The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.

Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. Patients suffering from severe AD eventually progress to develop asthma and allergic rhinitis, in a process known as the "atopic march." Signaling between epithelial cells and innate immune cells via the cytokine thymic stromal lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here, we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.

Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis.

BACKGROUND: Dysregulation of nucleocytoplasmic shuttling of histone deacetylase 4 (HDAC4) is associated with several neurodevelopmental and neurodegenerative disorders. Consequently, understanding the roles of nuclear and cytoplasmic HDAC4 along with the mechanisms that regulate nuclear entry and exit is an area of concerted effort. Efficient nuclear entry is dependent on binding of the transcription factor MEF2, as mutations in the MEF2 binding region result in cytoplasmic accumulation of HDAC4. It is well established that nuclear exit and cytoplasmic retention are dependent on 14-3-3-binding, and mutations that affect binding are widely used to induce nuclear accumulation of HDAC4. While regulation of HDAC4 shuttling is clearly important, there is a gap in understanding of how the nuclear and cytoplasmic distribution of HDAC4 impacts its function. Furthermore, it is unclear whether other features of the protein including the catalytic site, the MEF2-binding region and/or the ankyrin repeat binding motif influence the distribution and/or activity of HDAC4 in neurons. Since HDAC4 functions are conserved in Drosophila, and increased nuclear accumulation of HDAC4 also results in impaired neurodevelopment, we used Drosophila as a genetic model for investigation of HDAC4 function. RESULTS: Here we have generated a series of mutants for functional dissection of HDAC4 via in-depth examination of the resulting subcellular distribution and nuclear aggregation, and correlate these with developmental phenotypes resulting from their expression in well-established models of neuronal morphogenesis of the Drosophila mushroom body and eye. We found that in the mushroom body, forced sequestration of HDAC4 in the nucleus or the cytoplasm resulted in defects in axon morphogenesis. The actions of HDAC4 that resulted in impaired development were dependent on the MEF2 binding region, modulated by the ankyrin repeat binding motif, and largely independent of an intact catalytic site. In contrast, disruption to eye development was largely independent of MEF2 binding but mutation of the catalytic site significantly reduced the phenotype, indicating that HDAC4 acts in a neuronal-subtype-specific manner. CONCLUSIONS: We found that the impairments to mushroom body and eye development resulting from nuclear accumulation of HDAC4 were exacerbated by mutation of the ankyrin repeat binding motif, whereas there was a differing requirement for the MEF2 binding site and an intact catalytic site. It will be of importance to determine the binding partners of HDAC4 in nuclear aggregates and in the cytoplasm of these tissues to further understand its mechanisms of action.

Effectiveness of mRNA COVID-19 Monovalent and Bivalent Vaccine Booster Doses Against Omicron Severe Outcomes Among Adults Aged ≥50 Years in Ontario, Canada: A Canadian Immunization Research Network Study.

We estimated the effectiveness of booster doses of monovalent and bivalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults aged ≥50 years in Ontario, Canada. Monovalent and bivalent mRNA COVID-19 booster doses provided similar strong initial protection against severe outcomes. Uncertainty remains around waning of protection from these vaccines.

Access to primary care and mortality in excess for patients with cancer in France: Results from 21 French Cancer Registries.

BACKGROUND: The impact of geographical accessibility on cancer survival has been investigated in few studies, with most research focusing on access to reference care centers, using overall mortality and limited to specific cancer sites. This study aims to examine the association of access to primary care with mortality in excess of patients with the 10 most frequent cancers in France, while controlling for socioeconomic deprivation. METHODS: This study included a total of 151,984 cases diagnosed with the 10 most common cancer sites in 21 French cancer registries between 2013 and 2015. Access to primary care was estimated using two indexes: the Accessibilité Potentielle Localisée index (access to general practitioners) and the Scale index (access to a range of primary care clinicians). Mortality in excess was modelized using an additive framework based on expected mortality based on lifetables and observed mortality. FINDINGS: Patients living in areas with less access to primary care had a greater mortality in excess for some very common cancer sites like breast (women), lung (men), liver (men and women), and colorectal cancer (men), representing 46% of patients diagnosed in our sample. The maximum effect was found for breast cancer; the excess hazard ratio was estimated to be 1.69 (95% CI, 1.20-2.38) 1 year after diagnosis and 2.26 (95% CI, 1.07-4.80) 5 years after diagnosis. INTERPRETATION: This study revealed that this differential access to primary care was associated with mortality in excess for patients with cancer and should become a priority for health policymakers to reduce these inequalities in health care accessibility.

Indirect impact of childhood 13-valent pneumococcal conjugate vaccine (PCV13) in Canadian older adults: a Canadian Immunization Research Network (CIRN) retrospective observational study.

BACKGROUND: 13-valent pneumococcal conjugate vaccine (PCV13) has been part of publicly funded childhood immunisation programmes in Ontario and British Columbia (BC) since 2010. We assessed the indirect impact of infant PCV13 programmes on invasive pneumococcal disease (IPD) and all-cause pneumonia hospitalisation in older adults (aged ≥65 years) using a retrospective observational study. METHODS: We extracted monthly IPD and all-cause pneumonia cases from laboratory and health administrative databases between January 2005 and December 2018. Using a quasi-experimental difference-in-differences design, we calculated the ratio of risk ratios (RRRs) using incidence rates of IPD or all-cause pneumonia cases before (pre-PCV13 period) and after (PCV13 period) 2010 with rates of fractures as controls. RESULTS: The rates of all IPD or PCV serotype-specific IPD for older adults in both Ontario and BC did not change in 8 years after childhood PCV13 programme implementation. All-cause pneumonia increased in Ontario (RRR 1.38, 95% CI 1.11 to 1.71) but remained unchanged in BC. CONCLUSIONS: Indirect community protection of older adults from hospitalisation with pneumococcal disease stalled despite maturation of childhood PCV13 vaccination programmes in two Canadian provinces.

The Influence of Structural Brain Changes on Cognition in the Context of Healthy Aging: Exploring Mediation Effects Through gBAT-The Graphical Brain Association Tool.

The contribution of age-related structural brain changes to the well-established link between aging and cognitive decline is not fully defined. While both age-related regional brain atrophy and cognitive decline have been extensively studied, the specific mediating role of age-related regional brain atrophy on cognitive functions is unclear. This study introduces an open-source software tool with a graphical user interface that streamlines advanced whole-brain mediation analyses, enabling researchers to systematically explore how the brain acts as a mediator in relationships between various behavioral and health outcomes. The tool is showcased by investigating regional brain volume as a mediator to determine the contribution of age-related brain volume loss toward cognition in healthy aging. We analyzed regional brain volumes and cognitive testing data (Montreal Cognitive Assessment [MoCA]) from a cohort of 131 neurologically healthy adult participants (mean age 50 ± 20.8 years, range 20-79, 73% females) drawn from the Aging Brain Cohort Study at the University of South Carolina. Using our open-source tool developed for evaluating brain-behavior associations across the brain and optimized for exploring mediation effects, we conducted a series of mediation analyses using participant age as the predictor variable, total MoCA and MoCA subtest scores as the outcome variables, and regional brain volume as potential mediators. Age-related atrophy within specific anatomical networks was found to mediate the relationship between age and cognition across multiple cognitive domains. Specifically, atrophy in bilateral frontal, parietal, and occipital areas, along with widespread subcortical regions mediated the effect of age on total MoCA scores. Various MoCA subscores were influenced by age through atrophy in distinct brain regions. These involved prefrontal regions, sensorimotor cortex, and parieto-occipital areas for executive function subscores, prefrontal and temporo-occipital regions, along with the caudate nucleus for attention and concentration subscores, frontal and parieto-occipital areas, alongside connecting subcortical areas such as the optic tract for visuospatial subscores and frontoparietal areas for language subscores. Brain-based mediation analysis offers a causal framework for evaluating the mediating role of brain structure on the relationship between age and cognition and provides a more nuanced understanding of cognitive aging than previously possible. By validating the applicability and effectiveness of this approach and making it openly available to the scientific community, we facilitate the exploration of causal mechanisms between variables mediated by the brain.

Spatiotemporal deposition of cell wall polysaccharides in oat endosperm during grain development.

Oat (Avena sativa) is a cereal crop whose grains are rich in (1,3;1,4)-ß-D-glucan (mixed-linkage glucan or MLG), a soluble dietary fiber. In our study, we analyzed oat endosperm development in 2 Canadian varieties with differing MLG content and nutritional value. We confirmed that oat undergoes a nuclear type of endosperm development but with a shorter cellularization phase than barley (Hordeum vulgare). Callose and cellulose were the first polysaccharides to be detected in the early anticlinal cell walls at 11 days postemergence (DPE) of the panicle. Other polysaccharides such as heteromannan and homogalacturonan were deposited early in cellularization around 12 DPE after the first periclinal walls are laid down. In contrast to barley, heteroxylan deposition coincided with completion of cellularization and was detected from 14 DPE but was only detectable after demasking. Notably, MLG was the last polysaccharide to be laid down at 18 DPE within the differentiation phase, rather than during cellularization. In addition, differences in the spatiotemporal patterning of MLG were also observed between the 2 varieties. The lower MLG-containing cultivar AC Morgan (3.5% w/w groats) was marked by the presence of a discontinuous pattern of MLG labeling, while labeling in the same walls in CDC Morrison (5.6% w/w groats) was mostly even and continuous. RNA-sequencing analysis revealed higher transcript levels of multiple MLG biosynthetic cellulose synthase-like F (CSLF) and CSLH genes during grain development in CDC Morrison compared with AC Morgan that likely contributes to the increased abundance of MLG at maturity in CDC Morrison. CDC Morrison was also observed to have smaller endosperm cells with thicker walls than AC Morgan from cellularization onwards, suggesting the processes controlling cell size and shape are established early in development. This study has highlighted that the molecular processes influencing MLG content and deposition are more complex than previously imagined.

N-Aromatic Complexation in Tetraphenyl Porphyrin Iron (III)-Pyridine: Evidence of Spin-Flip via Gas-Phase Electronic Spectroscopy.

There is growing interest in the electronic properties of metalloporphyrins especially in relation to their interactions with other molecular species in their local environment. Here, UV-VIS laser photodissociation spectroscopy in vacuo has been applied to an iron-centred metalloporphyrin (FeTPP+) and its N-aromatic adduct with pyridine (py) to determine the electronic effect of complexation. Both the metalloporphyrin (FeTPP+) and pyridine adduct (FeTPP+⋅py) absorb strongly across the spectral region studied (652-302 nm: 1.91-4.10 eV). Notably, a large blue shift was observed for the dominant Soret band (41 nm) upon complexation (0.47 ± 0.02 eV), indicative of strong pyridine binding. Significant differences in the profiles (i.e. number and position of bands) of the electronic spectra are evident comparing FeTPP+ and FeTPP+⋅py. Time-dependent density functional theory calculations were used to assign the spectra, revealing that the FeIII spin-state flips from S = 3/2 to S = 5/2 upon complexation with pyridine. For FeTPP+, all bright spectral transitions are found to be π-π* in character, with electron density variously distributed across the porphyrin and/or its phenyl substituents. Similar electronic excitations are observed for FeTPP+⋅py, with an additional bright transition which involves charge transfer from the porphyrin to the pyridine moiety.

Switching from a 2-dose to a 1-dose program of gender-neutral routine vaccination against human papillomavirus in Canada: a mathematical modelling analysis.

BACKGROUND: Worldwide, countries are examining whether to implement 1-dose human papillomavirus (HPV) vaccination instead of using 2 doses. To inform policy, we sought to project the population-level impact and efficiency of switching from 2-dose to 1-dose gender-neutral routine HPV vaccination in Canada. METHODS: We used HPV-ADVISE, an individual-based transmission-dynamic model of HPV infections and diseases, to mathematically model vaccination programs in 2 provinces, Quebec, a province with high HPV vaccination coverage (around 85%), and Ontario, which has lower coverage (around 65%). We examined non-inferior and pessimistic scenarios of the efficacy (vaccine efficacy of 98% or 90%) and average vaccine duration (lifelong, 30 yr, or 25 yr) of 1 dose compared with 2 doses (98% vaccine efficacy, lifelong vaccine duration). Our main outcomes were the relative reduction in HPV-16 (by sex) and cervical cancers, and the number of doses needed to prevent 1 cervical cancer. RESULTS: Our model projected that 1-dose HPV vaccination would avert a similar number of cervical cancers as 2 doses in Canada, under various scenarios. Under the most pessimistic scenario (25-yr vaccine duration), 1-dose vaccination would avert fewer cervical cancers than 2 doses, by about 3 percentage points over 100 years. All 1-dose scenarios were projected to lead to elimination of cervical cancer (< 4 cervical cancers/100 000 female-years) and to be a substantially more efficient use of vaccine doses than a 2-dose scenario (1-dose v. no vaccination = 800-1000 doses needed to prevent 1 cervical cancer; incremental doses for 2-dose v. 1-dose vaccination > 10 000 doses needed to prevent 1 additional cervical cancer). INTERPRETATION: If the average duration of 1-dose protection is longer than 25 years, a 1-dose HPV vaccination program would protect those vaccinated during their peak ages of sexual activity and prevent a similar number of HPV-related cancers as a 2-dose program, while being a more efficient use of vaccine doses.

Twin Data Support a Sensitive Period for Singing Ability.

As with many other musical traits, the social environment is a key influence on the development of singing ability. While the familial singing environment is likely to be formative, its role relative to other environmental influences such as training is unclear. We used structural equation modeling to test relationships among demographic characteristics, familial environmental variables (early and current singing with family), vocal training, and singing ability in a large, previously documented sample of Australian twins (N = 1163). Notably, early singing with family, and to a lesser extent vocal training, predicted singing ability, whereas current singing with family did not. Early familial singing also mediated the relationship between sex and singing ability, with men who sang less with family during childhood showing poorer ability. Bivariate twin models between early familial singing and singing ability showed the phenotypic correlation was largely explained by shared environmental influences. This raises the possibility of a sensitive period for singing ability, with sociocultural expectations around singing potentially differentiating the developmental trajectories of this skill for men and women.

The integrated behavioral model of mental health help seeking (IBM-HS): A health services utilization theory of planned behavior for accessing care.

This article introduces the integrated behavioral model of mental health help seeking (IBM-HS), a theoretical model for understanding the constructs (e.g., systemic, predisposing, and enabling factors; mental health literacy; illness perceptions; perceived need; stigma; shame; perceived benefits, motivation) that influence people's decision making around seeking professional mental health care and their ultimate access to formal treatment. The IBM-HS is a help-seeking-specific adaptation of the empirically supported integrated behavioral model and integrative model, which are themselves evolutions of the theory of planned behavior and theory of reasoned action. The IBM-HS posits that help-seeking determinants (e.g., structural forces; cultural influences; past help-seeking experience; evaluated need; mental health perceptions, knowledge, and skills; social support) influence help-seeking beliefs (i.e., outcome beliefs, experiential beliefs, beliefs about others' expectations, beliefs about others' behavior, logistical beliefs), which in turn determine their respective help-seeking mechanisms (i.e., attitude, perceived norm, personal agency). These mechanisms collectively influence help-seeking intention, which drives prospective help-seeking behavior, subject to the moderating effects of determinants. Finally, prospective behavior has reciprocal feedback loop effects on certain determinants and beliefs. This article describes the need for the IBM-HS, the model's constructs and their interrelations, measurement considerations, and how the model can be used by scholarly and applied users to systematically understand people's intention to seek professional mental health care services and what helps or hinders them from utilizing this care. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Diagnosis of Acute Aortic Syndrome in the Emergency Department (DAShED) study: an observational cohort study of people attending the emergency department with symptoms consistent with acute aortic syndrome.

BACKGROUND: The diagnosis of acute aortic syndrome (AAS) is commonly delayed or missed in the ED. We describe characteristics of ED attendances with symptoms potentially associated with AAS, diagnostic performance of clinical decision tools (CDTs) and physicians and yield of CT aorta angiogram (CTA). METHODS: This was a multicentre observational cohort study of adults attending 27 UK EDs between 26 September 2022 and 30 November 2022, with potential AAS symptoms: chest, back or abdominal pain, syncope or symptoms related to malperfusion. Patients were preferably identified prospectively, but retrospective recruitment was also permitted. Anonymised, routinely collected patient data including components of CDTs, was abstracted. Clinicians treating prospectively identified patients were asked to record their perceived likelihood of AAS, prior to any confirmatory testing. Reference standard was radiological or operative confirmation of AAS. 30-day electronic patient record follow-up evaluated whether a subsequent diagnosis of AAS had been made and mortality. RESULTS: 5548 patients presented, with a median age of 55 years (IQR 37-72; n=5539). 14 (0.3%; n=5353) had confirmed AAS. 10/1046 (1.0%) patients in whom the ED clinician thought AAS was possible had AAS. 5/147 (3.4%) patients in whom AAS was considered the most likely diagnosis had AAS. 2/3319 (0.06%) patients in whom AAS was considered not possible did have AAS. 540 (10%; n=5446) patients underwent CT, of which 407 were CTA (7%). 30-day follow-up did not reveal any missed AAS diagnoses. AUROC (area under the receiver operating characteristic) curve for ED clinician AAS likelihood rating was 0.958 (95% CI 0.933 to 0.983, n=4006) and for individual CDTs were: Aortic Dissection Detection Risk Score (ADD-RS) 0.674 (95% CI 0.508 to 0.839, n=4989), AORTAs 0.689 (95% CI 0.527 to 0.852, n=5132), Canadian 0.818 (95% CI 0.686 to 0.951, n=5180) and Sheffield 0.628 (95% CI 0.467 to 0.788, n=5092). CONCLUSION: Only 0.3% of patients presenting with potential AAS symptoms had AAS but 7% underwent CTA. CDTs incorporating clinician gestalt appear to be most promising, but further prospective work is needed, including evaluation of the role of D-dimer. TRIAL REGISTRATION NUMBER: NCT05582967; NCT05582967.

Diagnostic accuracy of alternative biomarkers for acute aortic syndrome: a systematic review.

BACKGROUND: D-dimer is the only biomarker currently recommended in guidelines for the diagnosis of acute aortic syndrome (AAS). We undertook a systematic review to determine whether any alternative biomarkers could be useful in AAS diagnosis. METHODS: We searched electronic databases (including MEDLINE, EMBASE and the Cochrane Library) from inception to February 2024. Diagnostic studies were eligible if they examined biomarkers other than D-dimer for diagnosing AAS compared with a reference standard test in people presenting to the ED with symptoms of AAS. Case-control studies were identified but excluded due to high risk of bias. Selection of studies, data extraction and risk of bias assessments using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool were undertaken independently by at least two reviewers. We used narrative synthesis to summarise the findings. RESULTS: We identified 2017 citations, included 13 cohort studies (n=76-999), and excluded 38 case-control studies. Methodological quality was variable, with most included studies having unclear or high risk of bias and applicability concerns in at least one item of the QUADAS-2 tool. Only two studies reported biomarkers with sensitivity and specificity comparable to D-dimer (ie, >90% and >50%, respectively). Wang et al reported 99.1% sensitivity and 84.9% specificity for soluble ST2; however, these findings conflicted with estimates of 58% sensitivity and 70.8% specificity reported in another study. Chun and Siu reported 95.6% sensitivity and 56.1% specificity for neutrophil count, but this has not been confirmed elsewhere. CONCLUSION: There are many potential alternative biomarkers for AAS but few have been evaluated in more than one study, study designs are often weak and reported biomarker accuracy is modest or inconsistent between studies. Alternative biomarkers to D-dimer are not ready for routine clinical use. PROSPERO REGISTRATION NUMBER: CRD42022252121.

Consensus statement on the interhospital transfer of patients with acute aortic syndrome: TRAVERSING Delphi study.

BACKGROUND: Standardisation of referral pathways and the transfer of patients with acute aortic syndromes (AAS) to regional centres are recommended by NHS England in the Acute Aortic Dissection Toolkit. The aim of the Transfer of Thoracic Aortic Vascular Emergencies to Regional Specialist INstitutes Group study was to establish an interdisciplinary consensus on the interhospital transfer of patients with AAS to specialist high-volume aortic centres. METHODS: Consensus on the key aspects of interhospital transfer of patients with AAS was established using the Delphi method, in line with Conducting and Reporting of Delphi Studies guidelines. A national patient charity for aortic dissection was involved in the design of the Delphi study. Vascular and cardiothoracic surgeons, emergency physicians, interventional radiologists, cardiologists, intensivists and anaesthetists in the United Kingdom were invited to participate via their respective professional societies. RESULTS: Three consecutive rounds of an electronic Delphi survey were completed by 212, 101 and 58 respondents, respectively. Using predefined consensus criteria, 60 out of 117 (51%) statements from the survey were included in the consensus statement. The study concluded that patients can be taken directly to a specialist aortic centre if they have typical symptoms of AAS on the background of known aortic disease or previous aortic intervention. Accepted patients should be transferred in a category 2 ambulance (response time <18 min), ideally accompanied by transfer-trained personnel or Adult Critical Care Transfer Services. A clear plan should be agreed in case of a cardiac arrest occurring during the transfer. Patients should reach the aortic centre within 4 hours of the initial referral from their local hospital. CONCLUSIONS: This consensus statement is the first set of national interdisciplinary recommendations on the interhospital transfer of patients with AAS. Its implementation is likely to contribute to safer and more standardised emergency referral pathways to regional high-volume specialist aortic units.

Effectiveness and Duration of Protection of a Fourth Dose of Coronavirus Disease 2019 Messenger RNA Vaccine Among Long-term Care Residents in Ontario, Canada.

We estimated the effectiveness of a fourth dose of messenger RNA coronavirus disease 2019 vaccine against Omicron infections and severe outcomes over time among long-term care residents in Ontario, Canada. Fourth doses provide additional protection against Omicron-related outcomes, but the protection wanes over time, with more waning seen against infection than severe outcomes.

Protection conferred by COVID-19 vaccination, prior SARS-CoV-2 infection, or hybrid immunity against Omicron-associated severe outcomes among community-dwelling adults.

INTRODUCTION: We assessed protection from COVID-19 vaccines and/or prior SARS-CoV-2 infection against Omicron-associated severe outcomes during successive sublineage-predominant periods. METHODS: We used a test-negative design to estimate protection by vaccines and/or prior infection against hospitalization/death among community-dwelling, PCR-tested adults aged ≥50 years in Ontario, Canada between January 2, 2022 and June 30, 2023. Multivariable logistic regression was used to estimate the relative change in the odds of hospitalization/death with each vaccine dose (2-5) and/or prior PCR-confirmed SARS-CoV-2 infection (compared with unvaccinated, uninfected subjects) up to 15 months since the last vaccination or infection. RESULTS: We included 18,526 cases with Omicron-associated severe outcomes and 90,778 test-negative controls. Vaccine protection was high during BA.1/BA.2 predominance, but was generally <50% during periods of BA.4/BA.5 and BQ/XBB predominance without boosters. A third/fourth dose transiently increased protection during BA.4/BA.5 predominance (third-dose, 6-month: 68%, 95%CI 63%-72%; fourth-dose, 6-month: 80%, 95%CI 77%-83%), but was lower and waned quickly during BQ/XBB predominance (third-dose, 6-month: 59%, 95%CI 48%-67%; 12-month: 49%, 95%CI 41%-56%; fourth-dose, 6-month: 62%, 95%CI 56%-68%, 12-months: 51%, 95%CI 41%-56%). Hybrid immunity conferred nearly 90% protection throughout BA.1/BA.2 and BA.4/BA.5 predominance, but was reduced during BQ/XBB predominance (third-dose, 6-month: 60%, 95%CI 36%-75%; fourth-dose, 6-month: 63%, 95%CI 42%-76%). Protection was restored with a fifth dose (bivalent; 6-month: 91%, 95%CI 79%-96%). Prior infection alone did not confer lasting protection. CONCLUSION: Protection from COVID-19 vaccines and/or prior SARS-CoV-2 infections against severe outcomes is reduced when immune-evasive variants/subvariants emerge and may also wane over time. Our findings support a variant-adapted booster vaccination strategy with periodic review.

Rolling out PRIDE in All Who Served: Barriers and Facilitators for Sites Implementing an LGBTQ+ Health Education Group for Military Veterans.

BACKGROUND/OBJECTIVE: The Veterans Health Administration (VHA) PRIDE in All Who Served health education group (PRIDE) was developed to improve health equity and access to care for military veterans who are lesbian, gay, bisexual, transgender, queer, and/or other sexual/gender-diverse identities (LGBTQ+). This 10-week program rapidly spread to over 30 VHA facilities in 4 years. Veterans receiving PRIDE experience improved LGBTQ+ identity-related resilience and reductions in suicide attempt likelihood. Despite PRIDE's rapid spread across facilities, information is lacking on implementation determinants. The current study's goal was to clarify determinants of PRIDE group implementation and sustainment. METHODS: A purposive sample of VHA staff (N = 19) with experience delivering or implementing PRIDE completed teleconference interviews January-April 2021. The interview guide was informed by the Consolidated Framework for Implementation Research. Rapid qualitative matrix analysis was completed with methods to ensure rigor (e.g., triangulation and investigator reflexivity). RESULTS: Key barriers and facilitators of PRIDE implementation were heavily related to facility inner setting (what is happening inside the facility), including implementation readiness (e.g., leadership support for LGBTQ+-affirming programming, access to LGBTQ+-affirming care training) and facility culture (e.g., systemic anti-LGBTQ+ stigma). Several implementation process facilitators enhanced engagement at sites, such as a centrally facilitated PRIDE learning collaborative and a formal process of contracting/training for new PRIDE sites. DISCUSSION/CONCLUSION: Although aspects of the outer setting and larger societal influences were mentioned, the majority of factors impacting implementation success were at the VHA facility level and therefore may be more readily addressable through tailored implementation support. The importance of LGBTQ+ equity at the facility level indicates that implementation facilitation should ideally address institutional equity in addition to implementation logistics. Combining effective interventions with attention to local implementation needs will be required before LGBTQ+ veterans in all areas will benefit from PRIDE and other health equity-focused interventions.

Incorporating TechQuity in Virtual Care Within the Veterans Health Administration: Identifying Future Research and Operations Priorities.

BACKGROUND: The Covid-19 pandemic dramatically changed healthcare delivery, driving rapid expansion of synchronous (i.e., real-time) audio-only and video telehealth, otherwise known as virtual care. Yet evidence describes significant inequities in virtual care utilization, with certain populations more dependent on audio-only virtual care than video-based care. Research is needed to inform virtual care policies and processes to counteract current inequities in access and health outcomes. OBJECTIVE: Given the importance of incorporating equity into virtual care within the Veterans Health Administration (VHA), we convened a Think Tank to identify priorities for future research and virtual care operations focused on achieving equitable implementation of virtual care within the VHA. METHODS: We used participatory activities to engage clinicians, researchers, and operational partners from across the VHA to develop priorities for equitable implementation of virtual care. We refined priorities through group discussion and force-ranked prioritization and outlined next steps for selected priorities. KEY RESULTS: Think Tank participants included 43 individuals from the VHA who represented diverse geographical regions, offices, and backgrounds. Attendees self-identified their associations primarily as operations (n = 9), research (n = 28), or both (n = 6). We identified an initial list of 63 potential priorities for future research and virtual care operations. Following discussion, we narrowed the list to four priority areas: (1) measure inequities in virtual care, (2) address emerging inequities in virtual care, (3) deploy virtual care equitably to accommodate differently abled veterans, and (4) measure and address potential adverse consequences of expanded virtual care. We discuss related information, data, key partners, and outline potential next steps. CONCLUSIONS: This Think Tank of research and operational partners from across the VHA identified promising opportunities to incorporate equity into the design and implementation of virtual care. Although much work remains, the priorities identified represent important steps toward achieving this vital goal.

The "make or break" impact of family dynamics on psychological outcomes in focal epilepsy.

OBJECTIVE: Living with epilepsy can shape the dynamics of the whole family unit. The first objective of this study was to establish the reliability and validity of our purpose-built online family mapping tool: "Living with Epilepsy." Our second objective was to identify distinct patterns of emotional closeness between family members (family typologies), and to explore (1) whether family typologies are shaped by epilepsy-related factors, and (2) which typologies confer optimal psychological outcomes to people with epilepsy. METHODS: Ninety-one adults with chronic epilepsy and their caregivers (n = 56) participated and 70 similarly aged healthy controls and 36 caregiver controls (N = 253). Purpose-built software assessed a range of epilepsy-specific psychosocial issues, including family mapping. Questionnaires validated for epilepsy evaluated mood and quality of life (QOL). RESULTS: The reliability and validity of the family mapping tool was established. Family maps revealed three typologies varying in emotional closeness, each with distinct patterns of healthy vs maladaptive family behavior: Extremely Close (32%), Close (54%), and Fractured (14%). There was no difference in the frequency of typology between epilepsy and control families (p > .05). Within the epilepsy cohort, however, patients with seizure onset in childhood largely belonged to the extreme typologies: Extremely Close (47%) or Fractured (42%). In comparison, those with adolescent or adult onset commonly belonged to the moderate typology: Close (53%). People with epilepsy from Extremely Close families reported significantly higher QOL (p = .013) and lower mood symptoms (p = .008) relative to other typologies; no such association was found for controls or caregivers (p > .05). SIGNIFICANCE: These findings suggest that adults whose epilepsy commenced in childhood are likely to have extreme family dynamics characterized by either being brought closer together or driven apart. Extremely close families appear highly adaptive for people with epilepsy, bringing benefits for mood and QOL not seen in their caregivers or controls. The results provide strong empirical support for the value of an emotionally supportive family when living with epilepsy and suggest that fostering healthy connections within epilepsy families can optimize long-term patient well-being.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.