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Abstract Background Individuals with Williams syndrome (WS) have an elevated risk for anxiety disorders throughout the life span, making it a research priority to identify the individual factors associated with anxiety. Most of the existing literature is based on questionnaire data and suggests that impaired executive functions (EF) increase the risk for anxiety in WS. The aim of this study was to use direct measures by trained clinicians to investigate the effects of general intelligence, inhibition, sustained attention, and working memory on anxiety in WS, to further elucidate potential underlying mechanisms. Method Twenty-four individuals with WS participated in the study (mean age: 29 years, range: 9–53 years), together with at least one of their parents. The MINI international neuropsychiatric interview for DSM-5 was completed to establish clinical diagnosis of anxiety, and the Clinical Global Impression Scale – Severity was used for an expert rating of symptom severity. Intellectual abilities were measured using the Wechsler scales, and attention and inhibition using the Conner’s Continuous Performance Test. In addition, a parent-report questionnaire measuring EF, learning and memory was collected. Results In contrast to the apriori hypothesis, there was no significant association between anxiety and core elements of EF such as working memory, sustained attention, and inhibition (i.e. the process of restraining one’s impulses or behaviour). Using ordinal logistic regression analyses, we showed that decreasing intelligence quotient (IQ) and age are associated with elevated anxiety. We confirmed these results in between-groups analyses (anxiety disorder vs no current anxiety disorder), and low IQ was associated with higher risk of having an anxiety diagnosis. In addition, Bayesian statistics gave substantial evidence for no significant association between anxiety and inhibition. Conclusion By using direct measures of psychological pathology and functioning, the current results provide a deeper characterisation of the WS phenotype and provide novel insights into the potential mechanisms underpinning anxiety.

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

We report an experimental infection of American mink with SARS-CoV-2 Omicron variant and show that mink remain positive for viral RNA for days, experience clinical signs and histopathologic changes, and transmit the virus to uninfected recipients. Preparedness is crucial to avoid spread among mink and spillover to human populations.

Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor ZEB2. Affected individuals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippocampal degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability. To get insights into GABAergic development and function in MWS we investigated ZEB2 haploinsufficient induced pluripotent stem cells (iPSC) of MWS subjects together with iPSC of healthy donors. Analysis of RNA-sequencing data at two time points of GABAergic development revealed an attenuated interneuronal identity in MWS subject derived iPSC with enrichment of differentially expressed genes required for transcriptional regulation, cell fate transition and forebrain patterning. The ZEB2 haploinsufficient neural stem cells (NSCs) showed downregulation of genes required for ventral telencephalon specification, such as FOXG1, accompanied by an impaired migratory capacity. Further differentiation into GABAergic interneuronal cells uncovered upregulation of transcription factors promoting pallial and excitatory neurons whereas cortical markers were downregulated. The differentially expressed genes formed a neural protein-protein network with extensive connections to well-established epilepsy genes. Analysis of electrophysiological properties in ZEB2 haploinsufficient GABAergic cells revealed overt perturbations manifested as impaired firing of repeated action potentials. Our iPSC model of ZEB2 haploinsufficient GABAergic development thus uncovers a dysregulated gene network leading to immature interneurons with mixed identity and altered electrophysiological properties, suggesting mechanisms contributing to the neuropathogenesis and seizures in MWS.

Abstract Pulmonary diseases alter lung mechanical properties, can cause loss of function, and necessitate use of mechanical ventilation, which can be detrimental. Investigations of lung tissue (local) scale mechanical properties are sparse compared to that of the whole organ (global) level, despite connections between regional strain injury and ventilation. We examine ex vivo mouse lung mechanics by investigating strain values, local compliance, tissue surface heterogeneity, and strain evolutionary behavior for various inflation rates and volumes. A custom electromechanical, pressure–volume ventilator is coupled with digital image correlation to measure regional lung strains and associate local to global mechanics by analyzing novel pressure–strain evolutionary measures. Mean strains at 5 breaths per minute (BPM) for applied volumes of 0.3, 0.5, and 0.7 ml are 5.0, 7.8, and 11.3%, respectively, and 4.7, 8.8, and 12.2% for 20 BPM. Similarly, maximum strains among all rate and volume combinations range 10.7%–22.4%. Strain values (mean, range, mode, and maximum) at peak inflation often exhibit significant volume dependencies. Additionally, select evolutionary behavior (e.g., local lung compliance quantification) and tissue heterogeneity show significant volume dependence. Rate dependencies are generally found to be insignificant; however, strain values and surface lobe heterogeneity tend to increase with increasing rates. By quantifying strain evolutionary behavior in relation to pressure–volume measures, we associate time‐continuous local to global mouse lung mechanics for the first time and further examine the role of volume and rate dependency. The interplay of multiscale deformations evaluated in this work can offer insights for clinical applications, such as ventilator‐induced lung injury.

Abigail C Burr,1,* Jalene V Velazquez,1,* Arzu Ulu,1 Rohan Kamath,1 Sang Yong Kim,1 Amanpreet K Bilg,1 Aileen Najera,1 Iman Sultan,1 Jon K Botthoff,2 Emma Aronson,3 Meera G Nair,1 Tara M Nordgren1 1Division of Biomedical Sciences, University of California Riverside, Riverside, CA, 92521, USA; 2Center for Conservation Biology, University of California Riverside, Riverside, CA, 92521, USA; 3Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, CA, 92521, USA*These authors contributed equally to this workCorrespondence: Tara M NordgrenDivision of Biomedical Sciences, University of California Riverside, 92521 University Avenue, Riverside, CA, 92521, USATel +1 951 827 3148Email tmnordgren@gmail.comPurpose: The Salton Sea, California’s largest lake, is designated as an agricultural drainage reservoir. In recent years, the lake has experienced shrinkage due to reduced water sources, increasing levels of aerosolized dusts in surrounding regions. Communities surrounding the Salton Sea have increased asthma prevalence versus the rest of California; however, a connection between dust inhalation and lung health impacts has not been defined.Methods: We used an established intranasal dust exposure murine model to study the lung inflammatory response following single or repetitive (7-day) exposure to extracts of dusts collected in regions surrounding the Salton Sea (SSDE), complemented with in vitro investigations assessing SSDE impacts on the airway epithelium.Results: In these investigations, single or repetitive SSDE exposure induced significant lung inflammatory cytokine release concomitant with neutrophil influx. Repetitive SSDE exposure led to significant lung eosinophil recruitment and altered expression of genes associated with allergen-mediated immune response, including Clec4e. SSDE treatment of human bronchial epithelial cells (BEAS-2B) induced inflammatory cytokine production at 5- and 24-hours post-treatment. When BEAS-2B were exposed to protease activity-depleted SSDE (PDSSDE) or treated with SSDE in the context of protease-activated receptor-1 and − 2 antagonism, inflammatory cytokine release was decreased. Furthermore, repetitive exposure to PDSSDE led to decreased neutrophil and eosinophilic influx and IL-6 release in mice compared to SSDE-challenged mice.Conclusion: These investigations demonstrate potent lung inflammatory responses and tissue remodeling in response to SSDE, in part due to environmental proteases found within the dusts. These studies provide the first evidence supporting a link between environmental dust exposure, protease-mediated immune activation, and respiratory disease in the Salton Sea region.Keywords: Salton Sea, dust exposure, lung inflammation, asthma, proteases, protease-activated receptors

The introduction of rotavirus A (RVA) vaccines has considerably reduced the RVA-associated mortality among children under 5 years of age worldwide. The ability of RVA to reassort gives rise to different combinations of surface proteins G (glycoprotein, VP7) and P (protease sensitive, VP4) RVA types infecting children. During the epidemiological surveillance of RVA in the Northwest Amazon region, an unusual rotavirus genotype G6P[8] was detected in feces of a 2-year-old child with acute gastroenteritis (AGE) that had been vaccinated with one dose of Rotarix® (RV1). The G6P[8] sample had a DS-1-like constellation with a Wa-like VP3 gene mono-reassortment similar to equine-like G3P[8] that has been frequently detected in Brazil previously. The results presented here reinforce the evolutionary dynamics of RVA and the importance of constant molecular surveillance.

Agriculture dust contains many organic immunogenic compounds, and organic dust exposure is strongly associated with the development of immune-mediated chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Chronic organic dust exposure from agriculture sources induces chronic lung inflammatory diseases and organic dust exposure has recently been linked to an increased risk of developing dementia. The cytokine interleukin-22 (IL-22) has been established as an important mediator in the resolution and repair of lung tissues. The omega-3 fatty acid metabolite aspirin-triggered Resolvin D1 (AT-RvD1) has shown efficacy in modulating the immune response in both pulmonary and neurological inflammation but has not been explored as a therapeutic in organic dust exposure-induced neuroinflammation. Investigating the link between IL-22 and AT-RvD1 may help in developing effective therapies for these immune-mediated diseases. We aimed to investigate the link between organic dust exposure and neuroinflammation, the role of IL-22 in the pulmonary and neurological immune response to organic dust exposure, and the immune-modulating therapeutic applications of AT-RvD1 in an IL-22 knock-out mouse model of organic dust exposure. C57BL/6J (WT) and IL-22 knock-out (KO) mice were repetitively exposed to aqueous agriculture organic dust extract (DE) 5 days per week for 3 weeks (15 total instillations) and treated with AT-RvD1 either once per week (3 total injections) or 5 times per week (15 total injections) for 3 weeks and allowed to recover for 3 days. We observed a significant pulmonary and neurological immune response to DE characterized by the development of inducible bronchus associated lymphoid tissue in the lung and gliosis in the frontal areas of the brain. We also observed that IL-22 knock-out increased pulmonary and neurological inflammation severity. Animals exposed to DE and treated with AT-RvD1 displayed reduced lung pathology severity and gliosis. Our data demonstrate that DE exposure contributes to neurological inflammation and that IL-22 is crucial to effective tissue repair processes. Our data further suggest that AT-RvD1 may have potential as a novel therapeutic for organic dust exposure-induced, immune-mediated pulmonary and neurological inflammation, improving outcomes of those with these diseases. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology Background: Limb-girdle muscular dystrophy recessive 1 (LGMDR1) is an autosomal recessive degenerative muscle disorder characterized by progressive muscular weakness caused by pathogenic variants in the CAPN3 gene. Desmoplastic small round cell tumors (DSRCT) are ultra-rare and aggressive soft tissue sarcomas usually in the abdominal cavity, molecularly characterized by the presence of a EWSR1::WT1 fusion transcript. Mouse models of muscular dystrophy, including LGMDR1, present an increased risk of soft tissue sarcomas. However, the DSRCT risk and general cancer risk in patients with LGMD is unknown. Here, we delineate the clinical, molecular, and genetic findings of a patient with LGMDR1 who developed a DSRCT. Case Report: The patient was a boy who was diagnosed at the age of 9 years with LGMDR1, caused by the biallelic pathogenic variants NP_000061.1:p.(Arg448Cys) and NP_000061.1:p.(Thr184ArgfsTer36) in CAPN3. At 17 years of age, a pathologic soft tissue mass was found in the right pelvis. Immunostaining was positive for Desmin and negative for Myogenin and MyoD1, and RNA sequencing showed a EWSR1::WT1 fusion transcript, confirming the diagnosis of DSRCT. The patient relapsed after 1 year and, following a second relapse, he was started on palliative treatment. No germline variants in childhood cancer predisposition genes were detected by whole genome sequencing Conclusions: We describe a patient with LGMDR1 who developed a DSRCT. Since associations between LGMD and pediatric cancer are hitherto unknown, further studies are warranted, as little information is currently published about the pediatric cancer risk in this patient group. [ABSTRACT FROM AUTHOR]

Background: Depression is a common and serious problem in older adults, but few have access to psychological treatments. Internet-delivered Cognitive Behavioral Therapy (ICBT) has the potential to improve access and has been found to be effective in adults with depression. The aim of this study was to examine the effects of tailored ICBT for depression in older adults aged 65 years or older. We also investigated if cognitive flexibility could predict outcome. Methods: Following online recruitment from the community, included participants were randomly allocated to either ten weeks of clinician guided ICBT (n = 50) or to an active control group in the form of non-directive support (n = 51). Primary depression outcome was the Geriatric Depression Scale (GDS-15). Several secondary outcomes were used, such as the Beck Depression Inventory (BDI-II) and the Patient Health Questionnaire (PHQ-9). Results: Both treatment and active control groups significantly reduced their levels of depression, and the treatment group showed significantly greater improvement on the GDS-15 and BDI-II, but not on the PHQ-9. Between-group effect sizes as Cohen's d were 0.78 (CI95% 0.36–1.20) on the GDS-15 and 0.53 (CI95% 0.11–0.94) on the BDI-II. Conclusions: Tailored ICBT is superior to an active control for older adults with depression. Between-group effects were smaller than in previous RCTs, most likely because of the use of an active control condition. Cognitive flexibility did not predict outcome. We conclude that ICBT can be used for older adults with depression, and thus increase access to psychotherapy for this group. Trial registration: This trial was retrospectively registered in clinicaltrials.gov (no. NCT05269524) the 8th of March 2022. [ABSTRACT FROM AUTHOR]

Background: Parents of teenagers who use illicit drugs experience a high degree of family burden and mental health issues but have received little attention in research. The aim of this study was to gain new knowledge of the situation of parents of teenage children with drug use. Method: Fifteen semi-structured qualitative interviews were conducted with parents who received support or treatment with their teenagers at outpatient treatment clinics in Sweden. The data was analyzed with thematic textual analysis. Results: Based on Scheff's theory of emotions, four central themes were identified in the parents' experiences: parental strategies, shame, coping with stress, and communication as a protective factor. Parents had a heavy family burden and reported problem-focused and emotion-focused behaviors which created shame, impaired communication between parent and child, and a lack of trust. Shame may shape the parents' discomfort in seeking help from relatives and professional support. Conclusions: Clinical practice should pay attention to the impact of shame, behavior patterns as vulnerabilities and protective factors, and how communication and understanding can be developed. We argue that Scheff's theory of emotions is useful to understand parents in crisis and that its concepts may be of use if applied in family support. [ABSTRACT FROM AUTHOR]

Background: Disparities in breast cancer mortality persist despite improvements in screening and therapeutic options. Understanding the impact of social determinants of health on disparate breast cancer outcomes is challenging due to heterogeneity of prior assessments. We examined the association between social vulnerability and breast cancer stage at diagnosis and mortality using a standardized measure of population risk for external stressors on health. Methods: Using institutional cancer registry data, female patients aged 18 or older diagnosed with breast cancer between 2012 and 2019 were assigned a 2018 Social Vulnerability Index (SVI) rank based upon home address census tract. We used multinomial logistic regression and Cox proportional hazards model to examine the relationships between SVI and breast cancer stage at diagnosis and all-cause mortality. Covariates included age and, when assessing mortality, cancer stage, comorbidities, body mass index, insurance type, and treatment regimen. Results: A total of 3,499 women with a median age of 59 (IQR 48–69) were included. 60% were White and 31% were Black. Median SVI was 0.36 (IQR 0.14–0.68) and median follow-up was 58 months (IQR 37.3–83.9). On adjusted analyses, each decile increase in SVI resulted in an 11% (OR 1.11, 95% CI 1.06–1.16, p <.001) and 15% (OR 1.15, 95% CI 1.09–1.21, p <.001) greater odds of presenting with Stage III or IV breast cancer, respectively, compared to DCIS. For patients who underwent surgery (N = 2916), each decile increase in SVI was associated with a 6% increase in all-cause mortality risk (HR 1.06, 95% CI 1.01–1.12, p =.01). Mortality risk was 1.5 times (HR 1.52, 95% CI 1.02–2.26, p =.04) greater for those in the most vulnerable quartile compared to the least vulnerable quartile. Conclusions: Women living in socially vulnerable communities presented with more advanced breast cancers and suffered worse survival. The SVI can be used to identify patients at risk for delayed cancer presentation and increased mortality. This tool can inform geographically targeted resource allocation and interventions aimed at reducing breast cancer care disparities. [ABSTRACT FROM AUTHOR]

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in FBN1, with a hitherto unknown association with cancer. Here, we present two females with MFS who developed pediatric neuroblastoma. Patient 1 presented with neonatal MFS and developed an adrenal neuroblastoma with unfavorable tumor genetics at 10 months of age. Whole genome sequencing revealed a germline de novo missense FBN1 variant (NP_000129.3:p.(Asp1322Asn)), resulting in intron 32 inclusion and exon 32 retention. Patient 2 was diagnosed with classic MFS, caused by a germline de novo frameshift variant in FBN1 (NP_000129.3:p.(Cys805Ter)). At 18 years, she developed high‐risk neuroblastoma with a somatic ALK pathogenic variant (NP_004295.2:p.(Arg1275Gln)). We identified 32 reported cases of MFS with cancer in PubMed, yet none with neuroblastoma. Among patients, we observed an early cancer onset and high frequency of MFS complications. We also queried cancer databases for somatic FBN1 variants, finding 49 alterations reported in PeCan, and variants in 2% of patients in cBioPortal. In conclusion, we report the first two patients with MFS and neuroblastoma and highlight an early age at cancer diagnosis in reported patients with MFS. Further epidemiological and functional studies are needed to clarify the growing evidence linking MFS and cancer. [ABSTRACT FROM AUTHOR]

Introduction: There are few accurate prognostic indications of the illness's development and severity for COVID‐19, despite certain biomarkers having been investigated. The unexpected nature of COVID‐19's course, which can quickly progress from asymptomatic to life‐threatening symptoms, lies at the heart of the disease's intricacy. Predicting SARS‐CoV‐2 pathogenicity through laboratory biomarkers and as such, identifying the patients' illness severity at the time of their initial admission would be crucial in improving patient care. In this study, we sought to evaluate the potential of hematological, biochemical, and inflammatory biomarkers in predicting the course of COVID‐19 at a tertiary hospital in western Kenya. Methods: This cross‐sectional study involved 48 COVID‐19 patients (16 asymptomatic; 16 moderate symptomatic; and 16 severe symptomatic) and 48 age‐sex‐matched COVID‐19‐negative clients attending the Moi Teaching and Referral Hospital, Kenya. Demographic information, self‐reported chronic illnesses, symptoms, and laboratory results were collected at recruitment. Results: Significantly, the severity of COVID‐19 was associated with; hemoglobin (p < 0.0001), white blood cells (p = 0.0022), hematocrit (p < 0.0001), blood urea nitrogen (p = 0.01), blood sodium (p = 0.0002), potassium (p = 0.0483), C‐reactive protein (p = 0.0002), and Lactate Dehydrogenase (p < 0.0001). Regression analysis of CRP revealed a strong positive correlation (p = 0.0006) whereas LDH revealed a weak positive correlation (p < 0.0001) with COVID‐19 disease severity. Discriminative accuracy was highest when asymptomatic was compared to severe COVID‐19 for CRP and LDH (AUC: 0.8867, 95% CI: 0.7532–1.000) and (AUC: 1.000, 95% CI: 1.000–1.000) respectively. Conclusion: The hematological indices, inflammatory and biochemical biomarkers studied have the potential to predict the course of COVID‐19. These parameters may be useful in helping design appropriate care for COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Introduction: With the rise of social media, online platforms have become a common way to access healthcare information. This study examines the quality of pediatric acute otitis media (AOM) videos on TikTok, a popular short‐form video social media platform. Methods: A TikTok search was conducted between 8/18 and 8/19/2023 using pediatric AOM hashtags: #pediatric acute otitis media management, #kid ear infections remedy, #child ear infections treatment, and #kid ear infection. Data collected include number of views/shares per day, uploader type (nonmedical influencer, lay individual, and medical professional), and content categories. The Patient Education Materials Assessment Tool for Audiovisual Material (PEMAT‐AV) and DISCERN questionnaire measured understandability, actionability, and quality of videos. Multivariable linear regression models were used (significance set at ≤0.05). Results: Of 166 videos, 38.6% (64) of uploaders were medical professionals, and 32.5% (54) were nonmedical influencers. Nonmedical influencer videos were viewed and shared significantly more than those by medical professionals (p < 0.05). Controlling for covariates, physicians were more likely to produce more beneficial and higher quality videos as compared with nonmedical influencers (β = 2.4 and 1.3, p < 0.01, respectively). However, physicians did not have significantly different ratings for understandability compared with nonmedical influencers (β = 0.45, p > 0.05). Discussion: AOM content on TikTok is often geared toward caretakers of symptomatic children. Although physician‐created AOM content was significantly higher quality, these videos reached a statistically smaller audience than those from nonmedical influencers. Addressing misinformation on social media platforms requires physicians to reach larger audiences by producing more actionable and understandable content. Level of Evidence: NA Laryngoscope, 134:5184–5192, 2024 [ABSTRACT FROM AUTHOR]

Background: Portable ex vivo lung perfusion during lung transplantation is a resource‐intensive technology. In light of its increasing use, we evaluated the cost‐effectiveness of ex vivo lung perfusion at a low‐volume lung transplant center in the USA. Methods: Patients listed for lung transplantation (2015–2021) in the United Network for Organ Sharing database were included. Quality‐of‐life was approximated by Karnofsky Performance Status scores 1‐year post‐transplant. Total transplantation encounter and 1‐year follow‐up costs accrued by our academic center for patients listed from 2018 to 2021 were obtained. Cost‐effectiveness was calculated by evaluating the number of patients attaining various Karnofsky scores relative to cost. Results: Of the 13 930 adult patients who underwent lung transplant in the United Network for Organ Sharing database, 13 477 (96.7%) used static cold storage and 453 (3.3%) used ex vivo lung perfusion, compared to 30/58 (51.7%) and 28/58 (48.3%), respectively, at our center. Compared to static cold storage, median total costs at 1 year were higher for ex vivo lung perfusion ($918 000 vs. $516 000; p = 0.007) along with the cost of living 1 year with a Karnofsky functional status of 100 after transplant ($1 290 000 vs. $841 000). In simulated scenarios, each Karnofsky‐adjusted life year gained by ex vivo lung perfusion was 1.00–1.72 times more expensive. Conclusions: Portable ex vivo lung perfusion is not currently cost‐effective at a low‐volume transplant centers in the USA, being 1.53 times more expensive per Karnofsky‐adjusted life year. Improving donor lung and/or recipient biology during ex vivo lung perfusion may improve its utility for routine transplantation. [ABSTRACT FROM AUTHOR]

Measures to control the spread of Covid-19 are challenging social work practice in terms of difficulties to deliver services to vulnerable groups. The aim of this study was to investigate how the Covid-19 pandemic affected social work with people who use drugs regarding ways of working, quality of work, accessibility, and staff motivation. A mixed methods approach was used which included an online survey (n = 81), and three qualitative focus group sessions with social workers in the field of addiction. We analysed the quantitative data through frequency calculations, cross tabulations and Pearson's χ2 test, and the qualitative data with qualitative textual analysis. The demand for physical distancing challenged important principles of social work such as social closeness, trust and accessibility, and led to a difficult work environment and fewer opportunities to conduct high quality social work, as well as a reduced likelihood of vulnerable clients receiving adequate assistance. Altered practices concerning client meetings negatively affected assessments, working alliances as well as motivation and energy in social work practice. Social workers on the frontline became the 'last outpost' when other services shut down, and 'digital bridges' between clients and other social workers. Social workers faced a difficult trade-off between protecting themselves and clients from the risk of infection and providing support to a vulnerable group. There were also examples of new practices and lessons learned, for example, the introduction of 'walks and talks' with clients and an increased knowledge of how and when to use digital tools for communication. [ABSTRACT FROM AUTHOR]

Background: Frailty is independently associated with adverse patient outcomes after surgery. The current standards of postoperative care rarely consider frailty status. Local Problem: There was no standardized protocol to optimize specialized postoperative care for frail patients at an academic medical center. Methods: A quasi-experimental pre-/postimplementation study design, using the Reach, Effectiveness, Adoption, Implementation, Maintenance implementation framework, was utilized. Interventions: A frailty-specific postoperative order set (FPOS) was developed, including tailored nursing care, activity levels, and nutritional goals. Results: There were significant improvements in nurse's self-reported familiarity with frailty (P = .003) and FPOS awareness (P < .001). The number of orders for delirium prevention, elimination, nutrition, sleep promotion, and sensory support increased (P < .001). Conclusions: Implementing an FPOS showed improvements in nurse frailty knowledge, awareness, and order set utilization. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi‐step, challenging, and time‐consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open‐source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter‐individual variability (IIV) model, the inter‐occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development. [ABSTRACT FROM AUTHOR]

Abstract Background The increasing incidence of type 2 diabetes mellitus [T2DM] has resulted in extensive research into the characteristics of successful primary diabetes care. Even if self‐management support and continuity are increasingly recognized as important, there is still a need for deeper understanding of how patients' experiences of continuity of care coincide with their needs for self‐management and/or self‐management support. Objective To gain a deeper understanding of how people with T2DM perceive Swedish primary diabetes care and self‐management support. Methods This qualitative study used focus groups as the means for data collection. Participants were identified through a purposive sampling method differing in age, sex, diabetes duration and latest registered glycated haemoglobin level. Twenty‐eight participants formed five focus groups. Qualitative content analysis was applied to interview transcripts. Results The main theme emerging from the focus group data was that diabetes care provided by national standards improved self‐management skills. Two themes that emerged from the analysis were (a) the importance of a clarification of structures and procedures in primary diabetes care and (b) health‐care staff ‘being there’ and providing support enables trust and co‐operation to enhance self‐management. Conclusions Individual patients' self‐management resources are strengthened if the importance of providing relational continuity, management continuity and informational continuity is considered. Patients also need assistance on ‘how’ self‐management activities should be performed. Patient contribution Prior to the study, one pilot focus group was conducted with patients to obtain their perspectives on the content of the planned focus groups; thus, patients were involved in both planning and conduct of the study.

The ongoing discussion about what constitutes historical consciousness is intensifying within the growing international community of history-education researchers. What started as an exploration of how life outside schools affects our historical thinking has become a key concept for structuring formal education. This shift has largely been positive; however, there are reasons for caution. If practical adaption means outlining, classifying, and measuring levels of achieved awareness, it also presents a risk of losing the initial reason for considering the wider influence on our perceptions and orientations. My reflection in this article concerns this paradox and how it can affect a complementary concept, use of history. Using examples from everyday historical representations in public life, namely song lyrics, the BLM, and Sweden’s approach to Covid 19, I demonstrate why history education requires a broad understanding of historical consciousness and a readiness to work with public uses of history.

Northern Eurasia is currently highly sensitive to climate change. Fires in this region can have significant impacts on regional air quality, radiative forcing and black carbon deposition in the Arctic which can accelerate ice melting. Using a MODIS-derived burned area dataset, we report that the total annual area burned in this region declined by 53 % during the 15-year period from 2002 to 2016. Grassland fires dominated this trend, accounting for 93 % of the decline in the total area burned. Grassland fires in Kazakhstan contributed 47 % of the total area burned and 84 % of the decline. A wetter climate and increased grazing are the principle driving forces for the decline. Our findings (1) highlight the importance of the complex interactions of climate–vegetation–land use in affecting fire activity and (2) reveal how the resulting impacts on fire activity in a relatively small region such as Kazakhstan can dominate the trends in burned areas across a much larger landscape of northern Eurasia.

Abstract Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

IntroductionHousehold-level psychosocial stress levels have been linked to child tooth brushing behaviors. Community health worker (CHW) interventions that target psychosocial factors in high-risk communities have been associated with changes in health behaviors.AimObserve changes in psychosocial factors over time and an association between psychosocial factors and CHW intervention dose amongst urban Chicago families.Patients and methodsParticipants (N = 420 families) were recruited from 10 community clinics and 10 Women, Infants, or Children (WIC) centers in Cook County, Illinois to participate in a clinical trial. Research staff collected participant-reported psychosocial factors (family functioning and caregiver reports of depression, anxiety, support, and social functioning) and characteristics of CHW-led oral health intervention visits (number, content, child engagement) at 0, 6, and 12 months. CHWs recorded field observations after home visits on household environment, social circumstances, stressors, and supports.ResultsParticipants across the cohort reported levels of psychosocial factors consistent with average levels for the general population for nearly all measures. Psychosocial factors did not vary over time. Social functioning was the only measure reported at low levels [32.0 (6.9); 32.1 (6.7); 32.7 (6.9); mean = 50 (standard deviation)] at 0, 6, and 12 months. We did not observe a meaningful difference in social functioning scores over time by exposure to CHW-led intervention visits (control arm, 0, 1, 2, 3, and 4 visits). Field observations made by CHWs described a range of psychosocial stress related to poverty, language barriers, and immigration status.ConclusionThe unexpectedly average and unchanging psychosocial factors over time, in the context of field observations of stress related to poverty, lack of support, immigration status, and language barriers, suggests that our study did not adequately capture the social determinants of health related to oral health behaviors or that measurement biases precluded accurate assessment. Future studies will assess psychosocial factors using a variety of instruments in an attempt to better measure psychosocial factors including social support, depression, anxiety, functioning, trauma and resilience within our urban population. We will also look at neighborhood-level factors of community distress and resilience to better apply the social ecologic model to child oral health behaviors.

The electronic structure of LiC6 has been investigated by soft X-ray absorption and emission spectroscopies. The results reveal that upon full lithiation of graphite, the Li 2s electrons are transferred into the carbon π* states in a near rigid-band behavior, resulting in the increased density of states near EF and the shift of σ* states to lower energies. In addition, the resonant inelastic X-ray scattering spectra of LiC6 do not show strong dispersive features as that of graphite, indicating that the crystal momentum is not conserved during the scattering process due to the delocalization of electrons in the intermediate state.