Obesity and vulnerability of the CNS

AbstractThe incidence of obesity is increasing worldwide, and is especially pronounced in developed western countries. While the consequences of obesity on metabolic and cardiovascular physiology are well established, epidemiological and experimental data are beginning to establish that the central nervous system (CNS) may also be detrimentally affected by obesity and obesity-induced metabolic dysfunction. In particular, data show that obesity in human populations is associated with cognitive decline and enhanced vulnerability to brain injury, while experimental studies in animal models confirm a profile of heightened vulnerability and decreased cognitive function. This review will describe findings from human and animal studies to summarize current understanding of how obesity affects the brain. Furthermore, studies aimed at identifying key elements of body–brain dialog will be discussed to assess how various metabolic and adipose-related signals could adversely affect the CNS. Overall, data suggest that obesity-induced alterations in metabolism may significantly synergize with age to impair brain function and accelerate age-related diseases of the nervous system. Thus, enhanced understanding of the effects of obesity and obesity-related metabolic dysfunction on the brain are especially critical as increasing numbers of obese individuals approach advanced age

State Firearm Laws and Interstate Firearm Deaths From Homicide and Suicide in the United States: A Cross-Sectional Analysis of Data by County

In a cross-sectional analysis of deaths from 2010 through 2014, states with strong gun laws had lower rates of firearm-related homicide and suicide than states with less regulation. Counties in states with less restrictive firearms laws had relatively lower rates of firearm-related homicide when they bordered states with strict gun laws. In contrast, rates of gun violence in areas with strong gun laws were unaffected by lenient laws in neighboring states. Restrictions on the sale and ownership of firearms may have measurable effects on rates of firearm deaths, with potential spillover across state lines

Interstate highway connections and traced gun transfers between the 48 contiguous United States

IMPORTANCE: Interstate gun flow has critical implications for gun violence prevention, as gun transfers across state lines can undermine local gun control policies. OBJECTIVE: To identify possible gun trafficking routes along interstate highways in the US. DESIGN, SETTING, AND PARTICIPANTS: This repeated-measures, ecological, cross-sectional study used data from the Bureau of Alcohol, Tobacco, Firearms and Explosives from January 1, 2010, to December 31, 2019, to examine associations between interstate connections via 13 highways that each spanned at least 1000 miles and interstate traced gun transfer counts for the 48 contiguous United States. Analyses were completed in November 2023. EXPOSURES: Characteristics of the origin states and the transportation connections between the destination state and the origin states. MAIN OUTCOMES AND MEASURES: The main outcome was the total count of guns used in crimes in each destination state per year that were originally purchased in the origin state. Bayesian conditional autoregressive Poisson models were used to examine associations between the count of guns used in crime traced to interstate purchases and interstate highway connections between origin and destination states. RESULTS: Between 2010 and 2019, 526 801 guns used in crimes in the contiguous 48 states were traced to interstate purchases. Northbound gun transfers along the Interstate 95 corridor were greater than expected to New Jersey (incidence rate ratio [IRR], 2.80; 95% credible interval [CrI], 1.01-7.68) and Maryland (IRR, 3.07; 95% CrI, 1.09-8.61); transfers were similarly greater along Interstate 15 southbound, Interstate 25 southbound, Interstate 35 southbound, Interstate 75 northbound and southbound, Interstate 10 westbound, and Interstate 20 eastbound and westbound. CONCLUSIONS AND RELEVANCE: This repeated-measures, ecological, cross-sectional study identified that guns used in crimes traced to interstate purchases moved routinely between states along multiple major transportation routes. Interstate gun transfers are a major contributor to gun crime, injury, and death in the US. National policies and interstate cooperation are needed to address this issue

Brief report: Using global positioning system (GPS) enabled cell phones to examine adolescent travel patterns and time in proximity to alcohol outlets

As adolescents gain freedom to explore new environments unsupervised, more time in proximity to alcohol outlets may increase risks for alcohol and marijuana use. This pilot study: 1) Describes variations in adolescents' proximity to outlets by time of day and day of the week, 2) Examines variations in outlet proximity by drinking and marijuana use status, and 3) Tests feasibility of obtaining real-time data to study adolescent proximity to outlets. U.S. adolescents (N = 18) aged 16–17 (50% female) carried GPS-enabled smartphones for one week with their locations tracked. The geographic areas where adolescents spend time, activity spaces, were created by connecting GPS points sequentially and adding spatial buffers around routes. Proximity to outlets was greater during after school and evening hours. Drinkers and marijuana users were in proximity to outlets 1½ to 2 times more than non-users. Findings provide information about where adolescents spend time and times of greatest risk, informing prevention efforts

Degradation of MinD Oscillator Complexes by Escherichia coli ClpXP

MinD is a cell division ATPase in Escherichia coli that os- cillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase–dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation

Absolute versus relative socioeconomic disadvantage and homicide: a spatial ecological case–control study of US zip codes

Background Homicide is a major cause of death and contributes to health disparities in the United States. This burden overwhelmingly affects people from racial and ethnic minority populations as homicide occurs more often in neighborhoods with high proportions of racial and ethnic minority residents. Research has identified that environmental factors contribute to variation in homicide rates between neighborhoods; however, it is not clear why some neighborhoods with high concentrations of racial and ethnic minority residents have high homicide rates while neighborhoods with similar demographic compositions do not. The aim of this study was to assess whether relative socioeconomic disadvantage, (i.e., income inequality), or absolute socioeconomic disadvantage (i.e., income) measured at the ZIP code- and state-levels, is associated with high homicide rates in US ZIP codes, independent of racial and ethnic composition. Methods This ecological case–control study compared median household income and income inequality in 250 ZIP codes with the highest homicide rate in our sample in 2017 (cases) to 250 ZIP codes that did not experience any homicide deaths in 2017 (controls). Cases were matched to controls 1:1 based on demographic composition. Variables were measured at both the ZIP code- and state-levels. Results Lower median household income at the ZIP code-level contributed most substantially to the homicide rate. Income inequality at the state-level, however, was additionally significant when controlling for both ZIP code- and state-level factors. Conclusions Area-based interventions that improve absolute measures of ZIP code socioeconomic disadvantage may reduce gaps in homicide rates

Overcoming barriers to engaging socio-economically disadvantaged populations in CHD primary prevention: a qualitative study

<p><b>Background:</b> Preventative medicine has become increasingly important in efforts to reduce the burden of chronic disease in industrialised countries. However, interventions that fail to recruit socio-economically representative samples may widen existing health inequalities. This paper explores the barriers and facilitators to engaging a socio-economically disadvantaged (SED) population in primary prevention for coronary heart disease (CHD).</p> <p><b>Methods:</b> The primary prevention element of Have a Heart Paisley (HaHP) offered risk screening to all eligible individuals. The programme employed two approaches to engaging with the community: a) a social marketing campaign and b) a community development project adopting primarily face-to-face canvassing. Individuals living in areas of SED were under-recruited via the social marketing approach, but successfully recruited via face-to-face canvassing. This paper reports on focus group discussions with participants, exploring their perceptions about and experiences of both approaches.</p> <p><b>Results:</b> Various reasons were identified for low uptake of risk screening amongst individuals living in areas of high SED in response to the social marketing campaign and a number of ways in which the face-to-face canvassing approach overcame these barriers were identified. These have been categorised into four main themes: (1) processes of engagement; (2) issues of understanding; (3) design of the screening service and (4) the priority accorded to screening. The most immediate barriers to recruitment were the invitation letter, which often failed to reach its target, and the general distrust of postal correspondence. In contrast, participants were positive about the face-to-face canvassing approach. Participants expressed a lack of knowledge and understanding about CHD and their risk of developing it and felt there was a lack of clarity in the information provided in the mailing in terms of the process and value of screening. In contrast, direct face-to-face contact meant that outreach workers could explain what to expect. Participants felt that the procedure for uptake of screening was demanding and inflexible, but that the drop-in sessions employed by the community development project had a major impact on recruitment and retention.</p> <p><b>Conclusion:</b> Socio-economically disadvantaged individuals can be hard-to-reach; engagement requires strategies tailored to the needs of the target population rather than a population-wide approach.</p&gt

A comparison and analysis of seven gun law permissiveness scales

Background Due to the differences in the way gun law permissiveness scales were created and speculation about the politically motivated underpinnings of the various scales, there have been questions about their reliability. Methods We compared seven gun law permissiveness scales, varying by type and sources, for an enhanced understanding of the extent to which choice of a gun law permissiveness scale could affect studies related to gun violence outcomes in the United States. Specifically, we evaluated seven different scales: two rankings, two counts, and three scores, arising from a range of sources. We calculated Spearman correlation coefficients for each pair of scales compared. Cronbach’s standardized alpha and Guttman’s lambda were calculated to evaluate the relative reliability of the scales, and we re-calculated Cronbach’s alpha after systematically omitting each scale to assess whether the omitted scale contributed to lower internal consistency between scales. Factor analysis was used to determine single factor loadings and estimates. We also assessed associations between permissiveness of gun laws and total firearm deaths and suicides in multivariable regression analyses. Results All pairs of scales were highly correlated (average Spearman’s correlation coefficient r = 0.77) and had high relative reliability (Cronbach’s alpha = 0.968, Guttman’s lambda = 0.975). All scales load onto a single factor. The choice of scale did not meaningfully change the parameter estimates for the associations between permissiveness of gun laws and gun deaths and suicides. Conclusion Gun law permissiveness scales are highly correlated despite any perceived political agenda, and the choice of gun law permissiveness scale has little effect on study conclusions related to gun violence outcomes

Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR\u27s effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation

Dengue illness impacts daily human mobility patterns in Iquitos, Peru

Background Human mobility plays a central role in shaping pathogen transmission by generating spatial and/or individual variability in potential pathogen-transmitting contacts. Recent research has shown that symptomatic infection can influence human mobility and pathogen transmission dynamics. Better understanding the complex relationship between symptom severity, infectiousness, and human mobility requires quantification of movement patterns throughout infectiousness. For dengue virus (DENV), human infectiousness peaks 0–2 days after symptom onset, making it paramount to understand human movement patterns from the beginning of illness. Methodology and principal findings Through community-based febrile surveillance and RT-PCR assays, we identified a cohort of DENV+ residents of the city of Iquitos, Peru (n = 63). Using retrospective interviews, we measured the movements of these individuals when healthy and during each day of symptomatic illness. The most dramatic changes in mobility occurred during the first three days after symptom onset; individuals visited significantly fewer locations (Wilcoxon test, p = 0.017) and spent significantly more time at home (Wilcoxon test, p = 0.005), compared to when healthy. By 7–9 days after symptom onset, mobility measures had returned to healthy levels. Throughout an individual’s symptomatic period, the day of illness and their subjective sense of well-being were the most significant predictors for the number of locations and houses they visited. Conclusions/Significance Our study is one of the first to collect and analyze human mobility data at a daily scale during symptomatic infection. Accounting for the observed changes in human mobility throughout illness will improve understanding of the impact of disease on DENV transmission dynamics and the interpretation of public health-based surveillance data