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Background: Medication review is integral in the pharmacological management of older inpatients., Objective: To assess the association of in-hospital medication changes with 28-day postdischarge clinical outcomes., Methods: Retrospective cohort of 2000 inpatients aged ≥75 years. Medication changes included the number of increases (medications started or dose-increased) and decreases (medications stopped or dose-decreased) for (i) all medications, (ii) Drug Burden Index (DBI)-contributing medications and (iii) Beers Criteria 2015 medications (potentially inappropriate medications, PIMs). Changes also included differences in (i) the number of medications, (ii) the number of PIMs and (iii) DBI score, at discharge versus admission. Associations with clinical outcomes (28-day ED visit, readmission and mortality) were ascertained using logistic regression, adjusted for age, gender and principal diagnosis. For mortality, sensitivity analysis excluded end-of-life patients due to higher death risk. Patients were stratified into : (i) ≤4, (ii) 5-9 and (iii) ≥10 discharge medications., Results: The mean age was 86 years (SD = 5.8), with 59.1% female. Medication changes reduced ED visits and readmission risk for patients prescribed five to nine discharge medications, with no associations in patients prescribed ≤4 and ≥ 10 medications. In the five to nine medications group, decreasing PIMs reduced risks of ED visit (adjusted odds ratio, aOR 0.55, 95% CI 0.34-0.91, P = .02) and readmission (aOR 0.62, 95% CI 0.38-0.99, P = .04). Decreasing DBI-contributing medications reduced readmission risk (aOR 0.71, 95% CI 0.51-0.99, P = .04). Differences in PIMs reduced ED visit risk (aOR 0.65, 95% CI 0.43-0.99, P = .04). There were no associations with mortality in sensitivity analyses in all groups., Discussion: Medication changes were associated with reduced ED visits and readmission for patients prescribed five to nine discharge medications., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Dietary metal ions significantly influence the lifespan and reproduction of Drosophila females. In this study, we show that not adding any of the metal ions to the diet adversely affects reproduction and lifespan. By contrast, food with no added Zn negatively impacts reproduction but does not adversely affect maternal lifespan, indicating it can dictate resource reallocation between key fitness traits. Specifically, it indicates that female flies stop producing eggs to conserve their body Zn for somatic maintenance. Although these data show that flies can sense varying dietary Zn levels to adjust their physiology, they cannot maximise egg production when faced with a choice between food with no added Zn or food with sufficient Zn to support maximum reproduction. Nonetheless, they can choose to preferentially oviposit on Zn-containing food, perhaps indicating a strategy to assure offspring survival. We also uncovered a role for the white gene in sustaining high levels of egg viability when Zn is diluted in the diet. These insights into the role of dietary metal ions, particularly Zn, point to a central role for these dietary micronutrients to indicate environmental quality and so govern trade-offs between lifespan and reproduction in flies., (© 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Pandemic-related restrictions in nursing homes have undermined the critical role that family and friend caregivers play in enhancing resident quality of life., Objective: We examined how family caregiver access restrictions in nursing homes were implemented and how they impacted the mutual well-being of and relationships between residents and their caregivers over time. Method s Between March 2021 and march 2022, 24 'designated caregivers' in Atlantic Canada were interviewed three times., Findings: We identified changes in family relationships and activities over time, constricted support networks, the increasing need for advocacy and monitoring, and the generally negative cumulative impacts of restrictions, especially during residents' end-of-life. Subsequent adaptations to access restrictions allowed caregivers to contribute to essential monitoring, care relationships, and advocacy roles., Discussion: We argue that the role of designated caregivers in nursing homes must be maintained during public health emergencies to ensure resident's supportive family relationships and general well-being.

Background: Despite the high incidence of blunt trauma in older adults, there is a lack of evidence-based guidance for computed tomography (CT) imaging in this population. We aimed to identify an algorithm to guide use of a pan-scan (head/cervical spine [C-spine]/torso) or a selective scan (head/C-spine ± torso). We hypothesized that a patient's initial history and examination could be used to guide imaging., Methods: We prospectively studied blunt trauma patients 65 years or older at 18 Level I/II trauma centers. Patients presenting >24 hours after injury or who died upon arrival were excluded. We collected history and physical elements and final injury diagnoses. Injury diagnoses were categorized into CT body regions of head/C-spine or Torso (chest, abdomen/pelvis, and thoracolumbar spine). Using machine learning and regression modeling as well as a priori clinical algorithms based, we tested various decision rules against our data set. Our priority was to identify a simple rule, which could be applied at the bedside, maximizing sensitivity and negative predictive value (NPV) to minimize missed injuries., Results: We enrolled 5,498 patients with 3,082 injuries. Nearly half (n = 2,587 [47.1%]) had an injury within the defined CT body regions. No rule to guide a pan-scan could be identified with suitable sensitivity/NPV for clinical use. A clinical algorithm to identify patients for pan-scan, using a combination of physical examination findings and specific high-risk criteria, was identified and had a sensitivity of 0.94 and NPV of 0.86. This rule would have identified injuries in all but 90 patients (1.6%) and would theoretically spare 11.9% (655) of blunt trauma patients a torso CT., Conclusion: Our findings advocate for head/C-spine CT in all geriatric patients with the addition of torso CT in the setting of positive clinical findings and high-risk criteria. Prospective validation of this rule could lead to streamlined diagnostic care of this growing trauma population., Level of Evidence: Diagnostic Tests or Criteria; Level II., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Previous research has shown that temporal prediction processes are associated with phase resets of low-frequency delta oscillations in a network of parietal, sensory and frontal areas during non-rhythmic sensory stimulation. Transcranial alternating current stimulation (tACS) modulates perceptually relevant brain oscillations in a frequency and phase-specific manner, allowing the assessment of their functional qualities in certain cognitive functions like temporal prediction., Objective: We addressed the relation between oscillatory activity and temporal prediction by using tACS to manipulate brain activity in a sinusoidal manner. This enables the investigation of the relevance of low-frequency oscillations' phase for temporal prediction., Methods: Delta tACS was applied over the left and right parietal cortex in two separate unimodal and crossmodal temporal prediction experiments. Participants judged either the visual or the tactile reappearance of a uniformly moving visual stimulus, which shortly disappeared behind an occluder. tACS was applied with six different phase shifts relative to sensory stimulation in both experiments. Additionally, a computational model was developed and analysed to elucidate oscillation-based functional principles for the generation of temporal predictions., Results: Only in the unimodal experiment, the application of delta tACS resulted in a phase-dependent modulation of temporal prediction performance. By considering the effect of sustained tACS in the computational model, we demonstrate that the entrained dynamics can phase-specifically modulate temporal prediction accuracy., Conclusion: Our results suggest that delta oscillatory phase contributes to unimodal temporal prediction. Crossmodal prediction may involve a broader brain network or cross-frequency interactions, extending beyond parietal delta phase and the scope of our current stimulation design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiovascular imaging with camera-on-tip endoscopes has the potential to provide physiologically relevant data on the tissue state and device placement that can improve clinical outcomes. In this work, we review the unmet clinical need for image-based in vivo cardiovascular diagnostics and guidance for minimally invasive procedures. We present a 7 Fr camera-on-tip endoscope with fibre-coupled multispectral illumination that includes methods for imaging in a blood-filled field of view (FOV). We demonstrate that the endoscope can be navigated from the femoral artery to cardiac regions such as the left atrium and left ventricle in a porcine model, where in vivo images of the cardiac walls are recorded. We further show that physiologically relevant parameters such as heart rate and respiration can be extracted from the images and that changes to tissue state can be inferred from the imaging data. Finally, a methodology for merging the imaging data with diffuse reflection spectroscopy (DRS) recorded through the optical fibre is outlined., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s).)

COVID-19 convalescent plasma (CCP) was one of the first therapies to receive emergency use authorization for management of COVID-19. We assessed the effectiveness of CCP in a propensity-matched analysis, and whether the presence of antibodies in the recipient at the time of treatment or the titer of antibodies in the administered CCP influenced clinical effectiveness. In an inpatient population within a single large health system, a total of 290 CCP patients were matched to 290 controls. While CCP increased titers of anti-SARS-CoV-2 RBD IgG titers post-CCP (p = <0.0001), no differences in 30-day survival were observed between CCP patients and controls in univariate and multivariate analyses. Survival at 30 days was numerically lower in recipients who were seronegative prior to CCP administration, compared to those with low titer and high titer anti-SARS-CoV-2 RBD IgG, respectively, but did not reach statistical significance (56% vs 82% vs 75%, p = 0.16). Patients who received 2 units of high-titer CCP had numerically better survival versus those who received fewer high-titer units, but this was not statistically significant (p = 0.08). CCP did not improve 30-day survival compared to propensity matched controls. Together these data support that CCP therapy provides limited benefit to hospitalized patients with SARS-CoV-2 infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Iasella et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Prosocial is a systems-level intervention framework that incorporates elements of acceptance and commitment therapy (ACT) with Ostrom's core design principles (CDPs) guiding effective organizations and collective action (Ostrom, 1990). We evaluated a Prosocial intervention to support teachers and staff in a specialized school. AB analysis supported improvements in group cohesion and values-behavior alignment during the intervention and pre-post analyses showed significant improvements in psychological flexibility and perceived stress of participants. These preliminary outcomes may support future empirical research on Prosocial in educational settings., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Association for Behavior Analysis International 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

In this paper, we present the design and fabrication of a novel chip-on-tip catheter, which uses a microcamera and optical fibres to capture in vivo images in a beating porcine heart thanks to a saline flush to clear the blood field. Here, we demonstrate the medical utility and mechanical robustness of this catheter platform system, which could be used for other optical diagnostic techniques, surgical guidance, and clinical navigation. We also discuss some of the challenges and system requirements associated with developing a miniature prototype for such a study and present assembly instructions. Methods of clearing the blood field are discussed, including an integrated flush channel at the distal end. This permits the capture of images of the endocardial walls. The device was navigated under fluoroscopic guiding, through a guiding catheter to various locations of the heart, where images were successfully acquired. Images were captured at the intra-atrial septum, in the left atrium after a trans-septal cross procedure, and in the left ventricle, which are, to the best of our knowledge, the first images captured in an in vivo beating heart using endoscopic techniques.

Antibody-oligonucleotide conjugates are a promising class of therapeutics for extrahepatic delivery of small interfering ribonucleic acids (siRNAs). These conjugates can be optimized for improved delivery and mRNA knockdown (KD) through understanding of structure-activity relationships. In this study, we systematically examined factors including antibody isotype, siRNA chemistry, linkers, conjugation chemistry, PEGylation, and drug-to-antibody ratios (DARs) for their impact on bioconjugation, pharmacokinetics (PK), siRNA delivery, and bioactivity. Conjugation site (cysteine, lysine, and Asn297 glycan) and DAR proved critical for optimal conjugate PK and siRNA delivery. SiRNA chemistry including 2' sugar modifications and positioning of phosphorothioates were found to be critical for delivery and duration of action. By utilizing cleavable and noncleavable linkers, we demonstrated the impact of linkers on PK and mRNA KD. To achieve optimal properties of antibody-siRNA conjugates, a careful selection of siRNA chemistry, DAR, conjugation sites, linkers, and antibody isotype is necessary.

Polyamines are ubiquitous biomolecules with a number of established functions in eukaryotic cells. In plant cells, polyamines have previously been linked to abiotic and biotic stress tolerance, as well as to the modulation of programmed cell death (PCD), with contrasting reports on their pro-PCD and pro-survival effects. Here, we used two well-established platforms for the study of plant PCD, Arabidopsis thaliana suspension cultures cells and the root hair assay, to examine the roles of the polyamines spermine and spermidine in the regulation of PCD. Using these systems for precise quantification of cell death rates, we demonstrate that both polyamines can trigger PCD when applied exogenously at higher doses, whereas at lower concentrations they inhibit PCD induced by both biotic and abiotic stimuli. Furthermore, we show that concentrations of polyamines resulting in inhibition of PCD generated a transient ROS burst in our experimental system, and activated the expression of oxidative stress- and pathogen response-associated genes. Finally, we examined PCD responses in existing Arabidopsis polyamine synthesis mutants, and identified a subtle PCD phenotype in Arabidopsis seedlings deficient in thermo-spermine. The presented data show that polyamines can have a role in PCD regulation; however, that role is dose-dependent and consequently they may act as either inhibitors, or inducers, of PCD in Arabidopsis., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background/objectives: The COVID-19 pandemic period from 2020 to 2022 had a significant impact on maternal infant health with mothers impacted more than their infants. We questioned whether there have been any lingering effects from the pandemic., Methods: We examined intermediate and long-term pandemic effects on maternal and neonatal outcomes before, during, and after the COVID-19 pandemic period. We reviewed mother-infant pairs from the following three epochs: (1) the pre-COVID-19 period, (2) the COVID-19 pandemic period, and (3) the post-pandemic period. The Case Mix Index (CMI) for the neonates from all three epochs were detailed., Results: Post-pandemic, we noted a rising trend of LGA infants (10%) and an increase in SGA infants (13%). For women in 2023, we noted an increase in hypertension, preeclampsia, diabetes, and a higher BMI than in the pre-pandemic period. There have also been more congenital anomalies (9%), and neonatal CMI increased in the post-pandemic period., Conclusions: Well after the pandemic period, maternal-infant health continues to be affected. For women, the increase in hypertension and diabetes during pregnancy is concerning. For infants, being LGA or SGA may have long-term consequences. The post-pandemic increase in infants with congenital anomalies compared to the pre-pandemic era is an area that needs ongoing review.

Background: Electronic medical record (EMR) systems provide timely access to clinical information and have been shown to improve medication safety. However, EMRs can also create opportunities for error, including system-related errors or errors that were unlikely or not possible with the use of paper medication charts. This study aimed to determine the detection and mitigation strategies adopted by a health district in Australia to target system-related errors and to explore stakeholder views on strategies needed to curb future system-related errors from emerging., Methods: A qualitative descriptive study design was used comprising semi-structured interviews. Data were collected from three hospitals within a health district in Sydney, Australia, between September 2020 and May 2021. Interviews were conducted with EMR users and other key stakeholders (e.g. clinical informatics team members). Participants were asked to reflect on how system-related errors changed over time, and to describe approaches taken by their organisation to detect and mitigate these errors. Thematic analysis was conducted iteratively using a general inductive approach, where codes were assigned as themes emerged from the data., Results: Interviews were conducted with 25 stakeholders. Participants reported that most system-related errors were detected by front-line clinicians. Following error detection, clinicians either reported system-related errors directly to the clinical informatics team or submitted reports to the incident information management system. System-related errors were also reported to be detected via reports run within the EMR, or during organisational processes such as incident investigations or system enhancement projects. EMR redesign was the main approach described by participants for mitigating system-related errors, however other strategies, like regular user education and minimising the use of hybrid systems, were also reported., Conclusions: Initial detection of system-related errors relies heavily on front-line clinicians, however other organisational strategies that are proactive and layered can improve the systemic detection, investigation, and management of errors. Together with EMR design changes, complementary error mitigation strategies, including targeted staff education, can support safe EMR use and development., (© 2024. The Author(s).)

Background: Endomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs, which may provide further insight into the pathophysiology of allograft rejection and injury., Methods: This is a retrospective observational study of 156 EMB evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood before EMB (up to 9 days). Diagnostic agreement between traditional histopathology, MMDx, and dd-cfDNA (threshold of 0.20%) was compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated., Results: MMDx characterized allograft tissue as no rejection (62.8%), antibody-mediated rejection (ABMR) (26.9%), T-cell-mediated rejection (TCMR) (5.8%), and mixed ABMR/TCMR (4.5%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (76.3% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters were correlated with dd-cfDNA scores, including DSAST, GRIT, HT1, QCMAT, and S4. For individual transcripts, tissue ROBO4 was significantly correlated with dd-cfDNA in both nonrejection and rejection as assessed by MMDx., Conclusions: Collectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA and expression of ROBO4 (a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of antibody-mediated rejection, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to acute cellular rejection., (Copyright © 2024. Published by Elsevier Inc.)

Background: Physicians and patient-facing caregivers have increasingly used mobile health (mHealth) technologies in the past several years, accelerating during the COVID-19 pandemic. However, barriers and feedback surrounding adoption remain relatively understudied and varied across health systems, particularly in rural areas., Objective: This study aims to identify provider adoption, attitudes, and barriers toward mHealth in a large, multisite, rural US health care system. We investigated (1) mHealth apps that providers use for their own benefit and (2) mHealth apps that a provider uses in conjunction with a patient., Methods: We surveyed all patient-seeing providers within the Marshfield Clinic Health System with a brief, 16-item, web-based survey assessing attitudes toward mHealth, adoption of these technologies, and perceived barriers faced by providers, their peers, and the institution. Survey results were summarized via descriptive statistics, with log-binomial regression and accompanying pairwise analyses, using Kruskal-Wallis and Jonckheere-Terpstra tests for significance, respectively. Respondents were grouped by reported clinical role and specialty., Results: We received a 38% (n/N=916/2410) response rate, with 60.7% (n=556) of those sufficiently complete for analyses. Roughly 54.1% (n=301) of respondents reported mHealth use, primarily around decision-making and supplemental information, with use differing based on provider role and years of experience. Self-reported barriers to using mHealth included a lack of knowledge and time to study mHealth technologies. Providers also reported concerns about patients' internet access and the complexity of mHealth apps to adequately use mHealth technologies. Providers believed the health system's barriers were largely privacy, confidentiality, and legal review concerns., Conclusions: These findings echo similar studies in other health systems, surrounding providers' lack of time and concerns over privacy and confidentiality of patient data. Providers emphasized concerns over the complexity of these technologies for their patients and concerns over patients' internet access to fully use mHealth in their delivery of care., (©Bryan P Weichelt, Rick Burke, Burney Kieke, Matt Pilz, Neel Shimpi. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 24.06.2024.)

Introduction: Special Operations Forces service members (SOF) are regularly exposed to traumatic and concussive events, increasing the prevalence of symptoms of post-traumatic stress disorder (PTSD) and depression, shortening potential years of service., Methods: This retrospective chart review presents preliminary data on a Human Performance Optimization (HPO) program that provided an average of 30 sessions of individualized alpha frequency repetitive transcranial magnetic stimulation (α-rTMS) to active-duty SOF as to reduce symptoms of PTSD and depression following traumatic brain injury. Scores from the PTSD Checklist for DSM-5, PROMIS Depression short form and Perceived Deficits Questionnaire (PDQ) were reviewed., Results: Significant reductions were noted after the HPO program in all clinical scales with an average 37% decrease in PCL-5 ( p <.01), 11.3% reduction in PROMIS depression T-scores ( p <.01), and 45.5% reduction in PDQ scales by session 30 ( p <.01), with side effects matching those commonly reported in rTMS. Importantly, the average PCL-5 score decreased from 42.9 to 27 by end of the treatment program, which is below the clinical threshold of 33 for presence of PTSD. For those with depression symptoms scores greater than cut off clinical thresholds at baseline, 46% resolved following treatment., Conclusion: This data provides preliminary support for safe application of α-rTMS for symptom reduction in active-duty special operations military personnel., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bailar-Heath, Burke, Thomas and Morrow.)

Programmed cell death (PCD) is fundamentally important for plant development, abiotic stress responses and immunity, but our understanding of its regulation remains fragmented. Building a stronger research community is required to accelerate progress in this area through knowledge exchange and constructive debate. In this Viewpoint, we aim to initiate a collective effort to integrate data across a diverse set of experimental models to facilitate characterisation of the fundamental mechanisms underlying plant PCD and ultimately aid the development of a new plant cell death classification system in the future. We also put forward our vision for the next decade of plant PCD research stemming from discussions held during the 31 st New Phytologist workshop, 'The Life and Death Decisions of Plant Cells' that took place at University College Dublin in Ireland (14-15 June 2023). We convey the key areas of significant progress and possible future research directions identified, including resolving the spatiotemporal control of cell death, isolation of its molecular and genetic regulators, and harnessing technical advances for studying PCD events in plants. Further, we review the breadth of potential impacts of plant PCD research and highlight the promising new applications of findings from this dynamically evolving field., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

Objectives: This study aimed to indicate the feasibility of a prototype electrical neuromodulation system using a closed-loop energy-efficient ultrasound-based mechanism for communication, data transmission, and recharging., Materials and Methods: Closed-loop deep brain stimulation (DBS) prototypes were designed and fabricated with ultrasonic wideband (UsWB) communication technology and miniaturized custom electronics. Two devices were implanted short term in anesthetized Göttingen minipigs (N = 2). Targeting was performed using preoperative magnetic resonance imaging, and locations were confirmed postoperatively by computerized tomography. DBS systems were tested over a wide range of stimulation settings to mimic minimal, typical, and/or aggressive clinical settings, and evaluated for their ability to transmit data through scalp tissue and to recharge the DBS system using UsWB., Results: Stimulation, communication, reprogramming, and recharging protocols were successfully achieved in both subjects for amplitude (1V-6V), frequency (50-250 Hz), and pulse width (60-200 μs) settings and maintained for ≥six hours. The precision of pulse settings was verified with <5% error. Communication rates of 64 kbit/s with an error rate of 0.05% were shown, with no meaningful throughput degradation observed. Time to recharge to 80% capacity was <9 minutes. Two DBS systems also were implanted in the second test animal, and independent bilateral stimulation was successfully shown., Conclusions: The system performed at clinically relevant implant depths and settings. Independent bilateral stimulation for the duration of the study with a 4F energy storage and full rapid recharge were achieved. Continuous function extrapolates to six days of continuous stimulation in future design iterations implementing application specific integrated circuit level efficiency and 15F storage capacitance. UsWB increases energy efficiency, reducing storage requirements and thereby enabling device miniaturization. The device can enable intelligent closed-loop stimulation, remote system monitoring, and optimization and can serve as a power/data gateway to interconnect the intrabody network with the Internet of Medical Things., Competing Interests: Conflict of Interest Emrecan Demirors, Tommaso Melodia, and Jorge Jimenez are cofounders of Bionet Sonar Inc and hold equity interest. Raffaele Guida and Ryan Burke were employees of the company at the time of the study. Bionet Sonar holds all rights for the technology and its personnel, and its founders led the design, development, fabrication, and feasibility testing of prototype devices, including data collection and analysis, decision to publish, and preparation of this manuscript. Joseph S. Neimat serves as a consultant for Medtronic and on a scientific advisory board for Abbott. Steven C. Koenig reports one conflict of interest (spouse is paid by Bionet Sonar for her assistance with grants administration activities but did not participate in any research and development activities and/or participation in the preparation of the manuscript)., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Increasing rates of fatal drug overdose (FDO) among youth since 2016 have been driven by fentanyl and polysubstance use. Suicide by youth also increased steadily since 2007. The manner of FDO may be accidental (i.e., unintentional) or suicidal (i.e., intentional). This report examines the rate of youth intentional and unintentional FDO as well as specific drug toxicology in Connecticut, between the years 2019 and 2021, compared to a 2016-2018 report., Methods: We reviewed N = 286 consecutive FDO files of youth, <26 years of age dated for 2019-2021 from the Connecticut Medical Examiner's office., Results: FDO attributed to fentanyl increased significantly from 2016 to 2018 to 2019 to 2021. Xylazine FDO emerged in 2019 and reached 16% in 2021. Intentional FDO rates doubled between these periods from 3.8% to 7.7%. Most FDOs involved individuals aged 20-25 years, whereas 10% were among those aged 15-19. For the first time since 2018, FDO among 10-14 years old was detected. Analysis of gender found no differences. Within each gender, however, FDO attributed to fentanyl increased significantly between these periods. The FDO rate for Hispanics increased significantly, while the rate for Whites decreased significantly., Discussion and Conclusions: The availability of high lethality potential drugs leading to youth FDO including an increasing rate of intentional FDO, is a public health concern. It is prudent to identify modifiable acute high-risk circumstances for intentional FDO and prevention-intervention evidence-based approach to reduce FDO., Scientific Significance: This is the first study of FDO among youth examining the manner of death by suicide., (© 2023 The American Academy of Addiction Psychiatry (AAAP).)

Objectives: One of the most pivotal decisions an emergency physician (EP) makes is whether to admit or discharge a patient. The emergency department (ED) work-up leading to this decision involves several resource-intensive tests. Previous studies have demonstrated significant differences in EP resource utilization, measured by lab tests, advanced imaging (magnetic resonance imaging [MRI], computed tomography [CT], ultrasound), consultations, and propensity to admit a patient. However, how an EP's years of experience may impact their resource utilization and propensity to admit patients has not been well characterized. This study seeks to better understand how EPs' years of experience, post-residency, relates to their use of advanced imaging and patient disposition., Methods: Ten years of ED visits were analyzed for this study from a single, academic tertiary care center in the urban Northeast United States. The primary outcomes were utilization of advanced imaging during the visit (CT, MRI, or formal ultrasound) and whether the patient was admitted. EP years of experience was categorized into 0-2 years, 3-5 years, 6-8 years, 9-11 years, and 12 or more years. Patient age, sex, Emergency Severity Index (ESI), and the attending EP's years of experience were collected. The relationship between EP years of experience and each outcome was assessed with a linear mixed model with a random effect for provider and patient age, sex, and ESI as covariates., Results: A total of 460,937 visits seen by 65 EPs were included in the study. Over one-third (37.6%) of visits had an advanced imaging study ordered and nearly half (49.5%) resulted in admission. Compared to visits with EPs with 0-2 years of experience, visits with EPs with 3-5 or 6-8 years of experience had significantly lower odds of advanced imaging occurring. Visits seen by EPs with more than 2 years of experience had lower odds of admission than visits by EPs with 0-2 years of experience., Conclusion: More junior EPs tend to order more advanced imaging studies and have a higher propensity to admit patients. This may be due to less comfort in decision-making without advanced imaging or a lower risk tolerance. Conversely, the additional clinical experience of the most senior EPs, with greater than 9 years of experience, likely impacts their resource utilization patterns such that their use of advanced imaging does not significantly differ from the most junior EPs., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

The more science advances, the more questions are asked. This compounding growth can make it difficult to keep up with current research directions. Furthermore, this difficulty is exacerbated for junior researchers who enter fields with already large bases of potentially fruitful research avenues. In this paper, we propose a novel task and a recommender system for research directions, RecSOI, that draws from statements of ignorance (SOIs) found in the research literature. By building researchers' profiles based on textual elements, RecSOI generates personalized recommendations of potential research directions tailored to their interests. In addition, RecSOI provides context for the recommended SOIs, so that users can quickly evaluate how relevant the research direction is for them. In this paper, we provide an overview of RecSOI's functioning, implementation, and evaluation, demonstrating its effectiveness in guiding researchers through the vast landscape of potential research directions., (© 2024. The Author(s).)

Objective: Electronic medication management (EMM) systems have been shown to introduce new patient safety risks that were not possible, or unlikely to occur, with the use of paper charts. Our aim was to examine the factors that contribute to EMM-related incidents and how these incidents change over time with ongoing EMM use., Methods: Incidents reported at 3 hospitals between January 1, 2010, and December 31, 2019, were extracted using a keyword search and then screened to identify EMM-related reports. Data contained in EMM-related incident reports were then classified as unsafe acts made by users and the latent conditions contributing to each incident., Results: In our sample, 444 incident reports were determined to be EMM related. Commission errors were the most frequent unsafe act reported by users (n = 298), whereas workarounds were reported in only 13 reports. User latent conditions (n = 207) were described in the highest number of incident reports, followed by conditions related to the organization (n = 200) and EMM design (n = 184). Over time, user unfamiliarity with the system remained a key contributor to reported incidents. Although fewer articles to electronic transfer errors were reported over time, incident reports related to the transfer of information between different computerized systems increased as hospitals adopted more clinical information systems., Conclusions: Electronic medication management-related incidents continue to occur years after EMM implementation and are driven by design, user, and organizational conditions. Although factors contribute to reported incidents in varying degrees over time, some factors are persistent and highlight the importance of continuously improving the EMM system and its use., Competing Interests: The authors disclose no conflict of interests., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Generative Artificial Intelligence (AI) provides unprecedented opportunities to improve injury surveillance systems in many ways, including the curation and publication of information related to agricultural injuries and illnesses. This editorial explores the feasibility and implication of ChatGPT integration in an international sentinel agricultural injury surveillance system, AgInjuryNews, highlighting that AI integration may enhance workflows by reducing human and financial resources and increasing outputs. In the coming years, text intensive natural language reports in AgInjuryNews and similar systems could be a rich source for data for ChatGPT or other more customized and fine-tuned LLMs. By harnessing the capabilities of AI and NLP, teams could potentially streamline the process of data analysis, report generation, and public dissemination, ultimately contributing to improved agricultural injury prevention efforts, well beyond any manually driven efforts.

Background: Current methods of intrapartum fetal monitoring based on heart rate, increase the rates of operative delivery but do not prevent or accurately detect fetal hypoxic brain injury. There is a need for more accurate methods of intrapartum fetal surveillance that will decrease the incidence of adverse perinatal and long-term neurodevelopmental outcomes while maintaining the lowest possible rate of obstetric intervention. Fetal pulse oximetry (FPO) is a technology that may contribute to improved intrapartum fetal wellbeing evaluation by providing a non-invasive measurement of fetal oxygenation status., Objective: This systematic review and meta-analysis aims to synthesise the evidence examining the association between intrapartum fetal oxygen saturation levels and adverse perinatal and long-term outcomes in the offspring., Methods: We will include randomised control trials (RCTs), cohort, cross-sectional and case-control studies which examine the use of FPO during labour as a means of measuring intrapartum fetal oxygen saturation and assess its effectiveness at detecting adverse perinatal and long-term outcomes compared to existing intrapartum surveillance methods. A detailed systematic search of PubMed, EMBASE, CINAHL, The Cochrane Library, Web of Science, ClinicalTrials.Gov and WHO ICTRP will be conducted following a detailed search strategy until February 2024. Three authors will independently review titles, abstracts and full text of articles. Two reviewers will independently extract data using a pre-defined data extraction form and assess the quality of included studies using the Risk of Bias tool for RCTs and Newcastle-Ottawa Scale for observational studies. The grading of recommendations, assessment, development, and evaluation (GRADE) approach will be used to evaluate the certainty of the evidence. We will use random-effects meta-analysis for each exposure-outcome association to calculate pooled estimates using the generic variance method. This systematic review will follow the Preferred Reporting Items for Systematic reviews and Meta-analyses and MOOSE guidelines., Prospero Registration: CRD42023457368 (04/09/2023)., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Mitchell JM et al.)

Identification of tumour margins during resection of the brain is critical for improving the post-operative outcomes. Due to the highly infiltrative nature of glioblastoma multiforme (GBM) and limited intraoperative visualization of the tumour margin, incomplete surgical resection has been observed to occur in up to 80 % of GBM cases, leading to nearly universal tumour recurrence and overall poor prognosis of 14.6 months median survival. This research presents a miniaturized, SiPMT-based optical system for simultaneous measurement of powerful DRS and weak auto-fluorescence for brain tumour detection. The miniaturisation of the optical elements confined the spatial separation of eight select wavelengths into footprint measuring 1.5 × 2 × 16 mm. The small footprint enables this technology to be integrated with existing surgical guidance instruments in the operating room. It's dynamic ability to subtract any background illumination and measure signal intensities across a broad range from pW to mWs make this design much more suitable for clinical environments as compared to spectrometer-based systems with limited dynamic ranges and high integration times. Measurements using optical tissue phantoms containing mixed fluorophores demonstrate correlation coefficients between the fitted response and actual concentration using PLS regression being 0.95, 0.87 and 0.97 for NADH, FAD and PpIX , respectively. These promising results indicate that our proposed miniaturized instrument could serve as an effective alternative in operating rooms, assisting surgeons in identifying brain tumours to achieving positive surgical outcomes for patients., Competing Interests: The authors declare that there are no conflicts of interest related to this article., (© 2024 The Author(s).)

Background: In absence of contraindications, same-day initiation (SDI) of antiretroviral therapy (ART) is recommended for people testing HIV-positive who are ready to start treatment. Until 2021, World Health Organization (WHO) guidelines considered the presence of TB symptoms (presumptive TB) a contraindication to SDI due to the risk of TB-immune reconstitution inflammatory syndrome (TB-IRIS). To reduce TB-IRIS risk, ART initiation was recommended to be postponed until results of TB investigations were available, and TB treatment initiated if active TB was confirmed. In 2021, the WHO guidelines changed to recommending SDI even in the presence of TB symptoms without awaiting results of TB investigations based on the assumption that TB investigations often unnecessarily delay ART initiation, increasing the risk for pre-ART attrition from care, and noting that the clinical relevance of TB-IRIS outside the central nervous system remains unclear. However, this guideline change was not based on conclusive evidence, and it remains unclear whether SDI of ART or TB test results should be prioritized in people with HIV (PWH) and presumptive TB., Design and Methods: SaDAPT is an open-label, pragmatic, parallel, 1:1 individually randomized, non-inferiority trial comparing two strategies for the timing of ART initiation in PWH with presumptive TB ("ART first" versus "TB results first"). PWH in Lesotho and Malawi, aged 12 years and older (re)initiating ART who have at least one TB symptom (cough, fever, night sweats or weight loss) and no signs of intracranial infection are eligible. After a baseline assessment, participants in the "ART first" arm will be offered SDI of ART, while those in the "TB results first" arm will be offered ART only after active TB has been confirmed or refuted. We hypothesize that the "ART first" approach is safe and non-inferior to the "TB results first" approach with regard to HIV viral suppression (<400 copies/ml) six months after enrolment. Secondary outcomes include retention in care and adverse events consistent with TB-IRIS., Expected Outcomes: SaDAPT will provide evidence on the safety and effects of SDI of ART in PWH with presumptive TB in a pragmatic clinical trial setting., Trial Registration: The trial has been registered on clinicaltrials.gov (NCT05452616; July 11 2022)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gerber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Diffuse reflectance spectroscopy (DRS) has been extensively studied in both preclinical and clinical settings for multiple applications, notably as a minimally invasive diagnostic tool for tissue identification and disease delineation. In this study, extended-wavelength DRS (EWDRS) measurements of ex vivo tissues ranging from ultraviolet through visible to the short-wave infrared region (355-1919 nm) are presented in two datasets. The first dataset contains labelled EWDRS measurements collected from bone cement samples and ovine specimens including 10 tissue types commonly encountered in orthopedic surgeries for data curation purposes. The other dataset includes labelled EWDRS measurements of primarily bone structures at different depths during stepwise drilling into intact porcine skulls until plunging into the cranial cavity. The raw data with code for pre-processing and calibration is publicly available for reuse on figshare. The datasets can be utilized not only for exploratory purposes in machine learning model construction, but also for knowledge discovery in the orthopedic domain to identify important features for surgical guidance, extract physiological parameters and provide diagnostic insights., (© 2024. The Author(s).)

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N -terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2- c ]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and ( R )-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-μM IC 50 against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays.

Background: Based on emerging evidence that brief periods of cessation from resistance training (RT) may re-sensitize muscle to anabolic stimuli, we aimed to investigate the effects of a 1-week deload interval at the midpoint of a 9-week RT program on muscular adaptations in resistance-trained individuals., Methods: Thirty-nine young men ( n  = 29) and women ( n  = 10) were randomly assigned to 1 of 2 experimental, parallel groups: An experimental group that abstained from RT for 1 week at the midpoint of a 9-week, high-volume RT program (DELOAD) or a traditional training group that performed the same RT program continuously over the study period (TRAD). The lower body routines were directly supervised by the research staff while upper body training was carried out in an unsupervised fashion. Muscle growth outcomes included assessments of muscle thickness along proximal, mid and distal regions of the middle and lateral quadriceps femoris as well as the mid-region of the triceps surae. Adaptions in lower body isometric and dynamic strength, local muscular endurance of the quadriceps, and lower body muscle power were also assessed., Results: Results indicated no appreciable differences in increases of lower body muscle size, local endurance, and power between groups. Alternatively, TRAD showed greater improvements in both isometric and dynamic lower body strength compared to DELOAD. Additionally, TRAD showed some slight psychological benefits as assessed by the readiness to train questionnaire over DELOAD., Conclusion: In conclusion, our findings suggest that a 1-week deload period at the midpoint of a 9-week RT program appears to negatively influence measures of lower body muscle strength but has no effect on lower body hypertrophy, power or local muscular endurance., Competing Interests: Brad J Schoenfeld serves on the scientific advisory board of Tonal Corporation, a manufacturer of fitness equipment. Michael Israetel is a cofounder of Renaissaince Periodization. The other authors declare that they have no competing interests., (©2024 Coleman et al.)

More research is needed into how "person-centered care" (PCC) manifests in home care (HC) worker-client relationships. Qualitative data were collected at three time points from twelve HC workers and others to better understand how approaches to care shape the pathways of older adult HC clients with chronic conditions in two Canadian health jurisdictions. This paper uses critical disability and intersectionality frameworks to highlight ways in which PCC enables social and instrumental benefits for workers' and clients. It also exposes difficulties in being flexible and developing interpersonal relationships because of HC policies. Workers also acknowledged risks when trying to prioritize client preferences, sometimes drawing distinctions between reasonable and unreasonable demands. Implications for enhanced training and support for workers around navigating flexibility and boundaries and using a relational approach to PCC are discussed, as are implications for policy-making that protect all parties., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Rates of cigarette use remain elevated among those living in rural areas. Depressive symptoms, risky alcohol use, and weight concerns frequently accompany cigarette smoking and may adversely affect quitting. Whether treatment for tobacco use that simultaneously addresses these issues affects cessation outcomes is uncertain., Methods: The study was a multicenter, two-group, randomized controlled trial involving mostly rural veterans who smoke (N = 358) receiving treatment at one of five Veterans Affairs Medical Centers. The study randomly assigned participants to a tailored telephone counseling intervention or referral to their state tobacco quitline. Both groups received guideline-recommended smoking cessation pharmacotherapy, selected using a shared decision-making approach. The primary outcome was self-reported seven-day point prevalence abstinence (PPA) at three and six months. The study used salivary cotinine to verify self-reported quitting at six months., Results: Self-reported PPA was significantly greater in participants assigned to Tailored Counseling at three (OR = 1.66; 95 % CI: 1.07-2.58) but not six (OR = 1.35; 95 % CI: 0.85-2.15) months. Post hoc subgroup analyses examining treatment group differences based on whether participants had a positive screen for elevated depressive symptoms, risky alcohol use, and/or concerns about weight gain indicated that the cessation benefit of Tailored Counseling at three months was limited to those with ≥1 accompanying concern (OR = 2.02, 95 % CI: 1.20-3.42). Biochemical verification suggested low rates of misreporting., Conclusions: A tailored smoking cessation intervention addressing concomitant risk factors enhanced short-term abstinence but did not significantly improve long-term quitting. Extending the duration of treatment may be necessary to sustain treatment effects., Competing Interests: Declaration of competing interest None of the authors has a conflict of interest to disclose related to this work., (Published by Elsevier Inc.)

Regimented resistance training (RT) has been shown to promote increases in muscle size. When engaging in RT, practitioners often emphasize the importance of appropriate exercise technique, especially when trying to maximize training adaptations (e.g., hypertrophy). This narrative review aims to synthesize existing evidence on what constitutes proper RT exercise technique for maximizing muscle hypertrophy, focusing on variables such as exercise-specific kinematics, contraction type, repetition tempo, and range of motion (ROM). We recommend that when trying to maximize hypertrophy, one should employ a ROM that emphasizes training at long muscle lengths while also employing a repetition tempo between 2 and 8 s. More research is needed to determine whether manipulating the duration of either the eccentric or concentric phase further enhances hypertrophy. Guidelines for body positioning and movement patterns are generally based on implied theory from applied anatomy and biomechanics. However, existing research on the impact of manipulating these aspects of exercise technique and their effect on hypertrophy is limited; it is therefore suggested that universal exercise-specific kinematic guidelines are followed and adopted in accordance with the above recommendations. Future research should investigate the impact of stricter versus more lenient exercise technique variations on hypertrophy.

Background: Incidental finding (IF) follow-up is of critical importance for patient safety and is a source of malpractice risk. Laboratory, imaging, or other types of IFs are often uncovered incidentally and are missed, not addressed, or only result after hospital discharge. Despite a growing IF notification literature, a need remains to study cost-effective non-electronic health record (EHR)-specific solutions that can be used across different types of IFs and EHRs., Objective: The objective of this study was to evaluate the utility and cost-effectiveness of an EHR-independent emergency medicine-based quality assurance (QA) follow-up program in which an experienced nurse reviewed laboratory and imaging studies and ensured appropriate follow-up of results., Methods: A QA nurse reviewed preceding-day abnormal studies from a tertiary care hospital, a community hospital, and an urgent care center. Laboratory values outside preset parameters or radiology over-reads resulting in clinically actionable changes triggered contact with an on-call emergency physician to determine an appropriate intervention and its implementation., Results: Of 104,125 visits with 1,351,212 laboratory studies and 95,000 imaging studies, 6530 visits had IFs, including 2659 laboratory and 4004 imaging results. The most common intervention was contacting a primary care physician (5783 cases [88.6%]). Twenty-one cases resulted in a patient returning to the ED, at an average cost of $28,000 per potential life-/limb-saving intervention., Conclusions: Although abnormalities in laboratory results and imaging are often incidental to patient care, a dedicated emergency department QA follow-up program resulted in the identification and communication of numerous laboratory and imaging abnormalities and may result in changes to patients' subsequent clinical course, potentially increasing patient safety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Significance: Wavelength selection from a large diffuse reflectance spectroscopy (DRS) dataset enables removal of spectral multicollinearity and thus leads to improved understanding of the feature domain. Feature selection (FS) frameworks are essential to discover the optimal wavelengths for tissue differentiation in DRS-based measurements, which can facilitate the development of compact multispectral optical systems with suitable illumination wavelengths for clinical translation., Aim: The aim was to develop an FS methodology to determine wavelengths with optimal discriminative power for orthopedic applications, while providing the frameworks for adaptation to other clinical scenarios., Approach: An ensemble framework for FS was developed, validated, and compared with frameworks incorporating conventional algorithms, including principal component analysis (PCA), linear discriminant analysis (LDA), and backward interval partial least squares (biPLS)., Results: Via the one-versus-rest binary classification approach, a feature subset of 10 wavelengths was selected from each framework yielding comparable balanced accuracy scores (PCA: 94.8 ± 3.47 % , LDA: 98.2 ± 2.02 % , biPLS: 95.8 ± 3.04 % , and ensemble: 95.8 ± 3.16 % ) to those of using all features (100%) for cortical bone versus the rest class labels. One hundred percent balanced accuracy scores were generated for bone cement versus the rest. Different feature subsets achieving similar outcomes could be identified due to spectral multicollinearity., Conclusions: Wavelength selection frameworks provide a means to explore domain knowledge and discover important contributors to classification in spectroscopy. The ensemble framework generated a model with improved interpretability and preserved physical interpretation, which serves as the basis to determine illumination wavelengths in optical instrumentation design., (© 2023 The Authors.)

Background: Most idiopathic pulmonary fibrosis (IPF) lung transplant recipients (IPF-LTRs) have short telomere (ST) length. Inherited mutations in telomere-related genes are associated with the development of T cell immunodeficiency. Despite this, IPF-LTRs with telomere-related rare variants are not protected from acute cellular rejection (ACR). We set out to determine the impact of both age and telomere length on the circulating T cell compartment and ACR burden of IPF-LTRs., Methods: We identified 106 IPF-LTRs who had telomere length testing using flowFISH (57 with short telomeres and 49 with long telomeres) as well as a subset from both cohorts who had cryopreserved PBMC at least 1 time point, 6 months posttransplantation. Circulating T cells from before transplantation and at 6 and 12 months posttransplantation were analyzed using multiparameter flow cytometry to study phenotype and functional capacity, and bulk T cell receptor sequencing was performed to study repertoire diversity. Linear regression was used to study the relationship of age and telomere length on early (within 1 year) and late (between 1 and 2 years) ACR., Results: IPF-LTRs with ST were found to have premature "aging" of their circulating T cell compartment, with age-agnostic elevations in posttransplant terminal differentiation of CD8 + T cells, increased granzyme B positivity of both CD8 + and CD4 + T cells, upregulation of the exhaustion marker, CD57, and chemotactic protein CCR5, and enhanced T cell receptor clonal expansion. Additionally, we found a significant decline in early ACR burden with increasing age, but only in the ST cohort., Conclusions: IPF-LTRs with ST have premature "aging" of their circulating T cell compartment posttransplantation and a clear age-related decline in ACR burden., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4 CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4 CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4 CRBN neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4 CRBN molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

The present study used a multiple baseline across skills design to evaluate use of an adapted LIFE skills curriculum (Dixon, 2021) to teach various cooking tasks to a young adult diagnosed with ASD, schizophrenia, and bipolar disorder. The participant learned and completed recipes and related vocational tasks. Results showed efficient task acquisition for all recipes and maintenance of vocational tasks during follow-up probes. Results have implications for the LIFE program, suggesting that it is a viable method for teaching LIFE skills to neurodivergent young adults., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© Association for Behavior Analysis International 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of patients with nontransplant short-TL are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for posttransplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL, and 26% of IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (P = .0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, P = .0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated that short-TL, rare variants, and lower pretransplant platelet counts were associated with BM dysfunction. Pretransplant TL measurement and genetic testing for rare telomere gene variants identified IPF-LTRs at increased risk for hematologic complications. Our findings support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Breast cancer metastasis to the colon is exceedingly rare, with only 17 reported cases in the literature thus far. This report describes a 67-year-old female who presented to the Emergency Department for large volume melena in the setting of bilateral metastatic ductal breast carcinoma, left triple negative and right HER2+, and T4N0M0 non-small cell lung cancer. On routine CT abdomen/pelvis imaging, the patient had a 7 cm mass arising from the transverse colon. Colonoscopy revealed a non-obstructing necrotic mass in the proximal descending colon. The patient underwent a partial colectomy, small bowel resection, and gastric wedge resection. The patient recovered from surgery and was discharged home with palliative services. The patient passed away four months after discharge due to numerous metastases., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Programmed cell death (PCD) facilitates selective, genetically controlled elimination of redundant, damaged, or infected cells. In plants, PCD is often an essential component of normal development and can mediate responses to abiotic and biotic stress stimuli. However, studying the transcriptional regulation of PCD is hindered by difficulties in sampling small groups of dying cells that are often buried within the bulk of living plant tissue. We addressed this challenge by using RNA sequencing and Arabidopsis thaliana suspension cells, a model system that allows precise monitoring of PCD rates. The use of three PCD-inducing treatments (salicylic acid, heat, and critical dilution), in combination with three cell death modulators (3-methyladenine, lanthanum chloride, and conditioned medium), enabled isolation of candidate core- and stimuli-specific PCD genes, inference of underlying regulatory networks and identification of putative transcriptional regulators of PCD in plants. This analysis underscored a disturbance of the cell cycle and mitochondrial retrograde signaling, and repression of pro-survival stress responses, as key elements of the PCD-associated transcriptional signature. Further, phenotyping of Arabidopsis T-DNA insertion mutants in selected candidate genes validated the potential of generated resources to identify novel genes involved in plant PCD pathways and/or stress tolerance., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

High hit rates from initial ligand-observed NMR screening can make it challenging to prioritize which hits to follow up, especially in cases where there are no available crystal structures of these hits bound to the target proteins or other strategies to provide affinity ranking. Here, we report a reproducible, accurate, and versatile quantitative ligand-observed NMR assay, which can determine K d values of fragments in the affinity range of low μM to low mM using transverse relaxation rate R 2 as the observable parameter. In this study, we examined the theory and proposed a mathematical formulation to obtain K d values using non-linear regression analysis. We designed an assay format with automated sample preparation and simplified data analysis. Using tool compounds, we explored the assay reproducibility, accuracy, and detection limits. Finally, we used this assay to triage fragment hits, yielded from fragment screening against the CRBN/DDB1 complex.

Emotional distress is a common, but poorly addressed, feature of moderate-severe traumatic brain injury (TBI). Previously identified sociodemographic, psychological, and injury-related factors account for only a small proportion of the variability in emotional distress post-TBI. Genetic factors may help to further understand emotional distress in this population. The catechol- O -methyltransferase (COMT) Val158 and brain-derived neurotrophic factor (BDNF) 66Met single-nucleotide polymorphisms (SNPs) have been identified as possible contributory factors to outcomes after TBI. We investigated whether the COMT Val158 and BDNF 66Met SNPs were associated with emotional distress 1 year after moderate-severe TBI, and whether these associations were moderated by age, sex, and TBI severity (as measured by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors (COMT, n  = 391; BDNF, n  = 311) provided saliva samples after admission to a TBI rehabilitation hospital. At a follow-up interview ∼1 year after injury, participants completed a self-report measure of emotional distress (Hospital Anxiety and Depression Scale; HADS). Multiple linear regression models were constructed for each SNP to predict total scores on the HADS. Neither COMT Val158 nor BDNF 66Met carriage status (carrier vs. non-carrier) significantly predicted emotional distress (COMT, p  = 0.49; BDNF, p  = 0.66). Interactions of SNP × age (COMT, p  = 0.90; BDNF, p  = 0.93), SNP × sex (COMT, p  = 0.09; BDNF, p  = 0.60), SNP × injury severity (COMT, p  = 0.53; BDNF, p  = 0.87), and SNP × sex × age (COMT, p  = 0.08; BDNF, p  = 0.76) were also non-significant. Our null findings suggest that COMT Val158 and BDNF 66Met SNPs do not aid the prediction of emotional distress 1 year after moderate-severe TBI, neither in isolation nor in interaction with age, sex and injury severity. The reporting of null findings such as ours is important to avoid publication bias and prompt researchers to consider the challenges of single-gene candidate studies in understanding post-TBI outcomes. Analyses in larger samples that incorporate multiple genetic factors and their relevant moderating factors may provide a greater understanding of the role of genetics in post-TBI emotional distress., Competing Interests: No competing financial interests exist., (© Chloe Anderson et al., 2023; Published by Mary Ann Liebert, Inc.)

Whole blood (WB) for trauma resuscitation in civilian populations has become more common. The utilization of WB in community trauma centers has not been reported. Previous studies have centered around large academic medical centers. We hypothesized that WB-based resuscitation compared to component-only resuscitation (CORe) would demonstrate a survival benefit and that WB resuscitation is safe, feasible, and benefits trauma patients regardless of setting. Our results indicate that receiving whole blood during resuscitation conferred a clear survival benefit to discharge, and this benefit was independent of ISS, age, gender, and initial SBP. We conclude WB should be incorporated into all resuscitation protocols for exsanguinating trauma patients and preferred over component therapy in all centers treating trauma patients.

Background: In Canada, publicly-funded home care programs enable older adults to remain and be cared for in their home for as long as possible but they often differ in types of services offered, and the way services are delivered. This paper examines whether these differing approaches to care shape the pathway that home care clients will take. Older adult client pathways refer to trajectories within, and out of, the home care system (e.g., improvement, long term care (LTC) placement, death)., Methods: A retrospective analysis of home care assessment data (RAI-HC was linked with health administrative data, long-term care admissions and vital statistics in Nova Scotia Health (NSH) and Winnipeg Regional Health Authority (WRHA). The study cohort consists of clients age 60 + years, admitted to home care between January 1, 2011 to December 31, 2013 and up to four years from baseline. Differences in home care service use, client characteristics and their pathways were tested across the two jurisdictions overall, and among the four discharge streams within jurisdictions using t-tests and chi-square tests of significance., Results: NS and WHRA clients were similar in age, sex, and marital status. NS clients had higher levels of need (ADL, cognitive impairment, CHESS) at base line and were more likely discharged to LTC (43% compared to 38% in WRHA). Caregiver distress was a factor correlated with being discharged to LTC. While a third remained as home care clients after 4 years; more than half were no longer in the community - either discharged to LTC placement or death. Such discharges occurred on average at around two years, a relatively short time period., Conclusions: By following older clients over 4 years, we provide enhanced evidence of client pathways, the characteristics that influence these paths, as well as the length of time to the outcomes. This evidence is central to identification of clients at risk in the community and aids in planning for future home care servicing needs that will allow more older adults to remain living in the community., (© 2023. The Author(s).)

Electronic medication management systems (EMMS) have been implemented in most acute care settings in Australia to reduce medication error rates. One of the key challenges related to the introduction of EMMS in hospitals is the uptake of informal "workarounds" by clinicians, including nurses. In this study, we aimed to examine one workaround in depth, nurses not documenting medication administration in the EMMS at the time of administration. We conducted a review of incident reports to identify the factors that contribute to this workaround occurring and the consequences or potential consequences of this workaround on patients. We identified a range of contributing factors, with factors relating to the user (e.g. nurses being time poor) occurring most frequently in incident reports. The most frequently seen consequence of this workaround was the patient receiving an additional dose. This research revealed that strategies to reduce the uptake of this workaround should consider user and organisational factors rather than just EMMS design alone.

To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag based on IMiDs/CELMoDs mechanism of action that improves and addresses the limitations of both PROTAC and previous IMiDs/CeLMoDs based tags. Using structural and sequence analysis, we systematically explored native and chimeric degron containing domains (DCDs) and evaluated their ability to induce degradation. We identified the optimal chimeric iTAG(DCD23 60aa) that elicits robust degradation of targets across cell types and subcellular localizations without exhibiting the well documented "hook effect" of PROTAC-based systems. We showed that iTAG can also induce target degradation by murine CRBN and enabled the exploration of natural neo-substrates that can be degraded by murine CRBN. Hence, the iTAG system constitutes a versatile tool to degrade targets across the human and murine proteome., Competing Interests: A.Sa. is a current employee of Monte Rosa Therapeutics Inc. I.C. is a stockholder and former Scientific Advisory Board member of Monte Rosa Therapeutics Inc. I.C. is a former employee of The Institute of Cancer Research which operates a reward to inventor’s scheme. This may result in financial rewards to employees when projects are commercially licensed. All other authors do not declare competing financial interests., (© 2023 The Authors.)

This study compared the effects of supervised versus unsupervised resistance training (RT) on measures of muscle strength and hypertrophy in resistance-trained individuals. Thirty-six young men and women were randomly assigned to one of two experimental, parallel groups to complete an 8-week RT programme: One group received direct supervision for their RT sessions (SUP); the other group performed the same RT programme in an unsupervised manner (UNSUP). Programme variables were kept constant between groups. We obtained pre- and post-study assessments of body composition via multi-frequency bioelectrical impedance analysis (MF-BIA), muscle thickness of the upper and lower limbs via ultrasound, 1 repetition maximum (RM) in the back squat and bench press, isometric knee extension strength, and countermovement jump (CMJ) height. Results showed the SUP group generally achieved larger increases in muscle thickness for the triceps brachii, all sites of the rectus femoris, and the proximal region of the vastus lateralis. MF-BIA indicated increases in lean mass favoured SUP. Squat 1RM was greater for SUP; bench press 1RM and isometric knee extension were similar between conditions. CMJ increases modestly favoured UNSUP. In conclusion, our findings suggest that supervised RT promotes greater muscular adaptations and enhances exercise adherence in young, resistance-trained individuals.

We sought to evaluate the efficacy of an equivalence-based instructional program to teach vocational information to a young adult. This work has the potential to aid in workplace or vocational programming to teach declarative information about employment settings. We directly reinforced a subset of relations [Employee names (A) to job titles (B) (A-B) and a job titles (B) to a job responsibilities (C) (B-C)] and tested for the untrained emergence of other relations [Employee names (A) to job responsibilities (C) (A-C) and job responsibilities (C) to employee names (A) (C-A)]. In a multiple baseline across employment settings, mastery was observed across trained and derived relations with implications for vocational training., Supplementary Information: The online version contains supplementary material available at 10.1007/s40617-023-00814-z., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© Association for Behavior Analysis International 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)