Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells.

The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that ß-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.

Regionally distinct trophoblast regulate barrier function and invasion in the human placenta.

The human placenta contains two specialized regions: the villous chorion where gases and nutrients are exchanged between maternal and fetal blood, and the smooth chorion (SC) which surrounds more than 70% of the developing fetus but whose cellular composition and function is poorly understood. Here, we use single cell RNA-sequencing to compare the cell types and molecular programs between these two regions in the second trimester human placenta. Each region consists of progenitor cytotrophoblasts (CTBs) and extravillous trophoblasts (EVTs) with similar gene expression programs. While CTBs in the villous chorion differentiate into syncytiotrophoblasts, they take an alternative trajectory in the SC producing a previously unknown CTB population which we term SC-specific CTBs (SC-CTBs). Marked by expression of region-specific cytokeratins, the SC-CTBs form a stratified epithelium above a basal layer of progenitor CTBs. They express epidermal and metabolic transcriptional programs consistent with a primary role in defense against physical stress and pathogens. Additionally, we show that SC-CTBs closely associate with EVTs and secrete factors that inhibit the migration of the EVTs. This restriction of EVT migration is in striking contrast to the villous region where EVTs migrate away from the chorion and invade deeply into the decidua. Together, these findings greatly expand our understanding of CTB differentiation in these distinct regions of the human placenta. This knowledge has broad implications for studies of the development, functions, and diseases of the human placenta.

G1/S restriction point coordinates phasic gene expression and cell differentiation.

Pluripotent embryonic stem cells have a unique cell cycle structure with a suppressed G1/S restriction point and little differential expression across the cell cycle phases. Here, we evaluate the link between G1/S restriction point activation, phasic gene expression, and cellular differentiation. Expression analysis reveals a gain in phasic gene expression across lineages between embryonic days E7.5 and E9.5. Genetic manipulation of the G1/S restriction point regulators miR-302 and P27 respectively accelerates or delays the onset of phasic gene expression in mouse embryos. Loss of miR-302-mediated p21 or p27 suppression expedites embryonic stem cell differentiation, while a constitutive Cyclin E mutant blocks it. Together, these findings uncover a causal relationship between emergence of the G1/S restriction point with a gain in phasic gene expression and cellular differentiation.

Beyond Maternal Tolerance: Education of Uterine Natural Killer Cells by Maternal MHC Drives Fetal Growth.

Reproductive immunology has moved on from the classical Medawar question of 60 years ago "why doesn't the mother reject the fetus?". Looking beyond fetal-maternal tolerance, modern reproductive immunology focuses on how the maternal immune system supports fetal growth. Maternal uterine natural killer (uNK) cells, in partnership with fetal trophoblast cells, regulate physiological vascular changes in the uterus of pregnant women and mice. These vascular changes are necessary to build the placenta and sustain fetal growth. NK cell functions in the uterus and elsewhere, including anti-viral and anti-tumour immunity mediated mostly by blood NK cells, are modulated by NK cell education, a quantifiable process that determines cellular activation thresholds. This process relies largely on interactions between self-MHC class I molecules and inhibitory NK cell receptors. By getting to know self, the maternal immune system sets up uNK cells to participate to tissue homeostasis in the womb. Placentation can be viewed as a form of natural transplantation unique in vertebrates and this raises the question of how uNK cell education or missing-self recognition affect their function and, ultimately fetal growth. Here, using combinations of MHC-sufficient and -deficient mice, we show that uNK cell education is linked to maternal and not fetal MHC, so that MHC-deficient dams produce more growth-restricted fetuses, even when the fetuses themselves express self-MHC. We also show that, while peripheral NK cells reject bone marrow cells according to the established rules of missing-self recognition, uNK cells educated by maternal MHC do not reject fetuses that miss self-MHC and these fetuses grow to their full potential. While these results are not directly applicable to clinical research, they show that NK education by maternal MHC-I is required for optimal fetal growth.

Hangings in Newfoundland and Labrador: A 40-year retrospective analysis of medical examiner data.

A comprehensive review of medical examiner data was undertaken of all hanging deaths in the Canadian Maritime province of Newfoundland and Labrador from 1982 to 2021. A total of 811 cases were identified representing suicidal, accidental, and undetermined manners of death. Variables examined included age; sex; seasonality; ligature type; location; time since death; prior attempts/suicidal ideation; presence/absence of a suicide note; and presence/absence of alcohol and drugs. Data subsets were generated, and additional analysis was conducted for hangings involving females; suicidal hangings occurring in the region of Labrador; and those who hanged themselves outdoors. Results indicate that females are choosing to kill themselves by hanging in rapidly increasing numbers. Outdoor suicides by hanging were more common in Newfoundland and Labrador (22.1%) than previously reported in Alberta (11.5%), Texas (5%), and Turkey (12-13%). Unique trends in seasonality were revealed, as were repeated incidents of suicidal clusters. The age distribution was skewed strongly toward youths (10 to 22 years of age), particularly in Labrador. Although Labrador represents only 5% of the total provincial population, it produced 20.1% of the total suicidal hangings in the study. The suicide rate in Canada has decreased by 24% over the past 40 years, yet the rates of suicidal hangings nationally and in Newfoundland and Labrador have increased during the same time period. With a better understanding of the circumstances under which people commit suicide by hanging within the province, it may be possible to target at-risk groups to prevent future cases.

Single nuclei RNA-seq of mouse placental labyrinth development.

The placenta is the interface between mother and fetus in all eutherian species. However, our understanding of this essential organ remains incomplete. A substantial challenge has been the syncytial cells of the placenta, which have made dissociation and independent evaluation of the different cell types of this organ difficult. Here, we address questions concerning the ontogeny, specification, and function of the cell types of a representative hemochorial placenta by performing single nuclei RNA sequencing (snRNA-seq) at multiple stages of mouse embryonic development focusing on the exchange interface, the labyrinth. Timepoints extended from progenitor-driven expansion through terminal differentiation. Analysis by snRNA-seq identified transcript profiles and inferred functions, cell trajectories, signaling interactions, and transcriptional drivers of all but the most highly polyploid cell types of the placenta. These data profile placental development at an unprecedented resolution, provide insights into differentiation and function across time, and provide a resource for future study.

Erratum: Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.

This corrects the article DOI: 10.1038/ncomms14922.

Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.

Revisiting rates of reactivation tuberculosis: a population-based approach.

RATIONALE: Reactivation tuberculosis (TB) occurs as a result of reactivation of latent TB infection (LTBI), and was reported to occur in the United States at a rate of 0.10 to 0.16 cases per 100 person-years in the 1950s; it has not been measured since. OBJECTIVES: To calculate the rate of reactivation TB in a U.S. community. METHODS: A population-based tuberculin skin test survey for LTBI was performed in western Palm Beach County, Florida, from 1998 to 2000 along with a cluster analysis of TB case isolates in the same area from 1997 to 2001. Reactivation (unclustered) TB was presumed to have arisen from the population with LTBI. MEASUREMENTS AND MAIN RESULTS: The rate of reactivation TB among persons with LTBI without HIV infection was 0.040 cases per 100 person-years (95% confidence interval [CI], 0.024-0.067) using the n method and 0.058 cases per 100 person-years (95% CI, 0.038-0.089) using the n-1 method. HIV infection was the strongest risk factor for reactivation (rate ratio [RR], 57; 95% CI, 27-120; P < 0.001). Among persons without HIV infection, reactivation was increased among those older than 50 years (RR, 3.8; 95% CI, 1.3-11) and among those born in the United States (RR, 3.2; 95% CI, 1.1-9.3). CONCLUSIONS: Rates of reactivation TB in this area have declined substantially since the 1950s. The greatest part of this decline may be attributed to the disappearance of old, healed TB in the population. If similar declines are seen in other areas of the United States, the cost-effectiveness of screening and treatment of LTBI may be substantially less than previously estimated.

Increased mortality in rural patients with HIV in New England.

Although patients with human immunodeficiency virus (HIV) infection who live in the rural United States receive less expert care and less antiretroviral treatment, the impact of living in rural areas on mortality from HIV infection is unstudied. We compared mortality rates in 327 rural and 317 urban patients with HIV infection in a retrospective cohort study using a multivariate logistic regression model. Rural patients with HIV infection were older at the end of follow-up (43.4 vs. 41.4 years, p = 0.002), and more likely white (93.0% vs. 77.9%, p < 0.001), and a greater proportion were men who have sex with men (55.5% vs. 36.1%, p < 0.001). While the mean year of diagnosis was 1994 in rural patients and 1995 in urban patients (p < 0.001), the mean CD4(+) T cell count at presentation was similar in the two groups: 376 vs. 351 cells/mul (p = 0.298). Rural patients in our cohort were more likely to receive antiretroviral medications at any CD4 count (73.7 vs. 62.1%, p =0.0016), and received PCP prophylaxis at comparable rates (23.5% vs. 25.6%,p =0.555). Mortality was higher in rural patients (10.4% vs. 6.0%, p = 0.028). The risk of mortality remained higher in rural patients when adjusting for age, sex, race, HIV risk factors, year of diagnosis, travel time, lack of insurance, and receipt of antiretroviral treatment or PCP prophylaxis in a logistic regression model (OR 2.11, 1.064 to 4.218, p = 0.047). Patients with HIV who live in rural areas have higher mortality rates than urban patients with HIV.

Environmental risk factors for infection with Mycobacterium avium complex.

Infection with Mycobacterium avium complex is acquired from the environment, but risk factors for M. avium complex infection and disease are poorly understood. To identify risk factors for infection, the authors performed a 1998-2000 cross-sectional study in western Palm Beach County, Florida, using a population-based random household survey. M. avium complex infection was identified by use of the M. avium sensitin skin test. Of 447 participants, 147 (32.9%) had a positive test reaction, 186 (41.6%) had a negative test reaction, and, for 114 (25.5%), test results were indeterminate. Among the 333 participants with positive or negative M. avium sensitin skin tests, age-adjusted independent predictors of M. avium complex infection in a multivariate model included Black race (odds ratio = 3.8, 95% confidence interval: 2.2, 6.6), birth outside the United States (odds ratio = 2.1, 95% confidence interval: 1.1, 3.9), and more than 6 years' cumulative occupational exposure to soil (odds ratio = 2.7, 95% confidence interval: 1.3, 6.0). Exposure to water, food, or pets was not associated with infection. Results indicate that soil is a reservoir for M. avium complex associated with human infection and that persons whose occupations involve prolonged soil exposure are at increased risk of M. avium complex infection.

Hepatitis C treatment for people with severe mental illness.

Over 4 million people in the United States are chronically infected with hepatitis C virus (HCV), and, if untreated, over 20% of these will progress to more serious disease. Persons with severe mental illness (SMI) have markedly elevated rates of HCV infection, but treatment of persons with SMI and HCV has been controversial. Effective antiviral treatment is available, but side effects include depression and other neuropsychiatric symptoms. This article reviews the available data on neuropsychiatric side effects of interferon (IFN) treatment, discusses the limitations of the current research, and makes recommendations regarding HCV treatment in persons with SMI.

Hepatitis C virus and HIV co-infection in people with severe mental illness and substance use disorders.

OBJECTIVES: The 5-7% of adults in the United States with severe mental illness (SMI), especially the 50% who are 'dually diagnosed' with co-occurring substance use disorders (SUD), are at an elevated risk of HIV and hepatitis C virus (HCV). However, little is known about HIV/HCV co-infection in this population. This paper examines the prevalence and correlates of HIV, hepatitis C, and HIV/HCV co-infection in a large, multisite sample of SMI clients. DESIGN: We conducted a re-analysis of data on prevalence and correlates of blood-borne infections in a multisite sample of SMI clients. METHODS: In 1997-1998, 755 SMI clients were tested for HIV, hepatitis B virus and HCV, and assessed for demographic, illness-related and other behavioral risk factors for blood-borne infections. The prevalence and correlates of co-infection were examined, as well as the knowledge, attitudes and risk behaviors of individuals with HCV mono-infection. RESULTS: Of the 755 participants, 623 (82.5%) were negative for both HIV and HCV, 23 (3.0%) were positive for HIV, 109 (14.4%) were positive for HCV, and 13 (1.7%) were co-infected with HIV and HCV. Overall, 2.5% of dually diagnosed participants were co-infected, whereas only 0.6% of SMI participants without a comorbid SUD diagnosis were co-infected. Co-infection was associated with psychiatric illness severity, ongoing drug abuse, poverty, homelessness, incarceration, urban residence and minority status. HCV-mono-infected clients continued to engage in high levels of risk behavior for HIV. CONCLUSION: In addition to efforts to identify and treat SMI patients with HIV/HCV co-infection, HCV-mono-infected clients should be targeted for prevention interventions.

Human immunodeficiency virus infection in a rural community in the United States.

In 1986, a population-based survey of human immunodeficiency virus (HIV) infection in a rural Florida community showed that HIV prevalence was 28/877 (3.2%, 95% confidence interval (CI): 2.0, 4.4). In 1998-2000, the authors performed a second population-based survey in this community and a case-control study to determine whether HIV prevalence and risk factors had changed. After 609 addresses had been randomly selected for the survey, 516 (85%) residents were enrolled, and 447 (73%) were tested for HIV. HIV prevalence was 7/447 (1.6%, 95% CI: 0.4, 2.7) in western Palm Beach County and 5/286 (1.7%, 95% CI: 0.2, 3.3) in Belle Glade (p=0.2 in comparison with 1986). Independent predictors of HIV infection in both 1986 and 1998-2000 were having a history of sexually transmitted disease, number of sex partners, and exchanging money or drugs for sex. A history of having sex with men was a risk factor among men in 1986 but not in 1998-2000; residence in specific neighborhoods was a risk factor in 1998-2000 but not in 1986. The authors conclude that heterosexually acquired HIV infection did not spread throughout the community between 1986 and 1998 but persisted at a low level in discrete neighborhoods. Interventions targeting HIV-endemic neighborhoods will be needed to further reduce HIV prevalence in this area.

The STIRR model of best practices for blood-borne diseases among clients with serious mental illness.

OBJECTIVE: Persons with severe mental illness have a markedly elevated risk of several blood-borne infections, including HIV, hepatitis B, and hepatitis C. Prevention, early detection, and treatment of these disorders are crucial interventions for high-risk populations. However, because of a number of barriers, most clients with severe mental illness do not receive these basic best-practice services. The authors describe a public health model intervention designed to deliver basic best-practice services for blood-borne diseases, as specified by the Centers for Disease Control and Prevention, to clients with severe mental illness and co-occurring substance use disorders. METHODS: The intervention, called STIRR (for screen, test, immunize, reduce risk, and refer), is brief (requiring approximately one hour per client) and is delivered at the site of mental health care by a mobile team of specialists. Clients are provided with risk screening, testing for HIV and hepatitis, immunization for hepatitis A and B, risk-reduction counseling, and treatment referral for blood-borne infections. Also described is a pilot study to evaluate this model in two publicly funded community mental health centers. RESULTS: At the first site, 137 (79 percent) of clients with severe mental illness were tested and immunized. At the second site, more than two-thirds of the clients of a dual diagnosis team participated (67 clients, or 68 percent). Intervention costs per client ranged from 194 dollars to 262 dollars. CONCLUSION: S: The STIRR approach has the potential to provide a basic, best-practice package of interventions for high-risk clients with severe mental illness.

Utility of dual skin tests to evaluate tuberculin skin test reactions of 10 to 14 mm in healthcare workers.

OBJECTIVE: To define the utility of 10- to 14-mm reactions to a Mycobacterium tuberculosis purified protein derivative (PPD) skin test for healthcare workers (HCWs). DESIGN: Blinded dual skin testing, using PPD and M. avium sensitin, of HCWs at a single medical center who had a 10- to 14-mm reaction to PPD when tested by personnel from the Occupational Health Department as part of routine annual screening. SETTING: A single tertiary-care academic medical center. PARTICIPANTS: Employees of the medical center who underwent routine annual PPD screening and were identified by the Occupational Health Department as having a reaction of 10 to 14 mm to PPD. RESULTS: Nineteen employees were identified as candidates and 11 underwent dual skin testing. Only 4 (36%) had repeat results for PPD in the 10- to 14-mm range, whether read by Occupational Health Department personnel or study investigators. For only 5 (45%) of the subjects did the Occupational Health Department personnel and study investigators concur (+/- 3 mm) on the size of the PPD reaction. Two of the 4 subjects with reactions of 10 to 14 mm as measured by the study investigators were M. avium sensitin dominant, 1 was PPD dominant, and 1 was nondominant. CONCLUSION: A reaction of 10 to 14 mm to PPD should not be used as an indication for the treatment of latent tuberculosis (TB) infection in healthy HCWs born in the United States with no known exposure to TB.

Fish tank exposure and cutaneous infections due to Mycobacterium marinum: tuberculin skin testing, treatment, and prevention.

In the present study, 8 patients with soft tissue infection due to Mycobacterium marinum are described, and contemporary data on treatment are reviewed. Six patients had positive cultures, all patients had cutaneous exposure to fish tanks, 7 had sporotrichoid lesions, and 2 had deep infection. All 7 tested patients had tuberculin skin test reactions > or =10 mm. Six patients with disease limited to the skin were successfully treated with 2-drug combination therapy, including clarithromycin, ethambutol, and rifampin. Optimal treatment should include 2 drugs for 1-2 months after resolution of lesions, typically 3-4 months in total. Deeper infections may require more prolonged treatment and surgical debridement. Positive tuberculin reactions may be due to infection with M. marinum. Persons with open skin lesions or immunosuppression should avoid cutaneous contact with fish tanks.

The five-site health and risk study of blood-borne infections among persons with severe mental illness.

This article outlines the history and rationale of a multisite study of blood-borne infections among persons with severe mental illness reported in this special section of Psychiatric Services. The general problem of blood-borne diseases in the United States is reviewed, particularly as it affects people with severe mental illness and those with comorbid substance use disorders. The epidemiology and natural history of three of the most important infections are reviewed: the human immunodeficiency virus (HIV), the hepatitis B virus, and the hepatitis C virus. Current knowledge about blood-borne diseases among people with severe mental illness as well as information on current treatment advances for hepatitis C are summarized. A heuristic model, based on the pragmatic, empirical, and conceptual issues that influenced the final study design, is presented. The specific rationale of the five-site collaborative design is discussed, as well as the sampling frames, measures, and procedures used at the participating sites. Alternative strategies for analyzing data deriving from multisite studies that use nonrandomized designs are described and compared. Finally, each of the articles in this special section is briefly outlined, with reference to the overall hypotheses of the studies.

Responding to blood-borne infections among persons with severe mental illness.

The Five-Site Health and Risk Study estimated prevalence rates of blood-borne infections, including the human immunodeficiency virus (HIV), hepatitis B, and hepatitis C, and addressed risk factors and correlates of infection among persons with severe mental illness. In this final article of the special section in this issue of Psychiatric Services, the authors review public health recommendations and best practices and discuss the implications of these results for community mental health care of clients with severe mental illness. Standard public health recommendations could be modified for use by community mental health providers. In addition, expansion of integrated dual disorders treatments and improving linkage with specialty medical care providers are recommended.