The Challenge of Genetic Variants of Uncertain Clinical Significance: A Narrative Review: Annals of Internal Medicine: Vol 175, No 7

Genomic tests expand diagnostic and screening opportunities but also identify genetic variants of uncertain clinical significance (VUSs). Only a minority of VUSs are likely to prove pathogenic when later reassessed, but resolution of the uncertainty is rarely timely. That uncertainty adds complexity to clinical decision making and can result in harms and costs to patients and the health care system, including the time-consuming analysis required to interpret a VUS and the potential for unnecessary treatment and adverse psychological effects. Current efforts to improve variant interpretation will help reduce the scope of the problem, but the high prevalence of rare and novel variants in the human genome points to VUSs as an ongoing challenge. Additional strategies can help mitigate the potential harms of VUSs, including testing protocols that limit identification or reporting of VUSs, subclassification of VUSs according to the likelihood of pathogenicity, routine family-based evaluation of variants, and enhanced counseling efforts. All involve tradeoffs, and the appropriate balance of measures is likely to vary for different test uses and clinical settings. Cross-specialty deliberation and public input could contribute to systematic and broadly supported policies for managing VUSs.

The Emperor Has No Ganey

Treating Opioid Withdrawal in the Hospital: A Role for Short-Acting Opioids

Impact of Hepatitis C Treatment Uptake on Cirrhosis and Mortality in Persons Who Inject Drugs: A Longitudinal, Community-Based Cohort Study: Annals of Internal Medicine: Vol 175, No 8

Background: Hepatitis C virus (HCV) infection can be cured, and the United States has joined the World Health Organization in calling for HCV elimination by 2030. However, historically low uptake of HCV treatment among people who inject drugs (PWID) threatens HCV elimination and exacerbates social and racial health disparities. Objective: To assess whether all-oral HCV treatments were accessed by PWID and reduced liver disease burden and mortality. Design: Community-based, longitudinal cohort study of persons with a history of injection drug use. Setting: Baltimore, Maryland. Participants: 1323 participants enrolled in the ALIVE (AIDS Linked to the IntraVenous Experience) study from 2006 to 2019 and chronically infected with HCV. Measurements: Liver stiffness measures (LSMs) by transient elastography, HCV RNA, and mortality from the National Death Index. Results: Among 1323 persons with evidence of chronic HCV infection at baseline, the median age was 49 years. Most were Black (82%), male (71%), and HIV-negative (66%). The proportion in whom HCV RNA was detected decreased from 100% (by definition) in 2006 to 48% in 2019. Across 10 350 valid LSMs, cirrhosis was detected in 15% of participants in 2006, 19% in 2015, and 8% in 2019. Undetectable HCV RNA was significantly associated with reduced odds of cirrhosis (adjusted odds ratio, 0.28 [95% CI, 0.17 to 0.45]) and reduced all-cause mortality risk (adjusted hazard ratio, 0.54 [CI, 0.38 to 0.77]). Limitation: Noninvasive markers of liver fibrosis have not been validated in persons with sustained virologic response. Conclusion: Many community-based PWID in Baltimore are receiving HCV treatment, which is associated with sharp decreases in liver disease and mortality. Additional efforts will be needed to reduce residual barriers to treatment and to eliminate HCV as a public health threat for PWID. Primary Funding Source: National Institutes of Health.

Human Papillomavirus Vaccine Impact and Effectiveness Through 12 Years After Vaccine Introduction in the United States, 2003 to 2018

Background: Human papillomavirus (HPV) vaccination was introduced in 2006 for females and in 2011 for males. Objective: To estimate vaccine impact and effectiveness against quadrivalent HPV vaccine (4vHPV)–type prevalent infection among sexually experienced U.S. females and vaccine effectiveness for sexually experienced U.S. males. Design: NHANES (National Health and Nutrition Examination Survey) conducted in 2003 to 2006 (prevaccine era) and in 2007 to 2010, 2011 to 2014, and 2015 to 2018 (vaccine eras). Setting: Nationally representative U.S. surveys. Participants: Sexually experienced participants aged 14 to 24 years. Intervention: U.S. HPV vaccination program. Measurements: Participant-collected cervicovaginal and penile specimens were tested for HPV DNA. The prevalences of 4vHPV and non-4vHPV types were estimated in each era for females and in 2013 to 2016 for males. Prevalences among the female population overall, vaccinated females, and unvaccinated females were compared in vaccine eras versus the prevaccine era (vaccine impact). Within each vaccine era, prevalence among vaccinated females was compared with that among unvaccinated females (vaccine effectiveness). Vaccine impact and effectiveness were estimated as (1 − prevalence ratio) · 100. Results: Among sexually experienced females aged 14 to 24 years, the impact on 4vHPV-type prevalence in 2015 to 2018 was 85% overall, 90% among vaccinated females, and 74% among unvaccinated females. No significant declines were found in non–4vHPV-type prevalence. Vaccine effectiveness ranged from 60% to 84% during vaccine eras for females and was 51% during 2013 to 2016 for males. Limitation: Self- or parent-reported vaccination history and small numbers in certain subgroups limited precision. Conclusion: Nationally representative data show increasing impact of the vaccination program and herd protection. Vaccine effectiveness estimates will be increasingly affected by herd effects. Primary Funding Source: Centers for Disease Control and Prevention.

Characteristics and Outcomes of Hospitalized Pregnant Women With Influenza, 2010 to 2019: A Repeated Cross-Sectional Study: Annals of Internal Medicine: Vol 175, No 2

Background: Pregnant women may be at increased risk for severe influenza-associated outcomes. Objective: To describe characteristics and outcomes of hospitalized pregnant women with influenza. Design: Repeated cross-sectional study. Setting: The population-based U.S. Influenza Hospitalization Surveillance Network during the 2010–2011 through 2018–2019 influenza seasons. Patients: Pregnant women (aged 15 to 44 years) hospitalized with laboratory-confirmed influenza identified through provider-initiated or facility-based testing practices. Measurements: Clinical characteristics, interventions, and in-hospital maternal and fetal outcomes were obtained through medical chart abstraction. Multivariable logistic regression was used to evaluate the association between influenza A subtype and severe maternal influenza-associated outcomes, including intensive care unit (ICU) admission, mechanical ventilation, extracorporeal membrane oxygenation, or in-hospital death. Results: Of 9652 women aged 15 to 44 years and hospitalized with influenza, 2690 (27.9%) were pregnant. Among the 2690 pregnant women, the median age was 28 years, 62% were in their third trimester, and 42% had at least 1 underlying condition. Overall, 32% were vaccinated against influenza and 88% received antiviral treatment. Five percent required ICU admission, 2% required mechanical ventilation, and 0.3% (n = 8) died. Pregnant women with influenza A H1N1 were more likely to have severe outcomes than those with influenza A H3N2 (adjusted risk ratio, 1.9 [95% CI, 1.3 to 2.8]). Most women (71%) were still pregnant at hospital discharge. Among 754 women who were no longer pregnant at discharge, 96% had a pregnancy resulting in live birth, and 3% experienced fetal loss. Limitation: Maternal and fetal outcomes that occurred after hospital discharge were not captured. Conclusion: Over 9 influenza seasons, one third of reproductive-aged women hospitalized with influenza were pregnant. Influenza A H1N1 was associated with more severe maternal outcomes. Pregnant women remain a high-priority target group for vaccination. Primary Funding Source: Centers for Disease Control and Prevention.

Video Teleconferencing for Disease Prevention, Diagnosis, and Treatment: A Rapid Review: Annals of Internal Medicine: Vol 175, No 2

Background: Video teleconferencing (VTC) as a substitute for in-person health care or as an adjunct to usual care has increased in recent years. Purpose: To assess the benefits and harms of VTC visits for disease prevention, diagnosis, and treatment and to develop an evidence map describing gaps in the evidence. Data Sources: Systematically searched PubMed, EMBASE, Web of Science, and the Cochrane Library from 1 January 2013 to 3 March 2021. Study Selection: Two investigators independently screened the literature and identified 38 randomized controlled trials (RCTs) meeting inclusion criteria. Data Extraction: Data abstraction by a single investigator was confirmed by a second investigator; 2 investigators independently rated risk of bias. Data Synthesis: Results from 20 RCTs rated low risk of bias or some concerns of bias show that the use of VTC for the treatment and management of specific diseases produces largely similar outcomes when used to replace or augment usual care. Nine of 12 studies where VTC was intended to replace usual care and 5 of 8 studies where VTC was intended to augment usual care found similar effects between the intervention and control groups. The remaining 6 included studies (3 intended to replace usual care and 3 intended to augment usual care) found 1 or more primary outcomes that favored the VTC group over the usual care group. Studies comparing VTC with usual care that did not involve in-person care were more likely to favor the VTC group. No studies evaluated the use of VTC for diagnosis or prevention of disease. Studies that reported harms found no differences between the intervention and control groups; however, many studies did not report harms. No studies evaluated the effect of VTC on health equity or disparities. Limitations: Studies that focused on mental health, substance use disorders, maternal care, and weight management were excluded. Included studies were limited to RCTs with sample sizes of 50 patients or greater. Component analyses were not conducted in the studies. Conclusion: Replacing or augmenting aspects of usual care with VTC generally results in similar clinical effectiveness, health care use, patient satisfaction, and quality of life as usual care for areas studied. However, included trials were limited to a handful of disease categories, with patients seeking care for a limited set of purposes. Primary Funding Source: Patient-Centered Outcomes Research Institute.

Vitamin D Deficiency Increases Mortality Risk in the UK Biobank: A Nonlinear Mendelian Randomization Study: Annals of Internal Medicine: Vol 175, No 11

Background: Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking. Objective: To assess genetic evidence for the causal role of low vitamin D status in mortality. Design: Nonlinear Mendelian randomization analyses. Setting: UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010. Participants: 307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data. Measurements: Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020. Results: There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L. Limitations: Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate. Conclusion: Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels. Primary Funding Source: National Health and Medical Research Council.

Capacitance

Association Between Socioeconomic Disadvantage and Decline in Function, Cognition, and Mental Health After Critical Illness Among Older Adults: A Cohort Study: Annals of Internal Medicine: Vol 175, No 5

Background: Older adults admitted to an intensive care unit (ICU) are at risk for developing impairments in function, cognition, and mental health. It is not known whether socioeconomically disadvantaged older persons are at greater risk for these impairments than their less vulnerable counterparts. Objective: To evaluate the association between socioeconomic disadvantage and decline in function, cognition, and mental health among older survivors of an ICU hospitalization. Design: Retrospective analysis of a longitudinal cohort study. Setting: Community-dwelling older adults in the National Health and Aging Trends Study (NHATS). Participants: Participants with ICU hospitalizations between 2011 and 2017. Measurements: Socioeconomic disadvantage was assessed as dual-eligible Medicare–Medicaid status. The outcome of function was defined as the count of disabilities in 7 activities of daily living and mobility tasks, the cognitive outcome as the transition from no or possible to probable dementia, and the mental health outcome as the Patient Health Questionnaire-4 score in the NHATS interview after ICU hospitalization. The analytic sample included 641 ICU hospitalizations for function, 458 for cognition, and 519 for mental health. Results: After accounting for sociodemographic and clinical characteristics, dual eligibility was associated with a 28% increase in disability after ICU hospitalization (incidence rate ratio, 1.28; 95% CI, 1.00 to 1.64); and nearly 10-fold greater odds of transitioning to probable dementia (odds ratio, 9.79; 95% CI, 3.46 to 27.65). Dual eligibility was not associated with symptoms of depression and anxiety after ICU hospitalization (incidence rate ratio, 1.33; 95% CI, 0.99 to 1.79). Limitation: Administrative data, variability in timing of baseline and outcome assessments, proxy selection. Conclusion: Dual-eligible older persons are at greater risk for decline in function and cognition after an ICU hospitalization than their more advantaged counterparts. This finding highlights the need to prioritize low-income seniors in rehabilitation and recovery efforts after critical illness and warrants investigation into factors leading to this disparity. Primary Funding Source: National Institute on Aging.