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Abstract Background Since 2013, the Veterans Health Administration (VHA) has advanced a person-centered, Whole Health (WH) System of Care, a shift from a disease-oriented system to one that prioritizes “what matters most” to patients in their lives. Whole Health is predicated on patient-provider interactions marked by a multi-level understanding of health and trusted relationships that promote well-being. Presently, WH implementation has been focused largely in primary care settings, yet the goal is to effect a system-wide transformation of care so that Veterans receive WH across VHA clinical settings, including specialty care. This sort of system-wide cultural transformation is difficult to implement. Methods This three-aim mixed methods study will result in a co-designed implementation blueprint for spreading WH from primary to specialty care settings. Taking HIV specialty care as an illustrative case- because of its diverse models of relationships to primary care - to explore how to spread WH through specialty care settings. We will use the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework to organize quantitative and qualitative data and identify key determinants of WH receipt among Veterans living with HIV. Through a co-design process, we develop an adaptable implementation blueprint that identifies and matches implementation strategies to different HIV specialty care configurations. Discussion This study will co-design a flexible implementation blueprint for spreading WH from VHA primary care throughout HIV specialty care settings. This protocol contributes to the science of end-user engagement while also answering calls for greater transparency in how implementation strategies are identified, tailored, and spread.

Abstract INTRODUCTION Depression is a risk factor and possible prodromal symptom of Alzheimer's disease (AD), but little is known about subsequent risk of developing depression in persons with AD. METHODS National matched cohort study was conducted of all 129,410 persons diagnosed with AD and 390,088 with all‐cause dementia during 1998–2017 in Sweden, and 3,900,880 age‐ and sex‐matched controls without dementia, who had no prior depression. Cox regression was used to compute hazard ratios (HRs) for major depression through 2018. RESULTS Cumulative incidence of major depression was 13% in persons with AD and 3% in controls. Adjusting for sociodemographic factors and comorbidities, risk of major depression was greater than two‐fold higher in women with AD (HR, 2.21; 95% confidence interval [CI], 2.11–2.32) or men with AD (2.68; 2.52–2.85), compared with controls. Similar results were found for all‐cause dementia. DISCUSSION Persons diagnosed with AD or related dementias need close follow‐up for timely detection and treatment of depression. Highlights In a large cohort, women and men with AD had >2‐fold subsequent risk of depression. Risks were highest in the first year (>3‐fold) but remained elevated ≥3 years later. Risk of depression was highest in persons aged ≥85 years at AD diagnosis. Persons with AD need close follow‐up for detection and treatment of depression.

Abstract Neurophysiological studies suggest that intrinsic brain oscillations influence sensory processing, especially of rhythmic stimuli like speech. Prior work suggests that brain rhythms may mediate perceptual grouping and selective attention to speech amidst competing sound, as well as more linguistic aspects of speech processing like predictive coding. However, we know of no prior studies that have directly tested, at the single-trial level, whether brain oscillations relate to speech-in-noise outcomes. Here, we combined electroencephalography while simultaneously measuring intelligibility of spoken sentences amidst two different interfering sounds: multi-talker babble or speech-shaped noise. We find that induced parieto-occipital alpha (7–15 Hz; thought to modulate attentional focus) and frontal beta (13–30 Hz; associated with maintenance of the current sensorimotor state and predictive coding) oscillations covary with trial-wise percent-correct scores; importantly, alpha and beta power provide significant independent contributions to predicting single-trial behavioral outcomes. These results can inform models of speech processing and guide noninvasive measures to index different neural processes that together support complex listening.

Background There is increasing recognition of the need to focus on the health and well-being of healthcare employees given high rates of burnout and turnover. Employee wellness programs are effective at addressing these issues; however, participation in these programs is often a challenge and requires large scale organizational transformation. The Veterans Health Administration (VA) has begun to roll out their own employee wellness program—Employee Whole Health (EWH)—focused on the holistic needs of all employees. This evaluation’s goal was to use the Lean Enterprise Transformation (LET) model for organizational transformation to identify key factors—facilitators and barriers—affecting the implementation of VA EWH. Methods This cross-sectional qualitative evaluation based on the action research model reflects on the organizational implementation of EWH. Semi-structured 60-minute phone interviews were conducted in February-April 2021 with 27 key informants (e.g., EWH coordinator, wellness/occupational health staff) knowledgeable about EWH implementation across 10 VA medical centers. Operational partner provided a list of potential participants, eligible because of their involvement in EWH implementation at their site. The interview guide was informed by the LET model. Interviews were recorded and professionally transcribed. Constant comparative review with a combination of a priori coding based on the model and emergent thematic analysis was used to identify themes from transcripts. Matrix analysis and rapid turnaround qualitative methods were used to identify cross-site factors to EWH implementation. Results Eight common factors in the conceptual model were found to facilitate and/or hinder EWH implementation efforts: [1] EWH initiatives, [2] multilevel leadership support, [3] alignment, [4] integration, [5] employee engagement, [6] communication, [7] staffing, and [8] culture. An emergent factor was [9] the impact of the COVID-19 pandemic on EWH implementation. Conclusions As VA expands its EWH cultural transformation nationwide, evaluation findings can (a) enable existing programs to address known implementation barriers, and (b) inform new sites to capitalize on known facilitators, anticipate and address barriers, and leverage evaluation recommendations through concerted implementation at the organization, process, and employee levels to jump-start their EWH program implementation.

Summary: Background: Hypoglycaemia from diabetes treatment causes morbidity and lower quality of life, and prevention should be routinely addressed in clinical visits. Methods: This mixed methods study evaluated how primary care providers (PCPs) assess for and prevent hypoglycaemia by analyzing audio-recorded visits from five Veterans Affairs medical centres in the US. Two investigators independently coded visit dialogue to classify discussions of hypoglycaemia history, anticipatory guidance, and adjustments to hypoglycaemia-causing medications according to diabetes guidelines. Findings: There were 242 patients (one PCP visit per patient) and 49 PCPs. Two thirds of patients were treated with insulin and 40% with sulfonylureas. Hypoglycaemia history was discussed in 78/242 visits (32%). PCPs provided hypoglycaemia anticipatory guidance in 50 visits (21%) that focused on holding diabetes medications while fasting and carrying glucose tabs; avoiding driving and glucagon were not discussed. Hypoglycaemia-causing medications were de-intensified or adjusted more often (p

Abstract Purpose This study explored Veteran and family member perspectives on factors that drive post-traumatic stress disorder (PTSD) therapy engagement within constructs of the Andersen model of behavioral health service utilization. Despite efforts by the Department of Veterans Affairs (VA) to increase mental health care access, the proportion of Veterans with PTSD who engage in PTSD therapy remains low. Support for therapy from family members and friends could improve Veteran therapy use. Methods We applied a multiple methods approach using data from VA administrative data and semi-structured individual interviews with Veterans and their support partners who applied to the VA Caregiver Support Program. We integrated findings from a machine learning analysis of quantitative data with findings from a qualitative analysis of the semi-structured interviews. Results In quantitative models, Veteran medical need for health care use most influenced treatment initiation and retention. However, qualitative data suggested mental health symptoms combined with positive Veteran and support partner treatment attitudes motivated treatment engagement. Veterans indicated their motivation to seek treatment increased when family members perceived treatment to be of high value. Veterans who experienced poor continuity of VA care, group, and virtual treatment modalities expressed less care satisfaction. Prior marital therapy use emerged as a potentially new facilitator of PTSD treatment engagement that warrants more exploration. Conclusions Our multiple methods findings represent Veteran and support partner perspectives and show that amid Veteran and organizational barriers to care, attitudes and support of family members and friends still matter. Family-oriented services and intervention could be a gateway to increase Veteran PTSD therapy engagement.

Abstract Background The Veterans Health Administration (VHA) is building a Whole Health system of care that aspires to empower and equip each Veteran to pursue a personally meaningful vision of health and well‐being. As part of this effort, VHA has developed Taking Charge of My Life and Health (TCMLH), a peer‐led, group‐based programme that seeks to support Veterans in setting and pursuing health and well‐being goals. Prior research showed TCMLH groups to positively impact Veteran outcomes; yet, little is known about Veterans' own experiences and perspectives. Methods We completed semi‐structured telephone interviews with 15 Veterans across 8 sites who had participated in TCMLH groups offered by the VHA in the virtual format between Summer 2020 and Fall 2021. Inductive thematic analysis was applied to interview transcripts to generate themes. Findings We identified five themes regarding Veterans' experiences with TCMLH: (1) navigating the virtual format; (2) internalizing the value of health engagement; (3) making healthy lifestyle changes; (4) forging social connections; and (5) taking on a more active role in healthcare. Conclusion Veterans perceived virtual TCMLH groups as meaningful and beneficial, yet also highlighted several challenges. Their perspectives speak to the need to supplement time‐limited programmes like TCMLH with ongoing, community‐based support. Virtual group‐based well‐being programmes are a promising innovation. Other healthcare systems may draw on VHA's experience while tailoring format and content to the needs of their patient populations. Patient or Public Contribution Veterans were involved as evaluation participants. A Veteran consultant, who is a coauthor on this paper, was engaged through the conceptualization of the evaluation, development of data collection materials (interview guide) and writing.

Abstract Introduction Infectious diseases are common causes of morbidity and mortality worldwide. Susceptibility to infection is highly heritable; however, little has been done to identify the genetic determinants underlying common infectious diseases. One GWAS was performed using 23andMe information about self-reported infections; we set out to confirm previous loci and identify new ones using medically diagnosed infections. Methods We used the electronic health record (EHR)-based biobank at Vanderbilt and diagnosis codes to identify cases of 12 infectious diseases in white patients: urinary tract infection, pneumonia, chronic sinus infections, otitis media, candidiasis, streptococcal pharyngitis, herpes zoster, herpes labialis, hepatitis B, infectious mononucleosis, tuberculosis (TB) or a positive TB test, and hepatitis C. We selected controls from patients with no diagnosis code for the candidate disease and matched by year of birth, sex, and calendar year at first and last EHR visits. We conducted GWAS using SAIGE and transcriptome-wide analysis (TWAS) using S-PrediXcan. We also conducted phenome-wide association study to understand associations between identified genetic variants and clinical phenotypes. Results We replicated three 23andMe loci (p ≤ 0.05): herpes zoster and rs7047299-A (p = 2.6 × 10–3) and rs2808290-C (p = 9.6 × 10–3;); otitis media and rs114947103-C (p = 0.04). We also identified 2 novel regions (p ≤ 5 × 10–8): rs113235453-G for otitis media (p = 3.04 × 10–8), and rs10422015-T for candidiasis (p = 3.11 × 10–8). In TWAS, four gene-disease associations were significant: SLC30A9 for otitis media (p = 8.06 × 10–7); LRP3 and WDR88 for candidiasis (p = 3.91 × 10–7 and p = 1.95 × 10–6); and AAMDC for hepatitis B (p = 1.51 × 10–6). Conclusion We conducted GWAS and TWAS for 12 infectious diseases and identified novel genetic contributors to the susceptibility of infectious diseases.

Herpesvirus entry requires the coordinated action of at least four viral glycoproteins. Virus-specific binding to a cellular receptor triggers a membrane fusion cascade involving the conserved gH/gL complex and gB. Although gB is the genuine herpesvirus fusogen, it requires gH/gL for fusion, but how activation occurs is still unclear. To study the underlying mechanism, we used a gL-deleted pseudorabies virus (PrV) mutant characterized by its limited capability to directly infect neighboring cells that was exploited for several independent serial passages in cell culture. Unlike previous revertants that acquired mutations in the gL-binding N-terminus of gH, we obtained a variant, PrV-ΔgLPassV99, that unexpectedly contained two amino acid substitutions in the gH transmembrane domain (TMD). One of these mutations, I662S, was sufficient to compensate for gL function in virus entry and in in vitro cell–cell fusion assays in presence of wild type gB, but barely for cell-to-cell spread. Additional expression of receptor-binding PrV gD, which is dispensable for cell–cell fusion mediated by native gB, gH and gL, resulted in hyperfusion in combination with gH V99. Overall, our results uncover a yet-underestimated role of the gH TMD in fusion regulation, further shedding light on the complexity of herpesvirus fusion involving all structural domains of the conserved entry glycoproteins.

Abstract Background The opioid crisis has necessitated new approaches to managing chronic pain. The Veterans Health Administration (VHA) Whole Health model of care, with its focus on patient empowerment and emphasis on nonpharmacological approaches to pain management, is a promising strategy for reducing patients’ use of opioids. We aim to assess whether the VHA’s Whole Health pilot program impacted longitudinal patterns of opioid utilization among patients with chronic musculoskeletal pain. Methods A cohort of 4,869 Veterans with chronic pain engaging in Whole Health services was compared with a cohort of 118,888 Veterans receiving conventional care. All patients were continuously enrolled in VHA care from 10/2017 through 3/2019 at the 18 VHA medical centers participating in the pilot program. Inverse probability of treatment weighting and multivariate analyses were used to adjust for observable differences in patient characteristics between exposures and conventional care. Patients exposed to Whole Health services were offered nine complementary and integrative health therapies alone or in combination with novel Whole Health services including goal-setting clinical encounters, Whole Health coaching, and personal health planning. Main measures The main measure was change over an 18-month period in prescribed opioid doses starting from the six-month period prior to qualifying exposure. Results Prescribed opioid doses decreased by -12.0% in one year among Veterans who began complementary and integrative health therapies compared to similar Veterans who used conventional care; -4.4% among Veterans who used only Whole Health services such as goal setting and coaching compared to conventional care, and -8.5% among Veterans who used both complementary and integrative health therapies combined with Whole Health services compared to conventional care. Conclusions VHA’s Whole Health national pilot program was associated with greater reductions in prescribed opioid doses compared to secular trends associated with conventional care, especially when Veterans were connected with complementary and integrative health therapies.

Asymmetric inheritance of organelles, proteins and RNAs occurs during stem cell division. Here the authors show the strength of pairing of homologous Stat92E loci, a stem cell-specific gene, changes immediately after the asymmetric division due to asymmetric inheritance of new histones to one of the daughter cells and is important for turning off gene expression in this cell as it differentiates.

Abstract Background The 2016 U.S. Centers for Disease Control Opioid Prescribing Guideline (CDC Guideline) is currently being revised amid concern that it may be harmful to people with chronic pain on long-term opioid therapy (CP-LTOT). However, a methodology to faithfully implement the CDC guideline, measure prescriber adherence, and systematically test its effect on patient and public health outcomes is lacking. We developed and tested a CDC Guideline implementation strategy (termed TOWER), focusing on an outpatient HIV-focused primary care setting. Methods TOWER was developed in a stakeholder-engaged, multi-step iterative process within an Information, Motivation and Behavioral Skills (IMB) framework of behavior change. TOWER consists of: 1) a patient-facing opioid management app (OM-App); 2) a progress note template (OM-Note) to guide the office visit; and 3) a primary care provider (PCP) training. TOWER was evaluated in a 9-month, randomized-controlled trial of HIV-PCPs (N = 11) and their patients with HIV and CP-LTOT (N = 40). The primary outcome was CDC Guideline adherence based on electronic health record (EHR) documentation and measured by the validated Safer Opioid Prescribing Evaluation Tool (SOPET). Qualitative data including one-on-one PCP interviews were collected. We also piloted patient-reported outcome measures (PROMs) reflective of domains identified as important by stakeholders (pain intensity and function; mood; substance use; medication use and adherence; relationship with provider; stigma and discrimination). Results PCPs randomized to TOWER were 48% more CDC Guideline adherent (p

Abstract Background The yeast genus Komagataella currently consists of seven methylotrophic species isolated from tree environments. Well-characterized strains of K. phaffii and K. pastoris are important hosts for biotechnological applications, but the potential of other species from the genus remains largely unexplored. In this study, we characterized 25 natural isolates from all seven described Komagataella species to identify interesting traits and provide a comprehensive overview of the genotypic and phenotypic diversity available within this genus. Results Growth tests on different carbon sources and in the presence of stressors at two different temperatures allowed us to identify strains with differences in tolerance to high pH, high temperature, and growth on xylose. As Komagataella species are generally not considered xylose-utilizing yeasts, xylose assimilation was characterized in detail. Growth assays, enzyme activity measurements and 13C labeling confirmed the ability of K. phaffii to utilize D-xylose via the oxidoreductase pathway. In addition, we performed long-read whole-genome sequencing to generate genome assemblies of all Komagataella species type strains and additional K. phaffii and K. pastoris isolates for comparative analysis. All sequenced genomes have a similar size and share 83–99% average sequence identity. Genome structure analysis showed that K. pastoris and K. ulmi share the same rearrangements in difference to K. phaffii, while the genome structure of K. kurtzmanii is similar to K. phaffii. The genomes of the other, more distant species showed a larger number of structural differences. Moreover, we used the newly assembled genomes to identify putative orthologs of important xylose-related genes in the different Komagataella species. Conclusions By characterizing the phenotypes of 25 natural Komagataella isolates, we could identify strains with improved growth on different relevant carbon sources and stress conditions. Our data on the phenotypic and genotypic diversity will provide the basis for the use of so-far neglected Komagataella strains with interesting characteristics and the elucidation of the genetic determinants of improved growth and stress tolerance for targeted strain improvement.

Abstract Background Parkinson’s disease (PD) complexity poses challenges for individuals with Parkinson’s, providers, and researchers. A recent multisite randomized trial of a proactive, telephone-based, nurse-led care management intervention - Care Coordination for Health Promotion and Activities in Parkinson’s Disease (CHAPS) - demonstrated improved PD care quality. Implementation details and supportive stakeholder feedback were subsequently published. To inform decisions on dissemination, CHAPS Model components require evaluations of their fidelity to the Chronic Care Model and to their implementation. Additionally, assessment is needed on whether CHAPS addresses care challenges cited in recent literature. Methods These analyses are based on data from a subset of 140 intervention arm participants and other CHAPS data. To examine CHAPS Model fidelity, we identified CHAPS components corresponding to the Chronic Care Model’s six essential elements. To assess implementation fidelity of these components, we examined data corresponding to Hasson’s modified implementation fidelity framework. Finally, we identified challenges cited in current Parkinson’s care management literature, grouped these into themes using open card sorting techniques, and examined CHAPS data for evidence that CHAPS met these challenges. Results All Chronic Care Model essential elements were addressed by 17 CHAPS components, thus achieving CHAPS Model fidelity. CHAPS implementation fidelity was demonstrated by adherence to content, frequency, and duration with partial fidelity to telephone encounter frequency. We identified potential fidelity moderators for all six of Hasson’s moderator types. Through card sorting, four Parkinson’s care management challenge themes emerged: unmet needs and suggestions for providers (by patient and/or care partner), patient characteristics needing consideration, and standardizing models for Parkinson’s care management. CHAPS activities and stakeholder perceptions addressed all these themes. Conclusions CHAPS, a supportive nurse-led proactive Parkinson’s care management program, improved care quality and is designed to be reproducible and supportive to clinicians. Findings indicated CHAPS Model fidelity occurred to the Chronic Care Model and fidelity to implementation of the CHAPS components was demonstrated. Current Parkinson’s care management challenges were met through CHAPS activities. Thus, dissemination of CHAPS merits consideration by those responsible for implementing changes in clinical practice and reaching people in need. Trial registration ClinicalTrials.gov as NCT01532986 , registered on January 13, 2012.

Background The Veterans Health Administration (VA) is undergoing a transformation in how healthcare is organized and provided. This transformation to a Whole Health System of Care encompasses the integration of complementary and integrative health services, education, and Whole Health coaching to develop Veterans’ self-care skills. During the COVID-19 pandemic, these services were provided via telehealth (tele-WH). Objective We sought to understand Veteran and provider perspectives on how tele-WH impacts Veteran engagement in Whole Health-aligned services and the impact on their well-being. Methods Semi-structured interviews were conducted with 51 providers who delivered tele-WH at 10 VA Medical Centers (VAMCs) and 19 Veterans receiving tele-WH at 6 VAMCs. Participants were asked about their experiences with tele-WH, what they perceived to be the impact of tele-WH on Veterans, and their preferences moving forward. Interviews were transcribed, and a content analysis was performed using a rapid approach. Results We identified 3 major themes that describe the perceived impact of tele-WH on Veterans. These include: (1) increased use of Whole Health-aligned services; (2) deeper engagement with Whole-Health aligned services; and (3) improvements in social, psychological, and physical well-being. Conclusion Tele-WH is perceived to be a strong complement to in-person services and is a promising mechanism for improving engagement with Whole Health-aligned services and promoting Veteran well-being. Future research is needed to measure outcomes identified in this study and to support more equitable access to telehealth for all.

African swine fever is a viral disease of swine caused by the African swine fever virus (ASFV). Currently, ASFV is spreading over the Eurasian continent and threatening global pig husbandry. One viral strategy to undermine an efficient host cell response is to establish a global shutoff of host protein synthesis. This shutoff has been observed in ASFV-infected cultured cells using two-dimensional electrophoresis combined with metabolic radioactive labeling. However, it remained unclear if this shutoff was selective for certain host proteins. Here, we characterized ASFV-induced shutoff in porcine macrophages by measurement of relative protein synthesis rates using a mass spectrometric approach based on stable isotope labeling with amino acids in cell culture (SILAC). The impact of ASFV infection on the synthesis of >2000 individual host proteins showed a high degree of variability, ranging from complete shutoff to a strong induction of proteins that are absent from naïve cells. GO-term enrichment analysis revealed that the most effective shutoff was observed for proteins related to RNA metabolism, while typical representatives of the innate immune system were strongly induced after infection. This experimental setup is suitable to quantify a virion-induced host shutoff (vhs) after infection with different viruses.

Abstract The negative effects of lignocellulose-derived inhibitors such as acetic acid and furaldehydes on microbial metabolism constitute a significant drawback to the usage of biomass feedstocks for the production of fuels and chemicals. The yeast Pichia pastoris has shown a great biotechnological potential for producing heterologous proteins and renewable chemicals. Despite its relevance, the performance of P. pastoris in presence of lignocellulose-derived inhibitors remains unclear. In this work, our results show for the first time the dose-dependent response of P. pastoris to acetic acid, furaldehydes (HMF and furfural), and sugarcane biomass hydrolysate, both at physiological and transcriptional levels. The yeast was able to grow in synthetic media with up to 6 g.L−1 acetic acid, 1.75 g.L−1 furaldehydes or hydrolysate diluted to 10% (v/v). However, its metabolism was completely hindered in presence of hydrolysate diluted to 30% (v/v). Additionally, the yeast was capable to co-consume acetic acid and glucose. At the transcriptional level, P. pastoris response to lignocellulose-derived inhibitors relays on the up-regulation of genes related to transmembrane transport, oxidoreductase activities, RNA processing, and the repression of pathways related to biosynthetic processes and central carbon metabolism. These results demonstrate a polygenetic response that involves detoxification activities, and maintenance of energy and cellular homeostasis. In this context, ALD4, OYE3, QOR2, NTL100, YCT1, and PPR1 were identified as target genes to improve P. pastoris tolerance. Altogether, this work provides valuable insights into the P. pastoris stress tolerance, which can be useful to expand its use in different bioprocesses.

Abstract Background Communication between health authorities and healthcare providers is an essential element of the response to public health emergencies. Although call centers can facilitate such communication, no published reports describing their outcomes exist. In advance of the expected COVID-19 outbreak in Israel, the Israel Center for Disease Control established a call center dedicated to queries from healthcare professionals. Methods The call center operated from February 5, 2020 (week 6) to May 14, 2020 (week 20). Data on calls received, including date and time, caller characteristics, questions and responses were recorded in a database designed for this purpose. The volume, sources and content of queries were analyzed. Results In 15 weeks of operation, the call center responded to 6623 calls. The daily number of calls ranged from 1 to 371 (mean 79.8, median 40), peaking on week 12, 2 weeks prior to a peak in new COVID-19 cases. Callers were predominantly physicians (62.4%), nurses (18.7%) and administrators (4.4%). Most worked in primary care clinics (74.2%) or hospitals (8.7%). Among physicians, 42.3% were family physicians or internists, and 10.0% were pediatricians. The issues most commonly addressed were home quarantine (21.6%), criteria for suspected cases (20.6%), and SARS-CoV2 testing (14.1%). Twenty-five percent of questions involved requests for clarifications of MOH guidelines regarding travel restrictions, clinic management, triage of symptomatic patients, routine medical and dental care, recommended precautions for health care workers with preexisting medical conditions, and other matters. A total of 119 queries were not resolved on the basis of existing guidelines and were referred to MOH headquarters. Conclusions This is the first report of a call center established to serve the needs of healthcare providers seeking guidance on COVID-19 management, and to facilitate communication of providers’ concerns to the central health authority. Our work indicates that a central call center for healthcare providers can facilitate the development, implementation and amendment of guidelines and should be an integral element of the early response to public health emergencies. Real-time analysis of the call data may reveal important trends requiring prompt attention.

Abstract Background A recent nurse-led proactive care management intervention, Care Coordination for Health Promotion and Activities in Parkinson Disease (CHAPS), improved care quality when compared to usual care in a randomized controlled trial. Therefore, stakeholder (patient participants, nurse care managers, and Parkinson disease (PD) specialists) perceptions of key intervention components merit evaluation to inform decisions about dissemination. Methods This multi-site study occurred in five southwest United States Veterans Health Administration medical centers. Stakeholders were surveyed on their perceptions of CHAPS including the CHAPS Assessment, CHAPS nurse care managers, the Siebens Domain Management Model™ (a practical clinical model), and the Siebens Health Care Notebook (Notebook) (self-care tool). Participants’ electronic medical records were abstracted for perceptions of the Notebook. Statistical analysis software was used to provide summary statistics; open card sorting methodology was used to identify themes and attributes in qualitative data including usability of some components. Results Participants, overall, highly rated their medication self-management, acknowledged some challenges with the CHAPS self-care tools, reported knowledge of PD specialist follow-up and PD red flags, and rated CHAPS nurse care managers as helpful. Nurse care manager responses indicated the CHAPS Assessment and Program highly facilitated care of their patients. Most all PD specialists would refer other patients to CHAPS. Nurse care manager and PD specialist responses indicated improved participant management of their PD. Three themes emerged in participant perceptions of the Notebook: Notebook Assets (e.g., benefits and features-liked); Deferring Notebook Review (e.g., no time to review); and Reasons for Not Using (e.g., participant preference). Shared attributes regarding the Siebens Domain Management Model and Notebook usability, reported by nurse care managers, were user-friendly, person/patient-centered, and organized. Some challenges to their use were also reported. Conclusions Overall, stakeholder perceptions of the proactive nurse-led CHAPS intervention indicated its value in the care of individuals with PD. Responses about the CHAPS Assessment, Siebens Domain Management Model, and Notebook self-care tool signified their usefulness. Stakeholders’ constructive suggestions indicated their engagement in CHAPS. These findings support CHAPS dissemination and contribute to research in care management. Trial registration ClinicalTrials.gov as NCT01532986 , registered on January 13, 2012.

Abstract Background A recent nurse-led, telephone-administered 18-month intervention, Care Coordination for Health Promotion and Activities in Parkinson’s Disease (CHAPS), was tested in a randomized controlled trial and improved care quality. Therefore, intervention details on nurse care manager activity (types and frequencies) and participant actions are needed to support potential dissemination. Activities include nurse care manager use of a holistic organizing framework, identification of Parkinson's disease (PD)-related problems/topics, communication with PD specialists and care coordination, participant coaching, and participant self-care actions including use of a notebook self-care tool. Methods This article reports descriptive data on the CHAPS intervention. The study setting was five sites in the Veterans Affairs Healthcare System. Sociodemographic data were gathered from surveys of study participants (community-dwelling veterans with PD). Nurse care manager intervention activities were abstracted from electronic medical records and logbooks. Statistical analysis software was used to provide summary statistics; closed card sorting was used to group some data. Results Intervention participants (n = 140) were primarily men, mean age 69.4 years (standard deviation 10.3) and community-dwelling. All received the CHAPS Initial Assessment, which had algorithms designed to identify 31 unique CHAPS standard problems/topics. These were frequently documented (n = 4938), and 98.6% were grouped by assigned domain from the Organizing Framework (Siebens Domain Management Model™). Nurse care managers performed 27 unique activity types to address identified problems, collaborating with participants and PD specialists. The two most frequent unique activities were counseling/emotional support (n = 387) and medication management (n = 349). Both were among 2749 total performed activities in the category Implementing Interventions (coaching). Participants reported unique self-care action types (n = 23) including use of a new notebook self-care tool. Conclusions CHAPS nurse care managers implemented multiple activities including participant coaching and care coordination per the CHAPS protocol. Participants reported various self-care actions including use of a personalized notebook. These findings indicate good quality and extent of implementation, contribute to ensuring reproducibility, and support CHAPS dissemination as a real-world approach to improve care quality. Trial registration ClinicalTrials.gov as NCT01532986 , registered on January 13, 2012.

Developments in wearable human medical and sports health trackers has offered new solutions to challenges encountered by eco-physiologists attempting to measure physiological attributes in freely moving animals. Near-infrared spectroscopy (NIRS) is one such solution that has potential as a powerful physio-logging tool to assess physiology in freely moving animals. NIRS is a non-invasive optics-based technology, that uses non-ionizing radiation to illuminate biological tissue and measures changes in oxygenated and deoxygenated hemoglobin concentrations inside tissues such as skin, muscle, and the brain. The overall footprint of the device is small enough to be deployed in wearable physio-logging devices. We show that changes in hemoglobin concentration can be recorded from bottlenose dolphins and gray seals with signal quality comparable to that achieved in human recordings. We further discuss functionality, benefits, and limitations of NIRS as a standard tool for animal care and wildlife tracking for the marine mammal research community.

Objective Veterans Healthcare Administration (VHA) conducted a large demonstration project of a holistic Whole Health approach to care in 18 medical centers, which included making complementary and integrative health (CIH) therapies more widely available. This evaluation examines patterns of service use among Veterans with chronic pain, comparing those with and without PTSD. Methods We assessed the use of Whole Health services in a cohort of Veterans with co-occurring chronic pain and PTSD ( n = 1698; 28.9%), comparing them to Veterans with chronic musculoskeletal pain only (n = 4170; 71.1%). Data was gathered from VA electronic medical records and survey self-report. Whole Health services were divided into Core Whole Health services (e.g., Whole Health coaching) and CIH services (e.g., yoga). Logistic regression was used to determine whether Veterans with co-occurring chronic pain and PTSD utilized more Whole Health services compared to Veterans with chronic pain but without PTSD. Results A total of 40.1% of Veterans with chronic pain and PTSD utilized Core Whole Health services and 53.2% utilized CIH therapies, compared to 28.3% and 40.0%, respectively, for Veterans with only chronic pain. Adjusting for demographics and additional comorbidities, Veterans with comorbid chronic pain and PTSD were 1.24 ( 95% CI : 1.12, 1.35, P ≤ .001) times more likely than Veterans with chronic pain only to use Core Whole Health services, and 1.23 ( 95% CI: 1.14, 1.31, P ≤ .001) times more likely to use CIH therapies. Survey results also showed high interest levels in Core Whole Health services and CIH therapies among Veterans who were not already using these services. Conclusion Early implementation efforts in VHA led to high rates of use of Core Whole Health and CIH therapy use among Veterans with co-occurring chronic pain and PTSD. Future assessments should examine how well these additional services are meeting the needs of Veterans in both groups.

Most people with cystic fibrosis (CF) are diagnosed following abnormal newborn screening (NBS), which begins with measurement of immunoreactive trypsinogen (IRT) values. A case report found low concentrations of IRT in an infant with CF exposed to the CF transmembrane conductance regulator (CFTR) modulator, elexacaftor–tezacaftor–ivacaftor (ETI), in utero. However, IRT values in infants born to mothers taking ETI have not been systematically assessed. We hypothesized that ETI-exposed infants have lower IRT values than newborns with CF, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID), or CF carriers. IRT values were collected from infants born in Indiana between 1 January 2020, and 2 June 2022, with ≥1 CFTR mutation. IRT values were compared to infants born to mothers with CF taking ETI followed at our institution. Compared to infants identified with CF (n = 51), CRMS/CFSPID (n = 21), and CF carriers (n = 489), ETI-exposed infants (n = 19) had lower IRT values (p < 0.001). Infants with normal NBS results for CF had similar median (interquartile range) IRT values, 22.5 (16.8, 30.6) ng/mL, as ETI-exposed infants, 18.9 (15.2, 26.5). IRT values from ETI-exposed infants were lower than for infants with abnormal NBS for CF. We recommend that NBS programs consider performing CFTR variant analysis for all ETI-exposed infants.

AllS single stars that are born with masses up to 8.5–10 M _⊙ will end their lives as white dwarf (WD) stars. In this evolutionary stage, WDs enter the cooling sequence, where the stars radiate away their thermal energy and are basically cooling. As these stars cool, they reach temperatures and conditions that cause the stars to pulsate. Using differential photometry to produce light curves, we can determine the observed periods of pulsation from the WD. We used the White Dwarf Evolution Code (WDEC) to calculate a grid of over one million models with various temperature, stellar mass, and mass of helium and hydrogen layers and calculated their theoretical pulsation periods. In this paper, we describe our approach to WD asteroseismology using WDEC models, and we present seismological studies for 29 observed DAVs in the Kepler and K2 data sets, 25 of which have never been analyzed using these observations and 19 of which have never been seismically analyzed in any capacity before. Learning about the internal structure of WDs places important constraints on the WD cooling sequence and our overall understanding of stellar evolution for low-mass stars.

Transcranial electrical stimulation (tES) is a non-invasive neuromodulatory technique that alters ongoing neural dynamics by injecting an exogenous electrical current through the scalp. Although tES protocols are becoming more common in both clinical and experimental settings, the neurophysiological mechanisms through which tES modulates cortical dynamics are unknown. Most existing tES protocols ignore the potential effect of phasic interactions between endogenous and exogenous currents by stimulating in an open-looped fashion. To better understand the mechanisms of closed-loop tES, we first instantiated a two-column Jansen and Rit model to simulate neuronal dynamics of pyramidal cells and interneurons. An echo-state network (ESN) reservoir computer inverted the dynamics of the model without access to the internal state equations. After inverting the model dynamics, the ESN was used as a closed-loop feedback controller for the neural mass model by predicting the current stimulation input for a desired future output. The ESN was used to predict the endogenous membrane currents of the model from the observable pyramidal cell membrane potentials and then inject current stimulation to destructively interfere with endogenous membrane currents, thereby reducing the energy of the PCs. This simulation approach provides a framework for a model-free closed-loop feedback controller in tES experiments.

Purpose. We investigated how health care systems should communicate with patients about possible exposures to blood-borne pathogens that may have occurred during their care. Our goal was to determine how best to communicate uncertain risk information in a way that would minimize harm to patients, maintain their trust, and encourage patients to seek follow-up treatment. Methods. Participants ( N = 1103) were randomized to receive one of six vignette surveys; 997 (98.4%) responded. All vignettes described the same event, but differed by risk level and recommendations (lower risk v. higher risk) and by communication mode (telephone, letter, social media). We measured participants’ perceived risk of blood-borne infection, trust in the health care system, and shared decision making about next clinical steps. Open-ended questions were analyzed using grounded thematic analysis. Results. When the vignette requested patients to undergo testing and practice certain health behaviors (higher risk), participants’ likelihood of seeking follow-up testing for blood-borne pathogens and their understanding of health issues increased. Perceived trust was unaffected by risk level or communication processes. Qualitative data indicated a desire for telephone communication from providers known to the patient. Limitations. It is not clear whether higher risk language or objective risk levels in vignettes motivated patients’ behavioral intentions. Conclusion. Using higher risk language when disclosing large-scale adverse events increased participants’ willingness to seek follow-up care. Implications. Health care organizations’ disclosures should focus on the next steps to take after health care exposures. This communication should involve helping patients to understand their personal health issues better, make them feel that they know which steps to take following the receipt of this information, and encouraging them to seek follow-up infectious disease testing in order to better take care of themselves.

This review discusses the links between the newly introduced concepts of digital twins and more classical finite element modeling, reduced order models, parametric modeling, inverse analysis, machine learning, and parameter identification. The purpose of this article is to demonstrate that development, as almost always is the case, is based on previously developed tools that are currently exploited since the technological tools for their implementation are available and the needs of their usage appear. This fact has rarely been declared clearly in the available literature. The need for digital twins in infrastructures arises due to the extreme loadings applied on energy-related infrastructure and to the higher importance that fatigue effects have. Digital twins promise to provide reliable and affordable models that accompany the structure throughout its whole lifetime, make fatigue and degradation prediction more reliable, and support effective predictive maintenance schemes.

The class III fusion protein glycoprotein B (gB) drives membrane fusion during entry and spread of herpesviruses. To mediate fusion, gB requires activation by the conserved gH/gL complex by a poorly defined mechanism.

Intimate partner violence (IPV) perpetrators were categorized based on whether they were generally violent (GV) or family only violent (FO) using self-report or arrest records. Classification criteria to assess recidivism in perpetrators of IPV were evaluated herein to determine the incremental validity of using a perpetrator’s criminal history in addition to their self-report information for categorization purposes. The concordance rates for categorizing subtypes of male perpetrators were compared for two methods, namely, self-report versus criminal history data. Categorizations were made based on self-reported history of violence and federal criminal records separately. Between measures consistency was defined as whether or not the self-report categorizations matched federal criminal record categorizations. It was hypothesized that self-report would not be sufficient as the sole method of categorizing male perpetrators, and the use of criminal history data would add to the validity of the categorization system. Self-reports of aggression were higher than criminal records of aggression. Using data sources together may yield the best outcomes for offenders and society. Implications are discussed.

Background The extreme southwest of Australia is a biodiversity hotspot region that has a Mediterranean-type climate and numerous endemic plant and animal species, many of which remain to be properly delimited. We refine species limits in Anarthria, a Western Australian endemic genus characterised by the occurrence of the greatest number of plesiomorphic character states in the restiid clade of Poales. In contrast to many other groups of wind-pollinated Australian Poales, Anarthria was traditionally viewed as having well-established species limits. All six currently recognised species, which are conspicuous members of some Western Australian plant communities, were described in the first half of the 19th century. They are traditionally distinguished from each other mainly using quantitative characters. Methods We examined extensive existing herbarium specimens and made new collections of Anarthria in nature. Scanning electron microscopy and light microscopy were used to study leaf micromorphology. Molecular diversity of Anarthria was examined using a plastid (trnL-F) and a low-copy nuclear marker (at103). This is the first study of species-level molecular diversity in the restiid clade using a nuclear marker. Results Material historically classified as Anarthria gracilis R.Br. actually belongs to three distinct species, A. gracilis s.str., A. grandiflora Nees and A. dioica (Steud.) C.I.Fomichev, each of which forms a well-supported clade in phylogenetic analyses. Both segregate species were described in the first half of the 19th century but not recognised as such in subsequent taxonomic accounts. Anarthria dioica was first collected in 1826, then wrongly interpreted as a species of Juncus (Juncaceae) and described as Juncus dioicus. We provide a formal transfer of the name to Anarthria and for the first time report its clear and qualitative diagnostic characters: an extremely short leaf ligule and distinctive pattern of leaf epidermal micromorphology. A long ligule is present in A. gracilis s.str. and A. grandiflora. These species differ from each other in leaf lamina morphology and anatomy and have mostly non-overlapping distribution ranges. The narrower definition of species provides a basis for future phylogeographic analyses in Anarthria. Our study highlights a need for more extensive use of nuclear DNA markers in Restionaceae. The use of the low copy nuclear marker at103 allowed a clade comprising all three ligulate species of Anarthria to be recognised. The ligule character is used here for the first time in the taxonomy of Anarthria and merits special attention in studies of other restiids. In general, our study uncovered a superficially hidden but, in reality, conspicuous diversity in a common group of wind-pollinated plants in the southwest of Western Australia.

Wildland fire behavior models are often initiated using the detection information listed in incident reports. This information carries an unknown amount of uncertainty, though it is often the most readily available ignition data. To determine the extent to which the use of detection information affects wildland fire forecasts, this research examines the range of burned area values and propagation directions resulting from different initiation point locations and times. We examined the forecasts for ten Colorado 2018 wildland fire case studies, each initiated from a set of 17 different point locations, and three different starting times (a total of 520 case study simulations). The results show that the range of forecast burned area and propagation direction values is strongly affected by the location of the initiation location, and to a lesser degree by the time of initiation.

Spatial selective attention greatly affects our processing of complex visual scenes, yet the way in which the brain selects relevant objects while suppressing irrelevant objects is still unclear. Evidence of these processes has been found using non-invasive electroencephalography (EEG). However, few studies have characterized these measures during attention to dynamic stimuli, and little is known regarding how these measures change with increased scene complexity. Here, we compared attentional modulation of the EEG N1 and alpha power (oscillations between 8–14 Hz) across three visual selective attention tasks. The tasks differed in the number of irrelevant stimuli presented, but all required sustained attention to the orientation trajectory of a lateralized stimulus. In scenes with few irrelevant stimuli, top-down control of spatial attention is associated with strong modulation of both the N1 and alpha power across parietal-occipital channels. In scenes with many irrelevant stimuli in both hemifields, however, top-down control is no longer represented by strong modulation of alpha power, and N1 amplitudes are overall weaker. These results suggest that as a scene becomes more complex, requiring suppression in both hemifields, the neural signatures of top-down control degrade, likely reflecting some limitation in EEG to represent this suppression.

Whereas TLR9 agonists are recognized as powerful stimulators of antitumor immunity, GM-CSF has had mixed reviews. In previously reported randomized trials we assessed the effects of local immune modulation in early-stage melanoma with CpG-B alone or with GM-CSF. Here we discuss the added value of GM-CSF and show sex-related differences.

Abstract Objective The objective of this paper is to demonstrate the utility of the CFIR framework for evaluating broad-scale change by discussing the challenges to be addressed when planning the assessment of broad-scale change and the solutions developed by the evaluation team to address those challenges. The evaluation of implementation of Patient-centered Care and Cultural Transformation (PCC&CT) within the Department of Veterans Affairs (VA) will be used as a demonstrative example. Patient-Centered Care (PCC) is personalized health care that considers a patient’s circumstances and goals. The Department of Veterans Affairs (VA) is working towards implementing PCC throughout its healthcare system, comprised of multiple interventions with a singular long-term goal of cultural transformation, however little is known about the factors influencing its implementation. This paper discusses the issues that arose using CFIR to qualitatively assess the factors influencing implementation of cultural transformation. Results Application of CFIR to this broad-scale evaluation revealed three strategies recommended for use in evaluating implementation of broad-scale change: (1) the need for adapted definitions for CFIR constructs (especially due to new application to broad-scale change), (2) the use of a mixed deductive-inductive approach with thematic coding to capture emergent themes not encompassed by CFIR, and (3) its use for expedited analysis and synthesis for rapid delivery of findings to operational partners. This paper is among the first to describe use of CFIR to guide the evaluation of a broad-scale transformation, as opposed to discrete interventions. The processes and strategies described in this paper provide a detailed example and structured approach that can be utilized and expanded upon by others evaluating implementation of broad-scale evaluations. Although CFIR was the framework selected for this evaluation, the strategies described in this paper including: use of adapted definitions, use of mixed deductive-inductive approach, and the approach for expedited analysis and synthesis can be transferred and tested with other frameworks.

Abstract Background Healthcare organizations increasingly are focused on providing care which is patient-centered rather than disease-focused. Yet little is known about how best to transform the culture of care in these organizations. We sought to understand key organizational factors for implementing patient-centered care cultural transformation through an examination of efforts in the US Department of Veterans Affairs. Methods We conducted multi-day site visits at four US Department of Veterans Affairs medical centers designated as leaders in providing patient-centered care. We conducted qualitative semi-structured interviews with 108 employees (22 senior leaders, 42 middle managers, 37 front-line providers and 7 staff). Transcripts of audio recordings were analyzed using a priori codes based on the Consolidated Framework for Implementation Research. We used constant comparison analysis to synthesize codes into meaningful domains. Results Sites described actions taken to foster patient-centered care in seven domains: 1) leadership; 2) patient and family engagement; 3) staff engagement; 4) focus on innovations; 5) alignment of staff roles and priorities; 6) organizational structures and processes; 7) environment of care. Within each domain, we identified multi-faceted strategies for implementing change. These included efforts by all levels of organizational leaders who modeled patient-centered care in their interactions and fostered willingness to try novel approaches to care amongst staff. Alignment and integration of patient centered care within the organization, particularly surrounding roles, priorities and bureaucratic rules, remained major challenges. Conclusions Transforming healthcare systems to focus on patient-centered care and better serve the “whole” patient is a complex endeavor. Efforts to transform healthcare culture require robust, multi-pronged efforts at all levels of the organization; leadership is only the beginning. Challenges remain for incorporating patient-centered approaches in the context of competing priorities and regulations. Through actions within each of the domains, organizations may begin to truly transform to patient-driven care.