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Abstract Background A functioning vascular access (VA) is crucial to providing adequate hemodialysis (HD) and considered a critically important outcome by patients and healthcare professionals. A validated, patient-important outcome measure for VA function that can be easily measured in research and practice to harvest reliable and relevant evidence for informing patient-centered HD care is lacking. Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) aims to assess the accuracy and feasibility of measuring a core outcome for VA function established by the international Standardized Outcomes in Nephrology (SONG) initiative. Methods VALID is a prospective, multi-center, multinational validation study that will assess the accuracy and feasibility of measuring VA function, defined as the need for interventions to enable and maintain the use of a VA for HD. The primary objective is to determine whether VA function can be measured accurately by clinical staff as part of routine clinical practice (Assessor 1) compared to the reference standard of documented VA procedures collected by a VA expert (Assessor 2) during a 6-month follow-up period. Secondary outcomes include feasibility and acceptability of measuring VA function and the time to, rate of, and type of VA interventions. An estimated 612 participants will be recruited from approximately 10 dialysis units of different size, type (home-, in-center and satellite), governance (private versus public), and location (rural versus urban) across Australia, Canada, Europe, and Malaysia. Validity will be measured by the sensitivity and specificity of the data acquisition process. The sensitivity corresponds to the proportion of correctly identified interventions by Assessor 1, among the interventions identified by Assessor 2 (reference standard). The feasibility of measuring VA function will be assessed by the average data collection time, data completeness, feasibility questionnaires and semi-structured interviews on key feasibility aspects with the assessors. Discussion Accuracy, acceptability, and feasibility of measuring VA function as part of routine clinical practice are required to facilitate global implementation of this core outcome across all HD trials. Global use of a standardized, patient-centered outcome measure for VA function in HD research will enhance the consistency and relevance of trial evidence to guide patient-centered care. Trial registration Clinicaltrials.gov: NCT03969225. Registered on 31st May 2019.

Abstract The migration of Homo erectus in Southeast Asia during Early Pleistocene is cardinal to our comprehension of the evolution of the genus Homo. However, the limited consideration of the rapidly changing physical environment, together with controversial datings of hominin bearing sites, make it challenging to secure the robust timeline needed to unveil the behavior of early humans. Here, we reappraise the first appearance datum of Javanese H. erectus by adding the most reliable age constraints based on cosmogenic nuclides $$^{10}$$ 10 Be and $$^{26}$$ 26 Al produced in situ to a compilation of earlier estimates. We find that H. erectus reached Java and dwelled at Sangiran, Java, ca. 1.8 Ma. Using this age as a baseline, we develop a probabilistic approach to reconstruct their dispersal routes, coupling ecological movement simulations to landscape evolution models forced by reconstructed geodynamic and climatic histories. We demonstrate that the hospitable terra firma conditions of Sundaland facilitated the prior dispersal of hominins to the edge of Java, where they conversely could not settle until the Javanese archipelago emerged from the sea and connected to Sundaland. The dispersal of H. erectus across Sundaland occurred over at least tens to hundreds kyr, a time scale over which changes in their physical environment, whether climatic or physiographic, may have become primary forcings on their behavior. Our comprehensive reconstruction method to unravel the peopling timeline of SE Asia provides a novel framework to evaluate the evolution of early humans.

Abstract Background A greater understanding of the county-level differences in human papillomavirus (HPV) vaccination rates could aid targeting of interventions to reduce HPV-related cancer disparities. Methods We conducted a mixed-methods study to compare the stakeholder-reported barriers and efforts to increase HPV vaccination rates between counties within the highest, middle, and lowest HPV vaccine initiation (receipt of the first dose) rates among 22 northern Florida counties. Between August 2018 and April 2019, we recruited stakeholders (n = 68) through purposeful and snowball sampling to identify potential participants who were most knowledgeable about the HPV vaccination activities within their county and would represent a variety of viewpoints to create a diverse picture of each county, and completed semi-structured interviews. County-level HPV vaccine initiation rates for 2018 were estimated from the Florida Department of Health’s immunization registry and population counts. Implementation strategies were categorized by level of importance and feasibility using the Expert Recommendations for Implementing Change (ERIC) taxonomy. We compared the barriers and implementation strategies for HPV vaccination between tercile groups of counties by HPV vaccine initiation rates: highest (18 stakeholders), middle (27 stakeholders), and lowest (23 stakeholders). Results The majority of the 68 stakeholders were female (89.7%), non-Hispanic white (73.5%), and represented a variety of clinical and non-clinical occupations. The mentioned barriers represented five themes: healthcare access, clinician practices, community partnerships, targeted populations, and cultural barriers. Within themes, differences emerged between county terciles. Within healthcare access, the highest rate county stakeholders focused on transportation, lowest rate county stakeholders focused on lack of clinicians, and middle county stakeholders mentioned both. The number of ERIC quadrant I strategies, higher feasibility, and importance described decreased with the tercile for HPV vaccination: highest = 6, middle = 5, and lowest =3 strategies. Conclusions The differing barriers and strategies between the highest, middle, and lowest vaccination rate counties suggest that a tailored and targeted effort within the lowest and middle counties to adopt strategies of the highest rate counties may reduce disparities.

Abstract Rare diseases are associated with difficulties in addressing unmet medical needs, lack of access to treatment, high prices, evidentiary mismatch, equity, etc. While challenges facing the development of drugs for rare diseases are experienced differently globally (i.e., higher vs. lower and middle income countries), many are also expressed transnationally, which suggests systemic issues. Pharmaceutical innovation is highly regulated and institutionalized, leading to firmly established innovation pathways. While deviating from these innovation pathways is difficult, we take the position that doing so is of critical importance. The reason is that the current model of pharmaceutical innovation alone will not deliver the quantity of products needed to address the unmet needs faced by rare disease patients, nor at a price point that is sustainable for healthcare systems. In light of the problems in rare diseases, we hold that re-thinking innovation is crucial and more room should be provided for alternative innovation pathways. We already observe a significant number and variety of new types of initiatives in the rare diseases field that propose or use alternative pharmaceutical innovation pathways which have in common that they involve a diverse set of societal stakeholders, explicitly address a higher societal goal, or both. Our position is that principles of social innovation can be drawn on in the framing and articulation of such alternative pathways, which we term here social pharmaceutical innovation (SPIN), and that it should be given more room for development. As an interdisciplinary research team in the social sciences, public health and law, the cases of SPIN we investigate are spread transnationally, and include higher income as well as middle income countries. We do this to develop a better understanding of the social pharmaceutical innovation field’s breadth and to advance changes ranging from the bedside to system levels. We seek collaborations with those working in such projects (e.g., patients and patient organisations, researchers in rare diseases, industry, and policy makers). We aim to add comparative and evaluative value to social pharmaceutical innovation, and we seek to ignite further interest in these initiatives, thereby actively contributing to them as a part of our work.

Abstract Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multivariate GWAS to tease apart variants associated with problematic alcohol use (ALCP-total) through either a shared risk for externalizing (EXT) or a problematic alcohol use-specific risk (ALCP-specific). SNPs associated with ALCP-specific were primarily related to alcohol metabolism. Genetic correlations showed ALCP-specific was predominantly associated with alcohol use and other forms of psychopathology, but not other forms of substance use. Polygenic scores for ALCP-total were associated with multiple forms of substance use, but polygenic scores for ALCP-specific were only associated with alcohol phenotypes. Polygenic scores for both ALCP-specific and EXT show different patterns of associations with alcohol misuse across development. Our results demonstrate that focusing on both shared and specific risk can better characterize pathways of risk for substance use disorders. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice.

Abstract Background This update summarises key changes made to the protocol since the publication of the original protocol for the NAVKIDS2 trial of patient navigators for children with chronic kidney disease (CKD) experiencing social disadvantage and provides the statistical analysis plan (SAP) which has not previously been published. Methods/design The original protocol was published in BMC Nephrology ( https://doi.org/10.1186/s12882-019-1325-y ) prior to the commencement of trial recruitment. During the course of the trial, some key methodological changes needed to be made including changes to eligibility criteria (addition of patients with CKD stages 1–2, broadening of financial status eligibility criterion, addition of patients living in rural/remote areas, modification of age eligibility to 0–16 years, addition of limits related to the language spoken by family, guidance regarding families with multiple eligible children), changes to sites, reduction of sample size, addition of virtual options for consent and study procedures in response to the COVID-19 pandemic, removal of staggered recruitment across sites, addition of outcomes, and changes to the timing and number of assessments. This update summarises the changes made and their rationale and provides the detailed plan for statistical analysis of the trial. These changes have been finalised prior to the completion of study follow-up and the commencement of data analysis. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001152213 . Prospectively registered on 12 July 2018

Predicting adaptive phenotypic evolution depends on invariable selection gradients and on the stability of the genetic covariances between the component traits of the multivariate phenotype. We describe the evolution of six traits of locomotion behavior and body size in the nematode Caenorhabditis elegans for 50 generations of adaptation to a novel environment. We show that the direction of adaptive multivariate phenotypic evolution can be predicted from the ancestral selection differentials, particularly when the traits were measured in the new environment. Interestingly, the evolution of individual traits does not always occur in the direction of selection, nor are trait responses to selection always homogeneous among replicate populations. These observations are explained because the phenotypic dimension with most of the ancestral standing genetic variation only partially aligns with the phenotypic dimension under directional selection. These findings validate selection theory and suggest that the direction of multivariate adaptive phenotypic evolution is predictable for tens of generations.

In this study, we assess the scattering of light and auto-fluorescence from single bacterial cells to address the challenge of fast (

Summary: Staphylococcus (S.) epidermidis is the most common nosocomial coagulase-negative staphylococci infection in preterm infants. Clinical signs of infection are often unspecific and novel markers to complement diagnosis are needed. We investigated proteomic alterations in mouse brain after S. epidermidis infection and in preterm infant blood. We identified lipocalin-2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. We further proved that LCN2 protein expression was associated with endothelial cells but not astrocyte reactivity. By combining network analysis and differential expression approaches, we identified LCN2 linked to blood C-reactive protein levels in preterm infants born

Climate change is a problem that causes many environmental issues that impact the productivity of livestock species. One of the major issues associated with climate change is an increase of the frequency of hot days and heat waves, which increases the risk of heat stress for livestock species. Dairy cattle have been identified as being susceptible to heat stress due to their high metabolic heat load. Studies have shown heat stress impacts several biological processes that can result in large economic consequences. When heat stress occurs, dairy cattle employ several physiological and cellular mechanisms in order to dissipate heat and protect cells from damage. These mechanisms require an increase and diversion in energy toward protection and away from other biological processes. Therefore, in turn heat stress in dairy cattle can lead numerous issues including reductions in milk production and reproduction as well as increased risk for disease and mortality. This indicates a need to select dairy cattle that would be thermotolerant. Various selection strategies to confer thermotolerance have been discussed in the literature, including selecting for reduced milk production, crossbreeding with thermotolerant breeds, selecting based on physiological traits and most recently selecting for enhanced immune response. This review discusses the various issues associated with heat stress in dairy cattle and the pros and cons to the various selection strategies that have been proposed to select for thermotolerance in dairy cattle.

Weight cycling is a major challenge in obesity management. Caloric restriction is known to promote this phenomenon, but the impact of macronutrient changes during dieting remains unclear. This study aimed to determine the role of macronutrient changes in weight maintenance without caloric restriction by alternating between two hypercaloric diets: a high-carbohydrate, high-fat Western diet (WD) and a low-carbohydrate, high-fat diet (LCHDF). Obesity was induced in 8-week-old C57BL/6 male mice by 10 weeks of WD feeding. Then, the mice were subjected to 12 weeks of LCHFD interspersed with WD (I-WD), 3 periods of 2-week LCHFD followed by 2 periods of 3-week WD, or 12 weeks of continuous WD (C-WD). C-WD and I-WD mice were compared to standard diet (SD) mice. In the I-WD group, each LCHFD period decreased weight gain, but mice regained weight after WD resumption. I-WD mice exhibited obesity, dyslipidemia, and glucose intolerance, similarly to the C-WD mice. I-WD mice also developed nonalcoholic steatohepatitis, associated with an increase in type-III collagen gene expression and a decrease in FGF21 protein levels, in comparison with SD. I-WD mice developed weight cycling despite maintaining a high caloric consumption, suggesting that changes in macronutrients during dieting are also a trigger of weight regain.

Microglial cells are now recognized as the "gate-keepers" of healthy brain microenvironment with their disrupted functions adversely affecting neurovascular integrity, neuronal homeostasis, and network connectivity. The perception that these cells are purely toxic under neurodegenerative conditions has been challenged by a continuously increasing understanding of their complexity, the existence of a broad array of microglial phenotypes, and their ability to rapidly change in a context-dependent manner to attenuate or exacerbate injuries of different nature. Recent studies have demonstrated that microglial cells exert crucial physiological functions during embryonic and postnatal brain development, some of these functions being unique to particular stages of development, and extending far beyond sensing dangerous signals and serving as antigen presenting cells. In this focused review we cover the roles of microglial cells in regulating embryonic vasculogenesis, neurogenesis, and establishing network connectivity during postnatal brain development. We further discuss context-dependent microglial contribution to neonatal brain injuries associated with prenatal and postnatal infection and inflammation, in relation to neurodevelopmental disorders, as well as perinatal hypoxia-ischemia and arterial focal stroke. We also emphasize microglial phenotypic diversity, notably at the ultrastructural level, and their sex-dependent influence on the pathophysiology of neurodevelopmental disorders.

Individuals born preterm have higher rates of neurodevelopmental disorders such as schizophrenia, autistic spectrum, and attention deficit/hyperactivity disorders. These conditions are often sexually dimorphic and with different developmental trajectories. The etiology is likely multifactorial, however, infections both during pregnancy and in childhood have emerged as important risk factors. The association between sex- and age-dependent vulnerability to neuropsychiatric disorders has been suggested to relate to immune activation in the brain, including complex interactions between sex hormones, brain transcriptome, activation of glia cells, and cytokine production. Here, we will review sex-dependent effects on brain development, including glia cells, both under normal physiological conditions and following perinatal inflammation. Emphasis will be given to sex-dependent effects on brain regions which play a role in neuropsychiatric disorders and inflammatory reactions that may underlie early-life programming of neurobehavioral disturbances later in life.

Abstract Background Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics. Methods Women undergoing (neo)adjuvant anthracycline‐cyclophosphamide and taxane‐based chemotherapy participated in this study (56 ± 12 years). Two muscle biopsies were collected from the vastus lateralis muscle before the first and after the last chemotherapy administration. Mitochondrial respiratory capacity, reactive oxygen species production, and western blotting analyses were performed. Results Among the 11 patients, we found a decrease in key markers of mitochondrial quantity, reaching −52.0% for citrate synthase protein levels (P = 0.02) and −38.2% for VDAC protein levels (P = 0.04). This mitochondrial content loss is likely explained by reduced mitochondrial biogenesis, as evidenced by a decrease in PGC‐1α1 protein levels (−29.5%; P = 0.04). Mitochondrial dynamics were altered, as documented by a decrease in MFN2 protein expression (−33.4%; P = 0.01), a key marker of mitochondrial outer membrane fusion. Mitochondrial fission is a prerequisite for mitophagy activation, and no variation was found in either key markers of mitochondrial fission (Fis1 and DRP1) or mitophagy (Parkin, PINK1, and Mul1). Two contradictory hypotheses arise from these results: defective mitophagy, which probably increases the number of damaged and fragmented mitochondria, or a relative increase in mitophagy through elevated mitophagic potential (Parkin/VDAC ratio; +176.4%; P

BackgroundDigital mental health interventions (DMHIs) represent a promising solution to address the growing unmet mental health needs and increase access to care. Integrating DMHIs into clinical and community settings is challenging and complex. Frameworks that explore a wide range of factors, such as the Exploration, Preparation, Implementation, Sustainment (EPIS) framework, can be useful for examining multilevel factors related to DMHI implementation efforts. ObjectiveThis paper aimed to identify the barriers to, facilitators of, and best practice recommendations for implementing DMHIs across similar organizational settings, according to the EPIS domains of inner context, outer context, innovation factors, and bridging factors. MethodsThis study stems from a large state-funded project in which 6 county behavioral health departments in California explored the use of DMHIs as part of county mental health services. Our team conducted interviews with clinical staff, peer support specialists, county leaders, project leaders, and clinic leaders using a semistructured interview guide. The development of the semistructured interview guide was informed by expert input regarding relevant inner context, outer context, innovation factors, and bridging factors in the exploration, preparation, and implementation phases of the EPIS framework. We followed a recursive 6-step process to conduct qualitative analyses using inductive and deductive components guided by the EPIS framework. ResultsOn the basis of 69 interviews, we identified 3 main themes that aligned with the EPIS framework: readiness of individuals, readiness of innovations, and readiness of organizations and systems. Individual-level readiness referred to the extent to which clients had the necessary technological tools (eg, smartphones) and knowledge (digital literacy) to support the DMHI. Innovation-level readiness pertained to the accessibility, usefulness, safety, and fit of the DMHI. Organization- and system-level readiness concerned the extent to which providers and leadership collectively held positive views about DMHIs as well as the extent to which infrastructure (eg, staffing and payment model) was appropriate. ConclusionsThe successful implementation of DMHIs requires readiness at the individual, innovation, and organization and system levels. To improve individual-level readiness, we recommend equitable device distribution and digital literacy training. To improve innovation readiness, we recommend making DMHIs easier to use and introduce, clinically useful, and safe and adapting them to fit into the existing client needs and clinical workflow. To improve organization- and system-level readiness, we recommend supporting providers and local behavioral health departments with adequate technology and training and exploring potential system transformations (eg, integrated care model). Conceptualizing DMHIs as services allows the consideration of both the innovation characteristics of DMHIs (eg, efficacy, safety, and clinical usefulness) and the ecosystem around DMHIs, such as individual and organizational characteristics (inner context), purveyors and intermediaries (bridging factor), client characteristics (outer context), as well as the fit between the innovation and implementation settings (innovation factor).

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Currently, cardiovascular disease risk algorithms play a role in primary prevention. However, this is complicated by a lack of powerfully predictive biomarkers that could be observed in individuals before the onset of overt symptoms. A key potential biomarker for heart disease is the vascular endothelial growth factor (VEGF-A), a molecule that plays a pivotal role in blood vessel formation. This molecule has a complex biological role in the cardiovascular system due to the processes it influences, and its production is impacted by various CVD risk factors. Research in different populations has shown single nucleotide polymorphisms (SNPs) may affect circulating VEGF-A plasma levels, with some variants associated with the development of CVDs, as well as CVD risk factors. This minireview aims to give an overview of the VEGF family, and of the SNPs reported to influence VEGF-A levels, cardiovascular disease, and other risk factors used in CVD risk assessments.