Normophosphatemic familial tumoral calcinosis (NFTC) is an autosomal recessive disorder characterized by calcium deposition in skin and mucosae and associated with unremitting pain and life-threatening skin infections. A homozygous missense mutation (p.K1495E), resulting in SAMD9 protein degradation, was recently shown to cause NFTC in five families of Jewish-Yemenite origin. In this study, we evaluated another Jewish-Yemenite NFTC kindred. All patients were compound heterozygous for two mutations in SAMD9: K1495E and a previously unreported nonsense mutation, R344X, predicted to result in a markedly truncated molecule. Screening of unaffected population-matched controls revealed heterozygosity for K1495E and R344X only in individuals of Jewish-Yemenite ancestry, but not in more than 700 control samples of other origins, including 93 non-Jewish Yemenite. These data may be suggestive of positive selection, considering the rarity of NFTC and the small size of the Jewish-Yemenite population; alternatively, they may reflect genetic drift or the effect of a population-specific modifier trait. Calcifications in NFTC generally develop over areas subjected to repeated trauma and are associated with marked inflammatory manifestations, indicating that SAMD9 may play a role in the inflammatory response to tissue injury. We therefore assessed the effect of cellular stress and tumor necrosis factor-alpha (TNF-alpha), a potent pro-inflammatory cytokine, on SAMD9 gene expression. Whereas exogenous hydrogen peroxide and heat shock did not affect SAMD9 transcription, osmotic shock was found to markedly upregulate SAMD9 expression. In addition, incubation of endothelial cells with TNF-alpha caused a dose-related, p38-dependant increase in SAMD9 expression. These data link NFTC and SAMD9 to the TNF-alpha signaling pathway, suggesting a role for this system in the regulation of extra-osseous calcification.

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This study examines the impact of neighborhood and individual level factors as predictors of violent victimization in a sample of high-school students in Toronto, Canada. Individual factors include school and family effects, alcohol use, and a variety of demographic measures. The neighborhood elements in this study include neighborhood disadvantage (Wilson, 1996) and collective efficacy (Sampson, Raudenbush, & Earls, 1997) concepts in the forefront of research on crime. The research not only examines the direct effect of these variables but also the interaction of the macro-and micro-level variables as correlates of victimization. The results indicate that the neighborhood disadvantage is critical in the explanation of violent victimization. Moreover, the relationship between alcohol use and victimization varies by neighborhood disadvantage.

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Abstract. Introduction: Culture-negative (CN) prosthetic joint infections (PJIs) account for approximately 10 % of all PJIs and present significant challenges for clinicians. We aimed to explore the significance of CN PJIs within a large prospective cohort study, comparing their characteristics and outcomes with culture-positive (CP) cases. Methods: The Prosthetic joint Infection in Australia and New Zealand Observational (PIANO) study is a prospective, multicentre observational cohort study that was conducted at 27 hospitals between 2014 and 2017. We compared baseline characteristics and outcomes of all patients with CN PJI from the PIANO cohort with those of CP cases. We report on PJI diagnostic criteria in the CN cohort and apply internationally recognized PJI diagnostic guidelines to determine optimal CN PJI detection methods. Results: Of the 650 patients with 24-month outcome data available, 55 (8.5 %) were CN and 595 were CP. Compared with the CP cohort, CN patients were more likely to be female (32 (58.2 %) vs. 245 (41.2 %); p = 0.016), involve the shoulder joint (5 (9.1 %) vs. 16 (2.7 %); p = 0.026), and have a lower mean C-reactive protein (142 mg L−1 vs. 187 mg L−1; p = 0.016). Overall, outcomes were superior in CN patients, with culture negativity an independent predictor of treatment success at 24 months (adjusted odds ratio, aOR, of 3.78 and 95 %CI of 1.65–8.67). Suboptimal diagnostic sampling was common in both cohorts, with CN PJI case detection enhanced using the Infectious Diseases Society of America PJI diagnostic guidelines. Conclusions: Current PJI diagnostic guidelines vary substantially in their ability to detect CN PJI, with comprehensive diagnostic sampling necessary to achieve diagnostic certainty. Definitive surgical management strategies should be determined by careful assessment of infection type, rather than by culture status alone.

This study examines the effect of neighborhood, school, and family indicators on adolescent drinking. The Toronto Drugs, Alcohol, and Violence International (DAVI) data were collected in 2001-2002. The sample was stratified both by region (city vs. outskirts) and by the socio-economic status of the schools. Two schools from each stratum were randomly selected and 910 students completed the survey. The survey contains extensive measures of substance use, violence, and mental health. The study uses cluster analysis and multinomial logits to examine the variation in the effect of schools, family, and demographic indicators on alcohol use across neighborhood contexts. Study implications and suggestions for future research are included. The study was partially funded by NIDA grant #R01-DA11691-01A1.

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