Publications by Year: 2025

This study aimed to determine if sodium-glucose co-transporter-2 inhibitors (SGLT2i) use in diabetic patients leads to erythrocytosis and increases the incidence of arterial and venous thrombosis events. This is a retrospective cohort study using records from over 50 U.S. healthcare organizations. Adults with type 2 diabetes who received SGLT2i therapy were compared to those on glucagon-like peptide-1 receptor agonists (GLP1RA) or dipeptidyl peptidase-4 inhibitors (DPP4i). The primary outcome was the risk of erythrocytosis, defined by elevated hemoglobin and hematocrit levels. Secondary outcomes included arterial and venous thromboembolic events. Propensity score matching was applied to balance baseline characteristics, and Cox proportional hazards regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Results demonstrated that compared to SGLT2i use, DPP4i use was associated with a significantly higher risk of erythrocytosis in both male (hemoglobin > 16.5 g/dL: HR 1.954 [1.909-2.001]) and female (hemoglobin > 16 g/dL: HR 1.873 [1.803-1.947]) patients with type 2 diabetes. Similarly, GLP1RA use was associated with a significantly higher risk of erythrocytosis in both male (HR 1.605 [1.573, 1.636] and female (HR 1.697 [1.640, 1.755]) patients compared to SGLT2i use. Compared with DPP4i users, SGLT2i users had less cardiovascular events, except for increased stroke/TIA in females (HR 1.744 [1.654-1.839]). Compared with GLP1RA, SGLT2i use was associated with a decrease risk of MACE in both men and women, but higher risk for other cardiovascular and peripheral vascular events. Among SGLT2i users, those who developed erythrocytosis had increased incidence of thromboembolic events compared to those without erythrocytosis. Lastly, among SGLT2i patients treated for their erythrocytosis, the men who discontinued SGLT2i had increased risks of stroke/TIA, MI, and limb ischemia, while women had increased risk of stroke/TIA, MI, and venous thrombosis. Those who received anti-platelet therapy were associated with elevated risks of stroke/TIA, MI, venous thrombosis, and limb ischemia. In contrast, patients who receive phlebotomy had no significant difference in the outcomes. Therefore, regular monitoring of hematologic parameters is recommended for early detection and modified therapeutic strategies should be considered to reduce complication risks. Further studies are needed to establish effective strategies to reduce complications in this population.

BACKGROUND: Early identification of cognitive impairment and brain pathology associated with Alzheimer's disease (AD) is essential to maximize benefits from lifestyle interventions and emerging pharmacologic disease-modifying treatments (DMT). Digital cognitive assessments (DCAs) can quickly capture an array of metrics that can be used to train machine-learning (ML) models to concurrently evaluate different outcomes. DCAs have the potential to optimize clinical workflows and enable efficient assessment of cognitive function and the likelihood of a given underlying pathology.

METHODS: We assessed the ability of a multimodal ML-enabled DCA, the Digital Clock and Recall (DCR), to concurrently estimate brain amyloid-beta (Aβ) status and detect cognitive impairment, as compared with traditional cognitive assessments, including the MMSE, RAVLT, a DCA, Cognivue®, and blood-based biomarkers in 930 participants from the Bio-Hermes-001 clinical study.

RESULTS: Aβ42/40, p-tau181, APS, and p-tau217 poorly classified cognitive impairment (AUCs: 0.61; 0.63; 0.63; 0.70, respectively), but accurately classified Aβ status (AUCs: 0.81; 0.78; 0.85, 0.89, respectively). MMSE, RAVLT, and Cognivue poorly classified Aβ status (AUCs: 0.70, 0.73, 0.70, respectively). However, separate multimodal, DCR-based ML classification models, run in parallel, accurately classified both cognitive impairment (AUC = 0.83) and Aβ-PET status (AUC = 0.81).

CONCLUSIONS: DCAs that leverage digital technologies to generate advanced metrics, such as the DCR, enable accurate and efficient detection of cognitive impairment associated with AD pathology. They have the potential to empower health systems and primary care providers to help their patients make timely treatment decisions.

Freshly ejaculated mammalian sperm have poor fertilizing ability, with fertility only gained after sperm undergo capacitation and the acrosome reaction. To visualize exposed Fc receptors (FcRs), which occur during the acrosome reaction and whose absence has been related to infertility, a novel sperm FcR binding assay (FcR assay) was developed to assess fertilizing potential of sperm in proof-of-concept studies. A competition binding assay between sperm FcR and exogenously added FcR was used to assess whether the FcR was a functioning ligand in bull sperm. Once FcR was confirmed as a functional ligand, time-based expression of FcR was then evaluated in bull and human sperm using the FcR assay. This FcR assay was then used to evaluate fertility outcomes in cattle with cryopreserved intrauterine insemination (IUI) sperm, and to evaluate sperm FcR expression in patients undergoing IUI treatment in a prospective observational study. Time-based analyses of ejaculates from bull and human sperm demonstrated characteristic, reproducible sinusoidal patterns of FcR expression that corresponded to high and low periods of fertility potential in each species. The pregnancy rate in cattle approached statistical significance using the FcR assay results to inform optimum insemination timing windows versus conventional untimed methods (73.0% vs. 68.4%, respectively; p = 0.06; 95% confidence interval [CI]: 0.98, 1.57) with a 4.4% increase in the overall pregnancy rate. In patients undergoing IUI treatment, FcR expression patterns were identified where sperm were at their optimal fertilizing state, with overall pregnancy rates increasing from 21% to 42% (p = 0.01) when inseminations occurred during the windows where the fertilizing potential of the sperm was deemed optimal. These results suggest that sperm fertility potential is quantifiable in semen samples using our novel sperm FcR assay. Importantly, the FcR assay has the ability to identify optimal fertility windows in real-time, and also in the procedure ejaculates.

BACKGROUND: Online adaptive radiation therapy (ART) is a relatively new process, and it is recommended that institutions starting an online ART program conduct a risk analysis to identify potential hazards. While Failure Modes and Effects Analysis (FMEA) is common, Systems-Theoretic Process Analysis (STPA) has also been used to evaluate online ART workflows.

PURPOSE: An STPA hazard analysis was performed for a CT-guided online ART system in a multi-vendor environment. The goal was to identify potential risks and mitigations to guide the development of adaptive workflows and the quality management (QM) program.

METHODS: The STPA hazard analysis was performed in four steps. First, process maps for online ART were generated to describe the interactions between users and systems. In the second step, the process maps were refined to a single control structure diagram model. In the third step, potential unsafe control actions (UCAs) were enumerated by the physicists involved in the analysis. Finally, mitigation strategies to address the UCAs were identified.

RESULTS: A total of 496 UCAs were identified for 119 control actions, of which 239 (48.2%) were prioritized for mitigation due to having low or medium levels of detectability. The most frequent causal scenarios were accidental omission (20.1%), rushing (17.2%), and lack of training (15.9%). The most common consequences were delays (26.8%) and having to repeat work (13.5%). The two mitigation strategies considered to address the most causal scenarios were requiring trained adaptive staff (28.9%) and having physics oversight (19.9%).

CONCLUSIONS: The STPA led to valuable insights into the potential causes of unsafe control actions and various mitigation strategies that were used to develop the QM program. Notably, most UCAs were attributable to interactions between users and the system, rather than system failures. It is recommended that every institution starting an online ART program perform a risk assessment for their environment.

INTRODUCTION: Same-day initiation (SDI) of antiretroviral therapy is recommended for people presenting with HIV who have no contraindications. We reviewed the evidence on SDI interventions in low- and middle-income countries (LMICs).

METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials of SDI in adults diagnosed with HIV in LMICs. We searched MEDLINE, Embase and the Cochrane Library up to December 2024. Primary outcomes were viral suppression and retention in care 6-12 months after enrolment. Based on a qualitative assessment of the complex trial interventions, we considered two subgroups: (1) interventions newly introducing SDI and (2) interventions improving SDI implementation in settings where it was already routinely available. We conducted random-effects meta-analysis, assessed risk of bias using the ROBUST instrument and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of evidence.

RESULTS: We identified 12 eligible trials, 7 introducing and 5 improving SDI. The trial interventions introducing SDI were sufficiently similar for meta-analysis. Introducing SDI likely has an important benefit for viral suppression (relative risk (RR) 1.18, 95% CI 1.06 to 1.30, moderate certainty) and retention in care (RR 1.12, 95% CI 1.00 to 1.25, low certainty) at 6-12 months The five trials improving SDI were too heterogeneous for meaningful meta-analysis. Individually, they showed either low to very low certainty for an important effect or, when implementing SDI in patients with tuberculosis (TB) symptoms, moderate to high certainty for little to no effect on viral suppression and retention in care.

CONCLUSION: Newly introducing SDI likely improves viral suppression and retention in care. However, the impact of interventions to improve SDI where already available is less clear. Two studies provided evidence against the concern that SDI may have adverse effects in participants with TB symptoms.

PROSPERO REGISTRATION NUMBER: CRD42023482522.

Background: The imperative to integrate primary palliative care (PPC) into primary health care provides a compelling rationale for U.S.-based educational initiatives to prepare frontline health providers to deliver PPC across settings. Physicians, advanced practice registered nurses (APRNs), and physician assistants (PAs) are positioned as autonomous decision-makers. Therefore, their education should include PPC fundamentals critical to high-quality serious illness care. Objective: To conduct an integrative review of best teaching practices in PPC education for medical, APRN, and PA students preparing for frontline provider roles in the United States. Methods: A systematic search of peer-reviewed literature published between 2011 and 2025 was conducted. Studies describing PPC educational interventions or curricula for medical, APRN, or PA students were included. Data extraction and thematic synthesis were guided by the National Consensus Project Clinical Practice Guidelines for Quality Palliative Care and Kirkpatrick's model of assessing educational outcomes. Results: A total of 1691 articles were identified. After screening 1256 titles and abstracts and reviewing 292 full-text articles, 64 studies met inclusion criteria. Most studies focused on medical students (94%), with fewer addressing APRN (13%), PA (2%), or interprofessional cohorts (16%). A majority were descriptive or nonempirical (88%) and focused on structural and process-oriented components of PPC education (89%). Eighty-four percent employed multifaceted teaching approaches. Five consensus themes emerged as best practices: (1) multifaceted teaching strategies, (2) interprofessional education, (3) reflective and/or humanities-based experiences, (4) early and repeated exposure, and (5) availability of teaching resources. Conclusion: While the literature supports improvements in learners' knowledge, skills, and attitudes, few studies evaluate higher-level outcomes such as long-term skill retention or impact on patient and system-level care. This review provides lessons learned and evidence-informed recommendations to guide curricular development and identifies key gaps to inform future educational research to better prepare frontline health professions students in delivering high-quality PPC.

Organ shortage remains a major barrier in treating end-stage organ failure, with many patients dying while waiting or becoming medically unfit by the time an organ is offered. A substantial number of organs, particularly from older donors, remain unused due to concerns over age-related decline in quality. This review highlights emerging strategies to rejuvenate and optimize such organs by mitigating ischemia-reperfusion injury and reducing age-related immunogenicity. Advances in organ preservation, perfusion technologies, and novel therapies - including senotherapeutics, anti-inflammatory agents, and stem cell treatments - show promise in improving graft viability and bridging the gap between organ supply and demand.

BACKGROUND: Non-communicable diseases (NCDs) are the leading cause of death and morbidity worldwide, responsible for 7 out of 10 deaths, 86% occurring in low- and middle-income countries (LMICs). As the NCD burden on health systems increases, community health workers (CHWs) have become increasingly involved in NCD care provision and management. This study updates a 2015 review to synthesise and critically analyse the recent evidence base on the cost-effectiveness and affordability of CHW programmes addressing NCDs in LMICs.

METHODS: A scoping review searched 10 databases and the grey literature for original studies published between August 2015 and July 2024. Recognised search terms related to 'Community Health Workers' and 'Economic Evaluation(s)' in LMICs were used. Covidence software was employed to screen studies based on inclusion and exclusion criteria. Data on study methodology, costs and cost-related outcomes were then extracted, tabulated in a data-extraction form and analysed using Microsoft Excel.

RESULTS: We identified 20 studies with 52 different scenarios covering five areas: cardiovascular disease including hypertension (n=22 scenarios); human papillomavirus and cervical cancer screening (n=13); diabetes (n=12); mental health (n=4); and behavioural risk factors (n=1). Of the 44 scenarios assessing cost-effectiveness, 35 scenarios suggest that CHW programmes are cost-effective. 11 studies compared CHW programmes against an alternative (usual care) to generate an incremental cost-effectiveness ratio, evaluated against the country's gross domestic product per capita. Methodological heterogeneity across studies and inconsistencies or data gaps in reporting (most importantly the lack of CHW salary information) limits the usefulness of the data. Few studies assessed affordability, despite being equally relevant to decision-making.

CONCLUSIONS: More studies including economic evaluations (particularly for NCDs not found in our review), along with more robust and consistent reporting are needed.