COVID-19 hospitalization risk after outpatient nirmatrelvir/ritonavir use, January to August 2022, North Carolina.

BACKGROUND: In the USA, nirmatrelvir/ritonavir is authorized for the treatment of mild-to-moderate COVID-19 in patients at least 12 years of age, at high risk for progression to severe COVID-19. OBJECTIVES: To estimate the impact of outpatient nirmatrelvir/ritonavir on COVID-19 hospitalization risk in a US healthcare system. METHODS: We conducted a cohort study using electronic health records among outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. We evaluated the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 hospitalizations using machine-learning methods. RESULTS: Among 44 671 patients, 4948 (11%) received nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28 days of COVID-19 diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, have comorbidities and reside in areas with higher average socioeconomic status. The 28 day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%-0.17%) among nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%-0.60%) among non-recipients. For nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03-0.26); the fully adjusted HR was 0.16 (95% CI: 0.05-0.50). In the machine-learning model, the primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger age, vaccination, female gender and residence in a higher socioeconomic status area. CONCLUSIONS: COVID-19 hospitalization risk was reduced by 84% among nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a setting substantially different than the original clinical trials.

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006.

BACKGROUND: Case series have demonstrated that potentially lethal cutaneous squamous cell carcinomas arise in patients with recessive dystrophic epidermolysis bullosa (RDEB), although the magnitude of this risk is undefined. METHODS: Systematic case finding and data collection were performed throughout the continental United States (1986-2002) by the National EB Registry on 3280 EB patients to determine cumulative and conditional risks for squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and malignant melanoma (MM) within each major EB subtype, as well as the cumulative risk of death from each tumor. Study design was cross-sectional, with a nested randomly sampled longitudinal subcohort (N = 450). RESULTS: SCCs arose primarily in RDEB, especially the Hallopeau-Siemens subtype (RDEB-HS), first beginning in adolescence. Less frequently, SCCs occurred in junctional EB (JEB). Cumulative risks rose steeply in RDEB-HS, from 7.5% by age 20 to 67.8%, 80.2%, and 90.1% by ages 35, 45, and 55, respectively. In Herlitz JEB, the risk was 18.2% by age 25. SCC deaths occurred only in RDEB, with cumulative risks in RDEB-HS of 38.7%, 70.0%, and 78.7% by ages 35, 45, and 55, respectively. MM arose in RDEB-HS, with a cumulative risk of 2.5% by age 12. BCCs arose almost exclusively in the most severe EB simplex subtype (Dowling-Meara) (cumulative risk = 43.6% by age 55). LIMITATIONS: Mutational analyses were performed on only a minority of enrollees in the National EB Registry, preventing evaluation of the possible influence of specific genotypes on the risk of developing or dying from cutaneous SCCs. CONCLUSIONS: SCC is the most serious complication of EB within adults, especially those with RDEB-HS. By mid-adulthood, nearly all will have had at least one SCC, and nearly 80% will have died of metastatic SCC despite aggressive surgical resection. When compared with SCCs arising within the normal population, the remarkably high risk of occurrence of and then death from SCCs among RDEB patients suggests likely differences in pathogenesis. Additional studies of EB-derived tumors and SCC cell lines may not only provide new insights into the mechanisms of carcinogenesis but also means whereby these particular tumors may be prevented or more effectively treated.

Trends in added sugars from packaged beverages available and purchased by US households, 2007-2012.

Background: The US Food and Drug Administration's updated nutrition labeling requirements will include added sugars starting in July 2018, but no measure currently exists to identify the added sugar content of products and what it represents among purchases. Beverages are one of the first targets for reducing added sugar consumption, and hence are the focus here.Objective: Our goal was to estimate trends in added sugars in nonalcoholic packaged beverage products available in the United States and to estimate amounts of added sugars obtained from these beverages given the purchases of US households overall and by subpopulations.Design: On the basis of nutrition label data from multiple sources, we used a stepwise approach to derive the added sugar content of 160,713 beverage products recorded as purchased by US households in 2007-2012 (345,193 observations from 110,539 unique households). We estimated the amounts of added sugars obtained from packaged beverages US households reported buying in 2007-2008, 2009-2010, and 2011-2012, overall and by subpopulations based on household composition, race/ethnicity, and income. The key outcomes are added sugars in terms of per capita grams per day and the percentage of calories from packaged beverages.Results: Packaged beverages alone account for per capita consumption of 12 g/d of added sugars purchased by US households in 2007-2012, representing 32-48% of calories from packaged beverages. Whereas the absolute amount of added sugars from beverages has not changed meaningfully over time, the relative contribution of added sugars to calories from beverages has increased. Non-Hispanic black households and low-income households obtain both higher absolute and relative amounts of added sugars from beverages than non-Hispanic white households and high-income households (all P < 0.01).Conclusions: These results provide measures of added sugars from packaged beverages at both the product level and the population level in the United States and can be used for comparisons after the revised nutrition labels are implemented and for future monitoring.

Estimating added sugars in US consumer packaged goods: An application to beverages in 2007-08.

This study developed a method to estimate added sugar content in consumer packaged goods (CPG) that can keep pace with the dynamic food system. A team including registered dietitians, a food scientist and programmers developed a batch-mode ingredient matching and linear programming (LP) approach to estimate the amount of each ingredient needed in a given product to produce a nutrient profile similar to that reported on its nutrition facts label (NFL). Added sugar content was estimated for 7021 products available in 2007-08 that contain sugar from ten beverage categories. Of these, flavored waters had the lowest added sugar amounts (4.3g/100g), while sweetened dairy and dairy alternative beverages had the smallest percentage of added sugars (65.6% of Total Sugars; 33.8% of Calories). Estimation validity was determined by comparing LP estimated values to NFL values, as well as in a small validation study. LP estimates appeared reasonable compared to NFL values for calories, carbohydrates and total sugars, and performed well in the validation test; however, further work is needed to obtain more definitive conclusions on the accuracy of added sugar estimates in CPGs. As nutrition labeling regulations evolve, this approach can be adapted to test for potential product-specific, category-level, and population-level implications.