SD Reduction Research Articles

The effect of SGLT2 inhibition on brain-related phenotypes and aging: a drug target Mendelian randomization study.

Observational study suggested SGLT2 inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological, biological age and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs). We selected genetic variants associated with both expression levels of SLC5A2 (GTEx and eQTLGen data; N=129 to 31,684) and HbA1c levels (UK Biobank; N=344,182) and used them to proxy the effect of SGLT2 inhibition. Aging related outcomes, including parental longevity (N=389,166) and epigenetic clocks (N=34,710), and cognitive phenotypes, including cognitive function (N=300,486) and intelligence (N= 269,867) were derived from genome-wide association studies. Two-step MR were conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes, cognition. SGLT2 inhibition was associated with longer father's attained age (years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95%CI 1.95 to 11.15), better cognitive function (beta = 0.17, 95%CI 0.03 to 0.31) and higher intelligence (beta = 0.47, 95%CI 0.19 to 0.75). Two-step MR identified two IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where four and five IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence respectively (total proportion of mediation = 61.6% and 68.6% respectively). Our study supported that SGLT2 inhibition increases father's attained age, cognitive function and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether similar effect could be observed for users of SGLT2 inhibitors.

Abstract MP28: Declines in Plasma Levels of Nonnutritive Sweetener Erythritol Are Related to Two-Year Improvements in Atherosclerotic Cardiovascular Disease Risk Estimates Among Adults With Overweight and Obesity

Background: A potential adverse relationship between the consumption of low-calorie sweeteners and cardiovascular disease (CVD) risk has been proposed. High levels of circulating erythritol, a sugar alcohol (polyol) used as one of the non-nutritive sweeteners, have been recently linked to increased risks of major adverse cardiovascular events. However, associations of temporal changes in plasma erythritol and other polyols with cardiometabolic risk remain unclear. Hypothesis: We tested whether changes in plasma levels of non-nutritive sweetener erythritol and other polyols in response to weight-loss dietary interventions were associated with improved atherosclerotic cardiovascular disease (ASCVD) risk estimates and atherogenic lipoproteins among adults with overweight and obesity. Methods: This study included 804 adults (mean BMI: 32.7 [SD 3.9] kg/m 2 ) without diabetes or unstable CVD at baseline who participated in a 2-year intervention of weight-loss diets, the POUNDS Lost trial. Metabolomic profiling was performed to measure plasma erythritol and its precursor erythronate, other sugar alcohols, and low-calorie sweeteners at baseline and 6 months after randomization. The primary outcome was the change in 10-year ASCVD risk scores calculated by the validated pooled cohort equations. Two-year changes in lipid profiles and cholesterol [Chol] in lipoprotein subfractions defined by the presence or absence of apolipoprotein CIII (apoCIII) were analyzed as secondary outcomes. Results: The mean estimated value of the 10-year ASCVD risk was 4.0% at baseline; 16% of the participants were at intermediate or high ASCVD risk (score ≥7.5%). Higher levels of erythritol (per 1 SD increment: β 1.1% [SE 0.2%], p <.0001) and erythronate (β 1.3% [0.2%], p <.0001), as well as other sugar alcohols, such as mannitol-sorbitol, myoinositol, arabitol-xylitol ( p <.0001 for all), and low-calorie sweetener saccharin ( p = 0.02), but not acesulfame ( p =0.8), were related to a higher ASCVD risk at baseline after adjusting for BMI. There was large variability in the changes in metabolite levels across participants; greater decreases in erythritol in response to the interventions were significantly related to greater reductions in ASCVD risk estimates at 6 months (per 1 SD reduction: β -0.2% [SE 0.1%]; p =0.023) and at 2 years (β -0.3% [0.1%]; p = 0.015) after adjusting for covariates, including BMI, the initial metabolite levels, and baseline ASCVD risk. The 6-month decrease in erythritol was associated with long-term (2-year) improvements in atherogenic lipids, including Chol in VLDL+LDL with apoCIII ( p <0.05). Conclusions: Higher plasma levels of erythritol and other sugar alcohols were associated with greater 10-year ASCVD risk scores among adults with overweight and obesity. Weight-loss diet-induced decreases in erythritol levels were related to improved ASCVD risk and atherogenic lipid profiles.

Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis.

The impact of lipid-lowering medications on sepsis is still not well defined. A Mendelian randomization (MR) study was carried out to probe the causal connections between genetically determined lipids, lipid-reducing drugs, and the risk of sepsis. Data on total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and triglycerides (TG) were retrieved from the MR-Base platform and the Global Lipids Genetics Consortium in 2021 (GLGC2021). Our study categorized sepsis into two groups: total sepsis and 28-day mortality of sepsis patients (sepsis28). The inverse-variance weighted (IVW) method was the primary method used in MR analysis. Cochran's Q test and the MR-Egger intercept method were used to assess the heterogeneity and pleiotropy. In the MR analysis, we found that ApoA-I played a suggestively positive role in protecting against both total sepsis (OR, 0.863 per SD increase in ApoA-I; 95% CI, 0.780-0.955; P = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598-0.963; P = 0.023). HDL-C levels were also found to suggestively reduce the incidence of total sepsis (OR, 0.891 per SD increase in HDL-C; 95% CI, 0.802-0.990; P = 0.031). Reverse-MR showed that sepsis28 led to a decrease in HDL-C level and an increase in TG level. In drug-target MR, we found that HMGCR inhibitors positively protected against total sepsis (, 0.719 per SD reduction in LDL-C; 95% CI, 0.540-0.958; P = 0.024). LDL-C and HDL-C proxied CETP inhibitors were found to have a protective effect on total sepsis, with only LDL-C proxied CETP inhibitors showing a suggestively protective effect on sepsis28. In Mediated-MR, BMI exhibited a negative indirect effect in HMGCR inhibitors curing sepsis. The indirect impact of ApoA-I explained over 50% of the curative effects of CETP inhibitors in sepsis. Our MR study suggested that ApoA-I and HDL-C protected against sepsis, while HMGCR and CETP inhibitors showed therapeutic potential beyond lipid-lowering effects. ApoA-I explained the effects of CETP inhibitors. Our study illuminates how lipids affect sepsis patients and the effectiveness of new drugs, opening new avenues for sepsis treatment.

Reducing the margin in prostate radiotherapy: optimizing radiotherapy with a general-purpose linear accelerator using an in-house position monitoring system.

To study the feasibility of optimizing the Clinical Target Volume to Planning Target Volume (CTV-PTV) margin in prostate radiotherapy(RT) with a general-purpose linear accelerator using an in-house developed position monitoring system, SeedTracker. A cohort of 30 patients having definitive prostate radiotherapy treated within an ethics-approved prospective trial was considered for this study. The intrafraction prostate motion and the position deviations were measured using SeedTracker system during each treatment fraction. Using this data the CTV-PTV margin required to cover 90% of the patients with a minimum of 95% of the prescription dose to CTV was calculated using van Herk's formula. The margin calculations were performed for treatment scenarios both with and without applying the position corrections for observed position deviations. The feasibility of margin reduction with real-time monitoring was studied by assessing the delivered dose that incorporates the actual target position during treatment delivery and comparing it with the planned dose. This assessment was performed for plans generated with reduced CTV-PTV margin in the range of 7mm-3mm. With real-time monitoring and position corrections applied the margin of 2.0mm, 2.1mm and 2.1mm in LR, AP and SI directions were required to meet the criteria of 90% population to receive 95% of the dose prescription to CTV. Without position corrections applied for observed position deviations a margin of 3.1mm, 4.0mm and 3.0mm was required in LR, AP and SI directions to meet the same criteria. A mean ± SD reduction of 0.5 ± 1.8% and 3 ± 7% of V60 for the rectum and bladder can be achieved for every 1mm reduction of PTV margin. With position corrections applied, the CTV D99 can be delivered within -0.2 ± 0.3 Gy of the planned dose for plans with a 3mm margin. Without applying corrections for position deviations the CTV D99 was reduced by a maximum of 1.1 ± 1.1 Gy for the 3mm margin plan and there was a statistically significant difference between planned and delivered dose for 3mm and 4mm margin plans. This study demonstrates the feasibility of reducing the margin in prostate radiotherapy with SeedTracker system without compromising the dose delivery accuracy to CTV while reducing dose to critical structures.

1708-P: Comparing 9- vs. 12-Month Implantation in the Worldwide EndoBarrier (EB) Registry

Uncertainty exists re risk: benefit of proximal intestinal exclusion with EB, a novel endoscopic duodenal jejunal liner device for obesity, both with and without diabetes. In view of this, during 2017, an independent, secure, on line registry was established under the auspices of the Association of British Clinical Diabetologists, for the collection of safety and efficacy data worldwide. As of December 2022, data had been entered on 1022 patients, of whom 195 (age 51.6±10.3 years, 53% male, 81% white ethnicity, BMI 39.9±6.9kg/m2) had both 9- and 12-month data entered. EB had considerable impact on weight and HbA1c (Table). There was no difference between the mean±SD reduction in HbA1c or weight at 9- vs 12-months (HbA1c: 1.39±1.67% vs 1.38±1.66% (p=0.98); weight: 11.7±8.3kg vs 12.0±8.3kg (p=0.44). The higher the HbA1c the greater the fall but again no difference between 9- and 12-months (Table). In the full registry, 43/1022 (4.2%) experienced serious adverse events (SAE). 15/43 (34.9%) SAE would have been avoided by removal at 9-months (9 liver abscess, 4 GI bleed, one cholecystitis). It was particularly noteworthy that 9/13 (69.2%) liver abscess SAEs would have been avoided by removal at 9-months. This international data from the EB registry suggests that the benefits of EB are achieved in 9-months and a reduction in the recommended implantation period from 12- to 9-months would reduce SAEs, especially the liver abscess SAE. Disclosure R.E.Ryder: Other Relationship; Novo Nordisk, Speaker's Bureau; GI Dynamics, BioQuest. J.J.Mcmaster: None. J.Chisholm: None. L.Kow: None. J.C.Mason: None. R.V.Cohen: Advisory Panel; GI Dynamics, Research Support; Medtronic, Johnson & Johnson Medical Devices Companies. P.Sen gupta: Other Relationship; Novo Nordisk. M.Yadagiri: None. L.Munro: None. H.Frydenberg: None. S.Fishman: None. J.P.Byrne: Advisory Panel; Oxford Medical Products, Join Embla, Stock/Shareholder; Join Embla. J.P.Teare: None. C.De jonge: None. J.Greve: Advisory Panel; GI Dynamics. Funding Association of British Clinical Diabetologists

A meta-analysis on the effectiveness of food-waste reducing nudges

Food waste is a global concern and is increasingly addressed by various policies and campaigns, especially in the consumption stage. Among these efforts, a promising instrument is gentle interventions based on nudges. To investigate whether and how a nudge works, we develop a theoretical framework and conduct a meta-analysis to synthesize empirical effects of nudges on reducing consumption food waste. The meta-analysis’s summary effect size of cognitively-oriented nudges is a 0.27 SD (Cohen’s d) reduction in food waste, and that of behaviorally-oriented ones is a 0.54 SD reduction. The effects of nudges are robust across sampled populations (i.e., U.S. vs. non-U.S. samples) but vary across settings (i.e., public vs. private). We further map nudge interventions to the driving factors of food waste behaviors and reveal potential research gaps in the literature. Based on these findings, we discuss implications for policy making to reduce food waste.

Patiromer Treatment in Patients With CKD, Hyperkalemia, and Hyperphosphatemia: A Post Hoc Analysis of 3 Clinical Trials

Patients with chronic kidney disease (CKD), hyperkalemia (serum potassium [sK+]>5.0 mEq/L), and hyperphosphatemia experience poor clinical outcomes. Patiromer, a potassium binder that uses calcium as the exchange ion, may also reduce serum phosphorus (sP). We characterized the effect ofpatiromer on sP in patients with CKD, hyperkalemia, and hyperphosphatemia. A post hoc pooled analysis of individual-level data from the AMETHYST-DN, OPAL-HK, and TOURMALINE trials of patiromer. Patients with CKD and hyperkalemia. Patients treated with patiromer (8.4-33.6 g/day). Mean changes from baseline in sP, sK+, serum calcium (sCa2+), and serum magnesium (sMg2+) after 2 and 4 weeks of treatment. Descriptive statistics to summarize pooled data on the study outcomes from the 3 studies. We included 578 patients in the analysis. Of these participants, 86 patients (14.9%) had baseline hyperphosphatemia of whom 75.6% (65 of 86) had CKD stage 4/5 and 31.1% (153 of 492) with sP≤4.5mg/dL had CKD stage4/5. Among the patients with elevated sPand sK+at baseline, the mean±SD reduction insP and sK+after 4 weeks of patiromer treatment was-0.62±1.09mg/dL and-0.71± 0.51mEq/L,respectively. Additionally, the mean±SDreduction in sMg2+in these patients was -0.25±0.23mg/dL while sCa2+remained unchanged. Both sMg2+and sCa2+remained within the normal range. Patiromer was generally well tolerated, and no serious adverse events were considered related to patiromer. These were post hoc analyses, no placebo comparison was performed due to the design of the original studies, and the follow-up period was limited to 4 weeks. Reductions in sP and sK+to the normal range were observed after 2 weeks of patiromer treatment, and the reduction was sustained during 4 weeks of treatment among patients with non-dialysis-dependent CKD, hyperkalemia, and hyperphosphatemia. Future controlled trials are needed to establish if patiromer is useful to reduce both sK+and sP in hyperkalemic patients with CKD and hyperphosphatemia.

Long-term safety and efficacy, including anhedonia, of vortioxetine for major depressive disorder: findings from two open-label studies

Objective Evaluate the long-term safety and efficacy of vortioxetine in the management of major depressive disorder (MDD) in two open-label one-year studies, including a post-hoc analysis of its effects on symptoms related to anhedonia. Methods Both studies were 52-week, open-label, flexible-dose extension studies to evaluate the safety and efficacy of vortioxetine in adult patients with MDD following prior double-blind studies. Patients in the first study (NCT00761306) were flexibly treated with vortioxetine 5 or 10 mg/day (N = 74), and patients in the second study (NCT01323478) received vortioxetine 15 or 20 mg/day (N = 71). Results The safety and tolerability profile of vortioxetine was similar between the two studies; treatment-emergent adverse events with the highest incidence were nausea, dizziness, headache, and nasopharyngitis. Across both studies, improvements achieved during the preceding double-blind studies period were maintained, and additional improvements were observed with open-label treatment. Patients showed a mean ± SD reduction (improvement) in Montgomery and Åsberg Depression Rating Scale (MADRS) total score from open-label baseline to Week 52 of 4.3 ± 9.2 points in the 5–10 mg study, and 10.9 ± 10.0 in the 15–20 mg study. Post-hoc MMRM analyses of MADRS anhedonia factor scores also showed continued improvements over long-term treatment; patients showed a mean ± SE reduction from an open-label baseline to Week 52 of 3.10 ± 0.57 points in the 5–10 mg study, and 5.62 ± 0.60 in the 15–20 mg study. Conclusions Data from both studies confirm the safety and efficacy of flexibly dosed vortioxetine over 52 weeks of treatment and demonstrate that MADRS anhedonia factor scores continue to improve with long-term maintenance treatment.

Association of Right Ventricular Functional Parameters With Adverse Cardiopulmonary Outcomes: A Meta-analysis

We aimed to confirm that three-dimensional echocardiography-derived right ventricular ejection fraction (RVEF) is better associated with adverse cardiopulmonary outcomes than the conventional echocardiographic parameters. We performed a meta-analysis of studies reporting the impact of unit change of RVEF, tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and free-wall longitudinal strain (FWLS) on clinical outcomes (all-cause mortality and/or adverse cardiopulmonary outcomes). Hazard ratios (HRs) were rescaled by the within-study SDs to represent standardized changes. Within each study, we calculated the ratio of HRs related to a 1 SD reduction in RVEF versus TAPSE, or FAC, or FWLS, to quantify the association of RVEF with adverse outcomes relative to the other metrics. These ratios of HRs were pooled using random-effects models. Ten independent studies were identified as suitable, including data on 1,928 patients with various cardiopulmonary conditions. Overall, a 1 SD reduction in RVEF was robustly associated with adverse outcomes (HR= 2.64 [95% CI, 2.18-3.20], P<.001; heterogeneity: I2=65%, P=.002). In studies reporting HRs for RVEF and TAPSE, or RVEF and FAC, or RVEF and FWLS in the same cohort, head-to-head comparison revealed that RVEF showed significantly stronger association with adverse outcomes per SD reduction versus the other 3 parameters (vs TAPSE, HR= 1.54 [95% CI, 1.04-2.28], P=.031; vs FAC, HR= 1.45 [95% CI, 1.15-1.81], P=.001; vs FWLS, HR= 1.44 [95% CI, 1.07-1.95], P=.018). Reduction in three-dimensional echocardiography-derived RVEF shows stronger association with adverse clinical outcomes than conventional right ventricular functional indices; therefore, it might further refine the risk stratification of patients with cardiopulmonary diseases.

An Open-Label, Proof-of-Concept Study Assessing the Effects of Bromelain-Based Enzymatic Debridement on Biofilm and Microbial Loads in Patients With Venous Leg Ulcers and Diabetic Foot Ulcers

Background. Most chronic wounds contain biofilm, and debridement remains the centerpiece of treatment. Enzymatic debridement is an effective tool in removing nonviable tissue, however, there is little evidence supporting its effect on planktonic and biofilm bacteria. Objective. This study evaluated the effects of a novel BBD agent on removal of nonviable tissue, biofilm, and microbial loads in patients with chronic ulcers. Materials and Methods. Twelve patients with DFU or VLU were treated with up to 8 once-daily applications of BBD and then followed for an additional 2 weeks. Punch biopsy specimens were collected and analyzed for biofilm, and fluorescence imaging was used to measure bacterial load. Results. Ten patients completed treatment, and 7 achieved complete debridement within a median of 2 applications (range, 2–8). By the end of the 2-week follow-up period, the mean ± SD reduction in wound area was 35% ± 38. In all 6 patients who were positive for biofilm at baseline, the biofilm was reduced to single individual or no detected microorganisms by the end of treatment. Red fluorescence for Staphylococcus aureus decreased from a mean of 1.09 cm² ± 0.58 before treatment to 0.39 cm² ± 0.25 after treatment. BBD was safe and well tolerated. Conclusion. Preliminary data suggest that BBD is safe and that it can be used to effectively debride DFU and VLU, reduce biofilm and planktonic bacterial load, and promote reduction in wound size.

“CLINICAL EVALUATION OF THE EFFECT OF A NOVEL LACTOFERRIN CONTAINING TOOTHPASTE AS AN ADJUNCT TO SCALING AND ROOT PLANING IN IMPROVING PLAQUE CONTROL AND GINGIVAL HEALTHA RANDOMIZED CONTROLLED CLINICAL TRIAL”.

Aims and objectives: To evaluate the effect of a DENTE91® (novel lactoferrin based toothpaste) in comparison to Standard fluoride based toothpaste as an adjunct to scaling and root Planing in improving plaque control and gingival health. This was an examiner-blinded, parallel group, randomized, controlled trial enrolled total 10 Methodology: 0 healthy subjects aged 18 to 35 years (both inclusive) who had dental biofilm induced gingivitis, with at least 20 natural teeth, who exhibited no evidence of clinical attachment loss and was ready to give written informed consent were enrolled. Mean ± SD plaque Index score with Turesky–Gilmore–Glickman modification of Quingley Hein Results: plaque index (S) was statistically significant within Test group (1.44 ± 0.40) and Control group (1.79 ± 0.36) as compared to baseline (2.48 ± 0.43 in Test group and 2.72 ± 0.33 in Control group). Mean % ± SD reduction in plaque index score at Week 4 was 42.04% ± 11.04% in Test group and 34.19% ± 14.21% in Control group as compared to baseline. Reduction in plaque index was comparable between Dente 91® (Test group) and Standard fluoride based toothpaste. Mean ± SD gingival Index score based on Loe and Silness, 1963 method was statistically significant at Week 4 (0.76 ± 0.38 in Test group and 1.34 ± 0.56 in Control group) when compared to baseline (22.70 ± 0.67 in Test group and 2.65 ± 0.52 in Control group). Mean % ± SD reduction in gingival Index score at Week 4 was 71.29% ± 12.96% in Test group and 48.54% ± 21.94% in Control group as compared to baseline. Reduction in Gingival Index score was statistical significant (p=0.001) in Dente 91® (Test group) compared to Standard fluoride based toothpaste (Control group). The main Conclusion: finding was that Test group who had used DENTE91® toothpaste containing lactoferrin had significantly better gingival health status than the Control group in terms of gingival inflammation and gingival bleeding. Significant reduction in plaque index score was comparable between Test group and Control group.

Effects of Inhaled Corticosteroids on Bone in Asthma Patients

Background: Although inhaled corticosteroids are taken into the bloodstream, it is unclear how much damage they do to bones. The issue is crucial because 3% of people consistently use inhaled corticosteroids and could be doing for several decades. Method: In 195 adults (118 women) with asthmatic, aged 25 to 45, we examined the dose-response relationship between total inhaled corticosteroid dosage and bone mineralization concentration at the lumbar region and proximal femur. Participants had received only a little amount of systemic steroids and had routinely used an inhaled corticosteroid for a minimum of six months. Multiple regression analysis was employed to evaluate the total dosage of inhaled corticosteroid's impact on the density of bones from surveys, computerized general practitioners' data, and printed and handwritten general medical documents. Results: Treatment with inhaled corticosteroids lasted an average of 6 years (0–23), with a baseline total dose of 875 mg (87–4370). Both before and after adjusting for the influences of aging and gender, the results showed a negative correlation between the total dose of inhaled corticosteroid and skeletal mineral density at the lumbar region (L2-L4), femoral neck, and trochanter. An increase in inhaled corticosteroid dosage by twofold was linked to a 0•17 SD (95% CI 0•03-0•27) reduction in lumbar spine concentration of bone minerals... The femoral neck and trochanter all showed identical declines. The relationships remained strong after controlling for possible influencing variables such as regular exercise and previous use of oral, intranasal, cutaneous, and injectable corticosteroids. Conclusion: This investigation shows a link between the overall average dosage of inhaled corticosteroids and decreased bone mineralization concentration in asthmatic sufferers. Keywords: Corticosteroids, fracture, bone mineralization, inhaled, dosage, asthma, lumbar region, femur

Statins, Type 2 Diabetes, and Body Mass Index: A Univariable and Multivariable Mendelian Randomization Study.

Statins and possibly other lipid modifiers increase type 2 diabetes risk and body mass index (BMI). However, to what extent BMI mediates the diabetogenic effects of lipid modifiers remains unclear. We used Mendelian randomization (MR) to investigate the effects of commonly used lipid modifiers on type 2 diabetes risk and glycemic traits, and any mediation by BMI. Using established genetic variants to mimic commonly used lipid modifiers (ie, statins, PCSK9 inhibitors, and ezetimibe), we assessed their associations with type 2 diabetes risk, glycated hemoglobin (HbA1c), fasting insulin, fasting glucose, and BMI in the largest relevant genome-wide association studies (GWAS) in people of European ancestry, and where possible, in East Asians. We used multivariable MR to examine the role of lipid modifiers independent of BMI. Genetically mimicked effects of statins and ezetimibe, but not PCSK9 inhibitors were associated with higher risk of type 2 diabetes (odds ratio [OR] 1.74 [95% CI, 1.49 to 2.03]; 1.92 [1.22 to 3.02]; 1.06 [0.87 to 1.29] per SD reduction in low-density lipoprotein (LDL)-cholesterol). Of these lipid modifiers, only genetic mimics of statins were associated with higher BMI (0.33 SD [0.29 to 0.38] per SD reduction in LDL-cholesterol), which explained 54% of the total effect of statins on type 2 diabetes risk. Higher BMI mediated more than half of the diabetogenic effects of statins, which did not extend to other commonly used lipid modifiers. Further investigations are needed to clarify drug-specific mechanisms underlying the effects of lipid modifiers on type 2 diabetes.

24. Return to work, activities of daily living and disability improvement: twelve-month outcomes of an FDA IDE trial of decompression and tension band stabilization for degenerative spondylolisthesis

24. Return to work, activities of daily living and disability improvement: twelve-month outcomes of an FDA IDE trial of decompression and tension band stabilization for degenerative spondylolisthesis

Interventions for reducing weight bias in healthcare providers: An interprofessional systematic review and meta-analysis.

Weight bias is prevalent in many healthcare disciplines and negatively impacts the quality of care for patients with obesity. This warrants interventions to reduce weight bias shown by providers to improve care for individuals with obesity. However, past reviews have identified only marginal success in improving the attitudes and beliefs of healthcare providers about individuals with obesity. This systematic review and meta-analysis identifies and synthesizes recent peer-reviewed intervention studies aimed at reducing weight bias in healthcare students and professionals. The databases Embase, Cumulative Index to Nursing and Allied Health Literature, PsychINFO, PubMed and Google Scholar were searched for peer-reviewed studies published between 2016 and August 2021. Search terms included a combination of surrogate terms for the concepts of weight bias, intervention and healthcare students or professionals. The search yielded 1136 articles, and 14 articles met the inclusion criteria for the systematic review. Nineteen effect sizes from nine studies were included in the meta-analysis. Overall, the interventions in the included studies result in a 0.38 SD reduction (Hedge's g) in obesity-bias with 95% confidence intervals from -0.52 to -0.24, indicating a small to moderate effect size in the reduction of weight bias. Most studies included students and focused on evoking empathy or educating on the causality/controllability of obesity. Measurement tools, intervention type, limitations of the studies and recommendations for future research are discussed.

Perks and Pitfalls of Performance-Linked Reimbursement for Novel Drugs: The Case of Sacubitril-Valsartan.

Rising drug costs have increased interest in performance-linked reimbursement (PLR) contracts that tie payment to patient outcomes. PLR is theoretically attractive to payers interested in reducing the risk of overpaying for expensive drugs, to manufacturers working to improve early drug adoption, and to patients seeking improved access. Multiple PLR contracts were developed for sacubitril-valsartan. We evaluated how the characteristics of a PLR contract influence its performance. We used a published cost-effectiveness model of sacubitril-valsartan. We evaluated hypothetical PLR contracts that adjusted drug payment based on observed therapy effectiveness. Ideally, these contracts reduce the uncertainty around the value obtained with purchasing sacubitril-valsartan. By reducing the financial risk in covering an ineffective therapy, PLR incentivizes insurers to increase patient access. We measured the uncertainty in value as the SD of the incremental net monetary benefit (INMB), an estimate of therapy value incorporating costs and clinical benefits. We evaluated the change in INMB SD under a variety of different assumptions regarding contract design, therapy effectiveness, and population characteristics. Over 2 years, sacubitril-valsartan led to 0.042 additional quality-adjusted life-years at an incremental cost of $4916. Using a willingness-to-pay of $150 000 per quality-adjusted life-year, this led to a mean INMB across simulations of $1416 (SD, $1720). A PLR contract that adjusted payment based on cardiovascular mortality reduced the INMB SD moderately by 20.7% while a contract based on all-cause mortality was more effective (INMB SD reduction of 27.3%). A contract based on heart failure hospitalization reduction was ineffective. PLR effectiveness increased with greater uncertainty regarding therapy effectiveness or in sicker cohorts (eg, New York Heart Association Class III/IV heart failure). Contracts required precise estimates of treatment effect in addition to trust or verifiability between manufacturers and payers concerning patient selection. The development of accurate prospective estimates of treatment effectiveness using actual enrollee characteristics will be critical for successful PLR. If able to meet these requirements, PLRs could incentivize insurers to expand access to expensive treatments by reducing financial risk.

Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study.

Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. One SD increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% CI -0.044 to -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95% CI, -0.046 to -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95% CI, -0.049 to -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.

Use of Nalmefene in Routine Practice: Results from a French Prospective Cohort Study and a National Database Analysis.

AimsTwo complementary studies were used to assess the real-life use of nalmefene in alcohol-dependent patients and its impact on alcohol use health status.MethodsUSE-PACT was a prospective cohort study designed to evaluate the real-life effectiveness of nalmefene in the management of alcohol dependence, as assessed by total alcohol consumption (TAC) and number of heavy drinking days (HDD) at 1 year. USE-AM was a cohort study using data from the French nationwide claims database and was used to evaluate the external validity of the population in the prospective study.ResultsOverall, 256 of 700 new nalmefene users enrolled in the USE-PACT study had valid data at 1 year. After 1 year, patients treated with nalmefene showed a mean ± SD reduction from baseline in TAC (−41.5 ± 57.4 g/day) and number of HDD (−10.7 ± 11.7 days/4 weeks). Patients took a mean ± SD of 20.0 ± 12.0 tablets/4 weeks (median of 1 tablet/day) for the first 3 months and then reduced the dose. The proportion of patients who no longer took nalmefene gradually increased from 5% at 1 month to 52% at 1 year. The USE-AM study identified 486 patients with a first reimbursement for nalmefene in 2016; baseline characteristics confirmed external validity of the USE-PACT study. Overall, 46.3% of initial USE-AM prescriptions were made by GPs; most (91.8%) patients stopped treatment during follow-up. However, 15.2% of patients resumed treatment after stopping.ConclusionsIn this analysis of French routine practice, patients with alcohol dependence treated with nalmefene showed reduced alcohol consumption, and nalmefene was generally well tolerated.

Impact of social accountability monitoring on health facility performance: Evidence from Tanzania.

Social accountability programs are increasingly used to improve the performance of public service providers in low-income settings. Despite their growing popularity, evidence on the effectiveness of social accountability programs remains mixed. In this manuscript, we assess the impact of a social accountability intervention on health facility management exploring quasiexperimental variation in program exposure in Tanzania. We find that the social accountability intervention resulted in a 1.8 SD reduction in drug stockouts relative to the control group, but did not improve facility infrastructure maintenance. The results of this study suggest that social accountability programs may be effective in areas of health service provision that are responsive to changes in provider behavior but may not work in settings where improvements in outcomes are conditional on larger health systems features.

Effect of a plant-based bioequivalent inorganic nitrate ([formula omitted]) complex with vitamins, antioxidants and phytophenol rich food extracts in hypertensive individuals - A randomized, double-blind, placebo-controlled study

This study assessed efficacy of plant based bioequivalent nitrate complex, consist of vitamins, natural antioxidants and phytophenol rich food extracts to elevate nitric oxide (NO) bioavailability as determined by saliva conversion of nitrate (NO3-) to nitrite (NO2-) a required step to produce NO, in relationship to lowering blood pressure (BP) in both men and women. 67 individuals (26 men; mean age of 59.3±9.0yrs) with mean baseline systolic and diastolic BP >120 and 80mmHg respectively were randomized to receive daily dosing of 314mM NO3- or NO3- free (placebo) tablets in double-blinded study for 12 weeks (wks). Inorganic NO3- tablets consist of NO3- rich beetroot extract, thiamine nitrate, and potassium nitrate in the presence of ascorbic acid, to facilitate NO bioavailability. The primary endpoint of the study was reduction in BP at 12wks by improving endothelial function. At study conclusion, mean±SD reduction in systolic BP (SBP) in the inorganic NO3- group was 12.5±13.3mmHg (p=0.0007), as compared to 6.19±11.39mmHg (p=0.004) in the placebo group, for a placebo-corrected reduction of-6.31mmHg (95% CI 10.89-2.31, p=0.04). NO3- also reduced diastolic BP by 4.7±10.3mmHg (p=0.01), while no significant reduction in placebo group (1.98±9.38mmHg, p=0.24) was noted. Endothelial function improved at 12 weeks by 0.8±3.1 (p=0.03) in active group when compared to 0.1±1.8 (p=0.82) in placebo group. Endothelial function improved robustly reducing both systolic and diastolic BP in hypertensive individuals with daily supplementation of dietary NO3-. CLINICALTRIALS. NCT03909789.