesthetics prior to lip surgery. The NAM treatment has been a controversial treatment option with 51% of the cleft teams in Europe, 37% of teams in the USA and 25 of cleft teams in India adopting this methodology. This treatment adds to the already existing high burden of care for these patients. Furthermore, the supporting evidence for this technique is limited with no high-quality long-term clinical trials available on the effectiveness of this treatment. METHOD: The NAMUC study is an investigator-initiated, multi-centre, single-blinded randomized controlled trial with a parallel group design. The study will compare the effectiveness of NAM treatment provided prior to lip surgery against the no-treatment control group in 274 patients with non-syndromic unilateral complete cleft lip and palate. The primary endpoint of the trial is the nasolabial aesthetics measured using the Asher McDade index at 5 years of age. The secondary outcomes include dentofacial development, speech, hearing, cost-effectiveness, quality of life, patient perception, feeding and intangible benefits. Randomization will be carried out via central online system and stratified based on cleft width, birth weight and clinical trial site. DISCUSSION: We expect the results from this study on the effectiveness of treatment with NAM appliance in the long term along with the cost-effectiveness evaluation can eliminate the dilemma and differences in clinical care across the globe. TRIAL REGISTRATION: ClinicalTrials.gov CTRI/2022/11/047426 (Clinical Trials Registry India). Registered on 18 November 2022. The first patient was recruited on 11 December 2022. CTR India does not pick up on Google search with just the trial number. The following steps have to be carried out to pick up. How to search: ( https://ctri.nic.in/Clinicaltrials/advsearch.php -use the search boxes by entering the following details: Interventional trial > November 2022 > NAMUC).

Serial D-dimers after anticoagulant cessation in unprovoked venous thromboembolism: Data from the REVERSE cohort study.

INTRODUCTION: While several risk stratification tools have been developed to predict the risk of recurrence in patients with an unprovoked venous thromboembolism (VTE), only 1 in 4 patients are categorized as low-risk. Rather than a one-time measure, serial D-dimer assessment holds promise to enhance the prediction of VTE recurrence after oral anticoagulant (OAC) cessation. METHODS: Using the REVERSE cohort, we compared VTE recurrence among patients with normal D-dimer levels (<490 ng/mL among males under age 70, <500 ng/mL in others) at OAC cessation and 1-month follow-up, to those with an elevated D-dimer level at either timepoint. We also evaluated VTE recurrence based on absolute increase in D-dimer levels between the two timepoints (e.g., ∆D-dimer) according to quartiles. RESULTS: Among 214 patients with serial D-dimer levels measured at OAC cessation and 1-month follow-up, an elevated D-dimer level at either timepoint was associated with a numerically higher risk of recurrent VTE than patients with normal D-dimer levels at both timepoints (6.9 % vs. 4.2 % per year, hazard ratio 1.6; 95 % CI 0.9-2.7). Among women with <2 HERDOO2 criteria, a normal D-dimer level at both timepoints predicted a very low risk of recurrent VTE during follow-up (0.8 % per year, 95 % CI 0.1-2.8). Irrespective of baseline value, recurrent VTE risk was only 3 % per year (95 % CI 1.4-5.6) among patients in the lowest ∆D-dimer quartile. CONCLUSION: Serial normal D-dimer levels have the potential to identify patients at a low risk of recurrent VTE. In addition, ∆D-dimer, irrespective of its elevation above cutoff threshold, may predict recurrent VTE.

Indefinite Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Cost-Effectiveness Study.

BACKGROUND: Clinical practice guidelines recommend indefinite anticoagulation for a first unprovoked venous thromboembolism (VTE). OBJECTIVE: To estimate the benefit-harm tradeoffs of indefinite anticoagulation in patients with a first unprovoked VTE. DESIGN: Markov modeling study. DATA SOURCES: Systematic reviews and meta-analyses for the long-term risks and case-fatality rates of recurrent VTE and major bleeding. Published literature for costs, quality of life, and other clinical events. TARGET POPULATION: Patients with a first unprovoked VTE who have completed 3 to 6 months of initial anticoagulant treatment. TIME HORIZON: Lifetime. PERSPECTIVE: Canadian health care public payer. INTERVENTION: Indefinite anticoagulation with direct oral anticoagulants. OUTCOME MEASURES: Recurrent VTE events, major bleeding events, costs in 2022 Canadian dollars (CAD), and quality-adjusted life-years (QALYs). RESULTS OF BASE-CASE ANALYSIS: When compared with discontinuing anticoagulation after initial treatment in a hypothetical cohort of 1000 patients aged 55 years, indefinite anticoagulation prevented 368 recurrent VTE events, which included 14 fatal pulmonary emboli, but induced an additional 114 major bleeding events, which included 30 intracranial hemorrhages and 11 deaths from bleeding. Indefinite anticoagulation cost CAD $16 014 more per person and did not increase QALYs (-0.075 per person). RESULTS OF SENSITIVITY ANALYSIS: Model results were most sensitive to the case-fatality rate of major bleeding and the annual risk for major bleeding during extended anticoagulation. LIMITATION: The model assumed that risks for recurrent VTE and major bleeding measured in clinical trials at 1 year remained constant during extended anticoagulation. CONCLUSION: Clinicians should use shared decision making to incorporate individual patient preferences and values when considering treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Daily intranasal insulin at 40IU does not affect food intake and body composition: A placebo-controlled trial in older adults over a 24-week period with 24-weeks of follow-up.

Centrally administered insulin stimulates the reward system to reduce appetite in response to food intake in animal studies. In humans, studies have shown conflicting results, with some studies suggesting that intranasal insulin (INI) in relatively high doses may decrease appetite, body fat, and weight in various populations. These hypotheses have not been tested in a large longitudinal placebo-controlled study. Participants in the Memory Advancement with Intranasal Insulin in Type 2 Diabetes (MemAID) trial were enrolled in this study. This study on energy homeostasis enrolled 89 participants who completed baseline and at least 1 intervention visit (42 women; age 65 ± 9 years; 46 INI, 38 with type 2 diabetes) and 76 completed treatment (16 women, age 64 ± 9; 38 INI, 34 with type 2 diabetes). The primary outcome was the INI effect on food intake. Secondary outcomes included the effect of INI on appetite and anthropometric measures, including body weight and body composition. In exploratory analyses, we tested the interaction of treatment with gender, body mass index (BMI), and diagnosis of type 2 diabetes. There was no INI effect on food intake or any of the secondary outcomes. INI also showed no differential effect on primary and secondary outcomes when considering gender, BMI, and type 2 diabetes. INI did not alter appetite or hunger nor cause weight loss when used at 40 I.U. intranasally daily for 24 weeks in older adults with and without type 2 diabetes.

Protocol for a modelling study to assess the clinical and cost-effectiveness of indefinite anticoagulant therapy for first unprovoked venous thromboembolism.

INTRODUCTION: Deciding whether to stop or extend anticoagulant therapy indefinitely after completing at least 3 months of initial treatment for a first unprovoked venous thromboembolism (VTE) remains a challenge for clinicians, patients and policy makers. Guidelines suggest an indefinite duration of anticoagulant therapy in these patients, yet its benefits, harms and costs have not been formally assessed. The aim of this proposed modelling study is to assess the differences in clinical benefits, harms and costs of stopping versus continuing anticoagulant therapy indefinitely for a first unprovoked VTE. METHODS AND ANALYSIS: We will develop a probabilistic Markov model, adopting a 1-month cycle length and a lifetime horizon, to estimate life-years, quality-adjusted life-years, costs and the incremental cost-effectiveness ratios for a simulated population of patients with a first unprovoked VTE who will receive indefinite duration of anticoagulant therapy versus a population who will not receive extended treatment after completing 3 months of initial anticoagulant therapy. The economic evaluation will adopt a third-party payer perspective relating to a Canadian publicly funded healthcare system. Estimates for the probability of relevant clinical events will be informed by systematic reviews and meta-analyses, while costs and utility values will be obtained from published Canadian sources. Stratified analyses based on sex, age and site of initial VTE will also be performed to identify subgroups of patients with a first unprovoked VTE in whom continuing anticoagulant therapy indefinitely might prove to be clinically beneficial and cost-effective over stopping treatment. We will also conduct sensitivity and scenario analyses to assess robustness of study findings to changes in individual or groups of key parameters. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study. The results will be disseminated through presentations at relevant conferences and in a manuscript that will be submitted to a peer-reviewed journal.

Dropout risk and effectiveness of retention strategies in the Memory Advancement by Intranasal Insulin in Type 2 Diabetes (MemAID) Clinical Trial.

BACKGROUND: Effective recruitment and retention strategies are essential in clinical trials. METHODS: The MemAID trial consisted of 12 visits during 24 weeks of intranasal insulin or placebo treatment and 24 weeks of post-treatment follow-up in older people with and without diabetes. Enhanced retention strategies were implemented mid study to address high drop-out rate. Baseline variables used in Cox regression models to identify dropout risk factors were: demographics and social characteristics, functional measures, metabolic and cardiovascular parameters, and medications. RESULTS: 244 participants were randomized; 13 (5.3%) were discontinued due to adverse events. From the remaining 231 randomized participants, 65 (28.1%) dropped out, and 166 (71.9%) did not. The Non-retention group included 95 participants not exposed to retention strategies, of which 43 (45.2%) dropped out. The Retention group included 136 participants exposed to enhanced retention strategies, of which 22 (16.2%) dropped out. Dropout risk factors included being unmarried, a longer diabetes duration, using oral antidiabetics as compared to not using, worse executive function and chronic pain. After adjusting for exposure to retention strategies, worse baseline executive function composite score (p = 0.001) and chronic pain diagnosis (p = 0.032) were independently associated with a greater risk of dropping out. The probability of dropping out decreased with longer exposure to retention strategies and the dropout rate per month decreased from 4.1% to 1.8% (p = 0.04) on retention strategies. CONCLUSIONS: Baseline characteristics allow prediction of dropping out from a clinical trial in older participants. Retention strategies has been effective at minimizing the impact of dropout-related risk factors. TRIAL REGISTRATION: Clinical trials.gov NCT2415556 3/23/2015 (www. CLINICALTRIALS: gov).

Adverse Events Associated with Intra-Arterial Administration of Gadolinium-Based Contrast Agents: A Systematic Review and Meta-Analysis.

PURPOSE: To determine the risk of immediate hypersensitivity reactions (HRs), contrast-associated acute kidney injury (CA-AKI), nephrogenic systemic fibrosis (NSF), and gadolinium retention associated with use of intra-arterial gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched from 1988 (GBCAs approved for clinical use) to March 2021 for studies reporting adverse events associated with intra-arterial administration of GBCAs. The number of adverse events and GBCA administrations were used to calculate incidence in individual studies, and results across studies were pooled using random-effects meta-analysis. RESULTS: There were 72 studies (patients = 1,221) that reported on HR, 59 studies (patients = 1,142) that reported on CA-AKI, and 6 studies (patients = 291) that reported on NSF. No studies reported gadolinium retention as an outcome. Based on 5 events and 1,451 GBCA administrations, the incidence of HR per 100 administrations was 0.95 (95% CI, 0.52-1.51). Based on 90 events and 1,318 GBCA administrations, the incidence of CA-AKI per 100 administrations was 5.94 (95% CI, 3.92-8.34). Based on 7 events and 361 GBCA administrations, the incidence of NSF per 100 Group I GBCA administrations was 4.72 (95% CI, 0.35-13.70). There were no unconfounded NSF events after Group II GBCA administration. CONCLUSIONS: HRs to intra-arterial administration of GBCAs are rare, with no serious reactions. Limited data demonstrate a higher-than-expected rate of CA-AKI; however, multiple confounding factors were noted. Thus, any causative link of CA-AKI to GBCA remains controversial. Also, severe physiologic reactions (including life-threatening arrhythmias) during coronary angiography have been reported.

Genetic polymorphisms of IL6 gene -174G > C and -597G > A are associated with the risk of COVID-19 severity.

Coronavirus disease-2019 (COVID-19) is pro-inflammatory disorder characterized by acute respiratory distress syndrome. Interleukin-6, a cytokine secreted by macrophages, which mediates an inflammatory response, is frequently increased and associated with the severity in COVID-19 patients. The differential expression of IL6 cytokine in COVID-19 patients may be associated with the presence of single nucleotide polymorphisms (SNPs) in regulatory region of cytokine genes. The aim of this study is to investigate the role of two promoter polymorphisms of the IL6 gene (-597G > A and -174G > C) with the severity of COVID-19. The study included 242 patients, out of which 97 patients with severe symptoms and 145 patients with mild symptoms of COVID-19. Genotyping of two selected SNPs, rs1800795 (-174G > C) and rs1800797 (-597G > A) of promoter region of IL6 gene, was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In our study, individuals with GC genotypes of IL6 (-174G > C) polymorphism showed significantly higher risk of severity [adjusted odds (OR) 3.86, p <.001] but we did not observe any association of COVID-19 severity with rs1800797 (-597G > A) polymorphism. The COVID-19 severity was significantly higher in individuals having 'C' allele of IL6 (-174G > C) polymorphism (p = .014). Linkage disequilibrium between rs1800795 (-174G > C) and rs1800797 (-597G > A) showed that individuals having AC* haplotype significantly association with COVID-19 severity (p = .034). Our results suggest that 'C' allele of rs1800795 (-174G > C) polymorphism of IL6 may be the risk allele for severity of COVID-19 in North Indian population.

All-cause mortality after major gastrointestinal bleeding among patients receiving direct oral anticoagulants: a protocol for a systematic review and meta-analysis.

BACKGROUND: Gastrointestinal (GI) bleeding represents the single most frequent site of anticoagulant-related bleeding. Adverse outcomes after major GI bleeding including mortality are not well characterized and, as a result, may be underappreciated in clinical practice. We aim to conduct a systematic review and meta-analysis of the risk for 30-day all-cause mortality after major GI bleeding among patients receiving DOACs. METHODS: Electronic databases including MEDLINE, EMBASE, and Cochrane CENTRAL will be systematically searched to identify randomized controlled trials and prospective and retrospective cohort studies reporting 30-day all-cause mortality in adults with DOAC-related major GI bleeding. At least two investigators will independently perform study selection, risk of bias assessment, and data extraction. The proportion of deaths following a major GI event relative to the number of major GI bleeding events will be calculated for each individual study, and results across studies will be pooled using random-effects meta-analysis. We will assess risk of bias using criteria proposed by the GRADE group for prognostic studies. DISCUSSION: The findings of this systematic review and meta-analysis will provide clinicians and patients with estimates of mortality after the most common major bleeding event to support shared decision making about anticoagulation management. TRIAL REGISTRATION: PROSPERO CRD42022295815.

Effectiveness and Safety of Antibiotic Prophylaxis for Persons Exposed to Cases of Invasive Group A Streptococcal Disease: A Systematic Review.

Among close contacts of patients with invasive group A streptococcal (iGAS) infection, the benefits and harms of chemoprophylaxis are uncertain. We conducted a systematic review of studies that reported on persons who, after being exposed to a case of laboratory-confirmed or probable iGAS, received any antibiotic prophylaxis for the prevention of GAS infection or carriage. Thirty-seven studies including 26 outbreak investigations and 11 case series or reports were included with predominantly descriptive information that suggested that antibiotic prophylaxis may be effective in preventing GAS infection or GAS carriage, with very few serious adverse events. However, current available evidence is scant (with limited information on contacts of iGAS cases) and largely based on studies with weak design and small sample size. Therefore, definitive conclusions on effectiveness of antibiotic prophylaxis cannot be drawn. Well designed prospective studies are required to establish the benefit-harm profile of antibiotic prophylaxis for secondary prevention of GAS disease among close contacts of iGAS cases.

Role of exosomes in lung cancer: A comprehensive insight from immunomodulation to theragnostic applications.

Exosomes are 30 to 150 nm-diameter lipid bilayer-enclosed extracellular vesicles that enable cell-to-cell communication through secretion and uptake. The exosomal cargoes contain RNA, lipids, proteins, and metabolites which can be delivered to recipient cells in vivo. In a healthy lung, exosomes facilitate interaction between adaptive and innate immunity and help maintain normal lung physiology. However, tumor-derived exosomes in lung cancer (LC) can, on the other hand, restrict immune cell proliferation, cause apoptosis in activated CD8+ T effector cells, reduce natural killer cell activity, obstruct monocyte differentiation, and promote proliferation of myeloid-derived suppressor and regulatory T cells. In addition, exosomes in the tumor microenvironment may also play a critical role in cancer progression and the development of drug resistance. In this review, we aim to comprehensively examine the current updates on the role of exosomes in lung carcinogenesis and their potential application as a diagnostic, prognostic, and therapeutic tool in lung cancer.

Predicting major bleeding during extended anticoagulation for unprovoked or weakly provoked venous thromboembolism.

No clinical prediction model has been specifically developed or validated to identify patients with unprovoked venous thromboembolism (VTE) who are at high risk of major bleeding during extended anticoagulation. In a prospective multinational cohort study of patients with unprovoked VTE receiving extended anticoagulation after completing ≥3 months of initial treatment, we derived a new clinical prediction model using a multivariable Cox regression model based on 22 prespecified candidate predictors for the primary outcome of major bleeding. This model was then compared with modified versions of 5 existing clinical scores. A total of 118 major bleeding events occurred in 2516 patients (annual risk, 1.7%; 95% confidence interval [CI], 1.4-2.1). The incidences of major bleeding events per 100 person-years in high-risk and non-high-risk patients, respectively, were 3.9 (95% CI, 3.0-5.1) and 1.1 (0.8-1.4) using the newly derived creatinine, hemoglobin, age, and use of antiplatelet agent (CHAP) model; 3.3 (2.6-4.1) and 1.0 (0.7-1.3) using modified ACCP score, 5.3 (0.6-19.2) and 1.7 (1.4-2.0) using modified RIETE score, 3.1 (2.3-3.9) and 1.1 (0.9-1.5) using modified VTE-BLEED score, 5.2 (3.3-7.8) and 1.5 (1.2-1.8) using modified HAS-BLED score, and 4.8 (1.3-12.4) and 1.7 (1.4-2.0) using modified outpatient bleeding index score. Modified versions of the ACCP, VTE-BLEED, and HAS-BLED scores help identify patients with unprovoked VTE who are at high risk of major bleeding and should be considered for discontinuation of anticoagulation after 3 to 6 months of initial treatment. The CHAP model may further improve estimation of bleeding risk by using continuous predictor variables, but external validation is required before its implementation in clinical practice.

MemAID: Memory advancement with intranasal insulin vs. placebo in type 2 diabetes and control participants: a randomized clinical trial.

BACKGROUND: This study aimed at assessing the long-term effects of intranasal insulin (INI) on cognition and gait in older people with and without type 2 diabetes mellitus (T2DM). METHODS: Phase 2 randomized, double-blinded trial consisted of 24 week treatment with 40 IU of INI (Novolin® R, off-label use) or placebo (sterile saline) once daily and 24 week follow-up. Primary outcomes were cognition, normal (NW), and dual-task (DTW) walking speeds. Of 244 randomized, 223 completed baseline (51 DM-INI, 55 DM-Placebo, 58 Control-INI, 59 Control-Placebo; 109 female, 65.8 ± 9.1; 50-85 years old); 174 completed treatment (84 DM, 90 Controls); 156 completed follow-up (69 DM). RESULTS: DM-INI had faster NW (~ 7 cm/s; p = 0.025) and DTW on-treatment (p = 0.007; p = 0.812 adjusted for baseline difference) than DM-Placebo. Control-INI had better executive functioning on-treatment (p = 0.008) and post-treatment (p = 0.007) and verbal memory post-treatment (p = 0.004) than Control-Placebo. DM-INI increased cerebral blood flow in medio-prefrontal cortex (p < 0.001) on MRI. Better vasoreactivity was associated with faster DTW (p < 0.008). In DM-INI, plasma insulin (p = 0.006) and HOMA-IR (p < 0.013) decreased post-treatment. Overall INI effect demonstrated faster walking (p = 0.002) and better executive function (p = 0.002) and verbal memory (p = 0.02) (combined DM-INI and Control-INI cohort, hemoglobin A1c-adjusted). INI was not associated with serious adverse events, hypoglycemic episodes, or weight gain. CONCLUSION: There is evidence for positive INI effects on cognition and gait. INI-treated T2DM participants walked faster, showed increased cerebral blood flow and decreased plasma insulin, while controls improved executive functioning and verbal memory. The MemAID trial provides proof-of-concept for preliminary safety and efficacy and supports future evaluation of INI role to treat T2DM and age-related functional decline.

Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy.

The lung microbiome plays an essential role in maintaining healthy lung function, including host immune homeostasis. Lung microbial dysbiosis or disruption of the gut-lung axis can contribute to lung carcinogenesis by causing DNA damage, inducing genomic instability, or altering the host's susceptibility to carcinogenic insults. Thus far, most studies have reported the association of microbial composition in lung cancer. Mechanistic studies describing host-microbe interactions in promoting lung carcinogenesis are limited. Considering cancer as a multifaceted disease where epigenetic dysregulation plays a critical role, epigenetic modifying potentials of microbial metabolites and toxins and their roles in lung tumorigenesis are not well studied. The current review explains microbial dysbiosis and epigenetic aberrations in lung cancer and potential therapeutic opportunities.