Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne.

OBJECTIVES: To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1. METHODS: Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients. RESULTS: The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement. CONCLUSION: PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition.

Suicide Rates by Industry and Occupation - National Vital Statistics System, United States, 2021.

The suicide rate among the U.S. working-age population has increased approximately 33% during the last 2 decades. To guide suicide prevention strategies, CDC analyzed suicide deaths by industry and occupation in 49 states, using data from the 2021 National Vital Statistics System. Industry (the business activity of a person's employer or, if self-employed, their own business) and occupation (a person's job or the type of work they do) are distinct ways to categorize employment. The overall suicide rates by sex in the civilian noninstitutionalized working population were 32.0 per 100,000 among males and 8.0 per 100,000 among females. Major industry groups with the highest suicide rates included Mining (males = 72.0); Construction (males = 56.0; females = 10.4); Other Services (e.g., automotive repair; males = 50.6; females = 10.4); Arts, Entertainment, and Recreation (males = 47.9; females = 15.0); and Agriculture, Forestry, Fishing, and Hunting (males = 47.9). Major occupation groups with the highest suicide rates included Construction and Extraction (males = 65.6; females = 25.3); Farming, Fishing, and Forestry (e.g., agricultural workers; males = 49.9); Personal Care and Service (males = 47.1; females = 15.9); Installation, Maintenance, and Repair (males = 46.0; females = 26.6); and Arts, Design, Entertainment, Sports, and Media (males = 44.5; females = 14.1). By integrating recommended programs, practices, and training into existing policies, workplaces can be important settings for suicide prevention. CDC provides evidence-based suicide prevention strategies in its Suicide Prevention Resource for Action and Critical Steps Your Workplace Can Take Today to Prevent Suicide, NIOSH Science Blog.

TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.

Firearm Homicides and Suicides in Major Metropolitan Areas - United States, 2015-2016 and 2018-2019.

Firearm homicides and suicides represent an ongoing public health concern in the United States. During 2018-2019, a total of 28,372 firearm homicides (including 3,612 [13%] among youths and young adults aged 10-19 years [youths]) and 48,372 firearm suicides (including 2,463 [5%] among youths) occurred among U.S. residents (1). This report is the fourth in a series* that provides statistics on firearm homicides and suicides in major metropolitan areas. As with earlier reports, this report provides a special focus on youth violence, including suicide, recognizing the magnitude of the problem and the importance of early prevention efforts. Firearm homicide and suicide rates were calculated for the 50 most populous U.S. metropolitan statistical areas (MSAs)† for the periods 2015-2016 and 2018-2019, separated by a transition year (2017), using mortality data from the National Vital Statistics System (NVSS) and population data from the U.S. Census Bureau. Following a period of decreased firearm homicide rates among persons of all ages after 2006-2007 in large metropolitan areas collectively and nationally, by 2015-2016 rates had returned to levels comparable to those observed a decade earlier and remained nearly unchanged as of 2018-2019. Firearm suicide rates among persons aged ≥10 years have continued to increase in large MSAs collectively as well as nationally. Although the youth firearm suicide rate remained much lower than the overall rate, the youth rate nationally also continued to increase, most notably outside of large MSAs. The findings in this report underscore a continued and urgent need for a comprehensive approach to prevention. This includes efforts to prevent firearm homicide and suicide in the first place and support individual persons and communities at increased risk, as well as lessening harms after firearm homicide and suicide have occurred.

Changes in Suicide Rates - United States, 2019 and 2020.

Suicide was among the 10 leading causes of death in the United States in 2020 among persons aged 10-64 years, and the second leading cause of death among children and adolescents aged 10-14 and adults aged 25-34 years (1). During 1999-2020, nearly 840,000 lives were lost to suicide in the United States. During that period, the overall suicide rate peaked in 2018 and declined in 2019 and 2020 (1). Despite the recent decline in the suicide rate, factors such as social isolation, economic decline, family stressors, new or worsening mental health symptoms, and disruptions to work and school associated with the COVID-19 pandemic have raised concerns about suicide risk in the United States. During 2020, a total of 12.2 million U.S. adults reported serious thoughts of suicide and 1.2 million attempted suicide (2). To understand how changes in suicide death rates might have varied among subpopulations, CDC analyzed counts and age-adjusted suicide rates during 2019 and 2020 by demographic characteristics, mechanism of injury, county urbanization level, and state. From 2019 to 2020, the suicide rate declined by 3% overall, including 8% among females and 2% among males. Significant declines occurred in seven states but remained stable in the other states and the District of Columbia. Despite two consecutive years of declines, the overall suicide rate remains 30% higher compared with that in 2000 (1). A comprehensive approach to suicide prevention that uses data driven decision-making and implements prevention strategies with the best available evidence, especially among disproportionately affected populations (3), is critical to realizing further declines in suicide and reaching the national goal of reducing the suicide rate by 20% by 2025 (4).

Suicides Among American Indian or Alaska Native Persons - National Violent Death Reporting System, United States, 2015-2020.

Compared with the general U.S. population, American Indian or Alaska Native (AI/AN) persons, particularly those who are not Hispanic or Latino (Hispanic) AI/AN, are disproportionately affected by suicide; rates among this group consistently surpass those among all other racial and ethnic groups (1). Suicide rates among non-Hispanic AI/AN persons increased nearly 20% from 2015 (20.0 per 100,000) to 2020 (23.9), compared with a <1% increase among the overall U.S. population (13.3 and 13.5, respectively) (1). Understanding characteristics of suicide among AI/AN persons is critical to developing and implementing effective prevention strategies. A 2018 report described suicides in 18 states among non-Hispanic AI/AN persons only (2). The current study used 2015-2020 National Violent Death Reporting System (NVDRS) data among 49 states, Puerto Rico, and the District of Columbia to examine differences in suicide characteristics and contributing circumstances among Hispanic and non-Hispanic AI/AN populations, including multiracial AI/AN. Results indicated higher odds across a range of circumstances, including 10 of 14 relationship problems (adjusted odds ratio [aOR] range = 1.2-3.8; 95% CI range = 1.0-5.3) and six of seven substance use problems (aOR range = 1.2-2.3; 95% CI range = 1.1-2.5), compared with non-AI/AN persons. Conversely, AI/AN decedents had reduced odds of having any current known mental health condition, any history of mental health or substance use treatment, and other common risk factors (aOR range = 0.6-0.8; 95% CI = 0.2-0.9). Suicide is preventable. Communities can implement a comprehensive public health approach to suicide prevention that addresses long-standing inequities affecting AI/AN populations (3).

Vital Signs: Changes in Firearm Homicide and Suicide Rates - United States, 2019-2020.

INTRODUCTION: The majority of homicides (79%) and suicides (53%) in the United States involved a firearm in 2020. High firearm homicide and suicide rates and corresponding inequities by race and ethnicity and poverty level represent important public health concerns. This study examined changes in firearm homicide and firearm suicide rates coinciding with the emergence of the COVID-19 pandemic in 2020. METHODS: National vital statistics and population data were integrated with urbanization and poverty measures at the county level. Population-based firearm homicide and suicide rates were examined by age, sex, race and ethnicity, geographic area, level of urbanization, and level of poverty. RESULTS: From 2019 to 2020, the overall firearm homicide rate increased 34.6%, from 4.6 to 6.1 per 100,000 persons. The largest increases occurred among non-Hispanic Black or African American males aged 10-44 years and non-Hispanic American Indian or Alaska Native (AI/AN) males aged 25-44 years. Rates of firearm homicide were lowest and increased least at the lowest poverty level and were higher and showed larger increases at higher poverty levels. The overall firearm suicide rate remained relatively unchanged from 2019 to 2020 (7.9 to 8.1); however, in some populations, including AI/AN males aged 10-44 years, rates did increase. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: During the COVID-19 pandemic, the firearm homicide rate in the United States reached its highest level since 1994, with substantial increases among several population subgroups. These increases have widened disparities in rates by race and ethnicity and poverty level. Several increases in firearm suicide rates were also observed. Implementation of comprehensive strategies employing proven approaches that address underlying economic, physical, and social conditions contributing to the risks for violence and suicide is urgently needed to reduce these rates and disparities.

Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features.

BACKGROUND: Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. OBJECTIVES: We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy). METHODS: In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed. RESULTS: Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20. CONCLUSIONS: CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2.

Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation was observed during active disease in DADA2 and were significantly reduced after remission induction by anti-tumor necrosis factor (TNF) therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A1 and A3 adenosine receptors (ARs) and through reactive oxygen species- and peptidylarginine deiminase-dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A1/A3 AR antagonists, or by an A2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-α. Treatment with an A2AAR agonist decreased nuclear translocation of NF-κB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases.

Changes in Suicide Rates - United States, 2018-2019.

Suicide is the 10th leading cause of death in the United States overall, and the second and fourth leading cause among persons aged 10-34 and 35-44 years, respectively (1). In just over 2 decades (1999-2019), approximately 800,000 deaths were attributed to suicide, with a 33% increase in the suicide rate over the period (1). In 2019, a total of 12 million adults reported serious thoughts of suicide during the past year, 3.5 million planned a suicide, and 1.4 million attempted suicide (2). Suicides and suicide attempts in 2019 led to a lifetime combined medical and work-loss cost (i.e., the costs that accrue from the time of the injury through the course of a person's expected lifetime) of approximately $70 billion (https://wisqars.cdc.gov:8443/costT/). From 2018 to 2019, the overall suicide rate declined for the first time in over a decade (1). To understand how the decline varied among different subpopulations by demographic and other characteristics, CDC analyzed changes in counts and age-adjusted suicide rates from 2018 to 2019 by demographic characteristics, county urbanicity, mechanism of injury, and state. Z-tests and 95% confidence intervals were used to assess statistical significance. Suicide rates declined by 2.1% overall, by 3.2% among females, and by 1.8% among males. Significant declines occurred, overall, in five states. Other significant declines were noted among subgroups defined by race/ethnicity, age, urbanicity, and suicide mechanism. These declines, although encouraging, were not uniform, and several states experienced significant rate increases. A comprehensive approach to prevention that uses data to drive decision-making, implements prevention strategies from CDC's Preventing Suicide: A Technical Package of Policy, Programs, and Practices with the best available evidence, and targets the multiple risk factors associated with suicide, especially in populations disproportionately affected, is needed to build on initial progress from 2018 to 2019 (3).

Emergency Department Visits for Suspected Suicide Attempts Among Persons Aged 12-25 Years Before and During the COVID-19 Pandemic - United States, January 2019-May 2021.

Beginning in March 2020, the COVID-19 pandemic and response, which included physical distancing and stay-at-home orders, disrupted daily life in the United States. Compared with the rate in 2019, a 31% increase in the proportion of mental health-related emergency department (ED) visits occurred among adolescents aged 12-17 years in 2020 (1). In June 2020, 25% of surveyed adults aged 18-24 years reported experiencing suicidal ideation related to the pandemic in the past 30 days (2). More recent patterns of ED visits for suspected suicide attempts among these age groups are unclear. Using data from the National Syndromic Surveillance Program (NSSP),* CDC examined trends in ED visits for suspected suicide attempts† during January 1, 2019-May 15, 2021, among persons aged 12-25 years, by sex, and at three distinct phases of the COVID-19 pandemic. Compared with the corresponding period in 2019, persons aged 12-25 years made fewer ED visits for suspected suicide attempts during March 29-April 25, 2020. However, by early May 2020, ED visit counts for suspected suicide attempts began increasing among adolescents aged 12-17 years, especially among girls. During July 26-August 22, 2020, the mean weekly number of ED visits for suspected suicide attempts among girls aged 12-17 years was 26.2% higher than during the same period a year earlier; during February 21-March 20, 2021, mean weekly ED visit counts for suspected suicide attempts were 50.6% higher among girls aged 12-17 years compared with the same period in 2019. Suicide prevention measures focused on young persons call for a comprehensive approach, that is adapted during times of infrastructure disruption, involving multisectoral partnerships (e.g., public health, mental health, schools, and families) and implementation of evidence-based strategies (3) that address the range of factors influencing suicide risk.

Peer Companionship for Mental Health of Older Adults in Primary Care: A Pragmatic, Nonblinded, Parallel-Group, Randomized Controlled Trial.

OBJECTIVES: To determine whether peer companionship delivered by an aging services agency to socially-disconnected older adult primary care patients was associated with improvement in suicidal ideation depression, anxiety, and psychological connectedness. DESIGN: Pragmatic, nonblinded, parallel-group, randomized controlled trial comparing peer companionship, The Senior Connection (TSC), to care-as-usual (CAU). SETTING: Lifespan, a nonmedical, community-based aging services agency. PARTICIPANTS: Adult primary care patients ages 60 years or older who endorsed feelings of loneliness or being a burden on others. INTERVENTION: TSC was delivered by Lifespan volunteers who provided supportive visits and phone calls in the subjects' homes. CAU involved no peer companion assignment. MEASUREMENTS: The primary outcome was suicidal ideation assessed by the Geriatric Suicide Ideation Scale; secondary outcomes were depression, anxiety, and feelings of belonging and being a burden on others. Data were collected at baseline, 3-, 6-, and 12-months. RESULTS: Subjects (55% female) had a mean age of 71 years. There was no difference between groups in change in suicidal ideation or belonging. Subjects randomized to TSC had greater reduction in depression (PHQ-9; 2.33 point reduction for TSC versus 1.32 for CAU, p = 0.05), anxiety (GAD-7; TSC 1.52 versus CAU 0.28, p = 0.03), and perceived burden on others (INQ; 0.46 TSC versus 0.09 CAU, p <0.01). CONCLUSIONS: TSC was superior to CAU for improving depression, anxiety, and perceived burden, but not suicidal ideation. Although effect sizes were small, the low-cost and nationwide availability of peer companionship justify further examination of its effectiveness and scalability in improving mental health outcomes of socially disconnected older adults.

LET's CONNECT Community Mentorship Program for Adolescents with Peer Social Problems: A Randomized Intervention Trial.

This study examined the effectiveness of LET's CONNECT (LC), a community mentorship program based on the positive youth development model. Participants were 218 youth (66.5% girls), ages 12 to 15, who reported peer victimization, bullying perpetration, and/or low social connectedness. These youth were randomized to LC or the control group (community resource information). The LC program linked youth to community mentors who connected with youth and facilitated their involvement in social growth activities across a 16-month period. Outcomes were assessed at 6 and 16 months with self-report measures of social and community connectedness, thwarted belongingness, depression, self-esteem, and suicidal ideation and behavior. In intent-to-treat analyses, LC was associated with modest positive effects for social connectedness, self-esteem, and depression. It had no effects on suicidal ideation or behavior. Results suggest that LC has the potential to positively impact the developmental trajectories of youth dealing with the interpersonal challenges of victimization, bullying perpetration, or low social connectedness. LC implementation challenges and directions for further research are also discussed.

Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder that manifests with fever, early-onset vasculitis, strokes, and hematologic dysfunction. This study aimed to identify disease-causing variants by conventional Sanger and whole exome sequencing in two families suspected to have DADA2 and non-confirmatory genotypes. ADA2 enzymatic assay confirmed the clinical diagnosis of DADA2. Molecular diagnosis was important to accurately identify other family members at risk. METHODS: We used a variety of sequencing technologies, ADA2 enzymatic testing, and molecular methods including qRT-PCR and MLPA. RESULTS: Exome sequencing identified heterozygosity for the known pathogenic variant ADA2: c.1358A>G, p.Tyr453Cys in a 14-year-old female with a history of ischemic strokes, livedo, and vasculitis. No second pathogenic variant could be identified. ADA2 enzymatic testing in combination with quantitative RT-PCR suggested a loss-of-function allele. Subsequent genome sequencing identified a canonical splice site variant, c.-47+2T>C, within the 5'UTR of ADA2. Two of her unaffected siblings were found to carry the same two pathogenic variants. A homozygous 800-bp duplication comprising exon 7 of ADA2 was identified in a 5-year-old female with features consistent with Diamond-Blackfan anemia (DBA). The duplication was missed by Sanger sequencing of ADA2, chromosomal microarray, and exome sequencing but was detected by MLPA in combination with long-read PCR sequencing. The exon 7 duplication was also identified in her non-symptomatic father and younger sister. CONCLUSIONS: ADA2 pathogenic variants may not be detected by conventional sequencing and genetic testing and may require the incorporation of additional diagnostic methods. A definitive molecular diagnosis is crucial for all family members to make informed treatment decisions.

Tailored Activation of Middle-Aged Men to Promote Discussion of Recent Active Suicide Thoughts: a Randomized Controlled Trial.

PURPOSE: Middle-aged men are at high risk of suicide. While about half of those who kill themselves visit a primary care clinician (PCC) shortly before death, in current practice, few spontaneously disclose their thoughts of suicide during the visits, and PCCs seldom inquire about such thoughts. In a randomized controlled trial, we examined the effect of a tailored interactive computer program designed to encourage middle-aged men's discussion of suicide with PCCs. METHODS: We recruited men 35-74 years old reporting recent (within 4 weeks) active suicide thoughts from the panels of 42 PCCs (the unit of randomization) in eight offices within a single California health system. In the office before a visit, men viewed the intervention corresponding to their PCC's random group assignment: Men and Providers Preventing Suicide (MAPS) (20 PCCs), providing tailored multimedia promoting discussion of suicide thoughts, or control (22 PCCs), composed of a sleep hygiene video plus brief non-tailored text encouraging discussion of suicide thoughts. Logistic regressions, adjusting for patient nesting within physicians, examined MAPS' effect on patient-reported suicide discussion in the subsequent office visit. RESULTS: Sixteen of the randomized PCCs had no patients enroll in the trial. From the panels of the remaining 26 PCCs (12 MAPS, 14 control), 48 men (MAPS 21, control 27) were enrolled (a mean of 1.8 (range 1-5) per PCC), with a mean age of 55.9 years (SD 11.4). Suicide discussion was more likely among MAPS patients (15/21 [65%]) than controls (8/27 [35%]). Logistic regression showed men viewing MAPS were more likely than controls to discuss suicide with their PCC (OR 5.91, 95% CI 1.59-21.94; P = 0.008; nesting-adjusted predicted effect 71% vs. 30%). CONCLUSIONS: In addressing barriers to discussing suicide, the tailored MAPS program activated middle-aged men with active suicide thoughts to engage with PCCs around this customarily taboo topic.

Traumatic Brain Injury-Related Deaths From Firearm Suicide: United States, 2008-2017.

Objectives. To document the increasing influence of firearm suicide on the incidence of traumatic brain injury (TBI)-related death in the United States.Methods. We used national vital statistics data from 2008 to 2017 to identify TBI-related deaths, overall and by cause, among US residents. National counts stratified by year, sex, and age group (to facilitate age adjustment) were merged with corresponding population estimates to calculate incidence rates.Results. During the 10-year period beginning in 2008, when it became the leading cause of TBI-related death in the United States, firearm suicide accounted for nearly half (48.3%) of the increase in the absolute incidence of TBI-related death when combining all injury categories showing absolute increases. Rates of TBI-related firearm suicide increased among both males and females.Conclusions. Safe storage of firearms among people at risk and training of health care providers and community members to identify and support people who may be thinking of suicide are part of a comprehensive public health approach to suicide prevention.Public Health Implications. States, communities, and health care systems can save lives by prioritizing comprehensive suicide prevention.

Suicide Rates by Industry and Occupation - National Violent Death Reporting System, 32 States, 2016.

In 2017, nearly 38,000 persons of working age (16-64 years) in the United States died by suicide, which represents a 40% rate increase (12.9 per 100,000 population in 2000 to 18.0 in 2017) in less than 2 decades.* To inform suicide prevention, CDC analyzed suicide data by industry and occupation among working-age decedents presumed to be employed at the time of death from the 32 states participating in the 2016 National Violent Death Reporting System (NVDRS).†,§ Compared with rates in the total study population, suicide rates were significantly higher in five major industry groups: 1) Mining, Quarrying, and Oil and Gas Extraction (males); 2) Construction (males); 3) Other Services (e.g., automotive repair) (males); 4) Agriculture, Forestry, Fishing, and Hunting (males); and 5) Transportation and Warehousing (males and females). Rates were also significantly higher in six major occupational groups: 1) Construction and Extraction (males and females); 2) Installation, Maintenance, and Repair (males); 3) Arts, Design, Entertainment, Sports, and Media (males); 4) Transportation and Material Moving (males and females); 5) Protective Service (females); and 6) Healthcare Support (females). Rates for detailed occupational groups (e.g., Electricians or Carpenters within the Construction and Extraction major group) are presented and provide insight into the differences in suicide rates within major occupational groups. CDC's Preventing Suicide: A Technical Package of Policy, Programs, and Practices (1) contains strategies to prevent suicide and is a resource for communities, including workplace settings.

Syndromic Surveillance of Suicidal Ideation and Self-Directed Violence - United States, January 2017-December 2018.

Suicide is a growing public health problem in the United States, claiming approximately 47,000 lives in 2017 (1). However, deaths from suicide represent only a small part of a larger problem because each year millions of persons experience suicidal ideation and engage in suicidal and nonsuicidal self-directed violence, both risk factors for suicide (2). Emergency departments (EDs) are an important setting for monitoring these events in near real time (3-5). From 2001 to 2016, ED visit rates for nonfatal self-harm increased 42% among persons aged ≥10 years (1). Using data from CDC's National Syndromic Surveillance Program (NSSP), ED visits for suicidal ideation, self-directed violence, or both among persons aged ≥10 years during January 2017-December 2018 were examined by sex, age group, and U.S. region. During the 24-month period, the rate of ED visits for suicidal ideation, self-directed violence, or both increased 25.5% overall, with an average increase of 1.2% per month. Suicide prevention requires comprehensive and multisectoral approaches to addressing risk at personal, relationship, community, and societal levels. ED syndromic surveillance data can provide timely trend information and can support more targeted and prompt public health investigation and response. CDC's Preventing Suicide: A Technical Package of Policy, Programs, and Practices includes tailored suicide prevention strategies for health care settings (6).