Detection of Suicide Clusters using Small-Area Geographic Data from the Virginia Violent Death Reporting System, 2010 – 2015

Introduction: From 1999 to 2020, the suicide rate in Virginia increased from 13.1 to 15.9 per 100,000 persons aged 10 years and older. Few studies have examined spatial patterns of suicide geographies smaller than the county level. Methods: We analyzed data from suicide decedents aged ≥10 years from 2010 through 2015 in the Virginia Violent Death Reporting System. We identified spatial clusters of high suicide rates using spatially adaptive filtering with standardized mortality ratio (SMR) significantly higher than the state SMR (p \u3c 0.001). We compared demographic characteristics, method of injury, and suicide circumstances of decedents within each cluster to decedents outside any cluster. Results: We identified 13 high-risk suicide clusters (SMR between 1.7 and 2.0). Suicide decedents in the clusters were more likely to be older (40+ years), non-Hispanic white, widowed/divorced/separated, and less likely to have certain precipitating suicide circumstances than decedents outside the clusters. Suicide by firearm was more common in four clusters, and suicide by poisoning was more common in two clusters compared to the rest of the state. Conclusions: There are important differences between geographic clusters of suicide in Virginia. These results suggest that place-specific risk factors for suicide may be relevant for targeted suicide prevention

Transformation of SV40-immortalized human uroepithelial cells by 3-methylcholanthrene increases IFN- and Large T Antigen-induced transcripts

<p>Abstract</p> <p>Background</p> <p>Simian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, however gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. The commercially-available human uroepithelial cell lines were either SV40-immortalized (HUC) or SV40-immortalized and then 3-MC-transformed (HUC-TC).</p> <p>Results</p> <p>To characterize the SV40 - 3MC interaction, we compared human gene expression in these cell lines using a human cancer array and confirmed selected changes by RT-PCR. Many viral Large T Antigen (Tag) expression-related changes occurred in HUC-TC, and it is concluded that SV40 and 3-MC may act synergistically to transform cells. Changes noted in <it>IFP 9-27, 2'-5' OAS, IF 56, MxA </it>and <it>MxAB </it>were typical of those that occur in response to viral exposure and are part of the innate immune response. Because interferon is crucial to innate immune host defenses and many gene changes were interferon-related, we explored cellular growth responses to exogenous IFN-γ and found that treatment impeded growth in tumor, but not immortalized HUC on days 4 - 7. Cellular metabolism however, was inhibited in <it>both </it>cell types. We conclude that IFN-γ <it>metabolic </it>responses were functional in both cell lines, but IFN-γ <it>anti-proliferative </it>responses functioned only in tumor cells.</p> <p>Conclusions</p> <p>Synergism of SV40 with 3-MC or other environmental carcinogens may be of concern as SV40 is now endemic in 2-5.9% of the U.S. population. In addition, SV40-immortalization is a generally-accepted method used in many research materials, but the possibility of off-target effects in studies carried out using these cells has not been considered. We hope that our work will stimulate further study of this important phenomenon.</p

Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.American Federation for Aging ResearchNational Center for Research Resources (U.S.) (Grant UL1 RR024992)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant P30DK056341

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain.// Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1–21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.gov NCT02741856.// Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67–3.08; p = 0.35).// Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT

Quality Protein Maize Germplasm Characterized for Amino Acid Profiles and Endosperm Opacity

Quality protein maize (QPM) is improved over normal (non-QPM) maize in grain concentrations of the essential amino acids lysine and tryptophan. Quality protein maize has a long history as tropical adapted germplasm, but little effort has been made to incorporate temperate or sub-tropical germplasm for temperate adaptation and interactions between different modifier loci in these backgrounds are poorly understood. A design-II mating scheme including new temperate and subtropical lines produced 69 hybrids. Large hybrid genetic variation components resulted in substantial broad-sense heritability H2 estimates, specifically tryptophan (0.46) and endosperm opacity (0.82). A microbial assay for amino acid estimation proved robust across diverse environments with minimal genotype × environment (G×E) effects. Endosperm opacity had no G×E effects across both Texas and Iowa locations demonstrating stability for this trait. Endosperm opacity primarily followed an additive, midparent trend, with a few hybrids deviating from the trend (36%) suggesting a complex nature of multiple modifier loci across diverse germplasm. The top QPM hybrid outperformed the top commercial hybrid by 35 and 30% for lysine and tryptophan as a proportion of grain, respectively. QPM line Tx832 was a parent of top hybrids for lysine and tryptophan, and the highest noncommercial hybrids for methionine. Minimal correlations with yield and other traits suggest that future breeding should result in QPM hybrids with increasingly competitive yields

The PPAR-gamma agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function

<p>Abstract</p> <p>Background</p> <p>Inflammation is known to play a pivotal role in mediating neuronal damage and axonal injury in a variety of neurodegenerative disorders. Among the range of inflammatory mediators, nitric oxide and hydrogen peroxide are potent neurotoxic agents. Recent evidence has suggested that oligodendrocyte peroxisomes may play an important role in protecting neurons from inflammatory damage.</p> <p>Methods</p> <p>To assess the influence of peroxisomal activation on nitric oxide mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator activated receptor (PPAR) gamma agonist, pioglitazone in primary cortical neurons that were either exposed to a nitric oxide donor or co-cultured with activated microglia.</p> <p>Results</p> <p>Pioglitazone protected neurons and axons against both nitric-oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in the protein and gene expression of PPAR-gamma, which was associated with a concomitant increase in the enzymatic activity of catalase. In addition, the protection of neurons and axons against hydrogen peroxide-induced toxicity afforded by pioglitazone appeared to be dependent on catalase.</p> <p>Conclusions</p> <p>Collectively, these observations provide evidence that modulation of PPAR-gamma activity and peroxisomal function by pioglitazone attenuates both NO and hydrogen peroxide-mediated neuronal and axonal damage suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.</p

The Long-Term Consequences of the Global 1918 Influenza Pandemic: A Systematic Analysis of 117 IPUMS International Census Data Sets

Several country-level studies, including a prominent one for the United States, have identified long-term effects of in-utero exposure to the 1918 influenza pandemic (also known as the Spanish Flu) on economic outcomes in adulthood. In-utero conditions are theoretically linked to adult health and socioeconomic status through the fetal origins or Barker hypothesis. Historical exposure to the Spanish Flu provides a natural experiment to test this hypothesis. Although the Spanish Flu was a global phenomenon, with around 500 million people infected worldwide, there exists no comprehensive global study on its long-term economic effects. We attempt to close this gap by systematically analyzing 117 Census data sets provided by IPUMS International. We do not find consistent global long-term effects of influenza exposure on education, employment and disability outcomes. A series of robustness checks does not alter this conclusion. Our findings indicate that the existing evidence on long-term economic effects of the Spanish Flu is likely a consequence of publication bias