Cross-sectional and longitudinal analysis of health-related quality of life (HRQoL) in senior and geriatric dogs.

Advancements in veterinary medicine have resulted in increased life spans for dogs, necessitating a better understanding of quality of life for older dogs. This study aimed to evaluate quality of life (QoL) progression and its potential association with mortality in senior and geriatric dogs. The Canine Owner-Reported Quality of Life Questionnaire (CORQ), consisting of 17 questions across four domains (vitality, companionship, pain, and mobility) was employed. Higher scores indicated better quality of life, with 7 as the highest potential score for each question. In a cross-sectional analysis including 92 dogs, we found an inverse correlation between overall CORQ (and all domain scores) and fractional lifespan. The domain of vitality demonstrated the lowest scores, while companionship exhibited the highest. A longitudinal analysis, including 34 dogs, revealed that when dogs reach the geriatric stage (100% of their calculated lifespan), their expected overall CORQ is 5.95 out of 7, and dogs are expected to have a monthly decline of 0.05 units in the score. Cox proportional hazard analysis demonstrated a significant association between overall CORQ scores and mortality, with dogs scoring below 5.35 being at a higher risk of mortality. This study underscores the association between aging, declining quality of life, and increased mortality risk in aging dogs.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

Examining the feasibility of assisted index case testing for HIV case-finding: a qualitative analysis of barriers and facilitators to implementation in Malawi.

BACKGROUND: Assisted index case testing (ICT), in which health care workers take an active role in referring at-risk contacts of people living with HIV for HIV testing services, has been widely recognized as an evidence-based intervention with high potential to increase status awareness in people living with HIV. While the available evidence from eastern and southern Africa suggests that assisted ICT can be an effective, efficient, cost-effective, acceptable, and low-risk strategy to implement in the region, it reveals that feasibility barriers to implementation exist. This study aims to inform the design of implementation strategies to mitigate these feasibility barriers by examining "assisting" health care workers' experiences of how barriers manifest throughout the assisted ICT process, as well as their perceptions of potential opportunities to facilitate feasibility. METHODS: In-depth interviews were conducted with 26 lay health care workers delivering assisted ICT in Malawian health facilities. Interviews explored health care workers' experiences counseling index clients and tracing these clients' contacts, aiming to inform development of a blended learning implementation package. Transcripts were inductively analyzed using Dedoose coding software to identify and describe key factors influencing feasibility of assisted ICT. Analysis included multiple rounds of coding and iteration with the data collection team. RESULTS: Participants reported a variety of barriers to feasibility of assisted index case testing implementation, including sensitivities around discussing ICT with clients, privacy concerns, limited time for assisted index case testing amid high workloads, poor quality contact information, and logistical obstacles to tracing. Participants also reported several health care worker characteristics that facilitate feasibility (knowledge, interpersonal skills, non-stigmatizing attitudes and behaviors, and a sense of purpose), as well as identified process improvements with the potential to mitigate barriers. CONCLUSIONS: Maximizing assisted ICT's potential to increase status awareness in people living with HIV requires equipping health care workers with effective training and support to address and overcome the many feasibility barriers that they face in implementation. Findings demonstrate the need for, as well as inform the development of, implementation strategies to mitigate barriers and promote facilitators to feasibility of assisted ICT. TRIAL REGISTRATION: NCT05343390. Date of registration: April 25, 2022.

A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination.

Age-related decline in mobility and cognition are associated with cellular senescence and NAD + depletion in dogs and people. A combination of a novel NAD + precursor and senolytic, LY-D6/2, was examined in this randomized controlled trial. Seventy dogs with mild to moderate cognitive impairment were enrolled and allocated into placebo, low or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors. Fifty-nine dogs completed evaluations at the 3-month primary endpoint, and 51 reached the 6-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p = 0.02) with the largest decrease in the full dose group. No difference was detected between groups using in house cognitive testing. There were no significant differences between groups in changes in measured activity. The proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups, however this difference was not significant. Adverse events occurred equally across groups. All groups showed improvement in cognition, frailty, and activity suggesting placebo effect and benefits of trial participation. We conclude that LY-D6/2 improves owner-assessed cognitive function over a 3-month period and may have broader, but more subtle effects on frailty, activity and happiness as reported by owners.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Does a blended learning implementation package enhance HIV index case testing in Malawi? A protocol for a cluster randomised controlled trial.

INTRODUCTION: Index case testing (ICT) is an evidence-based approach that efficiently identifies persons in need of HIV treatment and prevention services. In Malawi, delivery of ICT has faced challenges due to limited technical capacity of healthcare workers (HCWs) and clinical coordination. Digitisation of training and quality improvement processes presents an opportunity to address these challenges. We developed an implementation package that combines digital and face-to-face modalities (blended learning) to strengthen HCWs ICT skills and enhance quality improvement mechanisms. This cluster randomised controlled trial will assess the impact of the blended learning implementation package compared with the standard of care (SOC) on implementation, effectiveness and cost-effectiveness outcomes. METHODS AND ANALYSIS: The study was conducted in 33 clusters in Machinga and Balaka districts, in Southern Malawi from November 2021 to November 2023. Clusters are randomised in a 2:1 ratio to the SOC versus blended learning implementation package. The SOC is composed of: brief face-to-face HCW ICT training and routine face-to-face facility mentorship for HCWs. The blended learning implementation package consists of blended teaching, role-modelling, practising, and providing feedback, and blended quality improvement processes. The primary implementation outcome is HCW fidelity to ICT over 1 year of follow-up. Primary service uptake outcomes include (a) index clients who participate in ICT, (b) contacts elicited, (c) HIV self-test kits provided for secondary distribution, (d) contacts tested and (e) contacts identified as HIV-positive. Service uptake analyses will use a negative binomial mixed-effects model to account for repeated measures within each cluster. Cost-effectiveness will be assessed through incremental cost-effectiveness ratios examining the incremental cost of each person tested. ETHICS AND DISSEMINATION: The Malawi National Health Science Research Committee, the University of North Carolina and the Baylor College of Medicine Institutional Review Boards approved the trial. Study findings will be disseminated through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05343390.

Phone-based psychosocial counseling for people living with HIV: Feasibility, acceptability and impact on uptake of psychosocial counseling services in Malawi.

People living with HIV experience psychosocial needs that often are not addressed. We designed an innovative low-resource model of phone-based psychosocial counseling (P-PSC). We describe cohort characteristics, acceptability, feasibility and utilization of P-PSC at health facilities supported by Baylor Foundation Malawi. Staff were virtually oriented at 120 sites concurrently. From facility-based phones, people with new HIV diagnosis, high viral load, treatment interruption or mental health concerns were referred without identifiable personal information to 13 psychosocial counselors via a WhatsApp group. Routine program data were retrospectively analyzed using univariate approaches and regressions with interrupted time series analyses. Clients utilizing P-PSC were 63% female, 25% youth (10-24 y) and 9% children (<10 y). They were referred from all 120 supported health facilities. Main referral reasons included new HIV diagnosis (32%), ART adherence support (32%) and treatment interruption (21%). Counseling was completed for 99% of referrals. Counseling sessions per month per psychosocial counselor increased from 77 before P-PSC to 216 in month 1 (95% CI = 82, 350, p = 0.003). Total encounters increased significantly to 31,642 in year 1 from ~6,000 during the 12 prior months, an over fivefold increase. P-PSC implementation at 120 remote facilities was acceptable and feasible with immediate, increased utilization despite few psychosocial counselors in Malawi.

Multinational patterns of second line antihyperglycaemic drug initiation across cardiovascular risk groups: federated pharmacoepidemiological evaluation in LEGEND-T2DM.

Objective: To assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin. Design: Federated pharmacoepidemiological evaluation in LEGEND-T2DM. Setting: 10 US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network in eight countries from 2011 to the end of 2021. Participants: 4.8 million patients (≥18 years) across US and non-US based databases with type 2 diabetes mellitus who had received metformin monotherapy and had initiated second line treatments. Exposure: The exposure used to evaluate each database was calendar year trends, with the years in the study that were specific to each cohort. Main outcomes measures: The outcome was the incidence of second line antihyperglycaemic drug use (ie, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulfonylureas) among individuals who were already receiving treatment with metformin. The relative drug class level uptake across cardiovascular risk groups was also evaluated. Results: 4.6 million patients were identified in US databases, 61 382 from Spain, 32 442 from Germany, 25 173 from the UK, 13 270 from France, 5580 from Scotland, 4614 from Hong Kong, and 2322 from Australia. During 2011-21, the combined proportional initiation of the cardioprotective antihyperglycaemic drugs (glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) increased across all data sources, with the combined initiation of these drugs as second line drugs in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased more significantly among populations with no cardiovascular disease compared with patients with established cardiovascular disease. No data source provided evidence of a greater increase in the uptake of these two drug classes in populations with cardiovascular disease compared with no cardiovascular disease. Conclusions: Despite the increase in overall uptake of cardioprotective antihyperglycaemic drugs as second line treatments for type 2 diabetes mellitus, their uptake was lower in patients with cardiovascular disease than in people with no cardiovascular disease over the past decade. A strategy is needed to ensure that medication use is concordant with guideline recommendations to improve outcomes of patients with type 2 diabetes mellitus.

Examining the feasibility of assisted index case testing for HIV case-finding: a qualitative analysis of barriers and facilitators to implementation in Malawi.

Background: Assisted index case testing, in which health care workers take an active role in referring at-risk contacts of people living with HIV for HIV testing services, has been widely recognized as an evidence-based intervention with high potential to increase PLHIV status awareness. Promising evidence for the approach has led to several attempts to scale assisted index case testing throughout eastern and southern Africa in recent years. However, despite effective implementation being at the heart of any assisted index case testing strategy, there is limited implementation science research from the perspective of the HCWs who are doing the "assisting". This study examines the feasibility of assisted index case testing from the perspective of health care workers implementing the approach in Malawi. Methods: In-depth interviews were conducted with 26 lay health care workers delivering assisted index case testing in Malawian health facilities. Interviews explored health care workers' experiences counselling index clients and tracing these clients' contacts, aiming to inform development of a blended learning implementation package. Transcripts were inductively analyzed using Dedoose coding software to identify and describe key factors influencing feasibility of assisted index case testing. Analysis included multiple rounds of coding and iteration with the data collection team. Results: Participants reported a variety of barriers to feasibility of assisted index case testing implementation, including privacy concerns, limited time for assisted index case testing amid high workloads, poor quality contact information, logistical obstacles to tracing, and challenges of discussing sexual behavior with clients. Participants also reported several health care worker characteristics that facilitate feasibility: robust understanding of assisted index case testing's rationale and knowledge of procedures, strong interpersonal skills, positive attitudes towards clients, and sense of purpose in their work. Conclusions: Findings demonstrate that maximizing assisted index case testing's potential to increase HIV status awareness requires adequately equipping health care workers with appropriate knowledge, skills, and support to address and overcome the many feasibility challenges that they face in implementation. Trial Registration Number: NCT05343390 Date of registration: April 25, 2022.

Reproducible variability: assessing investigator discordance across 9 research teams attempting to reproduce the same observational study.

OBJECTIVE: Observational studies can impact patient care but must be robust and reproducible. Nonreproducibility is primarily caused by unclear reporting of design choices and analytic procedures. This study aimed to: (1) assess how the study logic described in an observational study could be interpreted by independent researchers and (2) quantify the impact of interpretations' variability on patient characteristics. MATERIALS AND METHODS: Nine teams of highly qualified researchers reproduced a cohort from a study by Albogami et al. The teams were provided the clinical codes and access to the tools to create cohort definitions such that the only variable part was their logic choices. We executed teams' cohort definitions against the database and compared the number of subjects, patient overlap, and patient characteristics. RESULTS: On average, the teams' interpretations fully aligned with the master implementation in 4 out of 10 inclusion criteria with at least 4 deviations per team. Cohorts' size varied from one-third of the master cohort size to 10 times the cohort size (2159-63 619 subjects compared to 6196 subjects). Median agreement was 9.4% (interquartile range 15.3-16.2%). The teams' cohorts significantly differed from the master implementation by at least 2 baseline characteristics, and most of the teams differed by at least 5. CONCLUSIONS: Independent research teams attempting to reproduce the study based on its free-text description alone produce different implementations that vary in the population size and composition. Sharing analytical code supported by a common data model and open-source tools allows reproducing a study unambiguously thereby preserving initial design choices.