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Abstract Compact cell type-specific promoters are important tools for basic and preclinical research and clinical delivery of gene therapy. In this work, we designed novel MiniPromoters to target D1 and D2 type dopaminoceptive medium spiny neurons in the striatum by manually identifying candidate regulatory regions or employing the OnTarget webserver. We then empirically tested the designs in rAAV-PHP.B for specificity and robustness in three systems: intravenous injection in mice, intracerebroventricular injection in mice, and intracerebroventricular injection in non-human primates. Twelve MiniPromoters were designed from eight genes: seven manually and five using OnTarget. When delivered intravenously in mice, three MiniPromoters demonstrated highly selective expression in the striatum, with Ple389 (ADORA2A) showing high levels of dopamine D2-receptor cell co-localization. The same three MiniPromoters also displayed enriched expression in the striatum when delivered intracerebroventricularly in mice with high levels of DARPP32 co-localization. Finally, Ple389 (ADORA2A) was intracerebroventricularly injected in non-human primates and showed enriched expression in the striatum as in the mouse. Ple389 (ADORA2A) demonstrated expression in the medium spiny neurons in all three systems tested and exhibited the highest level of D2-MSNs and DARPP32 co-labeling in mice, demonstrating its potential as a tool for gene therapy approaches for Parkinson and Huntington disease treatment.

Abstract Sustainable diets can achieve considerable reductions in greenhouse gas emissions and improvements in human health, but changing dietary behavior remains a challenge. We assessed the impacts of two behavioral insights strategies on bridging the intention-action gap related to sustainable and healthy food choices amongst hospital cafeteria patrons. In a pilot survey of hospital staff (N = 1,165), 56% identified limited awareness and availability of sustainable food as barriers to purchasing, although 46% were extremely willing to try sustainable dishes. We examined increasing salience (Study 1), varying availability (Study 2a), and decreasing availability (Study 2b) on sustainable and healthy dish purchases in three hospital cafeterias. Each study ran for seven weeks from March to April, 2023. In total, 10,616 dishes were purchased. In Study 1, increasing salience was associated with significant uptake of sustainable and healthy dishes, but the effect disappeared once the salience intervention was removed. In Study 2a, increasing availability of sustainable dishes corresponded to a significant increase in purchases of sustainable dishes, while decreasing availability in Study 2b followed a downward trend in purchases, suggesting that availability drove dietary choices. We recommend hospitals consider these choice architecture interventions to support the adoption of sustainable and healthy diets.

Abstract Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant‐producing cells and lower surfactant‐protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12 mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term = 150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45 min before tissue collection. Lung function and structure were similar in control lambs (n = 16, 11 ewes) and lambs from asthma ewes (n = 14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n = 12, 8 ewes) compared to those from controls (P = 0.003) or asthma ewes (P = 0.008). Lung expression of surfactant protein genes SFTPA (P = 0.048) and SFTPB (P

Abstract Marine phytoplankton biomass and chlorophyll-a concentration are often estimated from pigment fluorescence measurements, which have become routine despite known variability in the fluorescent response for a given amount of chlorophyll-a. Here, we present a near-global, monthly climatology of chlorophyll-a fluorescence measurements from profiling floats combined with ocean color satellite estimates of chlorophyll-a concentration to illuminate seasonal biases in the fluorescent response and expand upon previously observed regional patterns in this bias. Global biases span over an order of magnitude, and can vary seasonally by a factor of 10. An independent estimate of chlorophyll-a from light attenuation shows similar global patterns in the chlorophyll-fluorescence bias when compared to biases derived from satellite estimates. Without accounting for these biases, studies or models using fluorescence-estimated chlorophyll-a will inherit the seasonal and regional biases described here.

Abstract The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.

Graptolites represent one of the most important index fossils for the lower to middle Paleozoic biostratigraphy worldwide. Compared to other regions, graptolite faunas exhibited a marked decrease in diversity in Argentina during the Silurian, what resulted in reduced and low-varied registers and denied biostratigraphic works in its territory. This study introduces new Silurian graptolite faunas from the Los Espejos Formation, Poblete Norte section, Central Precordillera of Argentina. A total of thirteen graptolitic levels were identified, containing Bohemograptus bohemicus, Lobograptus sp., Saetograptus argentinus argentinus, Saetograptus cf. S. varians, Uncinatograptus uncinatus notouncinatus, Uncinatograptus elsae sp. nov., and Uncinatograptus lisandroi sp. nov. The occurrence of Uncinatograptus spp. in association with B. bohemicus could indicate the presence of the lower Gorstian Neodiversograptus nilssoni Biozone. A few meters above, the finding of S. a. argentinus in association with S. cf. S. varians, U. u. notouncinatus, and Lobograptus sp. suggest the presence of the lower Gorstian Lobograptus progenitor Biozone. The upper graptolitic beds yield specimens of S. a. argentinus and B. bohemicus, suggesting late Gorstian to early Ludfordian ages. These new graptolite faunas allow to correlate more precisely with local (Precordillera and Famatina), regional (North Western Argentina and Bolivia) and global equivalent sections. This discovery introduces new graptolite faunas, first-time recorded in South America, proposes for the first time a graptolite biostratigraphy for the Ludlow of Precordillera, and complements so far insufficient knowledge on Ludlovian graptolitic faunas of the continent in a critical time in the history of this fossil group.

Abstract Background Occurrence of low blood taurine concentrations (B‐TauC) and predisposing factors to taurine deficiency in English Cocker Spaniels (ECS) are incompletely understood. Objectives Investigate the occurrence of low B‐TauC in a Swedish population of ECS and evaluate the association between B‐TauC and dog characteristics, clinical variables, and diet composition. Animals One‐hundred eighty privately owned ECS. Methods Dogs were prospectively recruited and underwent physical examination, blood analyses, and echocardiographic and ophthalmic examinations. Dogs with clinical signs of congestive heart failure (CHF) also underwent thoracic radiography. Taurine concentrations were analyzed in plasma (EDTA and heparin) and whole blood. Diets consumed by the dogs at the time of the examination were analyzed for dietary taurine‐ (D‐TauC), cysteine‐ (D‐CysC), and methionine concentrations (D‐MetC). Results Fifty‐three of 180 dogs (29%) had low B‐TauC, of which 13 (25%) dogs had clinical and radiographic signs of CHF, increased echocardiographic left ventricular (LV) dimensions and volumes, and impaired LV systolic function. Five (9%) dogs with low B‐TauC had retinal abnormalities. Dietary MetC, dietary animal protein source (red/white meat), and age were associated with B‐TauC in the final multivariable regression model (P

AbstractMarek’s disease virus (MDV) has become an increasingly virulent pathogen in the poultry industry despite vaccination efforts to control it. Brazil has experienced a significant rise of Marek’s disease (MD) outbreaks in recent years. Our study aimed to analyze the complete meq gene sequences to understand the molecular epidemiological basis of MD outbreaks in Brazilian vaccinated layer farms. We detected a high incidence rate of visceral MD (67.74%) and multiple circulating MDV strains. The most prevalent and geographically widespread genotype presented several clinical and molecular characteristics of a highly virulent strain and evolving under positive selective pressure. Phylogenetic and phylogeographic analysis revealed a closer relationship with strains from the USA and Japan. This study sheds light on the circulation of MDV strains capable of infecting vaccinated birds. We emphasize the urgency of adopting preventive measures to manage MDV outbreaks threatening the poultry farming industry.

Abstract Alzheimer’s disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. The complement pathway has been proposed as a therapeutic target. C5aR1 inhibition reduces plaque load, gliosis, and memory deficits in animal models, however, the cellular bases underlying this neuroprotection were unclear. Here, we show that the C5aR1 antagonist PMX205 improves outcomes in the Arctic48 mouse model of AD. A combination of single cell and single nucleus RNA-seq analysis of hippocampi derived from males and females identified neurotoxic disease-associated microglia clusters in Arctic mice that are C5aR1-dependent, while microglial genes associated with synapse organization and transmission and learning were overrepresented in PMX205-treated mice. PMX205 also reduced neurotoxic astrocyte gene expression, but clusters associated with protective responses to injury were unchanged. C5aR1 inhibition promoted mRNA-predicted signaling pathways between brain cell types associated with cell growth and repair, while suppressing inflammatory pathways. Finally, although hippocampal plaque load was unaffected, PMX205 prevented deficits in short-term memory in female Arctic mice. In conclusion, C5aR1 inhibition prevents cognitive loss, limits detrimental glial polarization while permitting neuroprotective responses, as well as leaving most protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for AD.

Abstract Background This protocol outlines a scoping review with the objective of identifying and exploring planetary health considerations within existing health guidelines and health technology assessments (HTA). The insights gained from this review will serve as a basis for shaping future Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidance on planetary health. Methods We will adhere to the JBI methodology for scoping reviews. We will conduct a comprehensive search and screening of results in all languages across various databases including MEDLINE, EMBASE, CINAHL, Global Health, Health Systems Evidence, Greenfile, and Environmental Issues. Additionally, we will supplement this search with resources such as the GIN library, BIGG database, Epistemonikos, GRADE guidelines repository, GRADEpro Guideline Development Tool Database, MAGICapp, NICE website, WHO websites, and a manual exploration of unpublished relevant documents using Google incognito mode. Two independent reviewers will screen and assess the full texts of identified documents according to the eligibility criteria. The following information from each full text will be extracted: document title; first author’s name; publication year; language; document type; document as a guideline or HTA; the topic/discipline; document purpose/study objective; developing/sponsoring organization; the country in which the study/guideline/HTA report was conducted; definition of planetary health or related concept provided; types of planetary health experts engaged; study methods; suggested methods to assess planetary health; use of secondary data on planetary health outcomes; description for use of life cycle assessment; description for assessing the quality of life cycle; population/intended audience; interventions; category; applicable planetary health boundaries; consideration of social justice/global equity; phase of intervention in life cycle related to planetary health addressed; the measure of planetary health impact; impact on biodiversity/land use; one health/animal welfare mention; funding; and conflict of interest. Data analysis will involve a combination of descriptive statistics and directed content analysis, with results presented in a narrative format and displayed in tables and graphs. Discussion The final review results will be submitted to open-access peer-reviewed journals for publication when they become available. The research findings will also be disseminated at relevant planetary health conferences and workshops. Systematic review registration Open Science Framework ( https://osf.io/3jmsa ).

Abstract Influenza A viruses in swine have considerable genetic diversity and continue to pose a pandemic threat to humans due to a potential lack of population level immunity. Here we describe a pipeline to characterize and triage influenza viruses for their pandemic risk and examine the pandemic potential of two widespread swine origin viruses. Our analysis reveals that a panel of human sera collected from healthy adults in 2020 has no cross-reactive neutralizing antibodies against a α-H1 clade strain (α-swH1N2) but do against a γ-H1 clade strain. The α-swH1N2 virus replicates efficiently in human airway cultures and exhibits phenotypic signatures similar to the human H1N1 pandemic strain from 2009 (H1N1pdm09). Furthermore, α-swH1N2 is capable of efficient airborne transmission to both naïve ferrets and ferrets with prior seasonal influenza immunity. Ferrets with H1N1pdm09 pre-existing immunity show reduced α-swH1N2 viral shedding and less severe disease signs. Despite this, H1N1pdm09-immune ferrets that became infected via the air can still onward transmit α-swH1N2 with an efficiency of 50%. These results indicate that this α-swH1N2 strain has a higher pandemic potential, but a moderate level of impact since there is reduced replication fitness and pathology in animals with prior immunity.

BackgroundLaparoscopic appendectomy (LA) is an effective treatment for the surgical care of appendicitis, with this minimally invasive approach allowing patients to typically spend less time in hospital and promptly return to normal life activities. Residents can acquire the competence and confidence needed in a safe learning environment prior to real patient encounters through simulation-based learning of these techniques. We propose a low cost, sustainable, high fidelity simulation-based training model for LA to compliment regular resident practice of these skills.MethodsA team dedicated to developing this surgical simulation training model was established, equipped with the clinical knowledge and model engineering expertise. We used concepts of design-based research (DBR) to iteratively develop this model at key intervals. Our LA training model underwent four stages of model development prior to unified stakeholder consensus that this model was deemed effective and suitable for integration into formative surgical simulation curricula.ResultsThis model simulates most of the key anatomical structures associated with performing an LA. In order to provide high fidelity haptic feedback, attempts were made to mimic the tensile properties of real tissue using different concentrations of silicone. The model can be utilized with laparoscopic box trainers of various sizes due to its scalability. It cost €9.67 to create, and single use appendix components cost €1.22 to build thereafter.ConclusionsSurgical residents can benefit from the platform that simulation-based education offers to develop the psychomotor skills necessary to perform LA in a safe learning environment. We describe a model for LA, which allows learners to develop their skill proficiency in this area under expert supervision.

Background The risk–benefit balance of statin use in healthy older people is uncertain. We describe the baseline characteristics of the STAREE (Statins in Reducing Events in the Elderly) trial, which is a randomized, double‐blind, placebo‐controlled trial among community‐dwelling older people; the trial evaluated the effect of atorvastatin 40 mg for the prevention of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke), and on disability‐free survival (survival free of both dementia and persistent physical disability). Methods and Results STAREE enrolled people aged ≥70 years from 1583 general practices across Australia with no history of clinical cardiovascular disease, diabetes, or dementia. Baseline data collected included demographic, clinical, cognitive (Modified Mini‐Mental State Examination), psychological (Center for Epidemiologic Studies Short Depression Scale), lifestyle, medical, physical, blood and urine measures, and quality of life. Demographic and clinical characteristics of study participants were then compared with publicly available landmark statin trials. A total of 9971 participants were recruited (mean±SD age 74.7±4.5 years, 4023 (40%) ≥75 years, 52% women) between July 2015 and March 2023. The mean low‐density lipoprotein cholesterol was 3.27 mmol/L (SD=0.72; 126 mg/dL). Hypertension was reported by 43% of participants and the mean blood pressure was 136/80 mm Hg. Compared with previous landmark statin trials that included primary prevention cohorts, STAREE is unique in including such a large number of older (≥75 years) independent‐living people. Conclusions STAREE is the largest primary prevention trial of statins powered to address the important clinical outcomes of major cardiovascular events, disability‐free survival, and cognition in older people. Registration https://www.clinicaltrials.gov; Unique identifier: NCT02099123.

Background: Neighborhood disadvantage, a social driver of health (SDOH), has been associated with adverse perinatal outcomes; yet little is known about its association with anesthetic choice. Objective: The purpose of this study is to assess the association of neighborhood disadvantage and anesthetic choice for cesarean deliveries. We hypothesize that people from the most disadvantaged neighborhoods are more likely to receive general anesthesia for cesarean deliveries compared to those from the most advantaged neighborhoods. Study design: This single-center retrospective cohort study identified index cesarean deliveries performed between 2008 and 2017. People were categorized into no, low, moderate, and high disadvantage neighborhood using the area deprivation index. The odds of receiving general anesthesia versus neuraxial anesthesia (epidural, spinal, or combined spinal-epidural) were compared using logistic regression models. Results: Of the 16,351 people with cesarean deliveries, 96.0% received neuraxial versus 4.0% general anesthesia. The rates of general anesthesia were 6.3%, 4.2%, 3.1%, and 2.4% for the high, moderate, low, and no disadvantage groups (P

Biopolymer networks from the intracellular to tissue scale display high rigidity and tensile stress while having coordinations well below the normal threshold for mechanical rigidity. The elastic filaments in these networks are often severed by enzymes in a tension-inhibited manner. The effects of such pruning on the mechanics of prestressed networks have not been studied. We show that networks pruned by a tension-inhibited method remain rigid at much lower coordinations than randomly pruned ones. These findings suggest a possible reason for the repeated evolution of tension-inhibited filament-severing proteins.

Articular cartilage injuries in the knee can lead to post-traumatic osteoarthritis if untreated, causing debilitating problems later in life. Standard surgical treatments fail to ensure long lasting repair of damaged cartilage, often resulting in fibrotic tissue. While there is a vast amount of research into cartilage regeneration, integrating engineered implants with cartilage remains a challenge. As cartilage is a load bearing tissue, it is imperative to evaluate tissue repair strategies and their ability to integrate under mechanical loading. This work established a dynamically loaded ex vivo model of cartilage repair using human cartilage explants. The model was used to assess the efficacy of a stem cell therapy delivered in a bioadhesive hydrogel comprised of photocrosslinkable gelatin methacryloyl (GelMA) and microbial transglutaminase to repair the model defect. Extensive neocartilage production and integration were observed via histology and immunohistochemistry after 28 days chondrogenic culture. Analysis of culture media allowed monitoring of glycosaminoglycan and type II collagen production over time. A mechanical assessment of integration via a push out test showed a 15-fold increase in push out strength over the culture duration. The model was successful in exhibiting robust chondrogenesis with transglutaminase or without, and under both culture conditions. The work also highlights several limitations of ex vivo models and challenges of working with bioreactors that must be overcome to increase their utility. This ex vivo model has the potential to delay the need for costly pre-clinical studies and provide a more nuanced assessment of cartilage repair strategies than is possible in vivo.

Abstract The strength and variability of the Southern Ocean carbon sink is a significant source of uncertainty in the global carbon budget. One barrier to reconciling observations and models is understanding how synoptic weather patterns modulate air-sea carbon exchange. Here, we identify and track storms using atmospheric sea level pressure fields from reanalysis data to assess the role that storms play in driving air-sea CO2 exchange. We examine the main drivers of CO2 fluxes under storm forcing and quantify their contribution to Southern Ocean annual air-sea CO2 fluxes. Our analysis relies on a forced ocean-ice simulation from the Community Earth System Model, as well as CO2 fluxes estimated from Biogeochemical Argo floats. We find that extratropical storms in the Southern Hemisphere induce CO2 outgassing, driven by CO2 disequilibrium. However, this effect is an order of magnitude larger in observations compared to the model and caused by different reasons. Despite large uncertainties in CO2 fluxes and storm statistics, observations suggest a pivotal role of storms in driving Southern Ocean air-sea CO2 outgassing that remains to be well represented in climate models, and needs to be further investigated in observations.

Abstract Background Chronic postsurgical pain (CPSP) is common following musculoskeletal and orthopedic surgeries and is associated with impairment and reduced quality of life. Several interventions have been proposed to reduce CPSP; however, there remains uncertainty regarding which, if any, are most effective. We will perform a systematic review and network meta-analysis of randomised trials to assess the comparative benefits and harms of perioperative pharmacological and psychological interventions directed at preventing chronic pain after musculoskeletal and orthopedic surgeries. Methods We will search MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to present, without language restrictions. We will include randomised controlled trials that as follows: (1) enrolled adult patients undergoing musculoskeletal or orthopedic surgeries; (2) randomized them to any pharmacological or psychological interventions, or their combination directed at reducing CPSP, placebo, or usual care; and (3) assessed pain at 3 months or more after surgery. Screening for eligible trials, data extraction, and risk-of-bias assessment using revised Cochrane risk-of-bias tool (RoB 2.0) will be performed in duplicate and independently. Our main outcome of interest will be the proportion of surgical patients reporting any pain at ≥ 3 months after surgery. We will also collect data on other patient important outcomes, including pain severity, physical functioning, emotional functioning, dropout rate due to treatment-related adverse event, and overall dropout rate. We will perform a frequentist random-effects network meta-analysis to determine the relative treatment effects. When possible, the modifying effect of sex, surgery type and duration, anesthesia type, and veteran status on the effectiveness of interventions will be investigated using network meta-regression. We will use the GRADE approach to assess the certainty evidence and categorize interventions from most to least beneficial using GRADE minimally contextualised approach. Discussion This network meta-analysis will assess the comparative effectiveness of pharmacological and psychological interventions directed at preventing CPSP after orthopedic surgery. Our findings will inform clinical decision-making and identify promising interventions for future research. Systematic review registration PROSPERO CRD42023432503.

Abstract Background Splenic abscess is a serious complication associated with infective endocarditis. There is still contradicting evidence regarding the optimal treatment pathway including timing of valve intervention and the approach for managing splenic foci. Case presentation We present a case of a hybrid staged approach in which we successfully performed a laparoscopic splenectomy following percutaneous abscess drainage and a delayed aortic valve replacement. Conclusions A multidisciplinary teamwork is fundamental in providing optimal care for patients with distant complications associated with infective endocarditis. Our hybrid approach seems safe and feasible.

Abstract Background Lifestyle choices, metformin, and dietary supplements may prevent GDM, but the effect of intervention characteristics has not been identified. This review evaluated intervention characteristics to inform the implementation of GDM prevention interventions. Methods Ovid, MEDLINE/PubMed, and EMBASE databases were searched. The Template for Intervention Description and Replication (TIDieR) framework was used to examine intervention characteristics (who, what, when, where, and how). Subgroup analysis was performed by intervention characteristics. Results 116 studies involving 40,940 participants are included. Group-based physical activity interventions (RR 0.66; 95% CI 0.46, 0.95) reduce the incidence of GDM compared with individual or mixed (individual and group) delivery format (subgroup p-value = 0.04). Physical activity interventions delivered at healthcare facilities reduce the risk of GDM (RR 0.59; 95% CI 0.49, 0.72) compared with home-based interventions (subgroup p-value = 0.03). No other intervention characteristics impact the effectiveness of all other interventions. Conclusions Dietary, physical activity, diet plus physical activity, metformin, and myoinositol interventions reduce the incidence of GDM compared with control interventions. Group and healthcare facility-based physical activity interventions show better effectiveness in preventing GDM than individual and community-based interventions. Other intervention characteristics (e.g. utilization of e-health) don’t impact the effectiveness of lifestyle interventions, and thus, interventions may require consideration of the local context.

Abstract Juvenile male zebra finches (Taeniopygia guttata) must be exposed to an adult tutor during a sensitive period to develop normal adult song. The pre-motor nucleus HVC (acronym used as a proper name), plays a critical role in song learning and production (cf. Broca’s area in humans). In the human brain, left-side hemispheric dominance in some language regions is positively correlated with proficiency in linguistic skills. However, it is unclear whether this pattern depends upon language learning, develops with normal maturation of the brain, or is the result of pre-existing functional asymmetries. In juvenile zebra finches, even though both left and right HVC contribute to song production, baseline molecular activity in HVC is left-dominant. To test if HVC exhibits hemispheric dominance prior to song learning, we raised juvenile males in isolation from adult song and measured neuronal activity in the left and right HVC upon first exposure to an auditory stimulus. Activity in the HVC was measured using the immediate early gene (IEG) zenk (acronym for zif-268, egr-1, NGFI-a, and krox-24) as a marker for neuronal activity. We found that neuronal activity in the HVC of juvenile male zebra finches is not lateralized when raised in the absence of adult song, while normally-reared juvenile birds are left-dominant. These findings show that there is no pre-existing asymmetry in the HVC prior to song exposure, suggesting that lateralization of the song system depends on learning through early exposure to adult song and subsequent song-imitation practice.

Abstract Ocean warming and acidification, decreases in dissolved oxygen concentrations, and changes in primary production are causing an unprecedented global redistribution of marine life. The identification of underlying ecological processes underpinning marine species turnover, particularly the prevalence of increases of warm-water species or declines of cold-water species, has been recently debated in the context of ocean warming. Here, we track changes in the mean thermal affinity of marine communities across European seas by calculating the Community Temperature Index for 65 biodiversity time series collected over four decades and containing 1,817 species from different communities (zooplankton, coastal benthos, pelagic and demersal invertebrates and fish). We show that most communities and sites have clearly responded to ongoing ocean warming via abundance increases of warm-water species (tropicalization, 54%) and decreases of cold-water species (deborealization, 18%). Tropicalization dominated Atlantic sites compared to semi-enclosed basins such as the Mediterranean and Baltic Seas, probably due to physical barrier constraints to connectivity and species colonization. Semi-enclosed basins appeared to be particularly vulnerable to ocean warming, experiencing the fastest rates of warming and biodiversity loss through deborealization.

Summary: Lymph node status is an important factor that influences outcomes in melanoma. Whilst certain anatomical areas have multiple-nodal basin drainage, limb melanomas are thought to have more predictable lymphatic drainage patterns, with lower limb melanomas reliably draining to the corresponding ipsilateral inguinal lymph node basin with occasional popliteal drainage. Here we share our unique experience of a patient with a lower limb melanoma demonstrating sentinel lymph nodes, and subsequent metastatic spread, in both the ipsilateral and contralateral inguinal lymph node basins, highlighting an important learning point with respect to our clinical examination of melanoma patients.

The successful development of germinal centers (GC) relies heavily on innate mechanisms to amplify the initial inflammatory cascade. In addition to their role in antigen presentation, innate cells are essential for the redirection of circulating lymphocytes toward the draining lymph node (dLN) to maximize antigen surveillance. Sphingosine-1-Phosphate (S1P) and its receptors (S1PR1-5) affect various aspects of immunity; however, the role of S1PR4 in regulating an immune response is not well understood. Here we use a footpad model of localized TH1 inflammation to carefully monitor changes in leukocyte populations within the blood, the immunized tissue, and the dLN. Within hours of immunization, neutrophils failed to adequately mobilize and infiltrate into the footpad tissue of S1PR4-/- mice, thereby diminishing the local vascular changes thought to be necessary for redirecting circulating cells toward the inflamed region. Neutrophil depletion with anti-Ly6G antibodies significantly reduced early tissue edema as well as the redirection and initial accumulation of naïve lymphocytes in dLN of WT mice, while the effects were less prominent or absent in S1PR4-/- dLN. Adoptive transfer experiments further demonstrated that the lymphocyte homing deficiencies in vivo were not intrinsic to the donor S1PR4-/- lymphocytes, but were instead attributed to differences within the S1PR4-deficient host. Reduced cell recruitment in S1PR4-/- mice would seed the dLN with fewer antigen-respondent lymphocytes and indeed, dLN hypertrophy at the peak of the immune response was severely diminished, with attenuated GC and activation pathways in these mice. Histological examination of the S1PR4-/- dLN also revealed an underdeveloped vascular network with reduced expression of the leukocyte tethering ligand, PNAd, within high endothelial venule regions, suggesting inadequate growth of the dLN meant to support a robust GC response. Thus, our study reveals that S1PR4 may link early immune modulation by neutrophils to the initial recruitment of circulating lymphocytes and downstream expansion and maturation of the dLN, thereby contributing to optimal GC development during an adaptive response.

IntroductionThe Portfolio Diet combines cholesterol-lowering plant foods for the management of cardiovascular disease risk. However, the translation of this dietary approach into clinical practice necessitates a user-friendly method for patients to autonomously monitor their adherence.ObjectiveThis study aimed to develop and validate the clinical-Portfolio Diet Score (c-PDS) as a food-based metric to facilitate self-tracking of the Portfolio Diet.MethodsUsing a simulation model to estimate the c-PDS, the validity was assessed in a secondary analysis of a completed trial of the Portfolio Diet in 98 participants with hyperlipidemia over 6 months. Concurrent and predictive validity of the estimated c-PDS were assessed against the reference measure (weighed 7-day diet records) and concomitant changes in LDL-C from baseline to 6 months. Bland–Altman analysis was used to assess the limits of agreement between the two methods.ResultsThe c-PDS was positively correlated with dietary adherence as measured using the 7-day diet records (r = 0.94, p

La cirugía bariátrica es una intervención quirúrgica cada vez más frecuente, teniendo en cuenta el alcance y el impacto que genera sobre numerosas patologías. La frecuencia de complicaciones posterior a la intervención también es un tema de interés en clínica. El riesgo tromboembólico tras la intervención es una de las consideraciones más importantes durante la recuperación de la cirugía bariátrica. Para el manejo de este riesgo tromboembólico se pueden utilizar distintas terapias, entre las que se destacan los anticoagulantes directos orales. A pesar de la eficacia y la seguridad general de este grupo farmacológico, diversos autores han planteado potenciales diferencias a considerar en el escenario del posoperatorio del paciente bariátrico. A la fecha, los metaanálisis solo han evaluado estudios observacionales para dar respuesta a este interrogante. Luego, reconociendo la importancia de conocer el rendimiento terapéutico de los anticoagulantes directos orales en una de las intervenciones cada vez más frecuentes, el objetivo de esta revisión es analizar el rendimiento de estos fármacos y el riesgo de tromboembolia posterior a cirugía bariátrica, según la evidencia más reciente.

The “Color Circle” is an important chromatic Gestalt in the visual arts. There is not really a formal equivalent in conventional colorimetry. The fact that the hues can be linearly ordered and that such an order is necessarily periodic was intuited by artists in the early 19th century, but only formally explained by Ostwald and later Schrödinger a century later. As with musical keys, various metrical orders are in common use. Is there such a thing as a “well tempered” order? We consider this an issue for experimental phenomenology. We discuss an attempt based on observations by 30 (nonartist) observers.

Early onset colorectal cancer (EOCRC) emerged as the fourth foremost contributor to cancer-related mortality among both genders in the late 1990s. Presently, EOCRC (

One of the key factors influencing aging and morbidity is the overall antioxidant status and regenerative capacity. In examining contributors to the antioxidant status, we analyzed the thiamine status in felines and the influence of age, gender, and body condition score. We measured erythrocytic B1-dependent specific transketolase (STKT) activity, an enzyme in the pentose phosphate pathway, in a group of 60 sexually intact, healthy, and specific pathogen-free felines (44 females, 16 males, aged 1–17 years) with thiamine diphosphate (TDP; 0.3 and 3 mM) and without it. Only two parameters (STKT activity with and without 0.3 mM TDP) decreased with age. After adjusting for age, statistical thresholds were established using these and other age-independent parameters, identifying 15 felines with subclinical thiamine deficiency. The red blood cell proteomics analysis revealed that the pentose phosphate shunt, glycolysis, and oxidative stress response were the most affected pathways in deficient felines, confirming the above diagnosis. Age emerged as the primary factor associated with thiamine deficiency, supported by the enrichment of neurodegenerative diseases with a proteotoxicity component; five young-adult felines showed marginal or acute B1 deficiency, and six were adult-mature with a more chronic deficiency, possibly linked to cognitive decline, all with an underweight to ideal body condition scores. Only three senior-adult felines were deficient and overweight-obese. Detecting thiamine deficiency emphasizes the need for more accurate reference values, the establishment of advanced preventive or therapeutic measures to enhance the well-being of aging companion animals, and potential extensions to human health, particularly concerning cognitive function.

Cook Inlet beluga (CIB), Delphinapterus leucas, have not recovered from subsistence overharvest despite conservation efforts initiated in 2000. Reasons for this lack of recovery are still unclear with anthropogenic noise identified as a high threat in this population’s recovery plan. Baseline information on CIB habitat use and soundscape characterization is crucial in evaluating impacts from anthropogenic activities. Using passive acoustic monitoring, we documented the seasonality and foraging occurrence of CIB, together with killer whale (Orcinus orca), harbor porpoise (Phocoena phocoena) and humpback whale (Megaptera novaeangliae), for one year in Chinitna and Tuxedni bays and rivers, two historically important but recently overlooked areas of their critical habitat in western lower Cook Inlet, Alaska. This area’s ecological interest converges with planned mining, marine renewable energy, offshore oil and gas production, and commercial shipping. Results revealed higher presence of harbor porpoise, killer whale, and humpback whale in Chinitna compared to Tuxedni but much lower CIB presence. CIB were not detected in Chinitna Bay but were in the river on 21 days September-February and one day in June. However, CIB were never detected feeding in Chinitna River. CIB acoustic crypsis and preferential use of very shallow habitat in Chinitna revealed a perceived predation risk from killer whales. In contrast, CIB were recorded foraging in both Tuxedni Bay and River and were detected September-April on 127 days making it an important winter foraging ground. Low levels of anthropogenic noise disturbance were quantified in both bays making them some of the most undisturbed sections of their critical habitat, but at the same time highly sensitive to further noise disturbance. Commercial shipping was the main noise source likely causing acoustic disturbance to CIB due to communication masking despite current low levels of temporal overlap with beluga presence. We recommend that applicable regulators consider restricting high sound producing anthropogenic activities in and adjacent to Tuxedni Bay from September 1st to May 15th when CIB are actively using this area. Managing future anthropogenic activities to minimize habitat degradation and acoustic disturbance in this winter foraging refuge will be a key component to support the recovery of this endangered population.

Abstract We use observations from the Southern Ocean (SO) biogeochemical profiling float array to quantify the meridional pattern of particle export efficiency (PEeff) during the austral productive season. Float estimates reveal a pronounced latitudinal gradient of PEeff, which is quantitatively supported by a compilation of existing ship‐based measurements. Relying on complementary float‐based estimates of distinct carbon pools produced through biological activity, we find that PEeff peaks near the region of maximum particulate inorganic carbon sinking flux in the polar antarctic zone, where net primary production (NPP) is the lowest. Regions characterized by intermediate NPP and low PEeff, primarily in the subtropical and seasonal ice zones, are generally associated with a higher fraction of dissolved organic carbon production. Our study reveals the critical role of distinct biogenic carbon pool production in driving the latitudinal pattern of PEeff in the SO.

Summary: The studies reported here focus on the impact of pre-existing CD4 T cell immunity on the first encounter with SARS-CoV-2. They leverage PBMC samples from plasma donors collected after a first SARS-CoV-2 infection, prior to vaccine availability and compared to samples collected prior to the emergence of SARS-CoV-2. Analysis of CD4 T cell specificity across the entire SARS-CoV-2 proteome revealed that the recognition of SARS-CoV-2-derived epitopes by CD4 memory cells prior to the pandemic are enriched for reactivity toward non-structural proteins conserved across endemic CoV strains. However, CD4 T cells after primary infection with SARS-CoV-2 focus on epitopes from structural proteins. We observed little evidence for preferential recall to epitopes conserved between SARS-CoV-2 and seasonal CoV, a finding confirmed through use of selectively curated conserved and SARS-unique peptides. Our data suggest that SARS-CoV-2 CD4 T cells elicited by the first infection are primarily established from the naive CD4 T cell pool.

Abstract Following localized infection, the entire plant foliage becomes primed for enhanced defense. However, specific genes induced during defense priming (priming-marker genes) and those showing increased expression in defense-primed plants upon rechallenge (priming-readout genes) remain largely unknown. In our Arabidopsis thaliana study, genes AT1G76960 (function unknown), CAX3 (encoding a vacuolar Ca2+/H+ antiporter), and CRK4 (encoding a cysteine-rich receptor-like protein kinase) were strongly expressed during Pseudomonas cannabina pv. alisalensis-induced defense priming, uniquely marking the primed state for enhanced defense. Conversely, PR1 (encoding a pathogenesis-related protein), RLP23 and RLP41 (both encoding receptor-like proteins) were similarly activated in defense-primed plants before and after rechallenge, suggesting they are additional marker genes for defense priming. In contrast, CASPL4D1 (encoding Casparian strip domain-like protein 4D1), FRK1 (encoding flg22-induced receptor-like kinase), and AT3G28510 (encoding a P loop-containing nucleoside triphosphate hydrolases superfamily protein) showed minimal activation in uninfected, defense-primed, or rechallenged plants, but intensified in defense-primed plants after rechallenge. Notably, mutation in only priming-readout gene NHL25 (encoding NDR1/HIN1-like protein 25) impaired both defense priming and systemic acquired resistance, highlighting its previously undiscovered pivotal role in systemic plant immunity.

Abstract Background Comprehensive geriatric assessment (CGA) involves a formal broad approach to assess frailty and creating a plan for management. However, the impact of CGA and its components on listing for kidney transplant in older adults has not been investigated. Methods We performed a single-center retrospective study of patients with end-stage renal disease who underwent CGA during kidney transplant candidacy evaluation between 2017 and 2021. All patients ≥ 65 years old and those under 65 with any team member concern for frailty were referred for CGA, which included measurements of healthcare utilization, comorbidities, social support, short physical performance battery, Montreal Cognitive Assessment (MoCA), and Physical Frailty Phenotype (FPP), and estimate of surgical risk by the geriatrician. Results Two hundred and thirty patients underwent baseline CGA evaluation; 58.7% (135) had high CGA (“Excellent” or “Good” rating for transplant candidacy) and 41.3% (95) had low CGA ratings (“Borderline,” “Fair,” or “Poor”). High CGA rating (OR 8.46; p

Abstract Limited studies are available on vitamin B6 status in domestic cats. To this end, we evaluated glutamate–oxaloacetate transaminase (GOT) activity in hemolysates with and without pyridoxal 5′-phosphate addition in two feline populations: a cohort of 60 healthy, domestic (sexually intact and specific pathogen-free) cats maintained under strictly controlled conditions with appropriate diets housed at the Feline Nutrition and Pet Care Center, and a cohort of 57 cats randomly selected between December 2022 to January 2023 that visited the Veterinary Medicine Teaching Hospital to seek care under different circumstances. The GOT activity expressed as the ratio with and without pyridoxal 5′-phosphate addition (primary activation ratio; PAR) decreased significantly with age in the healthy cohort. The PAR values normalized to age established a cut-off for vitamin B6 deficiency in both cohorts, identifying 17 of 101 animals as vitamin B6 deficient. Using machine learning, a partition-based model (decision tree) was built to identify the most important factors that predicted vitamin B6 deficiency while using the resulting tree to make predictions for new observations. This analysis, performed with all 101 cats, revealed that the diagnosis of an infectious, chronic or acute condition (0.55) was the main contributor, followed by age (0.26), and body condition score (optimal-overweight; 0.19). Thus, our study supports that vitamin B6 supplementation may be indicated in junior to adult animals diagnosed with an infectious, chronic, or acute conditions or healthy cats with body weight ranging from optimal to overweight. In older cats, even if healthy, underweight to optimal cats appear to be at risk of vitamin B6 deficiency.

Background An estimated 30% of veterans live with chronic pain, compared to 20% of Canadians in the general population. Veterans face health care challenges upon release from the military, increasing difficulties in obtaining chronic pain care.Aims We explored experiences of Canadian Armed Forces veterans living with chronic pain, their transition from military to civilian care, perceived barriers and facilitators to chronic pain care, and impacts of their pain on the domains of well-being.Methods We conducted a qualitative descriptive study using semistructured interviews. We used a deductive/inductive approach to derive themes and concepts from interview transcripts.Results Thirty-five veterans living with chronic pain participated. Participants reported that pain affected their lives in numerous ways, including negatively impacting relationships and limiting activities of daily living and leisure. They identified barriers to care, including lack of access to family doctors or health care services, reluctance to ask for help, and challenges in obtaining coverage for services from Veterans Affairs Canada. Facilitators included support from other veterans and online resources. Chronic pain had bidirectional effects on domains of well-being.Conclusions Experiences of pain varied among Canadian veterans, and military culture played a role in perceptions and management of pain. Barriers and facilitators to chronic pain care were highlighted from their time in the military into their transition to civilian care. Participants described the impact of chronic pain on their overall well-being. Determining whether these findings are relevant to a larger population of Canadian veterans will be important for future research and knowledge translation to improve chronic pain care for Canadian veterans.

Este trabajo evalúa la comunidad de nematodos de suelo en ambientes agrícolas y ganaderos con diferente intensidad de uso del suelo en el sudeste de la provincia de Buenos Aires. Se extrajeron nematodos de sitios con diferente intensidad de uso de la tierra: maíz (2 años consecutivos de labranza convencional [LC]), papa (1 año de LC), soja (siembra directa) y pasturas (con animales en pastoreo). Se identificaron 44 géneros de nematodos pertenecientes a 5 grupos tróficos. Los géneros más abundantes fueron Helicotylenchus, Pratylenchus y Cruznema. Se encontraron diferencias significativas en la estructura de la comunidad de nematodos entre los usos de suelo. La abundancia total y por grupos tróficos fue mayor en soja y pastura. Además, en relación con la composición de la comunidad de nematodos de vida libre (bacteriófagos, frugívoros, omnívoros y depredadores), los sitios con maíz y soja presentaron una mayor proporción de fungívoros, mientras que los sitios con papa y pastura mostraron una mayor proporción de bacteriófagos. En relación con los nematodos fitófagos, la comunidad asociada a sitios con mayor disturbio agrícola (maíz y papa) presentó un ensamble diferente y menos diverso que aquellas asociadas a sitios con menor disturbio (soja y pastura). Los índices nematológicos evidenciaron que las dinámicas sucesionales de las comunidades de nematodos se vieron afectadas debido a las prácticas de los usos de suelos. Esto se confirmó a través del análisis del perfil faunal, la mayoría de las cadenas tróficas, sin importar el tipo de uso del suelo, se vieron afectadas por las prácticas agronómicas mostrando redes tróficas maduras. Este trabajo constituye el primer reporte de la composición de las comunidades de nematodos de suelo en campos de producción agrícola y ganaderos del sudeste bonaerense, y contribuye a conocer la ecología de comunidades de los nematodos de suelo impactados por diferentes prácticas antropogénicas.

As the size and ubiquity of artificial intelligence and computational machine learning models grow, the energy required to train and use them is rapidly becoming economically and environmentally unsustainable. Recent laboratory prototypes of self-learning electronic circuits, such as “physical learning machines,” open the door to analog hardware that directly employs physics to learn desired functions from examples at a low energy cost. In this work, we show that this hardware platform allows for an even further reduction in energy consumption by using good initial conditions and a new learning algorithm. Using analytical calculations, simulations, and experiments, we show that a trade-off emerges when learning dynamics attempt to minimize both the error and the power consumption of the solution—greater power reductions can be achieved at the cost of decreasing solution accuracy. Finally, we demonstrate a practical procedure to weigh the relative importance of error and power minimization, improving the power efficiency given a specific tolerance to error.

Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.

Abstract As the primary site of T-cell development, the thymus dictates immune competency of the host. The rates of thymus function are not constant, and thymus regeneration is essential to restore new T-cell production following tissue damage from environmental factors and therapeutic interventions. Here, we show the alarmin interleukin (IL) 33 is a product of Sca1+ thymic mesenchyme both necessary and sufficient for thymus regeneration via a type 2 innate immune network. IL33 stimulates expansion of IL5-producing type 2 innate lymphoid cells (ILC2), which triggers a cellular switch in the intrathymic availability of IL4. This enables eosinophil production of IL4 to re-establish thymic mesenchyme prior to recovery of thymopoiesis-inducing epithelial compartments. Collectively, we identify a positive feedback mechanism of type 2 innate immunity that regulates the recovery of thymus function following tissue injury.

Abstract Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq −/− cells were viable, but grew slowly and had chromosomal instability. Brca1 mutant cells proficient in DNA end resection were significantly more dependent on Polθ for viability; here, treatment with Polθi elevated RPA foci, which persisted through mitosis. In an isogenic system, BRCA1 null cells were defective, but PALB2 and BRCA2 mutant cells exhibited active resection, and consequently stronger sensitivity to Polθi. Thus, DNA end resection is a critical determinant of Polθi sensitivity in HR-deficient cells, and should be considered when selecting patients for clinical studies.

Abstract Nature provides a rich source of information for the design of novel materials; yet there remain significant challenges in the design and manufacture of materials that replicate the form, function, and sustainability of biological solutions. Here, we identify key challenges and promising approaches to the development of materials informed by biology. These challenges fall into two main areas; the first relates to harnessing biological information for materials innovation, including key differences between biological and synthetic materials, and the relationship between structure and function. We propose an approach to materials innovation that capitalizes on biodiversity, together with high-throughput characterization of biological material architectures and properties, linked to environmental and ecological context. The second area relates to the design and manufacture of bioinformed materials, including the physical scale of material architectures and manufacturing scale up. We suggest ways to address these challenges and promising prospects for a bioinformed approach to materials innovation.

Abstract Background Precision prevention involves using the unique characteristics of a particular group to determine their responses to preventive interventions. This study aimed to systematically evaluate the participant characteristics associated with responses to interventions in gestational diabetes mellitus (GDM) prevention. Methods We searched MEDLINE, EMBASE, and Pubmed to identify lifestyle (diet, physical activity, or both), metformin, myoinositol/inositol and probiotics interventions of GDM prevention published up to May 24, 2022. Results From 10347 studies, 116 studies (n = 40940 women) are included. Physical activity results in greater GDM reduction in participants with a normal body mass index (BMI) at baseline compared to obese BMI (risk ratio, 95% confidence interval: 0.06 [0.03, 0.14] vs 0.68 [0.26, 1.60]). Combined diet and physical activity interventions result in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) than those with PCOS (0.62 [0.47, 0.82] vs 1.12 [0.78–1.61]) and in those without a history of GDM than those with unspecified GDM history (0.62 [0.47, 0.81] vs 0.85 [0.76, 0.95]). Metformin interventions are more effective in participants with PCOS than those with unspecified status (0.38 [0.19, 0.74] vs 0.59 [0.25, 1.43]), or when commenced preconception than during pregnancy (0.21 [0.11, 0.40] vs 1.15 [0.86–1.55]). Parity, history of having a large-for-gestational-age infant or family history of diabetes have no effect on intervention responses. Conclusions GDM prevention through metformin or lifestyle differs according to some individual characteristics. Future research should include trials commencing preconception and provide results disaggregated by a priori defined participant characteristics including social and environmental factors, clinical traits, and other novel risk factors to predict GDM prevention through interventions.

In summer 2022, highly pathogenic influenza A(H5N1) virus reached the herring gull (Larus argentatus subspecies smithsonianus) breeding colony on Kent Island, New Brunswick, Canada. Real-time monitoring revealed a self-limiting outbreak with low mortality. Proactive seabird surveillance is crucial for monitoring such limited outbreaks, protecting seabirds, and tracing zoonotic transmission routes.

Abstract This study evaluated the effect of the Certified Child Life Specialist (CCLS) on pediatric pain and pain management during routine immunization administration in the pediatric primary care clinic. Children 4–12 years of age (n = 125) presenting for a well child physical examination at a rural primary care clinic were selected to receive standard nursing care or standard nursing care plus CCLS support during routine immunization administration. Patient reported pain was measured using the Faces Pain Scale‐Revised (FPS‐R), and patient behavioral responses were measured during immunization administration using the Children's Emotional Manifestation Scale (CEMS). The performance of psychosocial interventions and administration of topical pain‐relieving interventions were measured between both groups. CCLS support was associated with fewer negative emotional behaviors during immunization administration among 7‐ to 12‐year‐old children and a significantly higher provision of psychosocial interventions and topical pain‐relieving interventions among all ages. This study demonstrates that the presence of a CCLS can increase the provision of psychosocial and pain‐relieving interventions and reduce distress during immunization administration in a busy pediatric primary care clinic.

Abstract The contribution of the gut microbiome to neuroinflammation, cognition, and Alzheimer’s disease progression has been highlighted over the past few years. Additionally, inhibition of various components of the complement system has repeatedly been demonstrated to reduce neuroinflammation and improve cognitive performance in AD mouse models. Whether the deletion of these complement components is associated with distinct microbiome composition, which could impact neuroinflammation and cognitive performance in mouse models has not yet been examined. Here, we provide a comprehensive analysis of conditional and constitutive knockouts, pharmacological inhibitors, and various housing paradigms for the animal models and wild-type controls at various ages. We aimed to determine the impact of C1q or C5aR1 inhibition on the microbiome in the Arctic and Tg2576 mouse models of AD, which develop amyloid plaques at different ages and locations. Analysis of fecal samples from WT and Arctic mice following global deletion of C1q demonstrated significant alterations to the microbiomes of Arctic but not WT mice, with substantial differences in abundances of Erysipelotrichales, Clostridiales and Alistipes. While no differences in microbiome diversity were detected between cohoused wildtype and Arctic mice with or without the constitutive deletion of the downstream complement receptor, C5aR1, a difference was detected between the C5aR1 sufficient (WT and Arctic) and deficient (C5ar1KO and ArcticC5aR1KO) mice, when the mice were housed segregated by C5aR1 genotype. However, cohousing of C5aR1 sufficient and deficient wildtype and Arctic mice resulted in a convergence of the microbiomes and equalized abundances of each identified order and genus across all genotypes. Similarly, pharmacologic treatment with the C5aR1 antagonist, PMX205, beginning at the onset of beta-amyloid plaque deposition in the Arctic and Tg2576 mice, demonstrated no impact of C5aR1 inhibition on the microbiome. This study demonstrates the importance of C1q in microbiota homeostasis in neurodegenerative disease. In addition, while demonstrating that constitutive deletion of C5aR1 can significantly alter the composition of the fecal microbiome, these differences are not present when C5aR1-deficient mice are cohoused with C5aR1-sufficient animals with or without the AD phenotype and suggests limited if any contribution of the microbiome to the previously observed prevention of cognitive and neuronal loss in the C5aR1-deficient AD models.

Abstract Background Political, financial, and pandemic crises in Lebanon have affected both provision of reproductive health services including family planning and modern contraception methods as well as women’s interest and ability to seek those services. This study aims to explore the impact of the compounding crises on the provision and use of family planning services including modern contraception methods for Syrian refugees in Lebanon focusing on the perspectives of Syrian refugee women. Methods We carried out 12 Focus Group Discussions (FGDs) with 119 Syrian refugee women recruited from two cities in West Bekaa, Lebanon from inside and outside the informal tented settlements. We used Skype video calls to moderate the FGDs due to the limited mobility at the time of the study because of Covid-19. We used thematic analyses to analyse the data. Results The crises seemed to exacerbate supply side barriers, which influenced provision of family planning services and women’s demand for them. These included Covid-19 regulations and maltreatment by staff at public health facilities, disruption of outreach reproductive health services that provide family planning and modern contraception, and reduced supply of modern contraception methods. On the demand side, women reported financial limitations in accessing and paying for services, concern over being infected with Covid-19, and concerns about insecurity. Conclusions We suggest possible interventions to address these challenges and better reach these populations. These include using mobile health technology (mHealth) that may provide contraceptive counselling and/or can inform refugee women about where they may receive family planning and modern contraception. These services may also support Syrian refugees to access care they are entitled to receive and may also address disruptions in service provision due to overlapping crises, including availability and rising costs of contraceptives. These can be coupled with mobile outreach reproductive health services that provide family planning. We also suggest considering the provision of Long Acting Reversible Contraception (LARC) for Syrian refugee women, which would reduce a barrier of needing to revisit health facilities to obtain an additional supply of contraception pills.

Convincing evidence of domain growth in the heating of ultrastable glasses suggests that the equilibration dynamics of supercooled liquids could be driven by a nucleation and growth mechanism. We investigate this possibility by simulating the equilibration dynamics of a model glass during both heating and cooling between poorly and well-annealed states. Though we do observe the growth of domains during heating, we find that domains are absent during cooling. This absence is inconsistent with classical nucleation theory. By comparing the equilibration dynamics of our glass with that of two models with kinetic constraints, we demonstrate that dynamical facilitation generically leads to heating driven by domain growth and cooling without domains. Our results provide strong evidence that dynamical facilitation, not nucleation and interfacial-tension-driven domain growth, is the driving mechanism for the equilibration dynamics of glass formers.