Anti-Interleukin-23 Autoantibodies in Adult-Onset Immunodeficiency.

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Clinical and functional spectrum of RAC2-related immunodeficiency.

ABSTRACT: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Treatment of Relapsing HPV Diseases by Restored Function of Natural Killer Cells.

Human papillomavirus (HPV) infections underlie a wide spectrum of both benign and malignant epithelial diseases. In this report, we describe the case of a young man who had encephalitis caused by herpes simplex virus during adolescence and currently presented with multiple recurrent skin and mucosal lesions caused by HPV. The patient was found to have a pathogenic germline mutation in the X-linked interleukin-2 receptor subunit gamma gene (IL2RG), which was somatically reverted in T cells but not in natural killer (NK) cells. Allogeneic hematopoietic-cell transplantation led to restoration of NK cytotoxicity, with normalization of the skin microbiome and persistent remission of all HPV-related diseases. NK cytotoxicity appears to play a role in containing HPV colonization and the ensuing HPV-related hyperplastic or dysplastic lesions. (Funded by the National Institutes of Health and the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources.).

Estimated mortality risk and use of palliative care services among home care clients during the last 6 months of life: a retrospective cohort study.

BACKGROUND: In Canada, only 15% of patients requiring palliative care receive such services in the year before death. We describe health care utilization patterns among home care users in their last 6 months of life to inform care planning for older people with varying mortality risks and evolving care needs as they decline. METHODS: Using population health administrative data from Ontario, we performed a retrospective cohort study involving home care clients aged 50 years and older who received at least 1 interRAI (Resident Assessment Instrument) Home Care assessment between April 2018 and September 2019. We report the proportion of clients who used acute care, long-term care, and palliative home care services within 6 months of their assessment, stratified by their predicted 6-month mortality risk using a prognostic tool called the Risk Evaluation for Support: Predictions for Elder-life in their Communities Tool (RESPECT) and vital status. RESULTS: The cohort included 247 377 adults, 11.9% of whom died within 6 months of an assessment. Among decedents, 50.6% of those with a RESPECT-estimated median survival of fewer than 3 months received at least 1 nonphysician palliative home care visit before death. This proportion declined to 38.7% and 29.5% among decedents with an estimated median survival between 3 and 6 months and between 6 and 12 months, respectively. INTERPRETATION: Many older adults in Ontario do not receive any palliative home care before death. Prognostic tools such as RESPECT may improve recognition of reduced life expectancies and palliative care needs of individuals in their final years of life.

Ascertaining the Francophone population in Ontario: validating the language variable in health data.

BACKGROUND: Language barriers can impact health care and outcomes. Valid and reliable language data is central to studying health inequalities in linguistic minorities. In Canada, language variables are available in administrative health databases; however, the validity of these variables has not been studied. This study assessed concordance between language variables from administrative health databases and language variables from the Canadian Community Health Survey (CCHS) to identify Francophones in Ontario. METHODS: An Ontario combined sample of CCHS cycles from 2000 to 2012 (from participants who consented to link their data) was individually linked to three administrative databases (home care, long-term care [LTC], and mental health admissions). In total, 27,111 respondents had at least one encounter in one of the three databases. Language spoken at home (LOSH) and first official language spoken (FOLS) from CCHS were used as reference standards to assess their concordance with the language variables in administrative health databases, using the Cohen kappa, sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV). RESULTS: Language variables from home care and LTC databases had the highest agreement with LOSH (kappa = 0.76 [95%CI, 0.735-0.793] and 0.75 [95%CI, 0.70-0.80], respectively) and FOLS (kappa = 0.66 for both). Sensitivity was higher with LOSH as the reference standard (75.5% [95%CI, 71.6-79.0] and 74.2% [95%CI, 67.3-80.1] for home care and LTC, respectively). With FOLS as the reference standard, the language variables in both data sources had modest sensitivity (53.1% [95%CI, 49.8-56.4] and 54.1% [95%CI, 48.3-59.7] in home care and LTC, respectively) but very high specificity (99.8% [95%CI, 99.7-99.9] and 99.6% [95%CI, 99.4-99.8]) and predictive values. The language variable from mental health admissions had poor agreement with all language variables in the CCHS. CONCLUSIONS: Language variables in home care and LTC health databases were most consistent with the language often spoken at home. Studies using language variables from administrative data can use the sensitivity and specificity reported from this study to gauge the level of mis-ascertainment error and the resulting bias.

Building evidence to advance health equity: a systematic review on care-related outcomes for older, minoritised populations in long-term care homes.

BACKGROUND: Advancing health equity requires more contextualised evidence. OBJECTIVES: To synthesise published evidence using an existing framework on the origins of health disparities and determine care-related outcome disparities for residents of long-term care, comparing minoritised populations to the context-specific dominant population. DESIGN: Systematic review. SUBJECTS: Residents of 24-hour long-term care homes. METHODS: The protocol was registered a priori with PROSPERO (CRD42021269489). Literature published between 1 January 2000 and 26 September 2021, was searched, including studies comparing baseline characteristics and outcomes in minoritised versus dominant populations. Dual screening, two-reviewer verification for extraction, and risk of bias assessments were conducted to ensure rigour. Studies were synthesized using a conceptual framework to contextualise evidence according to multi-level factors contributing to the development of care disparities. RESULTS: Twenty-one of 34 included studies demonstrated disparities in care outcomes for minoritised groups compared to majority groups. Thirty-one studies observed differences in individual-level characteristics (e.g. age, education, underlying conditions) upon entry to homes, with several outcome disparities (e.g. restraint use, number of medications) present at baseline and remaining or worsening over time. Significant gaps in evidence were identified, particularly an absence of literature on provider information and evidence on the experience of intersecting minority identities that contribute to care-related outcome disparities in long-term care. CONCLUSION: This review found differences in minoritised populations' care-related outcomes. The findings provide guidance for future health equity policy and research-supporting diverse and intersectional capacity building in long-term care.

Not too little, not too much: the impact of mutation types in Wiskott-Aldrich syndrome and RAC2 patients.

Primary immune deficiencies (PIDs) are genetic disorders impacting the appropriate development or functioning of any portion of the immune system. The broad adoption of high-throughput sequencing has driven discovery of new genes as well as expanded phenotypes associated with known genes. Beginning with the identification of WAS mutations in patients with severe Wiskott-Aldrich Syndrome, recognition of WAS mutations in additional patients has revealed phenotypes including isolated thrombocytopenia and X-linked neutropenia. Likewise RAC2 patients present with vastly different phenotypes depending on the mutation-ranging from reticular dysgenesis or severe neutrophil dysfunction with neonatal presentation to later onset common variable immune deficiency. This review examines genotype-phenotype correlations in patients with WAS (Wiskott-Aldrich Syndrome) and RAC2 mutations, highlighting functional protein domains, how mutations alter protein interactions, and how specific mutations can affect isolated functions of the protein leading to disparate phenotypes.

Patient-Reported Symptom Burden After Cancer Surgery in Older Adults: A Population-Level Analysis.

BACKGROUND: Older adults have unique needs for supportive care after surgery. We examined symptom trajectories and factors associated with high symptom burden after cancer surgery in older adults. PATIENTS AND METHODS: We conducted a population-level study of patients ≥ 70 years old undergoing cancer surgery (2007-2018) using prospectively collected Edmonton Symptom Assessment System (ESAS) scores. The monthly prevalence of moderate to severe symptoms (ESAS ≥ 4) for anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and poor wellbeing was computed over 12 months after surgery. RESULTS: Among 48,748 patients, 234,420 ESAS scores were recorded over 12 months after surgery. Moderate to severe tiredness (57.8%), poor wellbeing (51.9%), and lack of appetite (39.3%) were most common. The proportion of patients with moderate to severe symptoms was stable over the 1 month prior to and 12 months after surgery (< 5% variation for each symptom). There was no clinically significant change (< 5%) in symptom trajectory with the initiation of adjuvant therapy. CONCLUSIONS: Patient-reported symptom burden was stable for up to 1 year after cancer surgery among older adults. Neither surgery nor adjuvant therapy coincided with a worsening in symptom burden. However, the persistence of symptoms at 1 year may suggest gaps in supportive care for older adults. This information on symptom trajectory and predictors of high symptom burden is important to set appropriate expectations and improve patient counseling, recovery care pathways, and proactive symptom management for older adults after cancer surgery.

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Donor source and post-transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency.

GATA2 deficiency was described in 2011, and shortly thereafter allogeneic hematopoietic stem cell transplantation (HSCT) was shown to reverse the hematologic disease phenotype. However, there remain major unanswered questions regarding the type of conditioning regimen, type of donors, and graft-versus-host disease (GVHD) prophylaxis. We report 59 patients with GATA2 mutations undergoing HSCT at National Institutes of Health between 2013 and 2020. Primary endpoints were engraftment, reverse of the clinical phenotype, secondary endpoints were overall survival (OS), event-free survival (EFS), and the incidence of acute and chronic GVHD. The OS and EFS at 4 years were 85·1% and 82·1% respectively. Ninety-six percent of surviving patients had reversal of the hematologic disease phenotype by one-year post-transplant. Incidence of grade III-IV aGVHD in matched related donor (MRD) and matched unrelated donor recipients (URD) patients receiving Tacrolimus/Methotrexate for GVHD prophylaxis was 32%. In contrast, in the MRD and URD who received post-transplant cyclophosphamide (PT/Cy), no patient developed grade III-IV aGVHD. Six percent of haploidentical related donor (HRD) recipients developed grade III-IV aGVHD. In summary, a busulfan-based HSCT regimen in GATA2 deficiency reverses the hematologic disease phenotype, and the use of PT/Cy reduced the risk of both aGVHD and cGVHD.

Long-term Dependency Outcomes in Older Adults Following Hepato-Pancreato-Biliary Surgery for Cancer: A Population-based Analysis.

OBJECTIVE: To evaluate healthcare dependency following hepatopancreato-biliary cancer surgery in older adults (OA). SUMMARY BACKGROUND DATA: Functional outcomes are central to decisionmaking by OA, but long-term risks of dependency have not been described beyond 1 year in this population. METHODS: All patients over age 70 undergoing hepatectomy or pancreatec-tomy for cancer between 2007 and 2017 in Ontario were analyzed. Outcomes were 1) receipt of homecare and 2) time at home. Homecare was analyzed with cumulative incidence functions, and time at home with Kaplan-Meier and Cox multivariate models. RESULTS: A total of 902 and 1283 patients underwent hepatectomy and pancreatectomy, respectively. Homecare use was highest (72.3%) in postoperative month-1, decreasing to stabilize between year-1 (25.5%) and year-5 (18.3%). Repeated receipt of homecare was associated with female sex (HR 1.18, 95% CI 1.05-1.32), receipt of adjuvant therapy (HR 1.56, 1.37-1.78), and more recent year of surgery (HR 3.80, 3.05-4.72). The ratio of home nursing care versus personal support services reversed from 68%/26% in year-1, to 29/64% in year-5. High time at home (>350 days) at 1 and 5 years were 40.6% (95% CI 38.5%-42.6%) and 28.1% (25.9%-30.3%), respectively. The ratio of institution-days in acute care versus nursing homes went from 77%/14% in year-1 to 23%/70% in year-5. Low time at home was associated with duodenal (HR 1.45, 1.15-1.70) and pancreas cancer (HR 1.20, 1.02-1.42), and with rural residence (HR 1.24, 1.04-1.48). High time at home was associated with more recent year of surgery (HR 0.84, 0.76-0.93) and perioperative cancer therapy (HR 0.88, 0.78-0.99). Increasing age was neither associated with homecare receipt nor time at home. CONCLUSIONS: Following hepatopancreatobiliary cancer surgery, there is a high rate of long-term healthcare dependency for OA. There is an immediate high need for homecare that reaches a new baseline after 6 months, and the majority of OA will have at least 1 year with low time at home, most commonly the first year. These findings can aid in preoperative preparation and transitional care planning.

Initial treatment is associated with improved survival and end-of-life outcomes for patients with pancreatic cancer: a cohort study.

BACKGROUND: We describe the association between initial treatment and end-of-life (EOL) outcomes among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: This population-based cohort study included patients with PDAC who died from April 2010-December 2017 in Ontario, Canada using administrative databases. We used multivariable models to explore the association between index cancer treatment (no cancer-directed therapy, radiation, chemotherapy, surgery alone, and surgery and chemotherapy), and primary (mortality, healthcare encounters and palliative care) and secondary outcomes (location of death, hospitalizations, and receipt of chemotherapy within the last 30 days of life). RESULTS: In our cohort (N = 9950), 56% received no cancer-directed therapy, 5% underwent radiation, 27% underwent chemotherapy, 7% underwent surgery alone, and 6% underwent surgery and chemotherapy. Compared to no cancer-directed therapy, radiation therapy (HR = 0.63), chemotherapy (HR = 0.43) surgery alone (HR = 0.32), and surgery and chemotherapy (HR = 0.23) were all associated with decreased mortality. Radiation (AMD = - 3.64), chemotherapy (AMD = -6.35), surgery alone (AMD = -6.91), and surgery and chemotherapy (AMD = -6.74) were all associated with fewer healthcare encounters per 30 days in the last 6 months of life. Chemotherapy (AMD = -1.57), surgery alone (AMD = -1.65), and surgery and chemotherapy (AMD = -1.67) were associated with fewer palliative care visits (all p-values for estimates above < 0.05). Treatment groups were associated with lower odds of institutional death and hospitalization at EOL, and higher odds of chemotherapy at EOL. CONCLUSIONS: Receiving cancer-directed therapies was associated with higher survival, fewer healthcare visits, lower odds of dying in an institution and hospitalization at EOL, fewer palliative care visits, and higher odds of receiving chemotherapy at EOL.

Assessing the application of continuity of care indices in the last year of life: a retrospective population-based study.

Context: Most people spend the majority of their last year of life at home or in a home-like setting, receiving outpatient healthcare. Increasing numbers of physicians and teams, including palliative care providers, may become involved in care in addition to a usual provider such as a family physician. Continuity of care (CoC) near the end of life, although considered a marker of quality of care, may be interrupted despite the provision of high-quality care. Objective: To describe continuity of outpatient physician care in the last 12 months of life and determine patient and illness-related factors associated with high continuity. Study Design: Retrospective cohort study. Datasets: Linked population-based health administrative databases for Ontario, Canada, held at ICES. Population: Decedents aged 19 years or older, who died between January 1, 2013, and December 31, 2017. Outcome Measures: Continuity of care scores for the last 12 months of life, using the Usual Provider continuity (UPC), Bice-Boxerman continuity (CoC), and Sequential Continuity (SECON) indices. Multivariate models were used to determine factors associated with higher continuity scores (>= 0.75). Results: Decedents (n=322,445) were on average 76.3 years of age, 47.8% were female, and 13.2% resided in rural regions. Decedents had a mean of 16.2 outpatient physician encounters in the last year of life, from a mean of 3.8 different physician specialties. Mean continuity indices' scores (1 being perfect) were low: UPC= 0.36, CoC= 0.31, and SECON= 0.37. Proportions of decedents with high continuity were: UPC= 12.6%, CoC= 9.6%, and SECON= 12.9%. Decedents who experienced a terminal illness (i.e., cancer) end-of-life trajectory were least likely to experience high UPC (OR= 0.32; 95% CI= 0.30, 0.34). Having six or more comorbidities (OR= 0.65; 95% CI= 0.63, 0.66), and being in the highest quintile of outpatient physician encounters (i.e., >22 visits) (OR= 0.28; 95% CI= 0.27, 0.29) were also negatively associated with high UPC. Results were similar for other indices. Conclusions: Decedents experience low continuity of outpatient physician care in the last year of life, especially those with cancer, comorbidities, and frequent physician visits. Modifications to existing indices may be needed to serve as end-of-life care quality indicators.

Socioeconomic and Geographic Disparities in Emergency Department Visits due to Alcohol in Ontario: A Retrospective Population-level Study from 2003 to 2017.

OBJECTIVE: While the overall health system burden of alcohol is large and increasing in Canada, little is known about how this burden differs by sociodemographic factors. The objectives of this study were to assess sociodemographic patterns and temporal trends in emergency department (ED) visits due to alcohol to identify emerging and at-risk subgroups. METHODS: We conducted a retrospective population-level cohort study of all individuals aged 10 to 105 living in Ontario, Canada. We identified ED visits due to alcohol between 2003 and 2017 using defined International Classification of Diseases, 10th edition, codes from a pre-existing indicator. We calculated annual age- and sex-standardized, and age- and sex-specific rates of ED visits and compared overall patterns and changes over time between urban and rural settings and income quintiles. RESULTS: There were 829,662 ED visits due to alcohol over 15 years. Rates of ED visits due to alcohol were greater for individual living in the lowest- compared to the highest-income quintile neighbourhoods, and disparities (rate ratio lowest to highest quintile) increased with age from 1.22 (95% CI, 1.19 to 1.25) in 15- to 18-year-olds to 4.17 (95% CI, 4.07 to 4.28) in 55- to 59-year-olds. Rates of ED visits due to alcohol were significantly greater in rural settings (56.0 per 10,000 individuals, 95% CI, 55.7 to 56.4) compared to urban settings (44.8 per 10,000 individuals, 95% CI, 44.7 to 44.9), particularly for young adults. Increases in rates of visits between 2003 and 2017 were greater in rural versus urban settings (82 vs. 68% increase in age- and sex-standardized rates) and varied across sociodemographic subgroups with the largest annual increases in rates of visits in young (15 to 29) low-income women (6.9%, 95%CI, 6.7 to 7.3) and the smallest increase in older (45 to 59) high-income men (2.7, 95%CI, 2.4 to 3.0). CONCLUSION: Alcohol harms display unique patterns with the highest burden in rural and lower-income populations. Rural-urban and income-based disparities differ by age and sex and have increased over time, which offers an imperative and opportunity for further interventions by clinicians and policy makers.

Using Patient Simulation to Promote Best Practices in Fall Prevention and Postfall Assessment in Nursing Homes.

BACKGROUND: Fall-related injuries rise with age and are of particular concern for frail populations living in nursing homes. LOCAL PROBLEM: The Perley and Rideau Veterans' Health Centre is a large nursing home in Ontario, Canada. In 2019, we conducted internal audits of our Falls Prevention Program and identified notable variations in staff's response to a resident fall. INTERVENTIONS: We developed an in situ patient simulation program of a resident fall. METHODS: This was a mixed-methods evaluation of participants' perspectives of a simulation-based interprofessional education program for fall prevention. RESULTS: Participants indicated high-level support for simulation-based learning, with more than 80% of the participants expressing that they will apply these skills in the future when caring for a resident who falls. CONCLUSIONS: Our findings indicate that simulation-based training is well received by frontline workers in a nursing home setting and can be conducted as part of a typical shift with minimal disruption to resident care.

Implementation of smart supportive dementia technology in a hospital transitional care setting using human-centred design.

Supportive smart home technology, for older adults living with dementia and their informal care partners, has shown some benefits in private homes. In this study, a supportive smart home system is being implemented in a hospital alternative level of care setting. This case report describes how a team of researchers and healthcare managers are navigating the complexities of a hospital setting, using human-centred design and implementation strategies, to facilitate the implementation and adoption of the technology.

Lost in Translation: Lack of CD4 Expression due to a Novel Genetic Defect.

CD4 expression identifies a subset of mature T cells primarily assisting the germinal center reaction and contributing to CD8+ T-cell and B-cell activation, functions, and longevity. Herein, we present a family in which a novel variant disrupting the translation-initiation codon of the CD4 gene resulted in complete loss of membrane and plasma soluble CD4 in peripheral blood, lymph node, bone marrow, skin, and ileum of a homozygous proband. This inherited CD4 knockout disease illustrates the clinical and immunological features of a complete deficiency of any functional component of CD4 and its similarities and differences with other clinical models of primary or acquired loss of CD4+ T cells. The first inherited loss of any functional component of CD4, including soluble CD4, is clinically distinct from any other congenital or acquired CD4 T-cell defect and characterized by compensatory changes in T-cell subsets and functional impairment of B cells, monocytes, and natural killer cells.

Pandemic Preparedness and Beyond: Person-Centred Care for Older Adults Living in Long-Term Care during the COVID-19 Pandemic.

The increasing complexity of residents' needs, emphasis on social distancing and limited access to high-quality support presented challenges to patient-centred care during the pandemic. Yet the pandemic created an opportunity to explore novel approaches to achieving person-centred care within long-term care (LTC). We share three projects designed to enhance care delivery in the context of the pandemic: to address personhood needs during outbreaks, to improve the quality of medical care and to deliver personalized palliative and end-of-life care using a prediction algorithm. These projects enabled better care during the pandemic and will continue to advance person-centred care beyond the pandemic.

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. METHODS: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). RESULTS: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. CONCLUSION: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. CLINICAL IMPLICATIONS: HCT is a definitive cure for DADA2 with > 95% survival.

FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K.

The insulin-like growth factor 1 receptor (IGF1R) and phosphoinositide 3-kinase p110α (PI3K) are critical regulators of exercise-induced physiological cardiac hypertrophy and provide protection in experimental models of pathological remodeling and heart failure. Forkhead box class O1 (FoxO1) is a transcription factor that regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K activation in vitro, but its role in physiological hypertrophy in vivo was unknown. We generated cardiomyocyte-specific FoxO1 knockout (cKO) mice and assessed the phenotype under basal conditions and settings of physiological hypertrophy induced by 1) swim training or 2) cardiac-specific transgenic expression of constitutively active PI3K (caPI3KTg+). Under basal conditions, male and female cKO mice displayed mild interstitial fibrosis compared with control (CON) littermates, but no other signs of cardiac pathology were present. In response to exercise training, female CON mice displayed an increase (∼21%) in heart weight normalized to tibia length vs. untrained mice. Exercise-induced hypertrophy was blunted in cKO mice. Exercise increased cardiac Akt phosphorylation and IGF1R expression but was comparable between genotypes. However, differences in Foxo3a, Hsp70, and autophagy markers were identified in hearts of exercised cKO mice. Deletion of FoxO1 did not reduce cardiac hypertrophy in male or female caPI3KTg+ mice. Cardiac Akt and FoxO1 protein expressions were significantly reduced in hearts of caPI3KTg+ mice, which may represent a negative feedback mechanism from chronic caPI3K, and negate any further effect of reducing FoxO1 in the cKO. In summary, FoxO1 contributes to exercise-induced hypertrophy. This has important implications when one is considering FoxO1 as a target for treating the diseased heart.NEW & NOTEWORTHY Regulators of exercise-induced physiological cardiac hypertrophy and protection are considered promising targets for the treatment of heart failure. Unlike pathological hypertrophy, the transcriptional regulation of physiological hypertrophy has remained largely elusive. To our knowledge, this is the first study to show that the transcription factor FoxO1 is a critical mediator of exercise-induced cardiac hypertrophy. Given that exercise-induced hypertrophy is protective, this finding has important implications when one is considering FoxO1 as a target for treating the diseased heart.