The social vulnerability metric (SVM) as a new tool for public health

Objective

To derive and validate a new ecological measure of the social determinants of health (SDoH), calculable at the zip code or county level.

Data Sources and Study Setting

The most recent releases of secondary, publicly available data were collected from national U.S. health agencies as well as state and city public health departments.

Study Design

The Social Vulnerability Metric (SVM) was constructed from U.S. zip-code level measures (2018) from survey data using multidimensional Item Response Theory and validated using outcomes including all-cause mortality (2016), COVID-19 vaccination (2021), and emergency department visits for asthma (2018). The SVM was also compared with the existing Centers for Disease Control and Prevention's Social Vulnerability Index (SVI) to determine convergent validity and differential predictive validity.

Data Collection/Extraction Methods

The data were collected directly from published files available to the public online from national U.S. health agencies as well as state and city public health departments.

Principal Findings

The correlation between SVM scores and national age-adjusted county all-cause mortality was r = 0.68. This correlation demonstrated the SVM's robust validity and outperformed the SVI with an almost four-fold increase in explained variance (46% vs. 12%). The SVM was also highly correlated (r ≥ 0.60) to zip-code level health outcomes for the state of California and city of Chicago.

Conclusions

The SVM offers a measurement tool improving upon the performance of existing SDoH composite measures and has broad applicability to public health that may help in directing future policies and interventions. The SVM provides a single measure of SDoH that better quantifies associations with health outcomes.     

Genome-wide shifts in climate-related variation underpin responses to selective breeding in a widespread conifer

Locally adapted temperate tree populations exhibit genetic trade-offs among climate-related traits that can be exacerbated by selective breeding and are challenging to manage under climate change. To inform climatically adaptive forest management, we investigated the genetic architecture and impacts of selective breeding on four climate-related traits in 105 natural and 20 selectively bred lodgepole pine populations from western Canada. Growth, cold injury, growth initiation, and growth cessation phenotypes were tested for associations with 18,600 single-nucleotide polymorphisms (SNPs) in natural populations to identify “positive effect alleles” (PEAs). The effects of artificial selection for faster growth on the frequency of PEAs associated with each trait were quantified in breeding populations from different climates. Substantial shifts in PEA proportions and frequencies were observed across many loci after two generations of selective breeding for height, and responses of phenology-associated PEAs differed strongly among climatic regions. Extensive genetic overlap was evident among traits. Alleles most strongly associated with greater height were often associated with greater cold injury and delayed phenology, although it is unclear whether potential trade-offs arose directly from pleiotropy or indirectly via genetic linkage. Modest variation in multilocus PEA frequencies among populations was associated with large phenotypic differences and strong climatic gradients, providing support for assisted gene flow polices. Relationships among genotypes, phenotypes, and climate in natural populations were maintained or strengthened by selective breeding. However, future adaptive phenotypes and assisted gene flow may be compromised if selective breeding further increases the PEA frequencies of SNPs involved in adaptive trade-offs among climate-related traits.

Local adaptation of climate-related traits in widespread temperate conifers has been demonstrated for centuries using extensive long-term common garden experiments (1, 2). As early as the 17th century, foresters were instructed to recognize variation in desirable traits and select seed from trees with favorable phenotypes (3). Modern tree improvement programs systematically select upon genetic variation, primarily to achieve growth gains and meet economic objectives. Estimates of genetic variation and gains from selection made using quantitative genetic models assume many anonymous loci of small effect underlie both variation in continuously distributed phenotypes and their responses to selective breeding. However, the type, quantity, effect size, distribution, and dynamics of genes underlying locally adaptive phenotypic variation and responses to selective breeding in forest trees are still poorly understood (4).Directional selection over hundreds or thousands of generations has led to genomic features of domestication in agricultural crops including simplified genetic architectures underlying many traits, reduced genome-wide diversity, and numerous selective sweeps (5–7). Beyond high-gain, short-rotation clonal forestry [e.g., Eucalyptus spp. (8)], we know little about the effects of artificial selection on adaptive genetic variation in forest trees, yet many tree species undergo some degree of selective breeding. Two or three generations of conifer breeding is not expected to have the same magnitude of genetic effects seen in domesticated crops, but if artificial selection for increased productivity is detectable in conifer genomes, it may expose genetic relationships and potential sources of trade-offs between growth and climatically adaptive phenotypes.Climate-related adaptive traits are often intercorrelated due to pleiotropy, natural selection, or linkage disequilibrium (LD), so that strong directional selection on one trait can cause correlated responses in others. Pleiotropic allelic variants associated with phenotypes do not function in isolation. Antagonistic pleiotropic effects among traits can generate adaptive trade-offs among traits within populations, and limit gains from selection on a focal trait (9). Trait–trait correlations can also arise through strong selection acting in parallel on unlinked loci or from LD mediated by physical linkage of loci on chromosomes. Average genome-wide LD estimates in conifers appear to be low (10, 11) but may be greater (r² of 0.2–0.4) within genes under strong selection (12).Conifer studies have identified putatively adaptive phenotype-associated alleles on a locus-by-locus basis using quantitative trait loci (QTL) mapping or genotype–phenotype associations (GPAs) (also known as genome-wide association studies [GWAS]) (13). Genotype–environment association analyses in conifers have identified putatively adaptive environmentally associated loci (e.g., 14, 15), but loci are usually anonymous relative to adaptive phenotypes. All of these approaches are biased toward detecting loci with large phenotypic effects, but expectations that genome scans will discover individual adaptive loci with large effects or frequency differences among populations may be biologically and statistically unrealistic (16, 17). Conifer GPA studies typically detect relatively few statistically significant loci, and locus-by-locus analyses are insufficient to characterize adaptive genome-wide variation associated with adaptive traits and signatures of selective breeding. Multilocus tests for adaptive polygenic signatures of selection have been developed (e.g., refs. 18 and 19), but significant limitations remain (reviewed in refs. 20 and 21).Uncertainty about the effects of selective breeding on adaptive genetic variation is layered upon expectations that forest trees will become maladapted as climates shift (22). Efforts are being made to estimate maladaptation using genome-wide variation associated with adaptive traits and climate (23, 24), because conserving, managing, and efficiently redeploying genetic variation associated with adaptive phenotypes will be a necessary element of strategies to mitigate the effects of shifting climates on forest resources (25). Assisted gene flow strategies in temperate and subboreal forests generally aim to move trees to cooler climates in anticipation of future warming, but trees must then contend with the increased short- to medium-term risk of maladaptation to damaging frost. This means cold tolerance is, perhaps surprisingly, an important trait when planning for warming climates.Genetic approaches have the potential to efficiently and accurately characterize local adaptation to climate. Understanding whether this potential can be realized in a technically robust and operationally feasible way, and whether selection for faster growth compromises genetic variation associated with phenotypic adaptation to climate, has far-reaching implications for developing effective assisted gene flow strategies that mitigate negative climate change impacts on forest health and timber production (26, 27). In this context, our research objectives are to 1) identify the genetic architecture of climate-related adaptive traits in interior lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.); 2) identify genome-wide effects of artificial selection for increased productivity on climate-related traits; and 3) assess the implications of genetic responses to selection for assisted gene flow strategies.Our study combines climatic data, genotype data from ∼50,000 lodgepole pine single-nucleotide polymorphisms (SNPs), and seedling phenotypic data for height, cold injury, growth initiation, and growth cessation traits. These data were collected from a seedling common garden that sampled reforestation seed lots from 105 natural populations and 20 breeding populations from across the species’ range in Alberta (AB) and British Columbia (BC), Canada (Fig. 1 and SI Appendix, Table S1). For each of the four traits, we identify range-wide GPAs using 929 seedlings from all 105 natural populations. Then for the 1% most strongly phenotype-associated SNPs, we examine how artificial selection within breeding populations has changed allele frequencies at individual SNP loci, within individual seedlings, populations (breeding zones), and three climatic regions (Fig. 1). Using elements from the approach of Turchin et al. (18), we study changes in frequency of the alleles that have a positive effect on adaptive traits (positive effect alleles [PEAs]). At each SNP locus, a PEA is the allele associated with increasing numeric values of the respective phenotype, determined in this case through GPA analyses in the natural seedling populations. PEAs reported here are associated with greater seedling height, greater cold injury, delayed growth initiation, and delayed growth cessation. To parse physical genetic linkage from allelic associations due to other causes, we compare LD estimated from our natural seedlings with estimates of recombination among haploid megagametophytes from a single maternal parent, where physical linkage is the only cause of LD. Integrating genetic, climatic, and phenotypic data gives us a robust basis to detect the effects of artificial selection on climate-related genotypes that are relevant to breeding and assisted gene flow strategies.Open in a separate windowFig. 1.Geographic origins of the natural and selected seedling populations sampled from across the range of lodgepole pine in Alberta (AB) and British Columbia (BC). Natural populations are represented by filled circles; selected seedling breeding zones are represented by filled polygons. The three climatic regions we used were AB, BC-Central, and BC-South. AB breeding zones are formally identified as A, B1, B2, C, J, and K1. BC-Central breeding zone abbreviations are as follows: BV, Bulkley Valley; CP, Central Plateau; and PG, Prince George. BC-South breeding zone abbreviations are as follows: EK, East Kootenay; NE, Nelson; and TO, Thompson–Okanagan. Reprinted from ref. 35, with permission from Elsevier.     

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients

ObjectiveTo study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).Patients and MethodsThe Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).ResultsA total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.ConclusionThe identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.     

Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography–tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T_1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.     

Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD.We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies.Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P?=?.009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P?=?.037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD.An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.     

A Census of Midsize to Large Supermarkets in Toronto: A Cross-Sectional Analysis of the Consumer Nutrition Environment

Objective

Assess the consumer nutrition environment in midsize to large supermarkets by supermarket type and area-level socioeconomic variables.