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Abstract The rs6265 single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor is a common variant that alters therapeutic outcomes for individuals with Parkinson’s disease (PD). We previously investigated the effects of this SNP on the experimental therapeutic approach of neural grafting, demonstrating that young adult parkinsonian rats carrying the variant Met allele exhibited enhanced graft function compared to wild-type rats and also exclusively developed aberrant graft-induced dyskinesias (GID). Aging is the primary risk factor for PD and reduces graft efficacy. Here we investigated whether aging interacts with this SNP to further alter cell transplantation outcomes. We hypothesized that aging would reduce enhancement of graft function associated with this genetic variant and exacerbate GID in all grafted subjects. Unexpectedly, beneficial graft function was maintained in aged rs6265 subjects. However, aging was permissive to GID induction, regardless of genotype, with the greatest incidence and severity found in rs6265-expressing animals.

Background The objective of the PERSONAL‐CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID‐19 Pandemic) trial was to assess the efficacy and safety of smartphone‐enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID‐19 pandemic. Methods and Results This was an open‐label, remote, dose titration trial using daily home self‐monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5–7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10–12)/7 (95% CI, 6–7) mm Hg, P

The cell cycle-regulated DNA methyltransferase CcrM is conserved in most Alphaproteobacteria, but its role in bacteria with complex or multicentric genomes remains unexplored. Here, we compare the methylome, the transcriptome and the phenotypes of wild-type and CcrM-depleted Agrobacterium tumefaciens cells with a dicentric chromosome with two essential replication origins. We find that DNA methylation has a pleiotropic impact on motility, biofilm formation and viability. Remarkably, CcrM promotes the expression of the repABCCh2 operon, encoding proteins required for replication initiation/partitioning at ori2, and represses gcrA, encoding a conserved global cell cycle regulator. Imaging ori1 and ori2 in live cells, we show that replication from ori2 is often delayed in cells with a hypo-methylated genome, while ori2 over-initiates in cells with a hyper-methylated genome. Further analyses show that GcrA promotes the expression of the RepCCh2 initiator, most likely through the repression of a RepECh2 anti-sense RNA. Altogether, we propose that replication at ori1 leads to a transient hemi-methylation and activation of the gcrA promoter, allowing repCCh2 activation by GcrA and contributing to initiation at ori2. This study then uncovers a novel and original connection between CcrM-dependent DNA methylation, a conserved epigenetic regulator and genome maintenance in an Alphaproteobacterial pathogen., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Converging lines of preclinical and clinical research indicate that females, in stark contrast to males, display an increased prevalence of chronic pain. Females also demonstrate weaker analgesic efficacy in response to opioid therapies when compared with males. These sex-specific differences may be driven by dimorphic endogenous opioidergic responses. In rodent models, analgesia exhibited in males but not females was reversed by inhibiting endogenous opioidergic reception. In humans, the sex-specific endogenous system(s) supporting the direct attenuation of evoked pain has not been identified. To determine whether opioidergic blockade reverses self-regulated analgesia in males as compared to females, the present study combined two operationally analogous clinical trials ( n = 98; 51 females and 47 males). In a double-blinded, counterbalanced study involving healthy ( n = 39) and chronic low back pain ( n = 59) populations, a high-dose naloxone (μ-, κ-, δ-opioid antagonist) vs. placebo-saline cross-over design (15 mg/kg bolus +0.1 mg/kg/h) tested the hypothesis that endogenous opioids mediate analgesia in males but not females. An 11-point visual analog scale (VAS) (0 = no pain; 10 = worst pain imaginable) evaluated pain ratings in response to noxious heat stimulation (49 °C; calf). After baseline pain testing, participants were randomized to a validated four-session mindfulness meditation or sham mindfulness meditation training intervention. Participants practiced their respective meditation during noxious heat, intravenous high-dose naloxone, and placebo saline, respectively. In males and females, meditation significantly lowered evoked pain during saline infusion. Intravenous naloxone inhibited analgesia in males, but pain relief was well preserved in females. The present findings indicate that endogenous opioids mediate self-regulated analgesia in males but not females and underscore the need to establish sex-specific pain therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Individual Specific Networks (ISNs) are a tool used in computational biology to infer Individual Specific relationships between biological entities from omics data. ISNs provide insights into how the interactions among these entities affect their respective functions. To address the scarcity of solutions for efficiently computing ISNs on large biological datasets, we present ISN-tractor, a data-agnostic, highly optimized Python library to build and analyse ISNs. ISN-tractor demonstrates superior scalability and efficiency in generating Individual Specific Networks (ISNs) when compared to existing methods such as LionessR, both in terms of time and memory usage, allowing ISNs to be used on large datasets. We show how ISN-tractor can be applied to real-life datasets, including The Cancer Genome Atlas (TCGA) and HapMap, showcasing its versatility. ISN-tractor can be used to build ISNs from various -omics data types, including transcriptomics, proteomics, and genotype arrays, and can detect distinct patterns of gene interactions within and across cancer types. We also show how Filtration Curves provided valuable insights into ISN characteristics, revealing topological distinctions among individuals with different clinical outcomes. Additionally, ISN-tractor can effectively cluster populations based on genetic relationships, as demonstrated with Principal Component Analysis on HapMap data., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.

DNA replication in bacteria takes place on highly compacted chromosomes, where segregation, transcription, and repair must occur simultaneously. Within this dynamic environment, colocalization of sister replisomes has been observed in many bacterial species, driving the hypothesis that a physical linker may tether them together. However, replisome splitting has also been reported in many of the same species, leaving the principles behind replisome organization a long-standing puzzle. Here, by tracking the replisome β-clamp subunit in live Caulobacter crescentus, we find that rapid DNA segregation can give rise to a second focus which resembles a replisome, but does not replicate DNA. Sister replisomes can remain colocalized, or split apart to travel along DNA separately upon disruption of chromosome inter-arm alignment. Furthermore, chromosome arm-specific replication-transcription conflicts differentially modify replication speed on the two arms, facilitate the decoupling of the two replisomes. With these observations, we conclude that the dynamic chromosome organization flexibly shapes the organization of sister replisomes, and we outline principles which can help to reconcile previously conflicting models of replisome architecture., (© 2024. The Author(s).)

The COVID-19 pandemic amplified burnout and moral distress among healthcare professionals and accentuated the systemic gaps and limitations of current approaches to workforce well-being. The Schwartz Center for Compassionate Healthcare launched the Healing Healthcare Initiative (HHI) in response to these compounded challenges. Aligned with national recommendations, the HHI framework comprises six key principles and eight implementation domains that foster compassionate and trauma-informed organizational cultures. C-suite level executive teams from six diverse healthcare organizations were selected to participate in the year-long pilot. Organizational and executive team surveys identified siloed well-being efforts and gaps in knowledge and awareness that undermine meaningful progress. The HHI pilot offers executive teams a space for reflection and open conversations, fostering trust within the team, and reinforcing the commitment to employee well-being. The program supports leadership teams in creating a strategy to implement the HHI framework that engages frontline workers in co-designing organizational solutions for a thriving workforce., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Beth Lown, MD, is Chief Medical Officer of the Schwartz Center for Compassionate Healthcare. Julie Collier, PhD, is Senior Director of Programs of the Schwartz Center for Compassionate Healthcare. Drs. Gareis and Manning are employed at Goodman Research Group, Inc., a for-profit company that was contracted by the Schwartz Center for Compassionate Healthcare to conduct an external evaluation of the Healing Healthcare Initiative. Drs. Gareis and Manning are employed by an independent external evaluation firm, Goodman Research Group, Inc.

Medical imaging-based triage is a critical tool for emergency medicine in both civilian and military settings. Ultrasound imaging can be used to rapidly identify free fluid in abdominal and thoracic cavities which could necessitate immediate surgical intervention. However, proper ultrasound image capture requires a skilled ultrasonography technician who is likely unavailable at the point of injury where resources are limited. Instead, robotics and computer vision technology can simplify image acquisition. As a first step towards this larger goal, here, we focus on the development of prototypes for ultrasound probe securement using a robotics platform. The ability of four probe adapter technologies to precisely capture images at anatomical locations, repeatedly, and with different ultrasound transducer types were evaluated across more than five scoring criteria. Testing demonstrated two of the adapters outperformed the traditional robot gripper and manual image capture, with a compact, rotating design compatible with wireless imaging technology being most suitable for use at the point of injury. Next steps will integrate the robotic platform with computer vision and deep learning image interpretation models to automate image capture and diagnosis. This will lower the skill threshold needed for medical imaging-based triage, enabling this procedure to be available at or near the point of injury., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Drug overdose deaths are a growing epidemic in the United States owing in part to inadequate support from health care systems. In response, the Veterans Health Administration (VHA) plans to implement syringe service programs (SSPs) across VHA medical centers. This SSP education project aims to positively affect health care staff perceptions regarding SSPs and reduce the stigma surrounding substance use., Objectives: The purpose of this research was to allow Advanced Pharmacy Practice Experience (APPE) students to implement and assess an educational program regarding SSP enactment at this institution. Furthermore, the objectives of the educational program were to address the stigma associated with substance use and provide knowledge to staff about SSPs., Practice Description: Eleven complete and one abbreviated (no questionnaire) presentations were delivered by APPE students throughout the main facility and outpatient clinics, with presentations being delivered to physicians, nurses, and a range of other professions., Practice Innovation: APPE students developed educational content and pre- and postsurveys that were used to assess for changes in knowledge and perception surrounding substance use and SSPs., Evaluation Methods: The primary outcome was to assess individual pre- and postprogram survey responses using mean, SD, and mean change to measure the impact that the presentation had on individualized stigma., Results: A total of 104 completed surveys were analyzed in Microsoft Excel and subcategorized by profession; 10 of the 15 questions asked in the questionnaire yielded statistical significance when comparing pre- and postpresentation results (P < 0.05)., Conclusions: A presentation method developed and delivered by APPE students resulted in a statistically significant change in perception and knowledge, proving to be an effective method for educating health care staff on SSPs., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. Government. This material is the result of work supported with resources and the use of facilities at RLR VA Medical Center, Indianapolis, Indiana., (Published by Elsevier Inc.)

Objective: To determine the impact of pet ownership on older people's decision to move to supported accommodation., Methods: Online survey., Results: Older Australians who were current or past pet owners were invited to complete an online survey, with 193 participants providing valid data. Almost two-thirds of the respondents who said they did not intend to move in the foreseeable future (n = 85) said their pet was an important reason. When asked to rate which factors would be hardest to come to terms with if they had to move because they needed more assistance in future, three groups emerged: the first group (37%) thought the impact on their pet of moving would not be difficult and the pet was not an important reason for staying in their current home. The second group (36%) were the opposite; they believed there would be a negative impact on their pet if they moved and the pet was an important reason for them to stay. The final group (27%) thought their pet was not an important reason to stay in their current location but if they did have to move, the impact on the pet would be quite difficult. No one fell into the category of identifying that their pet was an important reason to stay but having to move would have no impact on the animal., Conclusions: Many older people think about their pets when making a decision to move house, including considering whether a move to supported accommodation will be difficult for their pet. A perceived absence of pet-friendly supported accommodation may be contributing to sub-optimal decision-making by older people., (© 2024 The Authors. Australasian Journal on Ageing published by John Wiley & Sons Australia, Ltd on behalf of AJA Inc’.)

Compassion fatigue is understood as the combination of secondary traumatic stress and cumulative burnout caused by reduced ability to cope with one's environment. As such, compassion fatigue can be a significant workplace hazard for nurses in oncology. Findings from this integrative review reveal a lack of awareness and understanding of compassion fatigue among oncology nurses even if this group has been identified as high risk for experiencing compassion fatigue. Strategies such as self-care, mindfulness, and resiliency-based interventions to cope with compassion fatigue are reviewed herein along with related effectiveness. Some studies underscore that prevention-focused rather than treatment-focused interventions for compassion fatigue may be more effective. The responsibility for promoting and protecting oncology nurses' well-being is essential and must be spearheaded by organizations, administration, educational institutions, care teams, and individual nurses., (© 2024 Canadian Association of Nurses in Oncology (CANO).)