Citations

Abstract Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimer’s and Huntington’s diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1α, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.

Abstract Background Emerging evidence suggests irreversible electroporation (IRE) with standard-of-care (SOC) chemotherapy may improve survival in patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) when compared to SOC alone. This study evaluates the overall survival (OS) and progression-free survival (PFS) of Stage 3 PDAC patients treated with SOC plus IRE with the NanoKnife System versus SOC alone. Methods This prospective, multicenter study included two cohorts from the DIRECT registry: an IRE cohort from sites offering IRE as part of clinical care, and a comparator SOC cohort of prospectively enrolled and contemporaneous retrospective patients. Enrollment spanned 08/05/2019 to 02/05/2023, with follow-up through at least 24 months, death, or loss to follow-up. Included were 137 patients (99 IRE; 38 SOC), aged ≥18 years with Stage 3 PDAC and no progression after three months of SOC therapy. Results Median (interquartile range) time from diagnosis to enrollment was 8 (6-10) months for IRE and 4 (3-6) for SOC (p<0.0001). Median OS and PSF from enrollment were 18 (95% confidence interval [CI]: 15-24) months and 9 (95% CI: 7-12) months for IRE, and 10 (95% CI: 8-14) months and 6 (5-8) months for SOC, respectively (p<0.0001 and p=0.009). Adverse events occurred in 80% (79/99) of IRE patients and 95% (36/38) of SOC patients; 29% (29/99) of the IRE cohort experiencing an IRE-related adverse event. Conclusions IRE was associated with improved OS versus SOC alone and may be an effective consolidative treatment for Stage 3 PDAC after three months of induction chemotherapy.

Personas and patient journey maps are poised to improve human-centered care delivery, and technology design. However, they remain largely underutilized in healthcare settings globally. A persona composite and a journey map inspired by narratives of medical students managing illness in addition to the rigors of academia is presented. This scoping review illustrates how journey mapping and personas are used in healthcare contexts to frame the experiences of patients; formal and informal caregivers; nurses; and physicians. The heterogeneous findings reveal that despite their promise the utility of these tools is largely unexplored in health informatics.

The European Health Data Space (EHDS) aims to enable both the primary use of health data for direct patient care (EHDS1) and the secondary use of data for research, innovation, and public health (EHDS2). While each pillar is supported by distinct infrastructures—MyHealth@EU for clinical continuity and HealthData@EU for trusted reuse—the lack of seamless integration between them poses significant technical, governance, and legal challenges. Existing standards such as HL7 CDA, HL7 FHIR, OHDSI OMOP, CDISC, EEHRxF, and HealthDCAT-AP, together with IHE integration profiles including XDS, XCA, XCPD, ATNA, and BPPC, provide a robust foundation but remain fragmented across domains. This paper introduces the EHDS Data Continuum, a proposed IHE integration profile designed to bridge EHDS1 and EHDS2 by harmonizing interoperability, data quality, privacy, and governance requirements across the full data lifecycle. By aligning primary and secondary use within a coherent technical and policy framework, the EHDS Data Continuum supports the realization of a trustworthy, interoperable, and citizen-centered European Health Data Space.

PURPOSE Taxanes are associated with a higher incidence of immediate hypersensitivity reactions (HSRs) compared with other classes of chemotherapeutic agents, even with premedication. This study evaluates whether a titrated infusion protocol reduces the rate of first-dose HSRs to taxanes. METHODOLOGY This was a retrospective cohort study conducted at a single-site hematology/oncology infusion center. The fixed-rate arm consisted of patients treated from January 2022 to July 2023 who received a fixed infusion rate for their first dose. The titration arm comprised patients treated from August 2023 to July 2024 who underwent a three-step titration protocol for their first dose. The primary end point was the rate of immediate HSRs during the first lifetime dose of docetaxel or paclitaxel. Secondary end points included HSR severity, HSRs during the first or second dose, and rate of treatment discontinuation because of HSRs. RESULTS Of 479 patients included (240 fixed-rate; 239 titration), HSRs occurred in 7.1% of the fixed-rate group and 11.3% of the titration group (odds ratio, 1.67 [95% CI, 0.89 to 3.15]; P = .1104). There were no differences in the severity of HSRs or in the rate of treatment discontinuation among both groups. CONCLUSION The use of a titrated infusion protocol for first lifetime dose taxanes did not significantly reduce the incidence or severity of immediate HSRs. These findings suggest that a titration protocol may not confer additional benefits over fixed-rate in this setting.

Background: The purpose of this study was to describe, and report the outcomes of, a surgical technique that combines reverse shoulder arthroplasty (RSA) using an allograft-prosthetic composite (APC) with a lower trapezius transfer (LTT) to the infraspinatus of the allograft extended with the inferior capsule. Methods: Between 2019 and 2023, 2 surgeons performed a total of 27 RSAs using an APC in conjunction with an LTT. Once the RSA APC reconstruction had been performed, cuff-capsule allograft tissue was passed posterior to the glenosphere and secured to the harvested lower trapezius. One shoulder was resected for periprosthetic joint infection; the remaining 26 shoulders were followed for a minimum of 2 years (mean, 2.7 years; range, 2 to 5 years). Results: The rate of revision or reoperation for humeral complications was 15% and included secondary bone grafting (2 shoulders), resection for infection (1 shoulder), and internal fixation of a periprosthetic fracture (1 shoulder). Other complications requiring surgery included hematoma treated with evacuation (2 shoulders), dislocation (1 shoulder), and glenosphere disassociation (1 shoulder). Preoperatively, 11 shoulders presented with pseudoparalysis, and the mean active elevation of the remaining 16 shoulders was 43°, with only 1 shoulder demonstrating >90° of active elevation. At the most recent follow-up, 3 shoulders were pseudoparalytic, 11 had <90° of active elevation, 8 had >90° of active elevation, and 3 had active elevation to 90°. The overall mean active elevation of the 25 shoulders that could be assessed was 79°. Preoperatively, only 4 (15%) of the 27 shoulders demonstrated active external rotation past neutral; at the most recent follow-up, 80% of surviving shoulders had active external rotation past neutral. Conclusions: LTT at the time of RSA using an APC has the potential to restore active external rotation in shoulders with proximal humeral bone loss and posterosuperior cuff deficiency. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

ABSTRACT The Burkholderia cepacia complex (BCC) is comprised of 24 species of Gram-negative bacteria that cause opportunistic infections. While antimicrobial susceptibility testing (AST) has historically been used to guide treatment for BCC infections, recent work highlighting problems with AST for these organisms led the Clinical and Laboratory Sciences Institute (CLSI) to remove disk diffusion (DD) and minimal inhibitory concentration (MIC) breakpoints for BCC from its M100 standards document. Epidemiological cut-off values (ECVs) may be helpful to clinicians in the absence of breakpoints, as they may be used to determine whether an isolate has a wild-type or non-wild-type phenotype. Here we present an analysis of BCC ECVs for ceftazidime (CAZ), levofloxacin (LVX), meropenem (MEM), minocycline (MIN), and trimethoprim-sulfamethoxazole (TMP-SMX). ECVs were calculated using MIC data from 3 previous studies and 3 independent laboratories for 1,896 BCC isolates. ECVs were 16 μg/ml for CAZ, 8 μg/ml for LVX, 16 μg/ml for MEM, and 8 μg/ml for MIN. The ECV for TMP-SMX varied depending on the analysis from 2 μg/ml, 8 μg/ml, and 16 μg/ml and therefore could not be reliably established. Challenges with establishing ECVs for BCC include limitations with the pooled MIC dataset, broad MIC distributions, and high ECVs that are above the obsolete susceptible MIC breakpoints. These challenges limit the clinical utility of ECVs for these organisms and supported removal of ECVs from the CLSI M100 standards document. IMPORTANCE The Burkholderia cepacia complex is a group of bacterial species that cause difficult-to-treat opportunistic infections. Recently, clinical breakpoints, which are used to determine whether organisms are susceptible to certain antimicrobials, were removed from Clinical and Laboratory Standards Institute (CLSI) standards for these organisms due to problems with antimicrobial susceptibility testing performance. Clinicians are now faced with the challenge of how to treat these complex infections without clinical breakpoints. Here we determine epidemiological cut-off values (ECVs) for relevant antimicrobials for the B. cepacia complex. While we established ECVs for four antimicrobials, we encountered significant challenges in our analyses, including limitations with data for these organisms and high ECVs that are not clinically useful. These challenges limit the practical use of these ECVs in helping guide clinicians on treatment and supported the eventual removal of ECVs from the CLSI M100 standards document.

Hodgkin lymphoma is one of the most common cancers in adolescents and young adults (AYAs), a population with distinct biological, clinical, and developmental characteristics. Yet care remains fragmented between pediatric and adult systems contributing to variability in treatment exposure and survivorship outcomes. We synthesized current evidence on AYA HL epidemiology, biology, treatment strategies, supportive care needs, long-term toxicity risk, and survivorship. AYAs have access to multiple efficacious treatment options with high cure rates, but long-term survivors face significant medical, psychosocial, and financial effects with notable risks for cardiopulmonary disease, secondary malignancies, fertility impairment, and unmet psychosocial needs. Harmonized pediatric-adult treatment frameworks, AYA-focused support, and developmentally tailored survivorship care are essential to improving outcomes for AYA HL survivors.