Mental health in society's margins: poor n-3 PUFA intake and psychological well-being of homeless youth.

Dietary intake of long-chain n-3 PUFA (n-3 PUFA), particularly EPA and DHA, has been associated with psychological well-being, but little is known about the n-3 PUFA intake of homeless youth. The current study determined the association between depression and anxiety symptoms and n-3 PUFA intake and erythrocytes status in homeless youth. Totally, 114 homeless youth aged 18-24 years were recruited from a drop-in centre. n-3 PUFA dietary intake was assessed using an FFQ, and erythrocytes status was determined by gas chromatography (GC). Linear regression models were used to determine the relationship between psychological well-being and n-3 PUFA intake and status. The mean intakes of EPA and DHA for all participants (0·06 ± 0·13 g/d and 0·11 ± 0·24 g/d) were well below recommended levels, and mean erythrocytes EPA + DHA (n-3 index) in the cohort (2·42 %) was lower than reported for healthy, housed adolescents and those with clinical depression. There was no association of n-3 PUFA intake and erythrocytes status with either depression or anxiety. However, the relationships of depression with dietary EPA (P = 0·017) and DHA (P = 0·008), as well as erythrocytes DHA (P = 0·007) and n 3-index (P = 0·009), were significantly moderated by sex even after adjusting for confounders. Specifically, among females, as the intake and status of these n-3 PUFA decreased, depression increased. Our findings show poor dietary intake and low erythrocytes status of n-3 PUFA among homeless youth, which is associated with depressive symptoms among females.

Interplay of heavy chain introns influences efficient transcript splicing and affects product quality of recombinant biotherapeutic antibodies from CHO cells.

Introns are included in genes encoding therapeutic proteins for their well-documented function of boosting expression. However, mis-splicing of introns in recombinant immunoglobulin (IgG) heavy chain (HC) transcripts can produce amino acid sequence product variants. These variants can affect product quality; therefore, purification process optimization may be needed to remove them, or if they cannot be removed, then in-depth characterization must be carried out to understand their effects on biological activity. In this study, HC transgene engineering approaches were investigated and were successful in significantly reducing the previously identified IgG HC splice variants to <0.5%. Subsequently, a comprehensive evaluation was conducted to understand the influence of the different introns in the HC genes on the expression of recombinant biotherapeutic antibodies. The data revealed an unexpected cooperation between specific introns for efficient splicing, where intron retention led to significant reductions in IgG expression of up to 75% for some intron combinations. Furthermore, it was shown that HC introns could be fully removed without significantly affecting productivity. This work paves the way for future biotherapeutic antibody transgene design with regard to inclusion of HC introns. By removing unnecessary introns, transgene mRNA transcript will no longer be mis-spliced, thereby eliminating HC splice variants and improving antibody product quality.

Patient emergency health-care use before hospital admission for COVID-19 and long-term outcomes in Scotland: a national cohort study.

BACKGROUND: It is unclear what effect the pattern of health-care use before admission to hospital with COVID-19 (index admission) has on the long-term outcomes for patients. We sought to describe mortality and emergency readmission to hospital after discharge following the index admission (index discharge), and to assess associations between these outcomes and patterns of health-care use before such admissions. METHODS: We did a national, retrospective, complete cohort study by extracting data from several national databases and linking the databases for all adult patients admitted to hospital in Scotland with COVID-19. We used latent class trajectory modelling to identify distinct clusters of patients on the basis of their emergency admissions to hospital in the 2 years before the index admission. The primary outcomes were mortality and emergency readmission up to 1 year after index admission. We used multivariable regression models to explore associations between these outcomes and patient demographics, vaccination status, level of care received in hospital, and previous emergency hospital use. FINDINGS: Between March 1, 2020, and Oct 25, 2021, 33 580 patients were admitted to hospital with COVID-19 in Scotland. Overall, the Kaplan-Meier estimate of mortality within 1 year of index admission was 29·6% (95% CI 29·1-30·2). The cumulative incidence of emergency hospital readmission within 30 days of index discharge was 14·4% (95% CI 14·0-14·8), with the number increasing to 35·6% (34·9-36·3) patients at 1 year. Among the 33 580 patients, we identified four distinct patterns of previous emergency hospital use: no admissions (n=18 772 [55·9%]); minimal admissions (n=12 057 [35·9%]); recently high admissions (n=1931 [5·8%]), and persistently high admissions (n=820 [2·4%]). Patients with recently or persistently high admissions were older, more multimorbid, and more likely to have hospital-acquired COVID-19 than patients with no or minimal admissions. People in the minimal, recently high, and persistently high admissions groups had an increased risk of mortality and hospital readmission compared with those in the no admissions group. Compared with the no admissions group, mortality was highest in the recently high admissions group (post-hospital mortality HR 2·70 [95% CI 2·35-2·81]; p<0·0001) and the risk of readmission was highest in the persistently high admissions group (3·23 [2·89-3·61]; p<0·0001). INTERPRETATION: Long-term mortality and readmission rates for patients hospitalised with COVID-19 were high; within 1 year, one in three patients had died and a third had been readmitted as an emergency. Patterns of hospital use before index admission were strongly predictive of mortality and readmission risk, independent of age, pre-existing comorbidities, and COVID-19 vaccination status. This increasingly precise identification of individuals at high risk of poor outcomes from COVID-19 will enable targeted support. FUNDING: Chief Scientist Office Scotland, UK National Institute for Health Research, and UK Research and Innovation.

Impacts of the COVID-19 Pandemic on United States Emergency Medicine Education: A Council of Residency Directors in Emergency Medicine (CORD) Task Force Survey-Based Analysis.

Introduction The COVID-19 pandemic presented unpredicted challenges to Emergency Medicine (EM) education. The rapid onset of the pandemic created clinical, operational, administrative, and home-life challenges for virtually every member of the medical education community, demanding an educational and professional response at all levels including undergraduate medical education (UME), graduate medical education (GME), and faculty. The Council of Residency Directors in Emergency Medicine (CORD) COVID-19 Educational Impact Task Force was established in 2021 to examine these effects and the response of the EM educational community. Methods The Task Force utilized consensus methodology to develop the survey instruments, which were revised using a modified Delphi process. Both open- and closed-answer questions were included in the survey, which was initially distributed electronically to attendees of the 2021 Virtual Academic Assembly. Results were analyzed quantitatively and qualitatively. Results Sixty-three individuals responded to the first part of the survey (which addressed issues related to UME and GME) and 41 individuals responded to the second part of the survey (which addressed faculty and wellness). The pandemic's influence on EM education was viewed in both a positive and negative light. The transition to virtual platforms had various impacts, including innovation and engagement via technology. Remote technology improved participation in didactics and allowed individuals to more easily participate in departmental meetings. However, this also led to a decreased sense of connection with peers and colleagues resulting in a mixed picture for overall engagement and effectiveness. The Task Force has developed a list of recommendations for best practices for EM programs and for EM organizations. Conclusion The survey results articulated the educational benefits and challenges faced by EM educators during the COVID-19 pandemic. Through the challenging times of the pandemic, many institutional and program-based innovations were developed and implemented to address the new educational environment. These approaches will provide invaluable educational tools for future training. This will also prepare the EM academic community to respond to future educational disruptions.

CHO synthetic promoters improve expression and product quality of biotherapeutic proteins.

When expressing complex biotherapeutic proteins, traditional expression plasmids and methods may not always yield sufficient levels of high-quality product. High-strength viral promoters commonly used for recombinant protein (rProtein) production in mammalian cells allow for maximal expression, but provide limited scope to alter their transcription dynamics. However, synthetic promoters designed to provide tunable transcriptional activity offer a plasmid engineering approach to more precisely regulate product quality, yield or to reduce product related contaminants. We substituted the viral promoter CMV with synthetic promoters that offer different transcriptional activities to express our gene of interest in Chinese hamster ovary (CHO) cells. Stable pools were established and the benefits of regulating transgene transcription on the quality of biotherapeutics were examined in stable pool fed-batch overgrow experiments. Specific control of gene expression of the heavy chain (HC):light chain (LC) of a Fab, and the ratio between the two HCs in a Duet mAb reduced levels of aberrant protein contaminants; and the controlled expression of the helper gene XBP-1s improved expression of a difficult-to-express mAb. This synthetic promoter technology benefits applications that require custom activity. Our work highlights the advantages of employing synthetic promoters for production of more complex rProteins.

KIAA0317 regulates SOCS1 stability to ameliorate colonic inflammation.

Dysregulated cytokine signalling is a hallmark of inflammatory bowel diseases. Inflammatory responses of the colon are regulated by the suppressor of cytokine signalling (SOCS) proteins. SOCS1 is a key member of this family, and its function is critical in maintaining an appropriate inflammatory response through the JAK/STAT signalling pathway. Dysregulation of SOCS1 protein has been identified as a causal element in colonic inflammatory diseases. Despite this, it remains unclear how SOCS1 protein is regulated. Here, we identify that SOCS1 protein is targeted for degradation by the ubiquitin proteasome system, mediated by the E3 ubiquitin ligase KIAA0317 during experimental colonic inflammation. We characterize the mechanism of protein-protein interaction and ubiquitin conjugation to SOCS1 and demonstrate that the modulation of SOCS1 protein level leads to stark effects on JAK/STAT inflammatory signalling. Together, these results provide insight into the regulation of colonic inflammation through a new mechanism of ubiquitin-based control of SOCS1 protein.

Accelerated cell culture process development and characterization for cilgavimab/tixagevimab (AZD7442) for the prevention and treatment of COVID-19.

The global COVID-19 pandemic ignited an unprecedented race to develop vaccines and antibody therapeutics. AstraZeneca's pursuit to provide AZD7442 (EVUSHELD), two long-acting, SARS-CoV-2 spike receptor binding domain-specific neutralizing monoclonal antibodies, to individuals at risk on highly accelerated timelines challenged our traditional ways of process development and spurred the rapid adoption of novel approaches. Conventional upstream development processes were replaced by agile strategies that combined technological advances and highly accelerated workflows. With calculated business risks and close cross-functional collaborations, this process paved the way for hyper accelerated antibody development from discovery through manufacturing, process validation, emergency use authorization filing, and global regulatory approvals. The result was initiation of commercial manufacturing at a contract manufacturing organization less than 6 months from the selection of cilgavimab and tixagevimab-a process that historically has taken close to 10 years.

Safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome: protocol for a multicentre, open-label, prospective, single-arm study.

INTRODUCTION: Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disease caused by excessive activation of part of the immune system called complement. Eculizumab is an effective treatment, controlling aHUS in 90% of patients. Due to the risk of relapse, lifelong treatment is currently recommended. Eculizumab treatment is not without problems, foremost being the risk of severe meningococcal infection, the burden of biweekly intravenous injections and the high cost.This paper describes the design of the Stopping Eculizumab Treatment Safely in aHUS trial that aims to establish whether a safety monitoring protocol, including the reintroduction of eculizumab for those who relapse, could be a safe, alternative treatment strategy for patients with aHUS. METHODS AND ANALYSIS: This is a multicentre, non-randomised, open-label study of eculizumab withdrawal with continuous monitoring of thrombotic microangiopathy-related serious adverse events using the Bayes factor single-arm design. 30 patients will be recruited to withdraw from eculizumab and have regular blood and urine tests for 24 months, to monitor for disease activity. If relapse occurs, treatment will be restarted within 24 hours of presentation. 20 patients will remain on treatment and complete health economic questionnaires only. An embedded qualitative study will explore the views of participants. ETHICS AND DISSEMINATION: A favourable ethical opinion and approval was obtained from the North East-Tyne & Wear South Research Ethics Committee. Outcomes will be disseminated via peer-reviewed articles and conference presentations. TRIAL REGISTRATION NUMBER: EudraCT number: 2017-003916-37 and ISRCTN number: ISRCTN17503205.

Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing.

The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.

Making Family-Centered Care for Adults in the ICU a Reality.

Despite the value of family-centered care (FCC) in intensive care units (ICUs), this approach is rarely a reality in this context. This article aims to increase the likelihood that ICU-based care incorporates best practices for FCC. Consistent with this goal, this article begins by overviewing FCC and its merits and challenges in ICUs. It then offers a systemic framework for conceptualizing FCC in this challenging environment, as such a model can help guide the implementation of this invaluable approach. This systemic framework combined with previous guidelines for FCC in the ICU are used to inform the series of recommended best practices for FCC in the ICU that balance the needs and realities of patients, families, and the interprofessional healthcare team. These best practices reflect an integration of the existing literature and previously published guidelines as well as our experiences as healthcare providers, family members, and patients. We encourage healthcare leaders and interprofessional ICU healthcare teams to adopt these best practices and modify them for the specific healthcare needs of the patients they serve and their families.

Implementing the battery-operated hand-held fan as an evidence-based, non-pharmacological intervention for chronic breathlessness in patients with chronic obstructive pulmonary disease (COPD): a qualitative study of the views of specialist respiratory clinicians.

INTRODUCTION: The battery-operated hand-held fan ('fan') is an inexpensive and portable non-pharmacological intervention for chronic breathlessness. Evidence from randomised controlled trials suggests the fan reduces breathlessness intensity and improves physical activity in patients with a range of advanced chronic conditions. Qualitative data from these trials suggests the fan may also reduce anxiety and improve daily functioning for many patients. This study aimed to explore barriers and facilitators to the fan's implementation in specialist respiratory care as a non-pharmacological intervention for chronic breathlessness in patients with chronic obstructive pulmonary disease (COPD). METHODS: A qualitative approach was taken, using focus groups. Participants were clinicians from any discipline working in specialist respiratory care at two hospitals. Questions asked about current fan-related practice and perceptions regarding benefits, harms and mechanisms, and factors influencing its implementation. Analysis used a mixed inductive/deductive approach. RESULTS: Forty-nine participants from nursing (n = 30), medical (n = 13) and allied health (n = 6) disciplines participated across 9 focus groups. The most influential facilitator was a belief that the fan's benefits outweighed disadvantages. Clinicians' beliefs about the fan's mechanisms determined which patient sub-groups they targeted, for example anxious or palliative/end-stage patients. Barriers to implementation included a lack of clarity about whose role it was to implement the fan, what advice to provide patients, and limited access to fans in hospitals. Few clinicians implemented the fan for acute-on-chronic breathlessness or in combination with other interventions. CONCLUSION: Implementation of the fan in specialist respiratory care may require service- and clinician-level interventions to ensure it is routinely recommended as a first-line intervention for chronic breathlessness in patients for whom this symptom is of concern, regardless of COPD stage.

Intergenerational transmission of trauma from mother to infant: the mediating role of disrupted prenatal maternal representations of the child.

Data from a multi-method, longitudinal study involving a community sample (N = 120) of pregnant women aged 18-42 were used to examine disrupted maternal representations of the child as a mechanism of the transmission of trauma from mother to infant. Using structural equation modeling, the best fitting model indicated that severity of mothers' childhood interpersonal trauma was associated with severity of disruption in prenatal representations of the child, which in turn was associated with less secure infant-mother attachment at 1 year of age. There was a significant indirect effect of maternal childhood interpersonal trauma on infant-mother attachment insecurity via disrupted prenatal maternal representations. Findings highlight an important mechanism of trauma transmission that could be targeted in interventions with mother-infant dyads.

Childhood abuse, posttraumatic stress symptoms, and alcohol misuse among African-American women.

The study explored associations among childhood abuse, post-traumatic stress symptoms (PTSS), and alcohol misuse in a sample of low-income African-American women (N = 172). Using bootstrapping techniques, a mediation effect was found of childhood physical and emotional abuse on alcohol misuse via PTSS symptom severity, avoidance, and hyperarousal, as well as for childhood sexual abuse on alcohol misuse via PTSS symptom severity and hyperarousal. Our results suggest that PTSS indicators, particularly symptom severity and hyperarousal, may be important mechanisms underlying the association of experiences of abuse during childhood and alcohol misuse in adulthood.

Disrupted caregiving behavior as a mediator of the relation between disrupted prenatal maternal representations and toddler social-emotional functioning.

The development of maternal representations of the child during pregnancy guides a mother's thoughts, feelings, and behavior toward her child. The association between prenatal representations, particularly those that are disrupted, and toddler social-emotional functioning is not well understood. The present study examined associations between disrupted prenatal representations and toddler social-emotional functioning and to test disrupted maternal behavior as a mediator of this association. Data were drawn from 109 women from a larger prospective longitudinal study (N=120) of women and their young children. Prenatal disrupted maternal representations were assessed using the Working Model of the Child Interview disrupted coding scheme, while disrupted maternal behavior was coded 12-months postpartum from mother-infant interactions. Mother-reported toddler social-emotional functioning was assessed at ages 12 and 24 months. Disrupted prenatal representations significantly predicted poorer toddler social-emotional functioning at 24 months, controlling for functioning at 12 months. Further, disrupted maternal behavior mediated the relation between disrupted prenatal representations and toddler social-emotional problems. Screening for disrupted representations during pregnancy is needed to facilitate referrals to early intervention and decrease the likelihood of toddler social-emotional problems.

Relationships between inflammatory and metabolic markers, exercise, and body composition in young individuals.

BACKGROUND AND AIMS: Physical exercise may help combat disease and elicits a possible "protective" anti-inflammatory effect on the body. Inflammatory cytokines, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), along with transcription factor, nuclear factor-kappa B (NFκB) in young (n=16, 21.1±2.1 years) individuals were examined in a cross-sectional descriptive study, to assess the effects of chronic stimulation on their expression and relationship with health parameters. METHODS: Fasting venous whole blood and lipid levels along with body composition measurements were obtained from young, healthy, endurance-trained NCAA Division III student-athletes and untrained individuals. Assays (ELISA) were conducted to analyze fasting plasma (CRP, IL-6, and TNFα) and isolated lymphocyte NF-κB activation (lymphocytes were isolated from whole blood samples through differential centrifugation and Ficoll-Paque). A Spearman's rank order correlation coefficient was used for associations between variables and a regression analysis was performed to determine which measurement accounted for the inflammation in this young and apparently healthy population. RESULTS: While the inflammatory markers were not associated with each other, CRP levels were associated with body composition and following regression analyses, body fat percentage (P>0.05) was a significant factor for elevated CRP. CONCLUSIONS: Chronic physical exercise eliciting lower body fat percentages in young adults may have a positive protective impact through anti-inflammatory status, minimizing disease risk in a young population. RELEVANCE FOR PATIENTS: Chronic physically active young adult patients may exhibit less inflammation and lower body fat levels which may decrease their risk for chronic disease.

Development and effectiveness of tabletop exercises in preparing health practitioners in violence prevention management: A sequential explanatory mixed methods study.

BACKGROUND: Workplace violence in healthcare remains a significant issue for healthcare professional, in terms of risk to patients and staff. One part of a workplace violence prevention and management programme is to educate staff in their response to critical events. Drawn from the disaster management literature, tabletop exercises were used in this study to simulate workplace violence and educate staff on the appropriate emergency response during a violent event. The use of tabletop exercise in this context is a novel approach to workplace violence prevention management. AIM AND OBJECTIVE: This study describes the development and effectiveness of tabletop exercises in preparing health practitioners in violence prevention and management emergency response systems. METHODS: Using a sequential explanatory mixed method design. The study comprised of two phases 1) quasi-experimental (quantitative) and 2) focus group (qualitative) to evaluate the effectiveness of the violence prevention management tabletop exercises. COREQ guidelines were followed the qualitative arm of the study and the TREND statement for the quantitative part of the study. RESULTS: Statistically significant improvements in healthcare professional confidence levels were found two weeks post the tabletop exercises. A post focus group revealed three categories concerning the participant's experiences of the tabletop exercises, (role clarity, adult learning and organisational support). CONCLUSION: Tabletop exercise may provide a, low cost, context specific novel approach to educating staff in emergency violence response systems at a tertiary referral hospital. Educators and policy makers may consider the use of tabletop exercises in the ongoing work in preparing health care staff for workplace violence. RELEVANCE TO CLINICAL PRACTICE: Successful tabletop exercises should consider a local ward level context, the use of adult learning principles, have high level organisational support and cover role clarity as a key learning area.

Examining the utility of the Violence Prevention Climate scale: In a metropolitan Australian general hospital.

AIM AND OBJECTIVES: To evaluate and examine the utility of the Violence Prevention Climate scale by generalist healthcare professionals. BACKGROUND: Workplace violence in general hospital settings remains a challenge for healthcare organisations. High rates of violence are still being reported towards healthcare workers, despite organisational violence prevention strategies being implemented. There is a major challenge to healthcare organisation in the measurement of the effectiveness of these interventions, traditionally completed via the reporting and monitoring of workplace violent incidents. A novel approach to measuring workplace violence is by studying hospital atmosphere or climate. DESIGN: A cross-sectional survey using the STARD guidelines was used. METHODS: The Violence Prevention Climate scale was completed by 194 healthcare staff working in the emergency department, medical/surgical wards, respiratory/infectious disease, spinal care, renal unit, corrections health, and rehabilitation and community services of a major Australian tertiary referral hospital. The Violence Prevention Climate scale has previously been validated and used in mental health settings, but not general hospital settings. A content analysis of an open-ended question on violence prevention management strategies was also conducted. RESULTS: Comprising of 14 items with two factors (patients and staff), the study revealed a 9-item staff factor scale that can be used in the general hospital setting, the patient factor did not show adequate reliability. The content analysis revealed seven categories of staff identified violence prevention and management strategies. CONCLUSIONS: The use of the 9-item scale across an organisation annually, or added to existing organisational workforce surveys, could prove to be practical way of measuring the social climate of violence in a general hospital setting. RELEVANCE TO CLINICAL PRACTICE: The results of which could guide clinical practice, workplace safety, policy and educational initiatives for the prevention and management of workplace violence.

Beyond Streamflow: Call for a National Data Repository of Streamflow Presence for Streams and Rivers in the United States.

Observations of the presence or absence of surface water in streams are useful for characterizing streamflow permanence, which includes the frequency, duration, and spatial extent of surface flow in streams and rivers. Such data are particularly valuable for headwater streams, which comprise the vast majority of channel length in stream networks, are often non-perennial, and are frequently the most data deficient. Datasets of surface water presence exist across multiple data collection groups in the United States but are not well aligned for easy integration. Given the value of these data, a unified approach for organizing information on surface water presence and absence collected by diverse surveys would facilitate more effective and broad application of these data and address the gap in streamflow data in headwaters. In this paper, we highlight the numerous existing datasets on surface water presence in headwater streams, including recently developed crowdsourcing approaches. We identify the challenges of integrating multiple surface water presence/absence datasets that include differences in the definitions and categories of streamflow status, data collection method, spatial and temporal resolution, and accuracy of geographic location. Finally, we provide a list of critical and useful components that could be used to integrate different streamflow permanence datasets.