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Abstract Background A dramatic decline in mental health of people worldwide in the early COVID-19 pandemic years has not recovered. In rural and remote Australia, access to appropriate and timely mental health services has been identified as a major barrier to people seeking help for mental ill-health. From 2020 to 2021 a care navigation model, Navicare, was co-designed with rural and remote communities in the Greater Whitsunday Region of Central Queensland in Australia. The Exploration, Preparation, Implementation and Sustainment (EPIS) framework was used to design and guide multiple aspects of a multisite study, The Bridging Study, to evaluate the implementation of Navicare in Australia. Methods A community-engaged hybrid effectiveness-implementation study design will focus on the tailored implementation of Navicare at three new sites as well as monitoring implementation at an existing site established since 2021. Study outcomes assessed will include sustained access as the co-primary outcome (measured using access to Navicare mental health referral services) and Proctor’s Implementation Outcomes of feasibility, acceptability, appropriateness, adoption, fidelity, implementation cost, and sustainability. Data collection for the implementation evaluation will include service usage data, community consultations, interviews, and workshops; analysed using mixed methods and guided by EPIS and other implementation frameworks. Pre-post effectiveness and cost-consequence study components are embedded in the implementation and sustainment phases, with comparison to pre-implementation data and value assessed for each EPIS phase using hospital, service, and resource allocation data. A scaling up strategy will be co-developed using a national roundtable forum in the final year of the study. Qualitative exploration of other aspects of the study (e.g., mechanisms of action and stakeholder engagement) will be conducted. Discussion Our study will use tailoring to local sites and a community-engaged approach to drive implementation of a mental health care navigation service in rural and remote Australia, with expected benefits to mental healthcare access. This approach is consistent with policy recommendations nationally and internationally as building blocks for rural health including the World Health Organization Framework for Action on Strengthening Health Systems to Improve Health Outcomes. Trial registration Prospectively registered on April 2, 2024, on the Australian New Zealand Clinical Trials Registry, no. ACTRN12624000382572. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386665&isReview=true .

Abstract Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy’s side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on “health-span” rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on “dementia worry” strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than “magic bullet”) clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

Abstract Background Cardiovascular diseases (CVD) affect over half a billion people worldwide and are the leading cause of global deaths. In particular, due to population aging and worldwide spreading of risk factors, the prevalence of heart failure (HF) is also increasing. HF accounts for approximately 36% of all CVD-related deaths and stands as the foremost cause of hospitalization. Patients affected by CVD or HF experience a substantial decrease in health-related quality of life compared to healthy subjects or affected by other diffused chronic diseases. Main body For both CVD and HF, prediction models have been developed, which utilize patient data, routine laboratory and further diagnostic tests. While some of these scores are currently used in clinical practice, there still is a need for innovative approaches to optimize CVD and HF prediction and to reduce the impact of these conditions on the global population. Epigenetic biomarkers, particularly DNA methylation (DNAm) changes, offer valuable insight for predicting risk, disease diagnosis and prognosis, and for monitoring treatment. The present work reviews current information relating DNAm, CVD and HF and discusses the use of DNAm in improving clinical risk prediction of CVD and HF as well as that of DNAm age as a proxy for cardiac aging. Conclusion DNAm biomarkers offer a valuable contribution to improving the accuracy of CV risk models. Many CpG sites have been adopted to develop specific prediction scores for CVD and HF with similar or enhanced performance on the top of existing risk measures. In the near future, integrating data from DNA methylome and other sources and advancements in new machine learning algorithms will help develop more precise and personalized risk prediction methods for CVD and HF.

Abstract Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Abstract Although neutralizing antibody is an established correlate of protection for measles, T cell-mediated responses play at least two critical roles in immunity to measles: first, through provision of ‘help’ enabling robust humoral immune responses; and second, through clearance of measles virus-infected cells. Previously, we identified 13 measles-derived peptides that bound to human leukocyte antigen (HLA) molecules in Priess cells infected with measles virus. In this study, we evaluated the immunogenicity of these peptides in a transgenic mouse model. Our results demonstrated that these peptides induced Th1-biased immune responses at varying levels. Of the 13 peptides, the top four immunogenic peptides were further selected for a viral challenge study in mice. A vaccine based on a combination of these four peptides reduced morbidity and weight loss after viral challenge compared to placebo. Our results emphasize the potential of T cell-mediated, peptide-based vaccines against measles.

Abstract Background Vitamin A is essential for physiological processes like vision and immunity. Vitamin A’s effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). Methods We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. Results Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p

Abstract Many actors have recently launched significant new initiatives in the domain of climate change and health. Given this important nexus, we undertook a review of funding patterns from 1985 – 2022, using the NIH RePORTER database for the United States and the Dimensions database globally. This includes an assessment of more than 9 million publicly funded projects across both databases with a collective budget of more than $3 trillion. We estimate that between 1985 and 2022 only 0.26% of research funding awarded by the NIH related to climate change, and only 0.70% of funded projects in the Dimensions database related to climate change and human health. Moreover, we thematically map funding patterns according to four thematic areas: changes in climate, the effects of climate change, health impacts, and interventions and strategies. More funding is needed to better anticipate and prepare for the projected health impacts of climate change.

Abstract In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.

Abstract Maintenance of water homeostasis is a fundamental cellular process required by all living organisms. Here, we use the single-celled green alga Chlamydomonas reinhardtii to establish a foundational understanding of osmotic-stress signaling pathways through transcriptomics, phosphoproteomics, and functional genomics approaches. Comparison of pathways identified through these analyses with yeast and Arabidopsis allows us to infer their evolutionary conservation and divergence across these lineages. 76 genes, acting across diverse cellular compartments, were found to be important for osmotic-stress tolerance in Chlamydomonas through their functions in cytoskeletal organization, potassium transport, vesicle trafficking, mitogen-activated protein kinase and chloroplast signaling. We show that homologs for five of these genes have conserved functions in stress tolerance in Arabidopsis and reveal a novel PROFILIN-dependent stage of acclimation affecting the actin cytoskeleton that ensures tissue integrity upon osmotic stress. This study highlights the conservation of the stress response in algae and land plants, and establishes Chlamydomonas as a unicellular plant model system to dissect the osmotic stress signaling pathway.

Abstract Background Implementation of new practices in team-based settings requires teams to work together to respond to new demands and changing expectations. However, team constructs and team-based implementation approaches have received little attention in the implementation science literature. This systematic review summarizes empirical research examining associations between teamwork and implementation outcomes when evidence-based practices and other innovations are implemented in healthcare and human service settings. Methods We searched MEDLINE, CINAHL, APA PsycINFO and ERIC for peer-reviewed empirical articles published from January 2000 to March 2022. Additional articles were identified by searches of reference lists and a cited reference search for included articles (completed in February 2023). We selected studies using quantitative, qualitative, or mixed methods to examine associations between team constructs and implementation outcomes in healthcare and human service settings. We used the Mixed Methods Appraisal Tool to assess methodological quality/risk of bias and conducted a narrative synthesis of included studies. GRADE and GRADE-CERQual were used to assess the strength of the body of evidence. Results Searches identified 10,489 results. After review, 58 articles representing 55 studies were included. Relevant studies increased over time; 71% of articles were published after 2016. We were unable to generate estimates of effects for any quantitative associations because of very limited overlap in the reported associations between team variables and implementation outcomes. Qualitative findings with high confidence were: 1) Staffing shortages and turnover hinder implementation; 2) Adaptive team functioning (i.e., positive affective states, effective behavior processes, shared cognitive states) facilitates implementation and is associated with better implementation outcomes; Problems in team functioning (i.e., negative affective states, problematic behavioral processes, lack of shared cognitive states) act as barriers to implementation and are associated with poor implementation outcomes; and 3) Open, ongoing, and effective communication within teams facilitates implementation of new practices; poor communication is a barrier. Conclusions Teamwork matters for implementation. However, both team constructs and implementation outcomes were often poorly specified, and there was little overlap of team constructs and implementation outcomes studied in quantitative studies. Greater specificity and rigor are needed to understand how teamwork influences implementation processes and outcomes. We provide recommendations for improving the conceptualization, description, assessment, analysis, and interpretation of research on teams implementing innovations. Trial registration This systematic review was registered in PROSPERO, the international prospective register of systematic reviews. Registration number: CRD42020220168.

Abstract Background Tissue non-specific alkaline phosphatase (TNSALP; encoded by the ALPL gene) has a critical role in the postnatal regulation of phosphate homeostasis, yet how TNSALP activity and expression are regulated during pregnancy remain largely unknown. This study tested the hypothesis that progesterone (P4) and/or interferon tau (IFNT) regulate TNSALP activity during pregnancy in sheep. Methods In Exp. 1, ewes were bred and received daily intramuscular injections of either corn oil vehicle (CO) or 25 mg progesterone in CO (P4) for the first 8 days of pregnancy and were hysterectomized on either Day 9, 12, or 125 of gestation. In Exp. 2, ewes were fitted with intrauterine catheters on Day 7 of the estrous cycle and received daily intramuscular injections of 50 mg P4 in CO and/or 75 mg progesterone receptor antagonist (RU486) in CO from Days 8 to 15, and twice daily intrauterine injections of either control proteins (CX) or IFNT (25 µg/uterine horn/d) from Days 11 to 15 (treatment groups: P4 + CX; P4 + IFNT; RU486 + P4 + CX; and RU486 + P4 + IFNT) and were hysterectomized on Day 16. Results In Exp. 1, endometria from ewes administered P4 had greater expression of ALPL mRNA than ewes administered CO on Day 12. TNSALP activity appeared greater in the epithelia, stratum compactum stroma, and endothelium of the blood vessels in the endometrium and myometrium from ewes administered P4 than ewes administered CO on Day 12. On Day 125, TNSALP activity localized to uterine epithelial and endothelial cells, independent of P4 treatment. TNSALP activity in placentomes appeared greater in P4 treated ewes and was detected in endothelial cells and caruncular tissue in P4 treated but not CO treated ewes. In Exp. 2, endometrial homogenates from ewes administered RU486 + P4 + CX had lower TNSALP activity those for P4 + CX and P4 + IFNT ewes. Immunoreactive TNSALP protein appeared greater in the mid- and deep-glandular epithelia in RU486 + P4 + CX treated ewes as compared to the other treatment groups. Enzymatic activity appeared greater on the apical surface of the deep glandular epithelia in endometria from ewes treated with RU486 + P4 + CX compared to the other treatment groups. Conclusions These results suggest that P4, but not IFNT, regulates the expression and activity of TNSALP in utero-placental tissues and has the potential to contribute to the regulation of phosphate availability that is critical for conceptus development during pregnancy.

Abstract Background The widespread use of physical activity trackers enables the collection of high-resolution health data, such as hourly step counts, to evaluate health promotion programmes. We aim to investigate how participants meet their daily step goals. Methods We used 24-h steps data from the National Steps ChallengeTM Season 3, wherein participants were rewarded with vouchers when achieving specified goals of 5000, 7500, and 10,000 steps per day. We extracted data from 3075 participants’ including a total of 52,346 participant-days. We modelled the hourly step counts using a two-part model, in which the distribution for step counts was allowed to depend on the sum of step counts up to the previous hour and participant demographics. Results Participants have a mean age of 44.2 years (standard deviation = 13.9), and 40.4% are males. We show that on weekdays, the hourly mean step counts among participants aged 60 and above are higher than participants aged 30 to 59 from the start of the day till 6 p.m. We also find that participants who accumulate at least 7000 steps by 7 p.m. are associated with higher success of achieving 10,000 steps. Conclusions We provide recommendations on the hourly targets to achieve daily goals, based on different participants’ characteristics. Future studies could experimentally test if prompts and nudges at the recommended times of day could promote reaching step goals.

Objective: To evaluate whether major adverse cardiac events (MACE) continue to be a major causative factor for mortality after noncardiac surgery. Patients and Methods: We performed retrospective study of 75,410 adult noncardiac surgery patients at Mayo Clinic Rochester, between January 1, 2016, and May 4, 2018. Electronic medical records were reviewed and data collected on all deaths within 30 days (n=692 patients) of surgery. The incidence of death due to MACE was calculated. Results: Postoperative MACE occurred in 150 patients (21.4 events per 10,000 patients; 95% CI, 18.2-25.2 events per 10,000 patients) with most occurring within 3 days of surgery (n=113). Postoperative MACE events were associated with atrial fibrillation with rapid rate response in 25 patients (16.7%), sepsis in 15 patients (10%), and bleeding in 15 patients (10%). There were 12 intraoperative deaths of which 9 were due to exsanguination (75%) and the remaining 3 (25%) due to cardiac arrest. Of the 56 deaths on the first 24 hours after surgery, 7 were due to hemorrhage, 17 due to cardiovascular causes, 20 due to sepsis, and 7 due to neurologic disease. The leading cause of total death over 30 days postoperatively was sepsis (28%), followed by malignancy (27%), cardiovascular disease (12%) neurologic disease (12%), and hemorrhage (5%). Conclusion: MACE was not the leading cause of death both intraoperatively and postoperatively.

Abstract People often interact with groups (i.e., ensembles) during social interactions. Given that group-level information is important in navigating social environments, we expect perceptual sensitivity to aspects of groups that are relevant for personal threat as well as social belonging. Most ensemble perception research has focused on visual ensembles, with little research looking at auditory or vocal ensembles. Across four studies, we present evidence that (i) perceivers accurately extract the sex composition of a group from voices alone, (ii) judgments of threat increase concomitantly with the number of men, and (iii) listeners’ sense of belonging depends on the number of same-sex others in the group. This work advances our understanding of social cognition, interpersonal communication, and ensemble coding to include auditory information, and reveals people’s ability to extract relevant social information from brief exposures to vocalizing groups.

Abstract Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants’ second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity.

Abstract The human microbiome plays a crucial role in human health. However, the influence of maternal factors on the neonatal microbiota remains obscure. Herein, our observations suggest that the neonatal microbiotas, particularly the buccal microbiota, change rapidly within 24–48 h of birth but begin to stabilize by 48–72 h after parturition. Network analysis clustered over 200 maternal factors into thirteen distinct groups, and most associated factors were in the same group. Multiple maternal factor groups were associated with the neonatal buccal, rectal, and stool microbiotas. Particularly, a higher maternal inflammatory state and a lower maternal socioeconomic position were associated with a higher alpha diversity of the neonatal buccal microbiota and beta diversity of the neonatal stool microbiota was influenced by maternal diet and cesarean section by 24–72 h postpartum. The risk of admission of a neonate to the newborn intensive care unit was associated with preterm birth as well as higher cytokine levels and probably higher alpha diversity of the maternal buccal microbiota.

Abstract Background and purpose The immune response changes during aging and the progression of Alzheimer’s disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in TEMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether TEMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults. Methods Study participants from a University of Kentucky Alzheimer’s Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aβ42/Aβ40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4+ and CD8+ central memory T cells (TCM), Naïve T cells, effector memory T cells (TEM), and effector memory CD45RA+ T cells (TEMRA) immune cell markers. Results CD8+ TEMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8+ TEMRAs based on cognitive scores and no associations between CD8+ TEMRAs and AD-related biomarkers. CD4+ TEMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with TEMRAs, but it did show an association with other T cell populations. Conclusion These findings suggest that the accumulation of CD8+ TEMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically-defined AD participants but included all ADRDs, this suggests that TEMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.

Abstract Background Patient participation in treatment decision making is a pillar of recovery-oriented care and is associated with improvements in empowerment and well-being. Although demand for increased involvement in treatment decision-making is high among veterans with serious mental illness, rates of involvement are low. Collaborative decision skills training (CDST) is a recovery-oriented, skills-based intervention designed to support meaningful patient participation in treatment decision making. An open trial among veterans with psychosis supported CDST’s feasibility and demonstrated preliminary indications of effectiveness. A randomized control trial (RCT) is needed to test CDST’s effectiveness in comparison with an active control and further evaluate implementation feasibility. Methods The planned RCT is a hybrid type 1 trial, which will use mixed methods to systematically evaluate the effectiveness and implementation feasibility of CDST among veterans participating in a VA Psychosocial Rehabilitation and Recovery Center (PRRC) in Southern California. The first aim is to assess the effectiveness of CDST in comparison with the active control via the primary outcome, collaborative decision-making behavior during usual care appointments between veterans and their VA mental health clinicians, and secondary outcomes (i.e., treatment engagement, satisfaction, and outcome). The second aim is to characterize the implementation feasibility of CDST within the VA PRRC using the Practical Robust Implementation and Sustainability Model framework, including barriers and facilitators within the PRRC context to support future implementation. Discussion If CDST is found to be effective and feasible, implementation determinants gathered throughout the study can be used to ensure sustained and successful implementation at this PRRC and other PRRCs and similar settings nationally. Trial registration ClinicalTrials.gov NCT04324944. Registered on March 27, 2020. Trial registration data can be found in Appendix 1.

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a prevalent, chronic, and impairing mental health disorder of childhood. Decades of empirical research has established a strong evidence-based intervention armamentarium for ADHD; however, limitations exist in regards to efficacy and effectiveness of these interventions. We provide an overview of select evidence-based interventions for children and adolescents, highlighting potential approaches to further improving the efficacy and effectiveness of these interventions. We conclude with broader recommendations for interventions, including considerations to moderators and under-explored intervention target areas as well as avenues to improve access and availability of evidence-based interventions through leveraging underutilized workforces and leveraging technology.

Over the course of revising the genus Rinorea (Violaceae) from Colombia, field observations and herbarium studies revealed seven new species. Several of the new species described here belong to species complexes that required examination of herbarium material from across the Neotropics. Each of the new species described here have oppositely arranged leaves and belong to Rinorea sect. Pubiflorae, a section restricted to the Neotropics. Two new species are segregated from the R. ovalifolia species complex: Rinorea chiribiquetensis from Chiribiquete National Park in the Colombian Amazon and Rinorea stevensii from the Orinoco River near the border of Colombia and Venezuela. Two new species are segregated from the Rinorea hirsuta species complex: Rinorea galeanoae-bernalii and Rinorea cogolloi, both from the eastern slopes of the Andean Central Cordillera along the mid-Magdalena River Valley in Colombia. From the widely distributed R. pubiflora species complex, we segregated one new species, Rinorea callejasii, from southeast Panama and the Chocó in Colombia. In addition to these five new taxa segregated from widely distributed species complexes, we discovered two previously unknown species with affinities to other Neotropical Rinorea. Rinorea aymardii is described from the Alto Orinoco-Casiquiare Biosphere Reserve in Venezuela and most closely resembles R. melanodonta from Colombia. Rinorea betancurii is segregated from R. macrocarpa and occurs in the Amazonian Regions of Colombia, Brazil, Peru and Venezuela. In this study, we provide descriptions, illustrations and distribution maps of the new species and make preliminary assessments of the risk of extinction using the IUCN Red List Categories and Criteria. We also furnish an identification key to the species of Rinorea sect. Pubiflorae in Colombia.

Introduction: The development of new and changing melanocytic lesions has been increasingly reported as an adverse dermatologic toxicity of BRAF inhibitor therapy. Melanocytic lesions and melanomas induced by BRAF inhibitor therapy that lack BRAF V600E expression have been less commonly described. One mechanism that has been proposed for the development of BRAF inhibitor-induced melanocytic lesions, including those lacking BRAF V600E expression, is the paradoxical activation of the MAPK signaling pathway in BRAF wild-type (BRAFWT) cells. Case Presentation: Herein, we report a rare case of a 39-year-old woman who developed numerous BRAF V600E-negative eruptive melanocytic nevi following encorafenib, cetuximab, and binimetinib combination therapy, the current standard of care for the treatment of BRAF-mutant metastatic colorectal cancer. Conclusion: Patients treated with BRAF inhibitors, with or without related combination therapies, who develop BRAFWT melanocytic lesions are at risk for developing both dysplastic nevi and melanoma, thereby warranting baseline dermatoscopic evaluation prior to the initiation of therapy as well as regular follow-up during and after treatment.

Preserving landscape connectivity in the Omo-Shasha-Oluwa Forest Reserves is crucial due to human-induced fragmentation, shrinking habitats, and disrupted migration routes for wildlife. From 2014 to 2016, we conducted surveys to gather large mammal presence data, mapping their distribution using the MaxEnt algorithm. Employing Circuitscape software and circuit theory concepts, we predicted connectivity patterns for six large mammal species. Our results consistently showed robust predictive performance, with Area Under the Curve (AUC) values exceeding 0.75 for species distribution models. Notably, we identified suitable habitat patches for seven key species, spanning 1760 km2 for C. civetta, 1515 km2 for T. Scriptus, 729 km2 for L. cyclotis, 1693 km2 for P. porcus, 1350 km2 for C. mona, 1406 km2 for P. maxwellii, and 1379 km2 for C. torquatus. Our analysis highlighted distance to human settlements as the most significant predictor for habitat models concerning T. Scriptus, C. civetta, P. maxwellii, C. torquatus, P. porcus, and C. mona, whereas land use type emerged as a critical factor for L. cyclotis. Furthermore, examination of maximum current flow patterns revealed varying degrees of connectivity among habitat patches, indicating potential bottlenecks to species movement, particularly across major rivers and in areas affected by human activities. These findings offer crucial insights for conservation efforts, guiding strategies to preserve wildlife metapopulation dynamics in the Omo-Shasha-Oluwa Forest Reserves landscape

Abstract Background With the increasing of novel therapeutics for the treatment of Biliary Tract Cancers (BTC), and the need to assess their socio-economic impacts for national licence approvals, it is as important as ever to have real-life data in national populations. Methods and results We performed an audit of the first 2 year-activity (Sep 2019-Sep 2021) of the centralized West-of-Scotland-BTC clinic. 122 patients accessed the service, including 68% with cholangiocarcinoma (CCA), 27% with gallbladder cancer (GBC), and 5% with ampulla of Vater carcinoma with biliary phenotype (AVC). Median age at diagnosis was 66 (28–84), with 30% of newly diagnosed patients being younger than 60 years-old. Thirty-five cases (29%) underwent surgery, followed by adjuvant-chemotherapy in 66%. 60% had recurrent disease (80% with distant relapse). Sixty-four patients (58%) started first-line Systemic-AntiCancer-Treatment (SACT). Of these, 37% received second line SACT, the majority of which had iCCA and GBC. Thirty-% of those who progressed received third line SACT. Conclusions About 30% of BTC were eligible for curative surgery. Fifty-eight and twenty% of the overall cohort of advanced BTC patients received first and second line SACT. Our data suggest that reflex genomic profiling may not be cost-effective until molecularly driven strategies are limited to second line setting.

Abstract Cohort and case-control data have suggested an association between low to moderate alcohol consumption and decreased risk of ischemic heart disease (IHD), yet results from Mendelian randomization (MR) studies designed to reduce bias have shown either no or a harmful association. Here we conducted an updated systematic review and re-evaluated existing cohort, case-control, and MR data using the burden of proof meta-analytical framework. Cohort and case-control data show low to moderate alcohol consumption is associated with decreased IHD risk – specifically, intake is inversely related to IHD and myocardial infarction morbidity in both sexes and IHD mortality in males – while pooled MR data show no association, confirming that self-reported versus genetically predicted alcohol use data yield conflicting findings about the alcohol-IHD relationship. Our results highlight the need to advance MR methodologies and emulate randomized trials using large observational databases to obtain more definitive answers to this critical public health question.

Abstract Background Policymaking is quickly gaining focus in the field of implementation science as a potential opportunity for aligning cross-sector systems and introducing incentives to promote population health, including substance use disorders (SUD) and their prevention in adolescents. Policymakers are seen as holding the necessary levers for realigning service infrastructure to more rapidly and effectively address adolescent behavioral health across the continuum of need (prevention through crisis care, mental health, and SUD) and in multiple locations (schools, primary care, community settings). The difficulty of aligning policy intent, policy design, and successful policy implementation is a well-known challenge in the broader public policy and public administration literature that also affects local behavioral health policymaking. This study will examine a blended approach of coproduction and codesign (i.e., Policy Codesign), iteratively developed over multiple years to address problems in policy formation that often lead to poor implementation outcomes. The current study evaluates this scalable approach using reproducible measures to grow the knowledge base in this field of study. Methods This is a single-arm, longitudinal, staggered implementation study to examine the acceptability and short-term impacts of Policy Codesign in resolving critical challenges in behavioral health policy formation. The aims are to (1) examine the acceptability, feasibility, and reach of Policy Codesign within two geographically distinct counties in Washington state, USA; (2) examine the impact of Policy Codesign on multisector policy development within these counties using social network analysis; and (3) assess the perceived replicability of Policy Codesign among leaders and other staff of policy-oriented state behavioral health intermediary organizations across the USA. Discussion This study will assess the feasibility of a specific approach to collaborative policy development, Policy Codesign, in two diverse regions. Results will inform a subsequent multi-state study measuring the impact and effectiveness of this approach for achieving multi-sector and evidence informed policy development in adolescent SUD prevention and treatment.

Background/Objective: Asthma is a common chronic medical condition among children and the most common diagnosis associated with interfacility transports for pediatric patients. As many as 40% of pediatric transfers may be unnecessary, resulting in potential delays in care and unnecessary costs. Our objective was to identify the patient-related factors associated with potentially unnecessary transfers for pediatric patients with asthma. Methods: We used patient care data from the California Department of Health Care Access and Information patient discharge and emergency department (ED) datasets to capture ED visits where a pediatric patient (age 2–17 years) presented with asthma and was transferred to another ED or acute care hospital. The outcome of interest was a potentially unnecessary transfer, defined as a visit where length of stay after transfer was

Abstract N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 μmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 μg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.

Abstract Heat waves pose a substantial and increasing risk to public health. Heat health early warning systems (HHEWSs) and response plans are increasingly being adopted to alert people to the health risks posed by days of extreme heat and recommend protective behaviors. However, evidence regarding the effectiveness of HHEWSs remains limited. We examined the impact of heat wave naming on heat-related beliefs and behaviors to ascertain the potential effectiveness of heat wave naming as a heat health risk communication and management tool. Specifically, we surveyed members of the public exposed to the proMETEO Sevilla HHEWS messaging campaign which in the summer of 2022 applied a name to heat waves considered to pose the greatest risk to public health. During the heat season we evaluated, the proMETEO Sevilla HHEWS campaign applied a name to one heat wave, heat wave “Zoe”. Our analysis of the post-survey of 2022 adults indicated that the 6% of participants who recalled the name Zoe unaided reported greater engagement in heat wave safety behaviors and more positive beliefs about naming heat waves and their local governments’ heat wave response. These results provide initial evidence for potential utility in naming heat waves as part of HHEWSs and HAPs.

Marine vertebrates, particularly green sea turtles, are especially vulnerable to plastic pollution through ingestion or entanglement. This study investigated wild juvenile green sea turtles (Chelonia mydas) from two Ecuadorian national parks (Galápagos and Machallilla) to assess the prevalence of plastic pollution in their feces and its potential impact on various health metrics. We analyzed fecal samples from 46 juvenile green sea turtles using Fourier transform infrared spectroscopy (FT-IR) to quantify microplastics (MPs). A complementary methodology using pressurized liquid extraction with double-shot pyrolysis-mass spectrometry gas chromatography (Pyr-GC/MS) was also employed to quantify synthetic polymer mass concentrations. The results from these analyses were compared with blood analytes. FT-IR analysis revealed a mean of 4.4±5.2 MPs/g in fecal samples, with the highest quantities found in the Galápagos Marine Reserve (GMR). The most common MPs shape identified were fibers (x̄= 3.8±4.5 MPs/g), and the predominant synthetic polymers were polyvinyl alcohol (PVOH) and polyacrylates (PMMA). The daily intake of MPs by the sampled turtles ranged from a minimum of 312±409 MPs/day to a maximum of 430±563 MPs/day. Pyr-GC/MS analysis detected polyethylene (PE) with a mean of 367±1158 µg/g and polypropylene (PP) with a mean of 155±434 µg/g in fecal samples, with the highest pollution levels observed in the GMR. Both FT-IR and Pyr-GC/MS techniques detected plastic pollution in 98% of the sampled population. Although both FT-IR and Pyr-GC/MS are reliable methods, they produced slightly different results due to methodological variations. However, both supported the finding that turtles in the GMR were exposed to higher rates of plastic ingestion. Despite the turtles appearing clinically healthy based on blood analysis, significant differences in eleven health metrics were observed between turtles classified as less at risk and those most at risk for plastic pollution. Further research is necessary to understand the potential health implications of these findings.

Persistent organic pollutants may negatively impact cognition; however, associations between persistent organic pollutants and changes in cognition among United States Hispanic/Latino adults have not been investigated. Herein, we examined the associations between 33 persistent organic pollutants and cognitive changes among 1837 Hispanic/Latino adults. At baseline (2008–2011; Visit 1), participants provided biospecimens in which we measured levels of 5 persistent pesticides or pesticide metabolites, 4 polybrominated diphenyl ethers and 2,2’,4,4’,5,5’-hexabromobiphenyl, and 24 polychlorinated biphenyls. At Visit 1 and again at Visit 2 (2015–2018), a battery of neurocognitive tests was administered which included the Brief-Spanish English Verbal Learning Test, Word Fluency Test, and Digit Symbol Substitution Test. To estimate the adjusted associations between changes in cognition and each POP, we used linear regression for survey data. Each doubling in plasma levels of polychlorinated biphenyls 146, 178, 194, 199/206, and 209 was associated with steeper declines in global cognition (βs range:-0.053 to −0.061) with stronger associations for the Brief-Spanish English Verbal Learning Test. Persistent organic pollutants, in particular polychlorinated biphenyls, were associated with declines in cognition over 7 years and may be a concern for Hispanic/Latino adults.

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150 mg/kg, SC) for 36 h and continuous intravenous infusion of vehicle (20 μL/h, IV). The NLX-precipitated withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8 μmol/kg/h, IV) for the full 36 h. NLX elicited pronounced withdrawal signs in rats treated for 48 h with morphine (150 mg/kg, SC), plus continuous infusion of vehicle (20 μL/h, IV) that began at the 36 h timepoint of morphine treatment. The NLX-precipitated withdrawal signs were reduced in rats that received a 12 h infusion of D-CYSee, but not D-cysteine, (both at 20.8 μmol/kg/h, IV) that began at the 36 h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders.

Abstract Long‐term implantable neural interfacing devices are crucial in neurostimulation for treating various neurological disorders. These devices rely heavily on electrodes and microelectrode arrays. As the invasiveness of these electrodes increases—particularly for peripheral and central nervous system applications—both potential benefits and risks of adverse side effects to the patient rise. To mitigate risks and enhance device performance and longevity, electrodes for such invasive applications must be thin, flexible, and have small contacts. However, these features typically reduce the geometric surface area and electrochemical performance of the electrodes, diminishing treatment benefits. This report explores the feasibility and advantages of using femtosecond laser hierarchical surface restructuring (HSR) technology to improve electrochemical performance without compromising the structural integrity of ultra‐thin (

ABSTRACT Neurotropic alphaherpesviruses, including herpes simplex virus type 1 and pseudorabies virus, establish a lifelong presence within the peripheral nervous system of their mammalian hosts. Upon entering cells, two conserved tegument proteins, pUL36 and pUL37, traffic DNA-containing capsids to nuclei. These proteins support long-distance retrograde axonal transport and invasion of the nervous system in vivo. To better understand how pUL36 and pUL37 function, recombinant viral particles carrying BioID2 fused to these proteins were produced to biotinylate cellular proteins in their proximity (

Food insecurity is a multidimensional and intricate problem, known to have significant implications for individuals, communities, and countries worldwide. Africa has become the continent that is experiencing this uncertainty the most. Food Security (FS) encompasses several aspects such as availability, accessibility, nutrient use, and supply system stability with time and, more recently, other obliges to governance/agency and sustainability. Knowing the interconnection between these aspects and the Ecosystems Services (ES) and understanding the relationship and interactions between FS and ES is important. Moreover, this knowledge may contribute to supporting policies that promote long-term sustainable and secure food systems. Hereby, a conceptual framework is presented, that examines interactions between food insecurity drivers and ecosystem change drivers and the combined influence on ES. Our review further introduces existing trade-offs between ES on account of agricultural intensification vs. key existing strategies to promote sustainable agricultural production. These strategies include climate-smart agriculture, sustainably managed land, and effective handling of water resources. In the end, the potential of Payment for Ecosystem Services (PES), as a suitable approach to ensuring these strategies are adopted, especially in African countries where sustainable financial incentives are currently under-explored is discussed. In resume, this review aims to make a conceptual contribution to understanding how drivers of food insecurity influence drivers of ecosystem changes, the impact of these influences on the services of ecosystems, and how sustainable agro approaches and PES introduction can help to reduce such negative impacts.

Abstract If, as previously hypothesized, the effective elastic response of the lithosphere is sensitive to the imposed stress regime, then it may vary in time and produce distinctive geomorphic responses. Such effects will be at their most crucial in landscapes of low relief. Motivated by the existence of numerous small endorheic (internally‐drained) basins in central Australia, we examine the influence of changing elastic response in the presence of large embedded loads in the lithosphere underlying stable continental interiors. Focusing on the western Lake Eyre Basin and adjoining Lake Lewis basin—an area with a close correlation between drainage pattern and extreme Bouguer gravity anomalies—we devise a set of numerical simulations that incorporate the flexural response to time‐transient horizontal stresses. The simulations demonstrate that transient changes in the effective elastic thickness can drive topographic changes in low‐relief landscapes, including drainage capture and the development of endorheic basins, consistent with field observations.

The network nature of focal epilepsy is exemplified by mesial temporal lobe epilepsy (mTLE), characterized by focal seizures originating from the mesial temporal neocortex, amygdala, and hippocampus. The mTLE network hypothesis is evident in seizure semiology and interictal comorbidities, both reflecting limbic network dysfunction. The network generating seizures also supports essential physiological functions, including memory, emotion, mood, and sleep. Pathology in the mTLE network often manifests as interictal behavioral disturbances and seizures. The limbic circuit is a vital network, and here we review one of the most common focal epilepsies and its comorbidities. We describe two people with drug resistant mTLE implanted with an investigational device enabling continuous hippocampal local field potential sensing and anterior nucleus of thalamus deep brain stimulation (ANT-DBS) who experienced reversible psychosis during continuous high-frequency stimulation. The mechanism(s) of psychosis remain poorly understood and here we speculate that the anti-epileptic effect of high frequency ANT-DBS may provide insights into the physiology of primary disorders associated with psychosis.

ABSTRACT The Gardnerella genus, comprising at least 13 species, is associated with the polymicrobial disorder bacterial vaginosis (BV). However, the details of BV pathogenesis are poorly defined, and the contributions made by individual species, including Gardnerella spp., are largely unknown. We report here that colony phenotypes characterized by size (large and small) and opacity (opaque and translucent) are phase variable and are conserved among all tested Gardnerella strains, representing at least 10 different species. With the hypothesis that these different variants could be an important missing piece to the enigma of how BV develops in vivo, we characterized their phenotypic, proteomic, and genomic differences. Beyond increased colony size, large colony variants showed reduced vaginolysin secretion and faster growth rate relative to small colony variants. The ability to inhibit the growth of Neisseria gonorrhoeae and commensal Lactobacillus species varied by strain and, in some instances, differed between variants. Proteomics analyses indicated that 127–173 proteins were differentially expressed between variants. Proteins with increased expression in large variants of both strains were associated with amino acid and protein synthesis and protein folding, whereas those increased in small variants were related to nucleotide synthesis, phosphate transport, ABC transport, and glycogen breakdown. Furthermore, whole genome sequencing analyses revealed an abundance of genes associated with variable homopolymer tracts, implicating slipped strand mispairing in Gardnerella phase variation and illuminating the potential for previously unrecognized heterogeneity within clonal populations. Collectively, these results suggest that phase variants may be primed to serve different roles in BV pathogenesis.IMPORTANCEBacterial vaginosis is the most common gynecological disorder in women of childbearing age. Gardnerella species are crucial to the development of this dysbiosis, but the mechanisms involved in the infection are not understood. We discovered that Gardnerella species vary between two different forms, reflected in bacterial colony size. A slow-growing form makes large amounts of the toxin vaginolysin and is better able to survive in human cervix tissue. A fast-growing form is likely the one that proliferates to high numbers just prior to symptom onset and forms the biofilm that serves as a scaffold for multiple BV-associated anaerobic bacteria. Identification of the proteins that vary between different forms of the bacteria as well as those that vary randomly provides insight into the factors important for Gardnerella infection and immune avoidance.

Introduction In pre-hospital settings, identifying a deteriorating child can be challenging, especially considering that the proportion of paediatric patients with acute illnesses is lower compared with adults. This challenge is exacerbated in pre-hospital settings, where information might be scarce. Physiological alterations indicating changes in a patient’s condition can be detected hours preceding a cardiac arrest. Therefore, maintaining continuous monitoring of the patient’s clinical condition is crucial to detecting any physiological changes promptly, facilitating early identification of critical illness. This scoping review aims to assess the extent, range and nature of published research related to recognising paediatric out-of-hospital clinical deterioration by pre-hospital staff.Methods and analysis This scoping review is registered with the Open Science Framework. The review will follow the Joanna Briggs Institute’s (JBI) methodology for scoping reviews. A systematic search of relevant databases (MEDLINE, EMBASE, Web of Science, CINAHL and Scopus) will be conducted. In this scoping review, all types of study designs including quantitative and qualitative studies will be considered. The inclusion is limited to English-language studies published between January 1990 and March 2024. Two independent reviewers (AG and SS) will conduct a thorough screening of titles and abstracts against the pre-defined inclusion criteria for the review. For the selected citations, the full texts will undergo detailed assessment by the two reviewers, ensuring alignment with the inclusion criteria. A quality assessment of the included studies will be done using the Mixed Methods Appraisal Tool. The findings will be presented using diagrams or tables, supplemented by narrative summaries following the JBI guidelines.Ethics and dissemination Ethical approval is not required. The findings will be disseminated through publication in a peer-reviewed journal and presentation at conferences and/or seminars.

Background Despite the effectiveness of cognitive remediation, it is not widely implemented because we do not know whether teams will accept it, how much therapist time is needed, whether there are factors which predict lower benefits, whether it is cost-effective and what is required for large-scale roll-out. Objective To understand the factors that will enhance implementation and benefits of cognitive remediation in Early Intervention Services. Design Four work packages: (1) focus groups and interviews exploring the development of satisfaction and preference measures for staff and service users; participant team interviews to collect data, before and after introducing cognitive remediation, to understand team dynamics; (2) an observational study of a newly developed therapist e-training programme; (3) a multiarm multistage four-arm randomised controlled trial comparing different amounts of therapist input with Treatment as Usual; and (4) an analysis of trial data to understand potential mediating and moderating factors that affect treatment benefits. Setting Early Intervention Services in the United Kingdom National Health Service. Participants Staff and service users in touch with Early Intervention Services. Interventions For the e-training, we piloted and then provided an e-learning system for training cognitive remediation therapists. For the randomised trial, we provided a cognitive remediation software programme (CIRCuiTS™,King’s College London, London) that was delivered in three conditions, all offering up to 42 sessions of cognitive remediation. The conditions were: Intensive (one to one with a therapist), Group treatment with a therapist, Independent with drop-in sessions. Main outcome measures Work package 1: We developed two satisfaction measures and tested a team dynamic model. Work package 2: Feasibility and acceptability questionnaire, time to complete e-training modules. Work package 3: The personal recovery measure – Goal Attainment Scale. Results Work package 1: The service user satisfaction with cognitive remediation was reliable and valid. Although it did not show statistically significant differences between the arms of the trial, the most preferred methods (Group and Intensive) had higher associated satisfaction. Team leadership and especially a flattened hierarchy, resources and time were identified as vital for implementation. Our team dynamic model supported the importance of leadership in influencing organisational climate, which then affected staff attitudes. However, this was only significant before staff had any experience of their patients receiving cognitive remediation. Although the sample was much smaller after therapy, this may indicate that experience of the beneficial therapy changes team dynamics. Work package 2: The e-training modules were completed by 43% of the recruited participants. They judged the training to be feasible and acceptable, but it did take longer to complete than expected. COVID-19 with the increased workload may have had some effects, but our data exploration shows that it was individuals who had most recently qualified who had the best outcomes. This may be because of a lighter workload or that they were more used to online training. Adaptations suggested are now being implemented. Work package 3: Following the interim analysis we closed two arms – Independent therapy and Treatment as Usual. Four hundred and forty-eight patients consented and 377 were eligible and completed baseline assessment. They were randomised: Group 134, Independent 65, Intensive 112 and Treatment as Usual 66. At post therapy, there were no differences between Group and Intensive or between Independent and Treatment as Usual, but the combined Group and Intensive versus Treatment as Usual was significant (mean difference: 5.734; standard error = 1.958; p = 0.003; lower confidence interval = 1.898 to upper confidence interval = 9.571). Our economic analysis showed that Group and Intensive cognitive remediation were not different with respect to quality-adjusted life-years (difference £150, 95% confidence interval –£1132 to £1905). Both conferred significant benefit compared with standard care (Group and Treatment as Usual: difference £257, 95% confidence interval –£1694 to £2615; Intensive vs. Treatment as Usual: difference £260, 95% CI –£1654 to £2239). Their cost–benefit for quality-adjusted life-year improvement was well below the National Institute for Health and Care Excellence threshold for adopting the intervention to National Health Service services. Work package 4: Cognition had a small mediation effect, and negative symptoms moderated the transfer of cognitive benefits to goal attainment. Limitations The trial suffered from recruitment difficulties which were overcome when we switched from block to individual randomisation. The final target was large enough to test our main outcomes and moderating and mediating variables. Conclusions Cognitive remediation should be provided in the National Health Service, involving a trained therapist on a Group or Intensive format with team and training support. Future work We have a large database and will continue to investigate factors that affect cognitive remediation benefits. Study registration This study is registered as ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0612-20002) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 4. See the NIHR funding and Awards website for further award information. Plain language summary Cognitive problems in people with schizophrenia predict functional recovery even with the best-possible rehabilitation opportunities. One psychological treatment, cognitive remediation can improve both cognitive and functional recovery, such as in social relationships and occupational achievements. We investigated the optimal way of delivering computerised cognitive remediation in Early Intervention Services by incorporating service user and staff views. Our work involved exploring what treatment factors are important to service users, developing two bespoke cognitive remediation satisfaction measures for service users and service providers. Our investigation of team dynamics suggested that a more flexible leadership style together with increasing resources might be most suited to successful delivery. One challenge for large-scale roll-out of cognitive remediation is therapist training opportunities, so we developed an online programme and then tested it in the United Kingdom and, with a few adaptations, it can be provided to the National Health Service. Although cognitive remediation is effective, we do not know how much therapist time produces therapy benefits, so we conducted a trial comparing three options for cognitive remediation treatment that differed in the amount of the therapist time (Independent, Group and Intensive). We compared these options with a no-treatment group. We investigated benefits of each option in 377 participants from Early Intervention Services. The main benefit assessed was whether participants could achieve their personal goals that were set before therapy began. Although we found no change in a social or occupational functioning scale rated by an observer, the Group and Intensive cognitive remediation produced significant achievements in the participants’ own personal goals compared with those who did not receive therapy or who carried out therapy on their own. We also found that any cognitive remediation therapy option improved thinking skills. Group and Intensive therapy were also cost-effective. Overall, cognitive remediation was acceptable and well liked by service users, so all our data suggest that it should be more easily accessible in the National Health Service. Scientific summary Cognitive remediation (CR) therapy is a psychological intervention targeting cognitive dysfunction associated with psychosis with the goal of improving functional outcomes. Cognitive remediation can improve cognitive and functional recovery, as well as increasing confidence and motivation. Evidence from the largest meta-analysis demonstrated that these effects are durable. National Health Service Early Intervention for psychosis services provide care soon after a diagnosis of psychosis to optimise recovery. Embedding CR in those services may confer long-lasting benefits such as improved social relationships and the opportunity to work or take part in further education. The overarching aim of the Enhancing Cognition and quality of Life in early PSychosiEs (ECLIPSE) research programme was to determine the optimal method of introducing computerised CR therapy (CIRCuiTS™) into NHS Early Intervention Services (EIS) considering improvement in cognitive and social function and cost-effectiveness. The programme was centred on work package 3 (WP3), a randomised, blinded multiarm multisite controlled trial comparing three CR implementation methods with each other and with routine clinical care [Treatment as Usual (TAU)]. To aid the interpretation of WP3 and bolster our recommendations to the NHS, WP1 included a series of studies investigating: patient and staff satisfaction with CR; preference for the methods of CR delivery; and the influence of team organisational climate. Although the CR was computerised and can be completed independently, its effects are boosted via learning, practice and feedback supervised by a therapist. WP2 was a series of studies to design and test an online CR therapist training package to use in their individual teams. Finally, WP4 examined mediators and moderators of the trial results to inform teams about how the clinical features of their individual patients may influence the effect of CR. In WP3, the CR modalities were: Intensive 1 : 1 therapist supervision; Group supervision with one therapist; and Independent (self-determined with infrequent access to therapist supervision). Participants were recruited from EIS in 12 mental health trusts, linked to 6 universities and serving diverse urban/rural populations. They were clinically stable and presented with a non-affective psychotic episode not

ABSTRACT We have investigated the function of inositol hexakisphosphate (IP6) and inositol pentakisphosphate (IP5) in the replication of murine leukemia virus (MLV). While IP6 is known to be critical for the life cycle of HIV-1, its significance in MLV remains unexplored. We find that IP6 is indeed important for MLV replication. It significantly enhances endogenous reverse transcription (ERT) in MLV. Additionally, a pelleting-based assay reveals that IP6 can stabilize MLV cores, thereby facilitating ERT. We find that IP5 and IP6 are packaged in MLV particles. However, unlike HIV-1, MLV depends upon the presence of IP6 and IP5 in target cells for successful infection. This IP6/5 requirement for infection is reflected in impaired reverse transcription observed in IP6/5-deficient cell lines. In summary, our findings demonstrate the importance of capsid stabilization by IP6/5 in the replication of diverse retroviruses; we suggest possible reasons for the differences from HIV-1 that we observed in MLV.IMPORTANCEInositol hexakisphosphate (IP6) is crucial for the assembly and replication of HIV-1. IP6 is packaged in HIV-1 particles and stabilizes the viral core enabling it to synthesize viral DNA early in viral infection. While its importance for HIV-1 is well established, its significance for other retroviruses is unknown. Here we report the role of IP6 in the gammaretrovirus, murine leukemia virus (MLV). We found that like HIV-1, MLV packages IP6, and as in HIV-1, IP6 stabilizes the MLV core thus promoting reverse transcription. Interestingly, we discovered a key difference in the role of IP6 in MLV versus HIV-1: while HIV-1 is not dependent upon IP6 levels in target cells, MLV replication is significantly reduced in IP6-deficient cell lines. We suggest that this difference in IP6 requirements reflects key differences between HIV-1 and MLV replication.

Summary: Clinical trial participation across disease areas, including Alzheimer's disease (AD), has been biased towards White participants of European ancestry. To support clinical decision-making across diverse populations, we must recognize and address barriers to trial participation. To inform the design of ALUMNI AD, a trial focused on historically underrepresented AD populations, we held advice-seeking fora with key stakeholders to understand barriers and identify potential solutions to maximize trial participation of underrepresented racial and ethnic groups in the US. Strategies identified from this process include: obtaining and implementing recommendations from community stakeholders; establishing a simple and inclusive prescreening and screening process; supporting participants and care partners; identifying and activating community-centric clinical sites; and demonstrating community commitment. While ALUMNI AD did not commence, we hope that our insights could be incorporated into future studies to improve diversity, equity, and inclusion in AD clinical research. Funding: This study was sponsored by Genentech, Inc.

Climate change is expected to outpace the rate at which populations of forest trees can migrate. Hence, in forestry there is growing interest in intervention strategies such as assisted migration to mitigate climate change impacts. However, until now the primary focus when evaluating candidates for assisted migration has been mean or maximum performance. We explore phenotypic plasticity as a potentially new avenue to help maintain the viability of species and populations in the face of climate change. Capitalizing on large, multi-site international provenance trials of four economically and ecologically important forest tree species (Fagus sylvatica, Picea abies, Picea engelmannii, Pinus contorta), we quantify growth stability as the width of the response function relating provenance growth performance and trial site climate. We found significant differences in growth stability among species, with P. engelmannii being considerably more stable than the other three species. Additionally, we found no relationship between growth performance and growth stability of provenances, indicating that there are fast-growing provenances with a broad climate optimum. In two of the four species, provenances’ growth stability showed a significant relationship with the climate of the seed source, the direction of which depends on the species. When taken together with data on growth performance in different climate conditions, a measure of growth stability can improve the choice of species and provenances to minimize future risks in forest restoration and reforestation.

Background. Solid organ transplant recipients have a high risk of severe outcomes from SARS-CoV-2 infection. A comprehensive understanding of the impact of the COVID-19 pandemic across multiple waves in the solid organ transplant population and how this compares to the general population is limited. We conducted a population-based cohort study using linked administrative healthcare databases from Ontario, Canada to answer this question. Methods. We included 15 306 solid organ transplant recipients and 12 160 904 individuals from the general population. Our primary outcome was the rate (per 100 person-years) of severe COVID-19 (ie, hospitalization or death with a positive SARS-CoV-2 test) occurring between January 25, 2020, and November 30, 2022. Results. Compared with the general population, solid organ transplant recipients had almost a 6 times higher rate of severe COVID-19 (20.39 versus 3.44 per 100 person-years), with almost 5.5 times as high a rate of death alone (4.19 versus 0.77 per 100 person-years). Transplant recipients with severe COVID-19 were substantially younger (60.1 versus 66.5 y) and had more comorbidities. The rate of severe COVID-19 declined over time in the solid organ transplant population, with an incidence rate of 41.25 per 100 person-years in the first wave (January 25, 2020, to August 31, 2020) and 18.41 in the seventh wave (June 19, 2022, to November 30, 2022, Omicron era). Conclusions. Solid organ transplant recipients remain at high risk of severe outcomes when they are infected with SARS-CoV-2. Resources and strategies to mitigate the impact of SARS-CoV-2 exposure are needed in this vulnerable patient population.

Artificial intelligence (AI) in radiology has rapidly increased in our field and stands to allow more accurate diagnosis, quicker interpretations, easier workflows, and improved image quality. However, with superior image quality produced with the help of AI algorithms, one could begin to discount or even eliminate the review of nonalgorithmic enhanced images. At least currently, these images remain important. This case report demonstrates a unique anomaly simulating disease resulting from AI-enhanced motion suppression. On the original images, patient motion and an atypical linear motion artifact is obvious. However, the images reproduced using our AI motion artifact suppression algorithm suppressed nearly all (but not all) of the motion artifact resulting in what appeared to be an osteochondral lesion in a child's knee. This case illustrates the necessity for the interpreting radiologist to review both original acquisitions as well as AI-enhanced images, at least for the time being.

Abstract Background Theory and correlational research indicate organizational leadership and climate are important for successful implementation of evidence-based practices (EBPs) in healthcare settings; however, experimental evidence is lacking. We addressed this gap using data from the WISDOM (Working to Implement and Sustain Digital Outcome Measures) hybrid type III effectiveness-implementation trial. Primary outcomes from WISDOM indicated the Leadership and Organizational Change for Implementation (LOCI) strategy improved fidelity to measurement-based care (MBC) in youth mental health services. In this study, we tested LOCI’s hypothesized mechanisms of change, namely: (1) LOCI will improve implementation and transformational leadership, which in turn will (2) mediate LOCI’s effect on implementation climate, which in turn will (3) mediate LOCI’s effect on MBC fidelity. Methods Twenty-one outpatient mental health clinics serving youth were randomly assigned to LOCI plus MBC training and technical assistance or MBC training and technical assistance only. Clinicians rated their leaders’ implementation leadership, transformational leadership, and clinic implementation climate for MBC at five time points (baseline, 4-, 8-, 12-, and 18-months post-baseline). MBC fidelity was assessed using electronic metadata for youth outpatients who initiated treatment in the 12 months following MBC training. Hypotheses were tested using longitudinal mixed-effects models and multilevel mediation analyses. Results LOCI significantly improved implementation leadership and implementation climate from baseline to follow-up at 4-, 8-, 12-, and 18-month post-baseline (all ps .05). LOCI’s improvement of clinic implementation climate from baseline to 12 months was mediated by improvement in implementation leadership from baseline to 4 months (proportion mediated [p m ] = 0.82, p = .004). Transformational leadership did not mediate LOCI’s effect on implementation climate (p = 0.136). Improvement in clinic implementation climate from baseline to 12 months mediated LOCI’s effect on MBC fidelity during the same period (p m = 0.71, p = .045). Conclusions LOCI improved MBC fidelity in youth mental health services by improving clinic implementation climate, which was itself improved by increased implementation leadership. Fidelity to EBPs in healthcare settings can be improved by developing organizational leaders and strong implementation climates. Trial registration ClinicalTrials.gov identifier: NCT04096274. Registered September 18, 2019.

Abstract Background Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. Methods We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. Results Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. Conclusions These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC. Graphical abstract

Abstract Since the start of the pandemic, many national responses, such as nationwide lockdowns, have been implemented to curb the spread of COVID-19. We aim to assess the impact of Singapore’s national responses on primary care utilisation. We performed an interrupted time series using acute and chronic primary care data of 3 168 578 visits between 1 September 2019 and 31 August 2020 over four periods: before any measures were put in place, during Disease Outbreak Response System Condition (DORSCON) Orange, when Circuit Breaker was instituted, and when Circuit Breaker was lifted. We found significant mean reductions in acute and chronic primary care visits immediately following DORSCON Orange and Circuit Breaker. DORSCON Orange was associated with − 2020 mean daily visits (95% CI − 2890 to − 1150). Circuit Breaker was associated with a further − 2510 mean daily visits (95% CI − 3660 to − 1360). Primary care utilisation for acute visits remained below baseline levels even after the Circuit Breaker was lifted. These significant reductions were observed in both acute and chronic visits, with acute visits experiencing a steeper drop during DORSCON Orange. Understanding the impact of COVID-19 measures on primary care utilisation will be useful for future public health planning.

Abstract Background Despite the increased risk of cervical cancer (CC) among women living with HIV (WLHIV), CC screening and treatment (CCST) rates remain low in Africa. The integration of CCST services into established HIV programs in Africa can improve CC prevention and control. However, the paucity of evidence on effective implementation strategies (IS) has limited the success of integration in many countries. In this study, we seek to identify effective IS to enhance the integration of CCST services into existing HIV programs in Nigeria. Methods Our proposed study has formative and experimental activities across the four phases of the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework. Through an implementation mapping conducted with stakeholders in the exploration phase, we identified a core package of IS (Core) and an enhanced package of IS (Core+) mostly selected from the Expert Recommendations for Implementing Change. In the preparation phase, we refined and tailored the Core and Core+ IS with the implementation resource teams for local appropriateness. In the implementation phase, we will conduct a cluster-randomized hybrid type III trial to assess the comparative effectiveness of Core versus Core+. HIV comprehensive treatment sites (k = 12) will be matched by region and randomized to Core or Core+ in the ratio of 1:1 stratified by region. In the sustainment phase, we will assess the sustainment of CCST at each site. The study outcomes will be assessed using RE-AIM: reach (screening rate), adoption (uptake of IS by study sites), IS fidelity (degree to which the IS occurred according to protocol), clinical intervention fidelity (delivery of CC screening, onsite treatment, and referral according to protocol), clinical effectiveness (posttreatment screen negative), and sustainment (continued integrated CCST service delivery). Additionally, we will descriptively explore potential mechanisms, including organizational readiness, implementation climate, CCST self-efficacy, and implementation intentions. Discussion The assessment of IS to increase CCST rates is consistent with the global plan of eliminating CC as a public health threat by 2030. Our study will identify a set of evidence-based IS for low-income settings to integrate evidence-based CCST interventions into routine HIV care in order to improve the health and life expectancy of WLHIV. Trial registration Prospectively registered on November 7, 2023, at ClinicalTrials.gov no. NCT06128304. https://classic.clinicaltrials.gov/ct2/show/study/NCT06128304

Abstract Background Cross-system interventions that integrate health, behavioral health, and social services can improve client outcomes and expand community impact. Successful implementation of these interventions depends on the extent to which service partners can align frontline services and organizational operations. However, collaboration strategies linking multiple implementation contexts have received limited empirical attention. This study identifies, describes, and specifies multi-level collaboration strategies used during the implementation of Ohio Sobriety Treatment and Reducing Trauma (Ohio START), a cross-system intervention that integrates services across two systems (child welfare and evidence-based behavioral health services) for families that are affected by co-occurring child maltreatment and parental substance use disorders. Methods In phase 1, we used a multi-site qualitative design with 17 counties that implemented Ohio START. Qualitative data were gathered from 104 staff from child welfare agencies, behavioral health treatment organizations, and regional behavioral health boards involved in implementation via 48 small group interviews about collaborative approaches to implementation. To examine cross-system collaboration strategies, qualitative data were analyzed using an iterative template approach and content analysis. In phase 2, a 16-member expert panel met to validate and specify the cross-system collaboration strategies identified in the interviews. The panel was comprised of key child welfare and behavioral health partners and scholars. Results In phase 1, we identified seven cross-system collaboration strategies used for implementation. Three strategies were used to staff the program: (1) contract for expertise, (2) provide joint supervision, and (3) co-locate staff. Two strategies were used to promote service access: (4) referral protocols and (5) expedited access agreements. Two strategies were used to align case plans: (6) shared decision-making meetings, and (7) sharing data. In phase 2, expert panelists specified operational details of the cross-system collaboration strategies, and explained the processes by which strategies were perceived to improve implementation and service system outcomes. Conclusions We identified a range of cross-system collaboration strategies that show promise for improving staffing, service access, and case planning. Leaders, supervisors, and frontline staff used these strategies during all phases of implementation. These findings lay the foundation for future experimental and quasi-experimental studies that test the effectiveness of cross-system collaboration strategies.

Abstract Background A myriad of federal, state, and organizational policies are designed to improve access to evidence-based healthcare, but the impact of these policies likely varies due to contextual determinants of, reinterpretations of, and poor compliance with policy requirements throughout implementation. Strategies enhancing implementation and compliance with policy intent can improve population health. Critically assessing the multi-level environments where health policies and their related health services are implemented is essential to designing effective policy-level implementation strategies. California passed a 2019 health insurance benefit mandate requiring coverage of fertility preservation services for individuals at risk of infertility due to medical treatments, in order to improve access to services that are otherwise cost prohibitive. Our objective was to document and understand the multi-level environment, relationships, and activities involved in using state benefit mandates to facilitate patient access to fertility preservation services. Methods We conducted a mixed-methods study and used the policy-optimized exploration, preparation, implementation, and sustainment (EPIS) framework to analyze the implementation of California’s fertility preservation benefit mandate (SB 600) at and between the state insurance regulator, insurer, and clinic levels. Results Seventeen publicly available fertility preservation benefit mandate-relevant documents were reviewed. Interviews were conducted with four insurers; 25 financial, administrative, and provider participants from 16 oncology and fertility clinics; three fertility pharmaceutical representatives; and two patient advocates. The mandate and insurance regulator guidance represented two “Big P” (system level) policies that gave rise to a host of “little p” (organizational) policies by and between the regulator, insurers, clinics, and patients. Many little p policies were bridging factors to support implementation across levels and fertility preservation service access. Characterizing the mandate’s functions (i.e., policy goals) and forms (i.e., ways that policies were enacted) led to identification of (1) intended and unintended implementation, service, and patient outcomes, (2) implementation processes by level and EPIS phase, (3) actor-delineated key processes and heterogeneity among them, and (4) inner and outer context determinants that drove adaptations. Conclusions Following the midstream and downstream implementation of a state health insurance benefit mandate, data generated will enable development of policy-level implementation strategies, evaluation of determinants and important outcomes of effective implementation, and design of future mandates to improve fit and fidelity.