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ObjectivePatient presentations to the emergency department (ED) for alcohol-involved injury represent a growing public health burden, but their characteristics and sequelae remain understudied. This study examined mortality rates among ED patients presenting with alcohol-involved injuries and assessed how mortality varied by injury intent and other characteristics.MethodThis retrospective cohort study used statewide, longitudinally linked ED patient record and mortality data from California. Participants comprised all residents presenting to a licensed ED in 2009-2012 with a nonfatal injury that involved comorbid diagnosis of alcohol use disorder (AUD; n = 261,222; 59.3% male). Injury intent was defined using International Classification of Diseases, 9th Revision, Clinical Modification external cause-of-injury codes. Cox regression was used to investigate factors associated with 12-month all-cause mortality rates. Age-, sex-, and race/ethnicity-adjusted standardized mortality ratios (SMRs) were calculated using statewide mortality data.ResultsMost ED injury visits involving an AUD diagnosis were coded as unintentional (75.9%). Following the index ED visit, all-cause mortality among AUD-involved injury patients was 5,205 per 100,000 person-years, five times higher than the demographically matched population (SMR = 5.3; 95% confidence interval [5.2, 5.4]). Adjusted Cox regression models indicated that patients whose index injury was unintentional, and whose AUD was for acute intoxication, had significantly higher mortality. Most deaths among unintentionally injured patients were from natural causes, whereas external-cause deaths were relatively more common in the other patient groups.ConclusionsAUD-involved injury presentations to the ED in California are common and associated with high patient mortality burden, which varies by injury intent. Interventions are needed to reduce excess mortality in these patients.

This study investigates a mechanistic link of bacterial biofilm-mediated host-pathogen interaction leading to immunological complications associated with breast implant illness (BII). Over 10 million women worldwide have breast implants. In recent years, women have described a constellation of immunological symptoms believed to be related to their breast implants. We report that periprosthetic breast tissue of participants with symptoms associated with BII had increased abundance of biofilm and biofilm-derived oxylipin 10-HOME compared with participants with implants who are without symptoms (non-BII) and participants without implants. S. epidermidis biofilm was observed to be higher in the BII group compared with the non-BII group and the normal tissue group. Oxylipin 10-HOME was found to be immunogenically capable of polarizing naive [CD4.sup.+] T cells with a resulting Th1 subtype in vitro and in vivo. Consistently, an abundance of [CD4.sup.+]Th1 subtype was observed in the periprosthetic breast tissue and blood of people in the BII group. Mice injected with 10-HOME also had increased Th1 subtype in their blood, akin to patients with BII, and demonstrated fatigue-like symptoms. The identification of an oxylipinmediated mechanism of immune activation induced by local bacterial biofilm provides insight into the possible pathogenesis of the implant-associated immune symptoms of BII., Introduction Breast implants were first introduced in 1962. Nearly 60 years later, their safety has continued to be controversial in the medical field, including a period of FDA-mandated restrictions on [...]

Adolescent suicide rates exhibit stark geographic disparities, with rates highest in rural areas. The causes of this disparity remain unclear. We investigated whether adolescent nonfatal suicidal ideation and attempt-leading risk factors for suicide-demonstrate the same rural/urban disparity. Using adolescent data from the 2011-2014 waves of the population-representative California Health Interview Survey (CHIS; N = 4,616), we estimated associations between residence in a rural area and suicidal ideation and suicide attempt, as well as access to psychological care. Survey-weighted logistic regression models controlled for individual- and family-level covariates. Results showed that rural adolescents were, compared to urban adolescents, substantially less likely to report recent suicidal ideation (OR = 0.25, 95% confidence interval [CI] = 0.10, 0.61) and suicide attempt (OR = 0.17, 95% CI = 0.05, 0.66). Suicidal youths in rural and urban areas were equally likely, however, to report receiving psychological care. In this study, rural adolescents in California reported lower rates of nonfatal suicidal behavior compared to urban peers. This pattern contrasts with rates of adolescent suicide fatality, which are higher in rural areas. Results suggest that reducing geographic disparities in youth suicide may require multifaceted public health approaches, in addition to better identification and treatment for high-risk adolescents.

Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV type K (HERV-K) HML-2 (HK2) family contains proviruses that are the most recent entrants into the human germ line and are transcriptionally active. In HIV-1 infection and cancer, HK2 genes produce retroviral particles that appear to be infectious, yet the replication capacity of these viruses and potential pathogenicity has been difficult to ascertain. In this report, we screened the efficacy of commercially available reverse transcriptase inhibitors (RTIs) at inhibiting the enzymatic activity of HK2 RT and HK2 genomic replication. Interestingly, only one provirus, K103, was found to encode a functional RT among those examined. Several nucleoside analogue RTIs (NRTIs) blocked K103 RT activity and consistently inhibited the replication of HK2 genomes. The NRTIs zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), and the nucleotide RTI inhibitor tenofovir (TDF), show efficacy in blocking K103 RT. HIV-1-specific nonnucleoside RTIs (NNRTIs), protease inhibitors (PIs), and integrase inhibitors (IIs) did not affect HK2, except for the NNRTI etravirine (ETV). The inhibition of HK2 infectivity by NRTIs appears to take place at either the reverse transcription step of the viral genome prior to HK2 viral particle formation and/or in the infected cells. Inhibition of HK2 by these drugs will be useful in suppressing HK2 infectivity if these viruses prove to be pathogenic in cancer, neurological disorders, or other diseases associated with HK2. The present studies also elucidate a key aspect of the life cycle of HK2, specifically addressing how they do, and/or did, replicate.IMPORTANCE Endogenous retroviruses are relics of ancestral virus infections in the human genome. The most recent of these infections was caused by HK2. While HK2 often remains silent in the genome, this group of viruses is activated in HIV-1-infected and cancer cells. Recent evidence suggests that these viruses are infectious, and the potential exists for HK2 to contribute to disease. We show that HK2, and specifically the enzyme that mediates virus replication, can be inhibited by a panel of drugs that are commercially available. We show that several drugs block HK2 with different efficacies. The inhibition of HK2 replication by antiretroviral drugs appears to occur in the virus itself as well as after infection of cells. Therefore, these drugs might prove to be an effective treatment by suppressing HK2 infectivity in diseases where these viruses have been implicated, such as cancer and neurological syndromes.

Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/-mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4-or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease. [ABSTRACT FROM AUTHOR]

Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of [FOXP3.sup.+] T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell-deficient Foxp3-Cre [Bcl6.sup.fl/fl] mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in the germinal center (GC) that work together to facilitate the production of Ag-specific IgE. Foxp3-Cre [Pten.sup.fl/fl] mice with augmented Tfr cell responses had markedly higher levels of peanut-specific IgE, revealing an active helper function by Tfr cells on Ag-specific IgE. The helper function of Tfr cells for IgE production involves IL-10, and the loss of IL-10 signaling by B cells led to a severely curtailed peanutspecific IgE response, decreased GCB cell survival, and loss of GC dark zone B cells after peanut sensitization. We thus reveal that Tfr cells have an unexpected helper role in promoting food allergy and may represent a target for drug development., Introduction Antibodies (Abs) that bind to antigen (Ag) with high affinity and help to eliminate pathogens and foreign substances are generated in the germinal center (GC) reaction (1-3). A specialized [...]

PurposeFew studies have compared acute use of alcohol in suicide decedents with that in a nonsuicide group. This study provides the first national analysis of acute use of alcohol before suicide compared with an estimate of acute use of alcohol in a living sample.MethodsPooled 2003-2011 National Violent Death Reporting System data were used to estimate the prevalence of postmortem blood alcohol content positivity (blood alcohol content >0.0 g/dL) and intoxication (blood alcohol content ≥0.08 g/dL). Population estimates of comparable use of alcohol (within the past 48 hours) were based on the National Epidemiologic Survey on Alcohol and Related Conditions.ResultsCompared with the living sample, male and female suicide decedents showed, respectively, a 1.83-fold (95% confidence interval [CI], 1.73-1.93) and 2.40-fold (95% CI, 2.24-2.57) increased risk of alcohol ingestion before their death after age, race/ethnicity, and chronic alcohol problems were controlled. Furthermore, male and female decedents exhibited, respectively, a 6.18-fold (95% CI, 5.57-6.86) and a 10.04-fold (95% CI, 8.67-11.64) increased risk of being intoxicated before their death after confounders were considered.ConclusionsThe findings underscore the crucial need to include among the essential components of suicide prevention policies programs that minimize the use of alcohol, particularly drinking to intoxication.