'The book's a conversation starter': a realist exploration of the salutogenic potential of reading for pleasure.

Reading for Wellbeing (RfW) is a pilot initiative, aimed at improving mental health and well-being through supporting access and increasing opportunities to read for pleasure. RfW was implemented across six North-East local authorities in England and employed Community Reading Workers to support access to books and reading for targeted populations. The current study used realist methodology to understand context, potential mechanisms of action, acceptability and reported outcomes. Data generation and analysis were conducted iteratively, using focus groups, interviews and observations.The analysis of the collated data highlighted that a positive attitude towards reading and a desire for social connections were significant motivators for engagement with RfW. This paper postulates eight programme theories relating to that context, which describe key mechanisms within RfW linked to engagement with reading, well-being, connections and practice. The paper concludes that previous notions of positivity associated with reading for pleasure enable participants to experience RfW as a positive social encounter. This positive social encounter enhances participants' multiple resistance resources such as increased sense of self-efficacy and connectedness that could impact on their sense of well-being.

Personalized Antihypertensive Treatment Optimization With Smartphone-Enabled Remote Precision Dosing of Amlodipine During the COVID-19 Pandemic (PERSONAL-CovidBP Trial).

BACKGROUND: The objective of the PERSONAL-CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID-19 Pandemic) trial was to assess the efficacy and safety of smartphone-enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID-19 pandemic. METHODS AND RESULTS: This was an open-label, remote, dose titration trial using daily home self-monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5-7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10-12)/7 (95% CI, 6-7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events. CONCLUSIONS: Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App-assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long-term care. REGISTRATION: URL: clinicaltrials.gov. Identifier: NCT04559074.

Genome sequences of 13 Bacillus anthracis Sterne bacteriophages isolated from soil in the western United States.

Bacillus anthracis, classified as a Tier 1 Select Agent by the Centers for Disease Control and Prevention (CDC), is the causative agent of anthrax in both humans and livestock. Herein, we report the full genome sequences of 13 bacteriophages that infect B. anthracis Sterne. These phages are grouped into four clusters and are similar to previously described Bacillus phages.

Semaphorin 6A in Retinal Ganglion Cells Regulates Functional Specialization of the Inner Retina.

To form functional circuits, neurons must settle in their appropriate cellular locations and then project and elaborate neurites to contact their target synaptic neuropils. Laminar organization within the vertebrate retinal inner plexiform layer (IPL) facilitates pre- and postsynaptic neurite targeting, yet, the precise mechanisms underlying establishment of functional IPL subdomains are not well understood. Here we explore mechanisms defining the compartmentalization of OFF and ON neurites generally, and OFF and ON direction-selective neurites specifically, within the developing IPL. We show that semaphorin 6A (Sema6A), a repulsive axon guidance cue, is required for delineation of OFF versus ON circuits within the IPL: in the Sema6a null IPL, the boundary between OFF and ON domains is blurred. Furthermore, Sema6A expressed by retinal ganglion cells (RGCs) directs laminar segregation of OFF and ON starburst amacrine cell (SAC) dendritic scaffolds, which themselves serve as a substrate upon which other retinal neurites elaborate. These results demonstrate for the first time that RGCs, the first neuron-type born within the retina, play an active role in functional specialization of the IPL. Retinal ganglion cell-dependent regulation of OFF and ON starburst amacrine cell dendritic scaffold segregation prevents blurring of OFF versus ON functional domains in the murine inner plexiform layer.

Effectiveness of Youth Risk Prevention Programs When Virtually Adapted.

PURPOSE: COVID-19 forced many youth risk prevention programs to be adapted to virtual formats. It remains unclear whether virtual programming is as effective as in-person programming. This study examined program logistics, differences in reach of at-risk youth and risk reduction in a youth substance use prevention program before and after being adapted to a virtual platform due to COVID-19. METHODS: Rural high school students in a substance use prevention program completed baseline and follow-up surveys. Data were included from two program cohorts, one in 2020 (In-person; N = 331) and the second in 2021 (virtual; N = 426). Survey data were analyzed to compare differences between cohorts in ability to reach at-risk youth and effects on risk reduction. Data on program logistics were drawn from open-ended facilitator questionnaires and site observation reports. These data were analyzed to understand benefits and challenges with virtual program implementation. RESULTS: In-person participants were older, in a higher grade, and reported higher rates of substance abuse, reported higher rates of substance use, sexual behaviors, and risky sex. Virtual program participants reported higher rates of unprotected sex and future intentions of unprotected sex. Neither program showed significant reduction in risk intermediary factors. Positive attitudes about the benefits of substance use increased during the virtual program. Thematic analysis revealed problems with implementing the virtual program, including low attendance and technology issues. DISCUSSION: In-person programs moved to virtual delivery may be less effective at reaching at-risk youth, may have smaller impact on risk prevention and may encounter logistical problems. Because previous research has found that technology-based interventions can be effective, future research should seek to evaluate how to strengthen evidence-based practices when delivery modality changes.

Seagrass ecosystem multifunctionality under the rise of a flagship marine megaherbivore.

Large grazers (megaherbivores) have a profound impact on ecosystem functioning. However, how ecosystem multifunctionality is affected by changes in megaherbivore populations remains poorly understood. Understanding the total impact on ecosystem multifunctionality requires an integrative ecosystem approach, which is especially challenging to obtain in marine systems. We assessed the effects of experimentally simulated grazing intensity scenarios on ecosystem functions and multifunctionality in a tropical Caribbean seagrass ecosystem. As a model, we selected a key marine megaherbivore, the green turtle, whose ecological role is rapidly unfolding in numerous foraging areas where populations are recovering through conservation after centuries of decline, with an increase in recorded overgrazing episodes. To quantify the effects, we employed a novel integrated index of seagrass ecosystem multifunctionality based upon multiple, well-recognized measures of seagrass ecosystem functions that reflect ecosystem services. Experiments revealed that intermediate turtle grazing resulted in the highest rates of nutrient cycling and carbon storage, while sediment stabilization, decomposition rates, epifauna richness, and fish biomass are highest in the absence of turtle grazing. In contrast, intense grazing resulted in disproportionally large effects on ecosystem functions and a collapse of multifunctionality. These results imply that (i) the return of a megaherbivore can exert strong effects on coastal ecosystem functions and multifunctionality, (ii) conservation efforts that are skewed toward megaherbivores, but ignore their key drivers like predators or habitat, will likely result in overgrazing-induced loss of multifunctionality, and (iii) the multifunctionality index shows great potential as a quantitative tool to assess ecosystem performance. Considerable and rapid alterations in megaherbivore abundance (both through extinction and conservation) cause an imbalance in ecosystem functioning and substantially alter or even compromise ecosystem services that help to negate global change effects. An integrative ecosystem approach in environmental management is urgently required to protect and enhance ecosystem multifunctionality.

The role of trauma and positive youth development in polysubstance use among rural middle school students: a latent class analysis.

BACKGROUND: Rural youth often begin developing polysubstance use and other risk behaviors during middle school. However, little polysubstance use research focuses on rural middle school youth. Our research uses Latent Class Analysis to understand existing patterns of rural middle school polysubstance use and risk and protective factors associated with polysubstance use. METHODS: We used survey data from a rural middle school pregnancy prevention program (N = 2,708). The survey included measures of demographics, lifetime substance use, trauma (adverse childhood experiences and bullying victimization) and aspects of youth development (parent communication on drugs and alcohol, parent connectedness and school connectedness). We used latent class analysis to produce participant polysubstance use profiles and multinomial regression to examine associations between polysubstance use, demographics, trauma and aspects of youth development. RESULTS: We categorized our participants into four latent classes. Our analysis classified 2.2% of participants as Regular Polysubstance users, 6.9% as Polysubstance experimenters, 19% as Vape + Alcohol experimenters and 71.9% as Non-Users. More adverse childhood experiences were associated with greater risk of polysubstance use and experimentation. Bullying was positively associated with greater risk of vape and alcohol experimentation. Higher reported parental and school connectedness were associated with lower risk of high frequency polysubstance use. Higher reported school connection was also associated with lower risk of polysubstance experimentation. CONCLUSION: Rural substance use prevention programs should begin during middle school, as polysubstance use development is common among rural middle schoolers. These programs should be trauma informed and focus on connectedness as a modifiable factor to reduce risk of polysubstance use development. TRIAL REGISTRATION: This article does not report results of a health care intervention on human participants.

Water motion and pH jointly impact the availability of dissolved inorganic carbon to macroalgae.

The supply of dissolved inorganic carbon to seaweeds is a key factor regulating photosynthesis. Thinner diffusive boundary layers at the seaweed surface or greater seawater carbon dioxide (CO2) concentrations increase CO2 supply to the seaweed surface. This may benefit seaweeds by alleviating carbon limitation either via an increased supply of CO2 that is taken up by passive diffusion, or via the down-regulation of active carbon concentrating mechanisms (CCMs) that enable the utilization of the abundant ion bicarbonate (HCO3-). Laboratory experiments showed that a 5 times increase in water motion increases DIC uptake efficiency in both a non-CCM (Hymenena palmata, Rhodophyta) and CCM (Xiphophora gladiata, Phaeophyceae) seaweed. In a field survey, brown and green seaweeds with active-CCMs maintained their CCM activity under diverse conditions of water motion. Whereas red seaweeds exhibited flexible photosynthetic rates depending on CO2 availability, and species switched from a non-CCM strategy in wave-exposed sites to an active-CCM strategy in sheltered sites where mass transfer of CO2 would be reduced. 97-99% of the seaweed assemblages at both wave-sheltered and exposed sites consisted of active-CCM species. Variable sensitivities to external CO2 would drive different responses to increasing CO2 availability, although dominance of the CCM-strategy suggests this will have minimal impact within shallow seaweed assemblages.

Deletion of Gremlin-2 alters estrous cyclicity and disrupts female fertility in mice†.

Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which have key functions during embryogenesis and adult physiology. While BMPs play essential roles in ovarian follicle development, the role of the DAN family in female reproductive physiology is less understood. We generated mice null for Grem2 to determine its role in female reproduction in addition to screening patients with primary ovarian insufficiency (POI) for variants in GREM2. Grem2-/- mice are viable, but female Grem2-/- mice have diminished fecundity and irregular estrous cycles. This is accompanied by significantly reduced production of ovarian anti-Müllerian hormone (AMH) from small growing follicles, leading to a significant decrease in serum AMH. Surprisingly, as AMH is a well-established marker of the ovarian reserve, morphometric analysis of ovarian follicles showed maintenance of primordial follicles in Grem2-/- mice like wild-type (WT) littermates. While Grem2 mRNA transcripts were not detected in the pituitary, Grem2 is expressed in hypothalami of WT female mice, suggesting the potential for dysfunction in multiple tissues composing the hypothalamic-pituitary-ovarian axis that contribute to the subfertility phenotype. Additionally, screening 106 women with POI identified one individual with a heterozygous variant in GREM2 that lies within the predicted BMP-GREM2 interface. In total, these data suggest that Grem2 is necessary for female fecundity by playing a novel role in regulating the HPO axis and contributing to female reproductive disease.

Drug screening with zebrafish visual behavior identifies carvedilol as a potential treatment for an autosomal dominant form of retinitis pigmentosa.

Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish autosomal dominant RP model. This model expresses a truncated human rhodopsin transgene (Q344X) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol may directly on rods as it affected the adrenergic pathway in the photoreceptor-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat autosomal dominant RP patients.

A case of Myhre syndrome mimicking juvenile scleroderma.

BACKGROUND: Myhre syndrome is a genetic disorder caused by gain of function mutations in the SMAD Family Member 4 (SMAD4) gene, resulting in progressive, proliferative skin and organ fibrosis. Skin thickening and joint contractures are often the main presenting features of the disease and may be mistaken for juvenile scleroderma. CASE PRESENTATION: We report a case of a 13 year-old female presenting with widespread skin thickening and joint contractures from infancy. She was diagnosed with diffuse cutaneous systemic sclerosis, and treatment with corticosteroids and subcutaneous methotrexate recommended. There was however disease progression prompting genetic testing. This identified a rare heterozygous pathogenic variant c.1499 T > C (p.Ile500Thr) in the SMAD4 gene, suggesting a diagnosis of Myhre syndrome. Securing a molecular diagnosis in this case allowed the cessation of immunosuppression, thus reducing the burden of unnecessary and potentially harmful treatment, and allowing genetic counselling. CONCLUSION: Myhre Syndrome is a rare genetic mimic of scleroderma that should be considered alongside several other monogenic diseases presenting with pathological fibrosis from early in life. We highlight this case to provide an overview of these genetic mimics of scleroderma, and highlight the molecular pathways that can lead to pathological fibrosis. This may provide clues to the pathogenesis of sporadic juvenile scleroderma, and could suggest novel therapeutic targets.

Ocean model resolution dependence of Caribbean sea-level projections.

Sea-level rise poses severe threats to coastal and low-lying regions around the world, by exacerbating coastal erosion and flooding. Adequate sea-level projections over the next decades are important for both decision making and for the development of successful adaptation strategies in these coastal and low-lying regions to climate change. Ocean components of climate models used in the most recent sea-level projections do not explicitly resolve ocean mesoscale processes. Only a few effects of these mesoscale processes are represented in these models, which leads to errors in the simulated properties of the ocean circulation that affect sea-level projections. Using the Caribbean Sea as an example region, we demonstrate a strong dependence of future sea-level change on ocean model resolution in simulations with a global climate model. The results indicate that, at least for the Caribbean Sea, adequate regional projections of sea-level change can only be obtained with ocean models which capture mesoscale processes.

Binary Fate Choice between Closely Related Interneuronal Types Is Determined by a Fezf1-Dependent Postmitotic Transcriptional Switch.

Many neuronal types occur as pairs that are similar in most respects but differ in a key feature. In some pairs of retinal neurons, called paramorphic, one member responds to increases and the other to decreases in luminance (ON and OFF responses). Here, we focused on one such pair, starburst amacrine cells (SACs), to explore how closely related neuronal types diversify. We find that ON and OFF SACs are transcriptionally distinct prior to their segregation, dendritic outgrowth, and synapse formation. The transcriptional repressor Fezf1 is selectively expressed by postmitotic ON SACs and promotes the ON fate and gene expression program while repressing the OFF fate and program. The atypical Rho GTPase Rnd3 is selectively expressed by OFF SACs and regulates their migration but is repressed by Fezf1 in ON SACs, enabling differential positioning of the two types. These results define a transcriptional program that controls diversification of a paramorphic pair.

Wave effects on seedling establishment of three pioneer marsh species: survival, morphology and biomechanics.

BACKGROUND AND AIMS: It is important to have an in-depth mechanistic understanding of tidal marsh establishment and dynamics to ensure the long-term persistence of these valuable ecosystems. As wave forcing may be expected to impact seedling establishment, we studied the effect of water-imposed drag forces on seedling survival, morphology and biomechanical properties of three marsh pioneer species that are dominant along the salinity gradient in many areas around the world: Spartina anglica (salt to brackish), Scirpus maritimus (brackish) and Phragmites australis (brackish to fresh). METHODS: Using a newly developed plant-shaking mesocosm (PSM) that mimicked water-imposed wave drag forces, the effect of wave stress on seedling survival was examined, together with impacts on morphology and biomechanical properties. KEY RESULTS: After 7 weeks of exposure to wave stress, lowered seedling survival and growth for all species was revealed. Wave treatments increased the root/shoot biomass ratio to enhance anchorage and made seedlings more flexible (i.e. reduced flexural rigidity), which might be regarded as a mixed outcome between a stress avoidance and stress tolerance strategy. CONCLUSIONS: The different biomechanical responses between the three dominant marsh pioneer species, overall, make them less resistant to external stress. Therefore, our results indicate that the likelihood of marshes becoming established is reduced if wave energy increases. Despite the different biomechanical response of these three pioneer species to waves, the seedlings of all species were found to have low resistance to external stresses.

Fifteen-minute consultation: A guide to managing a child with a new finding of neutropenia.

OBJECTIVE: To describe a structured approach for managing a child with a new finding of neutropenia. METHOD: Literature review and consensus practice of clinicians in our regional centre. CONCLUSION: Neutropenia may arise in a variety of situations from a well child with a physiological neutropenia to a sick infant with life-threatening infection. In most cases a thoughtful history and directed examination will help to identify the severity in order to determine an appropriate care pathway. SCENARIO: A 6-year-old boy presented earlier in the day to the acute assessment unit with lethargy and a sore throat. At handover time his blood results are phoned through and show that he is neutropenic.

Randomized Crossover Trial of the Impact of Morning or Evening Dosing of Antihypertensive Agents on 24-Hour Ambulatory Blood Pressure.

Some data suggest that nocturnal dosing of antihypertensive agents may reduce cardiovascular outcomes more than daytime dosing. This trial was designed to evaluate whether ambulatory blood pressure monitoring levels differ by timing of drug dosing. Patients aged 18 to 80 years with reasonably controlled hypertension (≤150/≤90 mm Hg) on stable therapy of ≥1 antihypertensive agent were recruited from 2 centers in London and Thessaloniki. Patients were randomized to receive usual therapy either in the morning (6 am-11 am) or evening (6 pm-11 pm) for 12 weeks when participants crossed over to the alternative timing for a further 12 weeks. Clinic blood pressures and a 24-hour recording were taken at baseline, 12, and 24 weeks and routine blood tests were taken at baseline. The study had 80% power to detect 3 mm Hg difference in mean 24-hour systolic blood pressure (α=0.05) by time of dosing. A 2-level hierarchical regression model adjusted for center, period, and sequence was used. Of 103 recruited patients (mean age, 62; 44% female), 95 patients (92%) completed all three 24-hour recordings. Mean 24-hour systolic and diastolic blood pressures did not differ between daytime and evening dosing. Similarly, morning and evening dosing had no differential impact on mean daytime (7 am-10 pm) and nighttime (10 pm-7 am) blood pressure levels nor on clinic levels. Stratification by age (≤65/≥65 years) or sex did not affect results. In summary, among hypertensive patients with reasonably well-controlled blood pressure, the timing of antihypertensive drug administration (morning or evening) did not affect mean 24-hour or clinic blood pressure levels. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01669928.

SCORE-IT (Selecting Core Outcomes for Randomised Effectiveness trials In Type 2 diabetes): a systematic review of registered trials.

BACKGROUND: Outcomes measured in clinical trials should be meaningful to patients, healthcare professionals and researchers, yet there is heterogeneity in the outcomes used across trials. This inconsistency impacts on the ability to compare findings and may mean that the results have little importance to healthcare professionals and the patients that they care for. The aim of the present study is to review the outcomes used in registered trials of therapies for type 2 diabetes mellitus as the first step in the development of a core outcome set for effectiveness trials in type 2 diabetes. METHODS: A systematic review of clinicaltrials.gov entries was completed for randomised, open (actively recruiting or in follow-up period), phase 3 and 4 trials of type 2 diabetes mellitus in adults. Trials of the treatment of diabetes complications, co-morbidities, prevention and surgery were excluded. Each trial was screened for eligibility and outcomes extracted from the primary and secondary outcomes data fields and free text study information. The outcomes were recorded verbatim and classified into core outcome domains according to the COMET taxonomy. RESULTS: A total of 354 trial registrations were reviewed for eligibility and 138 trials included. In total, 1444 outcomes were extracted with a median of eight outcomes per trial (range = 1-60). Outcomes were categorised into 30 different outcome domains according to the COMET taxonomy, but no single domain or outcome was measured in 100% of trials. The majority of trials (88%) included outcomes in the 'metabolism and nutrition' domain, such as lipids and lipoproteins (21%), HbA1c (18%), hypoglycaemia (14%), fasting plasma/blood glucose (11%), glycaemic variability (8%), postprandial response (8%) and insulin sensitivity (5%). Only 10% of trials included one or more patient reported outcomes; of these, 29% included the Diabetes Treatment Satisfaction Questionnaire. CONCLUSIONS: There is marked heterogeneity in the outcomes measured in registered therapeutic intervention trials for type 2 diabetes. The use of an agreed set of core outcomes will improve the consistency of reporting in clinical trials for type 2 diabetes. TRIAL REGISTRATION: The core outcome set study, of which this is a part, is registered in the COMET database, http://www.comet-initiative.org/studies/details/956 . Registered on 24 January 2017.

Establishing Wiring Specificity in Visual System Circuits: From the Retina to the Brain.

The retina is a tremendously complex image processor, containing numerous cell types that form microcircuits encoding different aspects of the visual scene. Each microcircuit exhibits a distinct pattern of synaptic connectivity. The developmental mechanisms responsible for this patterning are just beginning to be revealed. Furthermore, signals processed by different retinal circuits are relayed to specific, often distinct, brain regions. Thus, much work has focused on understanding the mechanisms that wire retinal axonal projections to their appropriate central targets. Here, we highlight recently discovered cellular and molecular mechanisms that together shape stereotypic wiring patterns along the visual pathway, from within the retina to the brain. Although some mechanisms are common across circuits, others play unconventional and circuit-specific roles. Indeed, the highly organized connectivity of the visual system has greatly facilitated the discovery of novel mechanisms that establish precise synaptic connections within the nervous system.