Publications by Year: 2025

Background: National guidelines recommend palliative care (PC) alongside life-sustaining treatment for older adults with severe trauma. However, outcomes associated with PC for these patients are not well-defined. Objectives: To determine frequency of inpatient PC process documentation in older adults with severe trauma and test associations with postdischarge health care utilization. Design: Retrospective cohort study using electronic health record data linked to Medicare claims. Setting/Subjects: We included adults ≥66 years old admitted to a large, regional U.S. health care system with severe trauma (2016-2018) using consensus criteria for serious illness in trauma. Measurements: Natural language processing was used to measure documentation of five inpatient PC processes: code status limitations, goals-of-care (GOC) conversations, hospice discussions, PC consultations, and health care proxy designations. Associations between PC processes and postdischarge health care utilization were tested using multivariable regression. Results: Among 1267 admissions, the median age was 82 years (interquartile range [IQR] 75-88), and median injury severity score (0-75, higher is worse) was 16 (IQR 9-21); ≥1 PC process was documented in 81%. Among those surviving hospitalization (87%), one-year mortality was 26%. Documentation of ≥1 PC process was not significantly associated with differences in mean hospital days (16 vs. 19), home days (306 vs. 307), emergency department visits (2.3 vs. 2.2), or intensive care unit days (0.6 vs. 0.9) at one year. PC processes were significantly associated with subsequent hospice enrollment (p < 0.01). Conclusions: PC was not associated with reduced health care utilization in older adults after trauma but was associated with one-year hospice enrollment. GOC conversations, specialty PC, and inpatient hospice discussions had low utilization, highlighting target areas for improvements in care delivery.

Ideally, the sequential monitoring of adverse events following post-licensed drugs and vaccines is correctly adjusted for confounding variables, such as gender and age, that may have an effect on the quality of the events. This is the idea behind the usual fully randomized, the placebo-control, and the self-control designs. Two prominent methods for conducting sequential analysis of the safety of post-market drugs and vaccines are the maximized sequential probability ratio test (MaxSPRT), and its conditional version, the CMaxSPRT. However, even when the assumption of sample homogeneity is realistic prior to the drug/vaccine administration, the effects caused by the drugs and vaccines on the risk of an adverse event, if any, can still vary according to observable covariates. For binomial and Poisson data, a straightforward sequential test method is introduced in order to accommodate a regression structure in the MaxSPRT. The proposed sequential regression test is also applicable for the CMaxSPRT, that is, the regression works for comparing historical and surveillance Poisson data with unknown heterogeneous baseline rates, taking into account seasonality and any other observable confounding covariates. To illustrate the usefulness of such a regression method, we describe the potential applications of the method to monitor vaccine-adverse events in Manitoba, Canada. The numeric results and examples were executed with the R Sequential package.

Angiotensin‑(1‑7) [Ang‑(1‑7)] exerts physiological effects in the brain mediated by its receptor, Mas. Recent studies have successfully demonstrated that Ang‑(1‑7) exerts neuroprotective effects following cerebral ischemia in a rat model. However, prior investigations utilized direct intracerebral cannulation for Ang‑(1‑7) delivery, potentially limiting human application. Hematopoietic stem cells (HSC) have been previously demonstrated to mobilize to the site of cerebral injury in response to stroke. Therefore, we sought to examine the therapeutic potential of HSC transduced via a lentivirus with Ang‑(1‑7) to migrate to the ischemic hemisphere and overexpress Ang‑(1‑7) following stroke. Animals were divided into 3 groups: Stroke + PBS, Stroke + HSC, Stroke + Ang‑(1‑7)‑transduced HSC. Bone marrow from separate animals was harvested and used for injection of the HSC, with or without lentivirus induced Ang‑(1‑7) transduction. A neurological assessment was performed at 72 hours post‑surgery. Ang‑(1‑7) transduced HSC secreted the peptide up to 72 hours post infection, in vitro. Stroked animals injected with the Ang‑(1‑7) infected HSC exhibited reduced behavioral deficits on the Bederson neurological assessment scale. These data suggest that HSC‑mediated delivery of Ang‑(1‑7) to ischemic brain appears to improve post‑stroke outcomes and may offer a novel route of therapeutic agent delivery to the brain.

The medical device regulation (MDR) was adopted in 2017 to replace the medical device directive (MDD). Key changes included more rigorous clinical evidence requirements, increased scrutiny of notified bodies, and improved traceability of medical devices, with the overarching aim to improve their safety and quality. For chronic haemodialysis, the impact of the MDR on devices has been substantial, resulting in niche devices being no longer available, and critical shortages, especially in paediatric nephrology. The Eudial board discussed these developments and concluded that the MDR has had a clear negative impact on innovation. In conjunction with other emerging economic macro-trends, this development heightens the potential for disruptions within critical supply chains. We offer actionable recommendations to optimise the benefits of the MDR and to minimise unintended consequences.

BACKGROUND: Deficiencies in non-technical skills (NTS) such as leadership and communication can lead to intraoperative inefficiency and error. However, the relationship between these skills and patient-level outcomes has yet to be synthesized. The aim of this study was to systematically review the evidence examining the relationship between intraoperative NTS and clinical outcomes.

METHODS: The PubMed, Embase, CENTRAL, CINAHL, and PsycINFO databases were searched for relevant studies published between inception and 1 November 2024. Eligible studies assessed NTS of operating room personnel, were conducted in non-simulated environments, and reported clinical outcomes. NTS were categorized into five core domains including leadership and communication. Patient-level outcomes comprised eight clinical measures including mortality and postoperative complications.

RESULTS: Of 6313 screened studies, 21 met the inclusion criteria. Included studies represented 8536 participants performing 251 180 procedures across 13 specialties. Eleven observational studies assessed NTS of surgical personnel via study participants or observers. Ten interventional studies introduced NTS team training initiatives. Twelve of 21 studies (57%) incorporating 247 036 of all procedures (98.4%) reported significant improvements in clinical outcomes. Nine of 11 observational studies (82%) reported significant improvement in clinical outcomes compared with 3 of 10 interventional studies (30%). No studies demonstrated a significant deterioration in clinical outcomes associated with improved NTS.

CONCLUSION: Published evidence shows a significant link between intraoperative NTS and patient-level outcomes. These findings reinforce the value of behavioural assessment in surgery, support evidence-based team training, and underscore the need to embed NTS into regulatory frameworks to improve surgical quality and safety worldwide.

BACKGROUND: Fibroblast activation protein (FAP) is a pan-cancer target. Its selective expression on the majority of solid tumors with minimal to absent expression in healthy tissues positions FAP as a promising target for radiotheranostic applications. Nanobodies (Nbs) have unique characteristics, including small size, high affinity, stability, and ease of modification, making them ideal candidates for cancer diagnostics and targeted radiotherapeutics. Llama-derived Nbs were generated and screened against full-length FAP, with three unique candidates selected from the library for further characterization. The lead candidate Nb159 was engineered for site-specific radiolabeling with 89Zr for PET imaging and with 177Lu coupled with PEG for therapeutic evaluation in mice bearing FAP-positive U87 tumor xenografts.

RESULTS: Nb159 exhibited exceptional picomolar binding affinity to FAP with stable interaction and slow dissociation. PET imaging with [89Zr]Zr-Nb159 demonstrated specific tumor uptake, peaking at 1 h post-injection, with rapid renal clearance and minimal uptake in non-target organs. A competitive binding study confirmed its specificity to FAP on U87 tumors, as pre-injection with a tenfold molar excess of unlabeled Nb159 reduced tumor uptake by   55% (3.78 ± 0.50 to 1.67 ± 0.26%ID/g). PEGylation of Nb159 improved its pharmacokinetic profile, yielding prolonged tumor accumulation and significantly reduced renal retention when co-injected with lysine. PET imaging further demonstrated target-specific uptake in FAP-positive U87 xenografts, which exhibited higher signal than FAP-negative HCT116 tumors, with SUVmean at 48 h of 0.45 ± 0.04 versus 0.09 ± 0.01 (P < 0.0001). In the therapeutic study, [177Lu]Lu-PEG-Nb159 demonstrated significant tumor growth inhibition with no observable toxicity. Mice treated with a single dose of [177Lu]Lu-PEG-Nb159 survived significantly longer compared to either [177Lu]Lu-DOTA (23 days, P < 0.001, HR: 0.06107) or vehicle (21 days, P < 0.0001, HR: 0.04017).

CONCLUSIONS: The lead candidate Nb159 holds promise as a versatile platform for FAP-targeted radiotheranostics, with [89Zr]Zr-Nb159 serving as an effective companion diagnostic and [177Lu]Lu-PEG-Nb159 demonstrating promising therapeutic potential. These findings support further development of Nb159-based radiopharmaceuticals for treatment of FAP positive tumors.

We explore strategies to harness ancestral diversity in PsychENCODE Consortium Genotype-Expression (GEx) reference panels (adult and developing brain) and Psychiatric Genomics Consortium GWAS data to improve genetically regulated expression (GReX) models and their use for Transcriptome-wide association study (TWAS) discoveries, uncovering previously unknown aspects of psychiatric functional genomics. We trained multiple GReX models on rigorously constructed GEx panel subsets, generated by downsampling, segregating, and/or mixing samples of Admixed African and European ancestries, and based on disease status. Ancestry-specific GReX genes were enriched in pathways involving mitochondrial functions, organelle structure, and metabolism. These models were integrated with ancestry-specific GWASs to conduct bipolar disorder, major depressive disorder, posttraumatic stress disorder, and schizophrenia TWAS. TWAS signals obtained by applying AA- and EUR-specific GReX models to an ancestry-specific GWAS were largely concordant, and mismatched-TWAS (e.g. AA-GReX applied to EUR-GWAS) revealed biologically meaningful signals missed by matched-TWAS. Shared signals across the four disorders were more prominent in the developing brain, involving genes such as H4C13, ZSCAN12P1, and FLOT1, and pathways related to megakaryocyte and muscle development, and neurotransmitter regulation. Overall, we demonstrate concordance in shared TWAS signals across GReX models and provide insight into GReX-specific detectable genes and pathways.

BACKGROUND: The WHO Safe Childbirth Checklist (SCC) has been implemented in diverse settings to improve the quality and safety of intrapartum care, but implementation strategies and their relationship with adoption and fidelity remain heterogeneous and incompletely described.

OBJECTIVES: To describe the landscape of SCC implementation, map the implementation strategies used and explore how these strategies were reported in relation to adoption and fidelity.

ELIGIBILITY CRITERIA: We included primary studies reporting SCC implementation in healthcare settings that described at least one implementation strategy, with no restrictions on country or language. Studies that did not report implementation strategies or did not involve SCC use in real-world care settings were excluded.

SOURCES OF EVIDENCE: We searched PubMed, Embase, CINAHL, Global Health and Global Index Medicus (June 2024), screened reference lists and consulted grey literature for the period 2009-2024.

CHARTING METHODS: This scoping review followed JBI methodology (Peters et al) and was reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. We extracted study characteristics and implementation findings, coded strategies using the Expert Recommendations for Implementing Change (ERIC) taxonomy and grouped them by clusters. Adoption (initial uptake) and fidelity (adherence to core components) were categorised following Proctor's implementation outcomes. We created a descriptive implementation intensity score and conducted exploratory analyses (tertiles, boxplot).

RESULTS: 34 studies described 19 SCC implementation projects across 16 countries. We identified 24 distinct ERIC strategies, with most projects using 5-11 strategies. Frequently reported strategies included educational meetings, audit and feedback, supervision, contextual adaptation and leadership or champions. Exploratory analyses did not show consistent associations between implementation intensity and adoption or fidelity. 'Change infrastructure' strategies (such as record system or equipment changes) were variably defined and warrant cautious interpretation. Adaptations (eg, translation and alignment with national guidelines) were common and aimed at improving local fit, but heterogeneous reporting limited cross-study comparability.

CONCLUSIONS: SCC implementation has relied on diverse, multicomponent strategies, yet reporting-especially of strategy content and adaptations-remains insufficient, constraining comparison and synthesis across settings. As a pragmatic bundle, implementers may prioritise brief team training, unit-level champions and leadership signals, point-of-care audit and feedback, light-touch SCC adaptation that preserves core content and structured supervision or peer coaching, combined with systematic inclusion of women and families through codesign and companion-mediated prompting. Using theory-informed frameworks (such as Exploration, Preparation, Implementation, and Sustainment and Consolidated Framework for Implementation Research [CFIR]) and standardised reporting tools (eg, Proctor's outcomes; Template for Intervention Description and Replication / Standards for Reporting Implementation Studies [TIDieR/StaRI]) can make SCC implementation strategies more transparent, comparable and scalable.

REGISTRATION: Open Science Framework: https://doi.org/10.17605/OSF.IO/RWY27.

BACKGROUND: Sexual minority men (SMM) living with HIV in Nigeria experience suboptimal outcomes on the HIV care continuum. Experiences of intersectional stigma has been linked to lower likelihood of engagement in HIV services, but little is known about the effects of intersectional stigma on HIV care outcomes for SMM in Nigeria. The current study explored experiences of intersectional stigma among SMM living with HIV in Lagos, Nigeria and its' impact on engagement in HIV care.

METHODS: Between January and February 2022, we conducted semi-structured individual interviews with 30 SMM living with HIV in Lagos, Nigeria and 38 healthcare providers that provide HIV prevention and care services to SMM.

RESULTS: We found that while participants described experiencing both HIV and sexual minority stigma, they believed sexual minority identity stigma to be more common than HIV-related stigma. Additionally, most participants believed they experience intersectional stigma, especially enacted and anticipated stigma, from their HIV status and sexual minority identity. Respondents utilized various strategies, both negative and positive, to cope with stigma including substance use, identity concealment, social isolation, support systems, and engaging in various hobbies as a form of self-care. Lastly, while most healthcare providers believe that stigma negatively influenced SMM ability to fully engage in HIV care, most SMM believed stigmatization had minimal to no effect on their engagement in HIV care.

DISCUSSION: Our findings underscore the importance of developing community (SMM specifically) informed, evidence-based health interventions aimed at reducing the effect of stigma on engagement in HIV care among Nigerian SMM living with HIV, to improve their overall health and quality of life.