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.

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.

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.

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.

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.

Key Considerations When Developing and Implementing Digital Technology for Early Detection of Dementia-Causing Diseases Among Health Care Professionals: Qualitative Study.

BACKGROUND: The World Health Organization (WHO) promotes using digital technologies to accelerate global attainment of health and well-being. This has led to a growth in research exploring the use of digital technology to aid early detection and preventative interventions for dementia-causing diseases such as Alzheimer disease. The opinions and perspectives of health care professionals must be incorporated into the development and implementation of technology to promote its successful adoption in clinical practice. OBJECTIVE: This study aimed to explore health care professionals' perspectives on the key considerations of developing and implementing digital technologies for the early detection of dementia-causing diseases in the National Health Service (NHS). METHODS: Health care professionals with patient-facing roles in primary or secondary care settings in the NHS were recruited through various web-based NHS clinical networks. Participants were interviewed to explore their experiences of the current dementia diagnostic practices, views on early detection and use of digital technology to aid these practices, and the challenges of implementing such interventions in health care. An inductive thematic analysis approach was applied to identify central concepts and themes in the interviews, allowing the data to determine our themes. A list of central concepts and themes was applied systematically to the whole data set using NVivo (version 1.6.1; QSR International). Using the constant comparison technique, the researchers moved backward and forward between these data and evolving explanations until a fit was made. RESULTS: Eighteen semistructured interviews were conducted, with 11 primary and 7 secondary care health care professionals. We identified 3 main categories of considerations relevant to health care service users, health care professionals, and the digital health technology itself. Health care professionals recognized the potential of using digital technology to collect real-time data and the possible benefits of detecting dementia-causing diseases earlier if an effective intervention were available. However, some were concerned about postdetection management, questioning the point of an early detection of dementia-causing diseases if an effective intervention cannot be provided and feared this would only lead to increased anxiety in patients. Health care professionals also expressed mixed opinions on who should be screened for early detection. Some suggested it should be available to everyone to mitigate the chance of excluding those who are not in touch with their health care or are digitally excluded. Others were concerned about the resources that would be required to make the technology available to everyone. CONCLUSIONS: This study highlights the need to design digital health technology in a way that is accessible to all and does not add burden to health care professionals. Further work is needed to ensure inclusive strategies are used in digital research to promote health equity.

Digital Endpoints for Assessing Instrumental Activities of Daily Living in Mild Cognitive Impairment: Systematic Review.

BACKGROUND: Subtle impairments in instrumental activities of daily living (IADLs) can be a key predictor of disease progression and are considered central to functional independence. Mild cognitive impairment (MCI) is a syndrome associated with significant changes in cognitive function and mild impairment in complex functional abilities. The early detection of functional decline through the identification of IADL impairments can aid early intervention strategies. Digital health technology is an objective method of capturing IADL-related behaviors. However, it is unclear how these IADL-related behaviors have been digitally assessed in the literature and what differences can be observed between MCI and normal aging. OBJECTIVE: This review aimed to identify the digital methods and metrics used to assess IADL-related behaviors in people with MCI and report any statistically significant differences in digital endpoints between MCI and normal aging and how these digital endpoints change over time. METHODS: A total of 16,099 articles were identified from 8 databases (CINAHL, Embase, MEDLINE, ProQuest, PsycINFO, PubMed, Web of Science, and Scopus), out of which 15 were included in this review. The included studies must have used continuous remote digital measures to assess IADL-related behaviors in adults characterized as having MCI by clinical diagnosis or assessment. This review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Ambient technology was the most commonly used digital method to assess IADL-related behaviors in the included studies (14/15, 93%), with passive infrared motion sensors (5/15, 33%) and contact sensors (5/15, 33%) being the most prevalent types of methods. Digital technologies were used to assess IADL-related behaviors across 5 domains: activities outside of the home, everyday technology use, household and personal management, medication management, and orientation. Other recognized domains-culturally specific tasks and socialization and communication-were not assessed. Of the 79 metrics recorded among 11 types of technologies, 65 (82%) were used only once. There were inconsistent findings around differences in digital IADL endpoints across the cognitive spectrum, with limited longitudinal assessment of how they changed over time. CONCLUSIONS: Despite the broad range of metrics and methods used to digitally assess IADL-related behaviors in people with MCI, several IADLs relevant to functional decline were not studied. Measuring multiple IADL-related digital endpoints could offer more value than the measurement of discrete IADL outcomes alone to observe functional decline. Key recommendations include the development of suitable core metrics relevant to IADL-related behaviors that are based on clinically meaningful outcomes to aid the standardization and further validation of digital technologies against existing IADL measures. Increased longitudinal monitoring is necessary to capture changes in digital IADL endpoints over time in people with MCI. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022326861; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=326861.

Leukemia: What Primary Care Physicians Need to Know.

Leukemia is caused by an abnormal proliferation of hematopoietic stem cells in the bone marrow. The four general subtypes are acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous. Acute lymphoblastic leukemia primarily occurs in children, whereas the other subtypes are more common in adults. Risk factors include certain chemical and ionizing radiation exposures and genetic disorders. Common symptoms include fever, fatigue, weight loss, joint pain, and easy bruising or bleeding. Diagnosis is confirmed with bone marrow biopsy or peripheral blood smear. Hematology-oncology referral is recommended in patients with suspected leukemia. Chemotherapy, radiation, targeted molecular therapy, monoclonal antibodies, or hematopoietic stem cell transplantation are common treatments. Complications from treatment include serious infections from immunosuppression, tumor lysis syndrome, cardiovascular events, and hepatotoxicity. Long-term sequelae in leukemia survivors include secondary malignancies, cardiovascular disease, and musculoskeletal and endocrine disorders. Five-year survival rates are highest in younger patients and those diagnosed with chronic myelogenous or chronic lymphocytic leukemia.

Finding Voices: a survey of young people's experiences of the ED.

BACKGROUND: Mental health presentations in young people are increasing. Recurrence of self-harm (SH) presentations is common and of great concern since self-harm is known to be a risk factor for suicide. Previous reports suggest that the ED experience for this group is poor. A study was carried out at the Royal Berkshire NHS Foundation Trust. The objective was to pilot new and existing measures to capture the perceived needs and expectations of young people attending ED following SH compared with those attending with suspected fractures (SFs). METHODS: Young people were approached to complete a questionnaire as they arrived in ED and again before they left. Questionnaires were a combination of pre-existing tools as well as piloting novel questions specific to the ED where no suitable tool previously existed. Satisfaction with the ED treatment was measured along with reattendance up to one year later. RESULTS: The survey was started in 2019 and suspended in March 2020 at the outset of the COVID-19 pandemic and subsequently closed, having screened 917 and recruited 104 adolescents. All the measures showed satisfactory psychometric properties with internal consistencies (alpha) of over 0.75. The two patient groups differed at baseline: it was found that the SH group had lower mood on the Short Mood and Feelings Questionnaire (p<0.001) and scored more highly on the Borderline Personality Features Scale for Children than the SF group (p<0.001) but the expectations of care across both groups was similar. Using the experience measures, the SH group was less satisfied with treatment than the SF group (p=0.0263). CONCLUSION: Our findings underline the similarities between the two groups in terms of their expectations of care. Terminating the study early at the outset of the COVID-19 pandemic has precluded any further firm conclusions to be drawn. Further research is needed.

An evidence-based protocol for sensory soothing in paediatric intensive care.

In recent years, an increasing body of literature has highlighted the significant sequelae of a paediatric intensive care unit admission for children and their families. More innovative bedside approaches are needed to support children's coping and development and help minimize the use of sedatives, given their known deleterious effects. To support nursing staff in managing agitation in critically ill infants and children, a 'Sensory Pyramid' program was built in collaboration with occupational therapists, child life specialists and critical care nursing staff at an academic medical center in the United States. Anchored in evidence-based and developmentally appropriate non-pharmacologic sensory soothing techniques, the protocol outlines escalating comfort interventions nurses can employ that are safe and feasible for implementation by bedside staff and families.

A family study implicates GBE1 in the etiology of autism spectrum disorder.

Autism spectrum disorders (ASD) are neurodevelopmental disorders with an estimated heritability of >60%. Family-based genetic studies of ASD have generally focused on multiple small kindreds, searching for de novo variants of major effect. We hypothesized that molecular genetic analysis of large multiplex families would enable the identification of variants of milder effects. We studied a large multigenerational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP). We identified a rare heterozygous variant in the gene encoding 1,4-ɑ-glucan branching enzyme 1 (GBE1) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP, and none of four tested unaffected individuals. We genotyped a community-acquired cohort of 389 individuals with ASD and identified three additional probands. Cascade analysis demonstrated that the variant was present in 11 of 13 individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. The variant was not enriched in the combined UK10K ASD cohorts of European ancestry but heterozygous GBE1 deletion was overrepresented in large ASD cohorts, collectively suggesting an association between GBE1 and ASD.

Treatment of Surgical Scars With Combination Pulsed Dye and Fractional Nonablative Laser: A Randomized Controlled Trial.

OBJECTIVE: To assess the effectiveness and safety of combined pulsed-dye laser (PDL) and NAFL for treatment of surgical scars. SUMMARY BACKGROUND DATA: PDL and NAFL have not been compared to healing by time alone. METHODS: Randomized controlled, single-blinded clinical trial at an urban, university hospital. Healthy adults' status post skin surgery with primary closure were randomized to either 3 sessions of combination PDL and NAFL every 2 to 8 weeks, or control of no treatment. At baseline and 36-week follow-up, Patient and observer Scar Assessment Scale and Scar Cosmesis Assessment and Rating were completed by participants and blinded physicians. The primary outcome was scar improvement, as measured by the score difference over time. RESULTS: Of 76 participants, 52 completed the study (July 2017 to June 2019). No severe adverse events were reported. Patient and observer Scar Assessment Scale assessments demonstrated improvement in total score in the laser group compared to controls, as reported by patients [mean difference (standard deviation), laser: 12.86 (6.91) vs control: 7.25 (6.34); P = 0.004] and blinded physicians [18.32 (8.69) vs 13.08 (9.63); P = 0.044]. Patients observed a greater improvement in scar thickness [3.68 (2.04) vs 1.88 (1.85); P = 0.002] and stiffness [3.57 (2.78) vs 1.50 (2.11); P = 0.004] with lasers, and physicians reported greater improvement in vascularity [3.71 (1.98) vs 1.71 (1.52); P = 0.0002]. The live Scar Cosmesis Assessment and Rating subscore for erythema improved significantly with lasers [1.04 (0.79) vs 0.42 (0.50); P = 0.001]. CONCLUSIONS AND RELEVANCE: Combined PDL and NAFL resulted in scar improvement. Scar thickness, stiffness, and erythema were improved. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03057964).