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As of August 2021, there were three COVID-19 vaccines available in the United States for the prevention of coronavirus 2019 (COVID-19). The purpose of this narrative review is to examine the early experience from the Emergency Use Authorization (EUA) of BNT162b2 (Pfizer, Inc./BioNTech), mRNA-1273 (Moderna, Inc.), and Ad26.COV2.S (Johnson and Johnson/Janssen Global Services, LLC) through July 2021. The EUA data from the clinical trials have largely been corroborated by real-world effectiveness investigations post-authorization. These studies indicate that immunity is obtained within 2weeks post-vaccination and may endure for 6months. The immunity conferred by the vaccines may also be effective against SARS-CoV-2 variants of concern. Additionally, populations not included in the emergency use authorization studies may also benefit from vaccination. This look back at the initial clinical experience can be used by the global community to inform and develop COVID-19 vaccine programs.

Hypertension and diabetes are the greatest factors influencing the progression of chronic kidney disease (CKD). Investigation into the role of nephron number in CKD alone or with hypertension has revealed a strong inverse relationship between the two; however, not much is known about the connection between nephron number and diabetic kidney disease. The heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, a novel model of nephron deficiency, provides a unique opportunity to study the association between nephron number and hypertension and diabetes on CKD. HSRA rats exhibit failure of one kidney to develop in 50−75% of offspring, whereas the remaining offspring are born with two kidneys. Rats born with one kidney (HSRA-S) develop significant renal injury with age compared with two-kidney littermates (HSRA-C). The induction of hypertension as a secondary stressor leads to significantly more renal injury in HSRA-S compared with HSRA-C rats and nephrectomized HSRA-C (HSRA-UNX) rats. The present study sought to address the hypothesis that nephron deficiency in the HSRA rat would hasten renal injury in the presence of a secondary stressor of hyperglycemia. HSRA animals did not exhibit diabetes-related traits at any age; thus, streptozotocin (STZ) was used to induce hyperglycemia in HSRA-S, HSRA-C, and HSRA-UNX rats. STZ- and vehicle-treated animals were followed for 15 wk. STZ-treated animals developed robust hyperglycemia, but in contrast to the response to hypertension, neither HSRA-S nor HSRA-UNX animals developed proteinuria compared with vehicle treatment. In total, our data indicate that hyperglycemia from STZ alone does not have a significant impact on the onset or progression of injury in young one-kidney HSRA animals. NEW & NOTEWORTHY The HSRA rat, a novel model of nephron deficiency, provides a unique opportunity to study the association between nephron number and confounding cardiovascular complications that impact kidney health. Although hypertension was previously shown to exacerbate renal injury in young HSRA animals, diabetic hyperglycemia did not lead to worse renal injury, suggesting that nephron number has limited impact on kidney injury, at least in this model.

ObjectiveTo examine the joint association of moderate-to-vigorous intensity physical activity (MVPA) and sedentary behavior with the risk of developing functional limitation 4 years later in adults with knee osteoarthritis (OA).MethodsUsing 48-month (baseline) accelerometry data from the Osteoarthritis Initiative, we classified participants as Active-Low Sedentary (≥ 1 10-min bout/week of MVPA, lowest tertile for standardized sedentary time), Active-High Sedentary (≥ 1 10-min bout/week of MVPA, top 2 tertiles for standardized sedentary time), Inactive-Low Sedentary (zero 10-min bouts/week of MVPA, lowest tertile for standardized sedentary time), and Inactive-High Sedentary (zero 10-minute bouts/week of MVPA, top 2 tertiles for standardized sedentary time) groups. Functional limitation was defined as > 12 seconds for the 5-repetition sit-to-stand test (5XSST) and < 1.22 m/s gait speed during the 20-meter walk test. To investigate the association of exposure groups with risk of developing functional limitation 4 years later, we calculated adjusted risk ratios (aRR; adjusted for potential confounders).ResultsOf 1091 and 1133 participants without baseline functional limitation, based on the 5XSST and 20-meter walk test, respectively, 15% and 21% developed functional limitation 4 years later. The Inactive-Low Sedentary and Inactive-High Sedentary groups had increased risk of developing functional limitations compared to the Active-Low Sedentary and Active-High Sedentary groups. The Inactive-Low Sedentary group had 72% (aRR 1.72, 95% CI 1.00–2.94) and 52% (aRR 1.52, 95% CI 1.03–2.25) more risk of developing functional limitation based on the 5XSST and 20-meter walk test, respectively, compared to the Active-Low Sedentary group.ConclusionRegardless of sedentary category, being inactive (zero 10-min bouts/week in MVPA) may increase the risk of developing functional limitation in adults with knee OA.

This study aimed to identify the incidence of ophthalmic complications of giant cell arteritis (GCA) among subjects with negative temporal artery biopsy (TAB) and to determine if duration of prednisone exposure relative to GCA diagnosis was associated with ophthalmic complications in TAB-negative subjects. The U.S. Veterans Health Administration (VHA) national database was queried for subjects between 1999 and 2017 with ICD-9/-10 diagnosis code for GCA, procedure code for TAB, and ICD-9/-10 diagnosis code for blindness, anterior or posterior ischemic optic neuropathy, or branch or central retinal artery occlusion. Pharmacy data regarding prednisone dispensation were collected. A Cox proportional hazard model was performed using ophthalmic complication by 1 year as the outcome variable in TAB-negative subjects, adjusting for age, TAB length, TAB laterality, and prednisone dose relative to GCA diagnosis date. Incident ophthalmic complication occurred by 1 year in 9.6% with positive TAB and in 6.2% with negative TAB. The majority of complications occurred within the first month for both groups. Compared to a reference group of prednisone initiation 0–14 days prior to GCA diagnosis, ophthalmic complications in TAB-negative subjects were significantly higher when prednisone initiation was delayed 14–28 days after GCA diagnosis. A substantial number of TAB-negative subjects accrued an incident ICD-9/-10 code for ophthalmologic complication within a year after diagnosis, most occurring within the first month. Delaying prednisone initiation 14–28 days after GCA diagnosis in TAB-negative subjects led to a 3.5-fold higher rate of ophthalmic events occurring by 1 year.

Methylxanthines, including caffeine and theophylline, are a class of natural and synthetic compounds with important roles in food, cosmetics, and medicine. These compounds are metabolized by bacteria using five enzymes from the Rieske non-heme iron oxygenase family, NdmABCDE. The NdmCDE complex is responsible for the N7-demethylation of 7-methylxanthine to xanthine and was originally described as being highly specific for 7-methylxanthine. Here, we report that the NdmCDE complex is also active toward theobromine, producing 3-methylxanthine due to N7-demethylation. Minimal activity was observed when the enzyme complex was tested with caffeine or paraxanthine, indicating that the presence of the N1-methyl group significantly inhibits N7-demethylase activity by NdmCDE. We also demonstrated positional promiscuity in the N3-demethylase, NdmB, which is able to carry out N1-demethylation of paraxanthine. The N1-demethylation by NdmB is limited to paraxanthine and was not observed when caffeine or theophylline were assayed. These newly discovered activities were observed when enzymes were overexpressed in E. coli and differ from results with purified enzymes assayed in vitro, indicating that they may behave differently in vivo. Furthermore, these results reveal promiscuity of bacterial N-demethylase enzymes that can be used to engineer new enzymes and bacterial strains for production of high-value methylxanthines.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over nine years, hazard ratios (aHR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders., A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI+MOST. Walking 0.2 meters/second slower during short- and standard-distance walk tests was associated with 23% (aHR[95%CI]; 1.23[1.10, 1.39]) and 25% (1.25[1.09, 1.43]) higher mortality risk, respectively. Walking

Background The gender gap in physician pay is often attributed in part to women working fewer hours than men, but evidence to date is limited by self-report and a lack of detail regarding ...

DESIGN: Exploratory secondary data analysis of a pilot randomized control trial conducted between 2015 and 2017. SETTING: Outpatient physical therapy clinic in an academic setting. PARTICIPANTS: 43 participants were randomized to the intervention or control group. Both groups received standard physical therapy (PT) after total knee replacement (TKR). INTERVENTIONS: Participants in the intervention group received a Fitbit, weekly step goals from their physical therapist, and up to six monthly phone calls after their discharge from PT (DC). MAIN OUTCOME MEASURES: The outcome, change in sedentary time (∆SED), was measured using a triaxial accelerometer (Actigraph GT3X) from initial evaluation (IE) to DC (short-term), and IE to 12 months (12M) after DC (long-term). Positive values represent a reduction in SED. We compared the short- and long-term ∆SED between the intervention and control groups using independent t-tests. RESULTS: Of the 43 participants [mean(SD) age 67.0 (7.0) years, BMI 31.5 (5.9) kg/m(2), 53% female], 36 participants had data at IE and DC (18 intervention, 18 control) and 27 had data at IE and 12M (12 intervention, 15 control). The between group difference in short-term ∆SED was [mean(95%CI)] 32.9 (−14.4, 80.1) minutes/day. The between group difference in long-term ∆SED was 59.2 (8.6, 109.7) minutes/day. CONCLUSION: Our preliminary results indicate that a physical therapist-administered physical activity intervention may reduce SED in adults after TKR. However, a full-clinical trial is needed to establish the effect on SED.

Health systems continue to grow in size. Financial integration-the ownership of hospitals or physician practices-often has anticompetitive effects that contribute to the higher prices for health care seen in the US. To determine whether the potential harms of financial integration are counterbalanced by improvements in quality, we surveyed nationally representative samples of hospitals (n = 739) and physician practices (n = 2,189), stratified according to whether they were independent or were owned by complex systems, simple systems, or medical groups. The surveys included nine scales measuring the level of adoption of diverse, quality-focused care delivery and payment reforms. Scores varied widely across hospitals and practices, but little of this variation was explained by ownership status. Quality scores favored financially integrated systems for four of nine hospital measures and one of nine practice measures, but in no case favored complex systems. Greater financial integration was generally not associated with better quality.

Children at high risk for sudden cardiac death (SCD) receive implantable cardioverter-defibrillators (ICD) for prevention, but the cost effectiveness of ICDs in children at intermediate risk is unclear. Our objective was to create a cost-effectiveness model to compare costs and outcomes in children at risk of SCD, with and without ICD. Utilizing hypertrophic cardiomyopathy as the proxy disease, a theoretical cohort of 8150 children was followed for 69 years. Model inputs were derived from the literature, with an incremental cost-effectiveness ratio (ICER) willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY) used to delineate cost effectiveness. Outcomes included prevalence of severe neurological morbidity (SNM), SCD, cost, and QALYs. In children at intermediate risk of SCD (4–6% over 5 years), ICD resulted in 56 fewer cases of SNM, 2686 fewer deaths. In children at high risk (> 6% over 5 years), ICD placement resulted in 74 fewer cases of SNM and 3663 fewer deaths from cardiac causes. The costs of ICD were higher, but placement was cost effective with an ICER of $3009 per QALY in intermediate risk children, but ICD therapy was a dominant strategy in high-risk children. Sensitivity analysis demonstrated ICD placement was cost-effective until the annual probability of SCD was

OBJECTIVES: Excess adiposity upregulates proinflammatory adipokines in infancy that have also been implicated in the pathogenesis of bronchiolitis. The association between excess adiposity and severity of disease in bronchiolitis is unclear. We sought to examine the association between adiposity and length of hospitalization and risk of PICU transfer in children with bronchiolitis. METHODS: We conducted a retrospective cohort study examining infants 24 months and younger hospitalized at an academic children’s hospital with bronchiolitis, grouped by weight status (BMI z score and ponderal index). Data were extracted from the medical record, including the following relevant covariates: age, sex, race and/or ethnicity, and International Classification of Diseases, 10th Revision codes. Outcomes included length of stay (LOS) and PICU transfer. We used multiple regression to examine the association between each anthropometric measure and LOS and likelihood of PICU transfer. RESULTS: There were 765 children in the final sample, 599 without a significant comorbidity (eg, prematurity, congenital heart disease). The median LOS was 2.8 days (interquartile range 1.7–4.9 days). LOS increased with increasing ponderal index quartile (P = .001). After accounting for age and significant comorbidities, we used multivariable regression to identify a significant association between increasing ponderal index and LOS (P = .04) and no association between BMI and LOS. Logistic regression did not reveal an association between either anthropometric measure and PICU transfer. CONCLUSIONS: In this study, we identified an association between a measure of excess adiposity in infants and length of hospitalization for bronchiolitis. Further work is needed to confirm this association, examine potential mechanisms, and account for other potential confounders.

Both the volume of economic sanctions and the reasons for their imposition have increased tremendously around the globe. In this context, several countries, including the United States and Canada, have introduced Magnitsky acts to enable their governments to act unilaterally to impose sanctions against foreign actors for gross violations of human rights and significant acts of corruption. This paper evaluates the legislative changes made to Canada’s sanction regime in 2016–2017 and explores how the new authorities have been applied following implementation (2017–2019). We find that, despite granting the Canadian government new authorities to undertake autonomous sanctions, the country has continued to cooperate with other states as it had done prior to the changes. We conclude that lawmakers never intended for Canada to use the new autonomous capabilities to “go it alone.” Instead, the symbolism represented by Canada taking a strong stance against human rights abuses globally was the driving force behind the Magnitsky Law’s passage.

Background Household contacts of patients with drug-resistant tuberculosis (TB) are at high risk for being infected with Mycobacterium tuberculosis and for developing TB disease. To guide regimen composition for the empirical treatment of TB infection and disease in these household contacts, we estimated drug-resistance profile concordance between index patients with drug-resistant TB and their household contacts. Methods We performed a systematic review and meta-analysis of studies published through 24 July 2018 that reported resistance profiles of drug-resistant TB index cases and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only. Results We identified 33 eligible studies that evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI], 40.7–67.6%; I2 = 85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI, 72.3–90.9%; I2 = 73%). Concordance estimates were similar in a subanalysis of 16 studies from high-TB-burden countries. There were insufficient data to perform a subanalysis among pediatric secondary cases. Conclusions Household contacts of patients with drug-resistant TB should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.

BACKGROUND Prostate cancer is the most common male cancer, with a wide range of treatment options. Payment reform to reduce unnecessary spending variation is an important strategy for reducing waste, but its magnitude and drivers within prostate cancer are unknown. METHODS In total, 38,971 men aged ≥66 years with localized prostate cancer who were enrolled in Medicare fee-for-service and were included in the Surveillance, Epidemiology, and End Results-Medicare database from 2009 to 2014 were included. Multilevel linear regression with physician and facility random effects was used to examine the contributions of urologists, radiation oncologists, and their affiliated facilities to variation in total patient spending in the year after diagnosis within geographic region. The authors assessed whether spending variation was driven by patient characteristics, disease risk, or treatments. Physicians and facilities were sorted into quintiles of adjusted patient-level spending, and differences between those that were high-spending and low-spending were examined. RESULTS Substantial variation in spending was driven by physician and facility factors. Differences in cancer treatment modalities drove more variation across physicians than differences in patient and disease characteristics (72% vs 2% for urologists, 20% vs 18% for radiation oncologists). The highest spending physicians spent 46% more than the lowest and had more imaging tests, inpatient care, and radiotherapy spending. There were no differences across spending quintiles in the use of robotic surgery by urologists or the use of brachytherapy by radiation oncologists. CONCLUSIONS Significant differences were observed for patients with similar demographics and disease characteristics. This variation across both physicians and facilities suggests that efforts to reduce unnecessary spending must address decision making at both levels.

This study sought to determine the effect of temporal artery biopsy (TAB) postfixation length, laterality, age, and prior prednisone exposure on TAB positivity utilizing the Veterans Health Administration national database.Subjects with procedure code for TAB between 1999 and 2017 were queried, and pathology reports were reviewed manually. Demographic, laboratory, and prescription data were extracted. Multivariate analyses and logistic regression were run using Stata, version 13.0.A total of 3,057 pathology reports were reviewed; 306 biopsies (10%) were designated positive. The likelihood of a positive TAB significantly correlated with TAB postfixation length of3.0 cm (odds ratio [OR] 1.58 [95% confidence interval (95% CI) 1.06, 2.36], P0.05) as well as with bilateral biopsy in 1 sitting (OR 1.83 [95% CI 1.29, 2.59], P0.01). Positive TAB also significantly correlated with age71 years. Prednisone administration up to and beyond 42 days prior to TAB did not influence TAB result.This retrospective study examined predictors of TAB positivity and utilized national data collected on US veterans over the span of 18 years. The results suggest consideration of pursuing initial bilateral TAB or achieving a TAB postfixation length of at least 3 cm to improve yield. The results also agree with prior studies showing that pre-TAB steroid exposure does not appear to affect yield even up to and beyond 42 days prior to biopsy.

Background There is a dearth of research to understand which children, among those who are exposed at home to tuberculosis (TB), are at the highest risk of TB disease, to tailor care. We sought to identify predictors of TB progression in children. Methods We conducted a prospective cohort study of children living with adults with pulmonary TB in Lima, Peru (2009–2012). We applied classification and regression tree analysis to examine potential predictors of incident TB disease during 12 months in 3 age groups (0–4, 5–9, and 10–14 years). We calculated the relative risk (RR) for top predictors in each age group. Results Among 4545 children 0–14 years old, 156 (3.4%) were diagnosed with TB within 1 year of household exposure to TB (3.4%, 2.3%, and 4.7% in children 0–4, 5–9, and 10–14 years old, respectively). The most important predictor of TB was having a positive tuberculin skin test (TST) result, with RRs of 6.6 (95% CI, 4.0–10.7), 6.6 (95% CI, 3.2–13.6), and 5.2 (95% CI, 3.0–9.0) in the age groups 0–4, 5–9, and 10–14 years, respectively. In young children with a positive TST, not using isoniazid preventive treatment further increased risk of disease (RR, 12.2 [95% CI, 3.8–39.2]). Conclusions We present a tool that identifies child household contacts at high risk of TB disease progression based on data collected during contact tracing. In addition to the use of TB preventive therapy for all children exposed at home to TB, those children at highest risk of progressing to TB disease may benefit from more frequent follow-up., We derived age-stratified clinical prediction tools to identify child household contacts at highest risk of tuberculosis disease progression within 1 year of exposure. Having a positive tuberculin skin test was the most important predictor of incident tuberculosis across all ages.

Key Points Question For older adults with multimorbidity, what are national trends in the presence and specialty of usual clinicians and their association with preventive care receipt and spending? Findings In this survey study of 25 490 Medicare beneficiary–years, participants were less likely to report a usual clinician or have a specialist in this role over the study period. Those with usual clinicians were more likely to report preventive care receipt, while those with specialist usual clinicians reported lower influenza vaccination rates specifically. Meaning In this study, older adults with multimorbidity were less likely to have a usual clinician over the study period, with implications for preventive care receipt., This survey study examines trends in the presence and specialty of usual clinicians and their association with preventive care receipt and spending among older US adults with at least 2 chronic conditions., Importance Declining primary care visit rates and increasing specialist visit rates among older adults with multimorbidity raise questions about the presence, specialty, and outcomes associated with usual clinicians of care for these adults. Objective To examine trends in the presence and specialty of usual clinicians and the association with preventive care receipt and spending. Design, Setting, and Participants This survey study used repeated cross-sectional analyses of Medicare Current Beneficiary Survey data from 2010, 2013, and 2016. Participants were community-dwelling Medicare Advantage and traditional Medicare members with at least 2 chronic conditions. Data were analyzed from March 1, 2020, to February 5, 2021. Main Outcomes and Measures Trends and factors associated with self-reported usual clinician presence and specialty. Multivariable regression was used to examine associations between usual clinician presence and specialty with preventive care receipt and spending, controlling for respondent sociodemographic and clinical characteristics. Results A total of 25 490 unweighted respondent-years were examined, representing 90 324 639 respondent-years across the United States. Overall, 58.4% of respondent-years belonged to women, and the mean (SD) age of respondents was 77.5 (7.5) years. From 2010 to 2016, those reporting usual clinicians dropped from 94.2% to 91.0% (P

OBJECTIVE Vancomycin carries risks of treatment failure and emergent resistance with underexposure and renal toxicity with overexposure. Children with overweight or obesity may have altered pharmacokinetics. We aimed to examine how body weight metrics influence vancomycin serum concentrations and to evaluate alternative dosing strategies. METHODS This was a multicenter retrospective cohort study across 3 large, academic hospitals. Patients aged 2 to 18 years old who received ≥3 doses of intravenous vancomycin were included. Weight metrics included total body weight, adjusted body weight, ideal body weight, body surface area, and allometric weight. Outcomes included vancomycin concentration and ratios of area under the curve (AUC) to minimum inhibitory concentration (MIC). Regression analyses were used to examine which body-weight identifier predicted outcomes. RESULTS Of the 1099 children, 45% were girls, mean age was 9.0 (SD = 5.4) years, 14% had overweight, and 17% had obesity. Seventy-five percent of children had vancomycin concentrations in the subtherapeutic range by trough 20 µg/mL or ratio of AUC to MIC >600 μg-hr/mL. Serum vancomycin concentrations were higher in children with overweight or obesity compared with children who were at a normal weight or underweight; the mean ratio of AUC to MIC also trended higher in the groups with overweight or obesity. CONCLUSIONS Most children received vancomycin regimens that produced suboptimal trough levels. Children with overweight or obesity experienced higher vancomycin trough levels than children of normal weight despite receiving lower total body weight dosing. Using the ratio of AUC to MIC was a better measure of drug exposure.

Maintaining the essential functions of mitochondria requires mechanisms to recognize and remove misfolded proteins. However, quality control (QC) pathways for misfolded mitochondrial proteins remain poorly defined. Here, we establish temperature-sensitive (ts-) peripheral mitochondrial outer membrane (MOM) proteins as novel model QC substrates in Saccharomyces cerevisiae. The ts- proteins sen2-1HAts and sam35-2HAts are degraded from the MOM by the ubiquitin-proteasome system. Ubiquitination of sen2-1HAts is mediated by the ubiquitin ligase (E3) Ubr1, while sam35-2HAts is ubiquitinated primarily by San1. Mitochondria-associated degradation (MAD) of both substrates requires the SSA family of Hsp70s and the Hsp40 Sis1, providing the first evidence for chaperone involvement in MAD. In addition to a role for the Cdc48-Npl4-Ufd1 AAA-ATPase complex, Doa1 and a mitochondrial pool of the transmembrane Cdc48 adaptor, Ubx2, are implicated in their degradation. This study reveals a unique QC pathway comprised of a combination of cytosolic and mitochondrial factors that distinguish it from other cellular QC pathways., eLife digest Proteins are molecules that need to fold into the right shape to do their job. If proteins lose that shape, not only do they stop working but they risk clumping together and becoming toxic, potentially leading to disease. Fortunately, the cell has quality control systems that normally detect and remove misfolded proteins before they can cause damage to the cell. First, sets of proteins known as chaperones recognize the misfolded proteins, and then another class of proteins attaches a molecular tag, known as ubiquitin, to the misshapen proteins. When several ubiquitin tags are attached to a protein, forming chains of ubiquitin, it is transported to a large molecular machine within the cell called the proteasome. The proteasome unravels the protein and breaks it down into its constituent building blocks, which can then be used to create new proteins. Proteins are found throughout the different compartments of the cell and quality control processes have been well-studied in some parts of the cell but not others. Metzger et al. have now revealed how the process works on the surface of mitochondria, the compartment that provides the cell with most of its energy. To do this, they used baker’s yeast, a model laboratory organism that shares many fundamental properties with animal cells, but which is easier to manipulate genetically. The quality control process was studied using two mitochondrial proteins that had been mutated to make them sensitive to changes in temperature. This meant that, when the temperature increased from 25°C to 37°C, these proteins would begin to unravel and trigger the clean-up operation. This approach has been used previously to understand the quality control processes in other parts of the cell. By removing different quality control machinery in turn from the yeast cells, Metzger et al. could detect which were necessary for the process on mitochondria. This showed that there were many similarities with how this process happen in other parts of the cell but that the precise combination of chaperones and enzymes involved was distinct. Furthermore, when the proteasome was not working, the misfolded proteins remained on the mitochondria, showing that they are not transported to other parts of the cell to be broken down. In the future, understanding this process could help to find potential drug targets for mitochondrial diseases. The next steps will be to see how well these findings apply to human and other mammalian cells.

This cross-sectional study examines the association between use of an insurance-owned patient-facing price estimator tool by pregnant individuals and out-of-pocket childbirth spending., Key Points Question What are the patterns and characteristics of price transparency tool use among pregnant individuals with commercial insurance? Findings In this cross-sectional study of 253 606 pregnant individuals, price transparency tool use increased from 5.9% in the 2011 to 2012 study period to 13.0% in the 2015 to 2016 study period. Higher coinsurance was associated with more price transparency tool use, whereas a previous cesarean delivery was associated with less use. Meaning Use of the price transparency tool was associated with higher childbirth spending; these tools may be used for informational and planning purposes by pregnant individuals., Importance When introduced a decade ago, patient-facing price transparency tools had low use rates and were largely not associated with changes in spending. Little is known about how such tools are used by pregnant individuals in anticipation of childbirth, a shoppable service with increasing out-of-pocket spending. Objective To measure changes over time in the patterns and characteristics of use of a price transparency tool by pregnant individuals, and to identify the association between price transparency tool use, coinsurance, and childbirth spending. Design, Setting, and Participants This descriptive cross-sectional study of 2 cohorts used data from a US commercial health insurance company that launched a web-based price transparency tool in 2010. Data on all price transparency tool queries for 2 periods (January 1, 2011, to December 31, 2012, and January 1, 2015, to December 31, 2016) were obtained. The sample included enrollees aged 19 to 45 years who had a delivery episode during 2 periods (November 1, 2011, to December 31, 2012, or November 1, 2015, to December 31, 2016) and were continuously enrolled for the 10 months prior to delivery (N = 253 606). Exposures Access to a web-based price transparency tool that provided individualized out-of-pocket price estimates for vaginal and cesarean deliveries. Main Outcomes and Measures The primary outcomes were searches on the price transparency tool by delivery mode (vaginal or cesarean), timing (first, second, or third trimester), and individual characteristics (age at childbirth, rurality, pregnancy risk status, coinsurance exposure, area educational attainment, and area median household income). Another outcome was the association of out-of-pocket childbirth spending with price transparency tool use. Results The sample included 253 606 pregnant individuals, of whom 131 224 (51.7%) were in the 2011 to 2012 cohort and 122 382 (48.3%) were in the 2015 to 2016 cohort. In the 2015 to 2016 cohort, the mean (SD) age was 31 years (5.2 years) and most individuals had coinsurance for delivery (94 251 [77.0%]). Price searching increased from 5.9% in the 2011 to 2012 cohort to 13.0% in the 2015 to 2016 cohort. In the 2015 to 2016 cohort, 43.9% of searchers’ first price query was in their first trimester. The adjusted probability of searching was lower for individuals with a high-risk pregnancy due to a previous cesarean delivery (11.5%; 95% CI, 11.0%-12.1%) vs individuals with low-risk pregnancy (13.4%; 95% CI, 12.9%-14.0%). Use increased monotonically with coinsurance, from 9.2% (95% CI, 8.7%-9.8%) among individuals with no coinsurance to 15.0% (95% CI, 14.4%-15.5%) among individuals with 11% or higher coinsurance. After adjusting for covariates, searching was positively associated with out-of-pocket delivery episode spending. Among patients with 11% coinsurance or higher, early and late searchers spent more out of pocket ($59.57 [95% CI, $33.44-$85.96] and $73.33 [95% CI, $32.04-$115.29], respectively), compared with never searchers. Conclusions and Relevance The results of this cross-sectional study indicate that the proportion of pregnant individuals who sought price information before childbirth more than doubled within the first 6 years of availability of a price transparency tool. These findings suggest that price information may help individuals anticipate their out-of-pocket childbirth costs.

Hundreds of gene therapies are undergoing clinical testing and are likely to be priced more than $1 million per course of treatment. The association that high prices will have with insurance coverage of gene therapy remains unclear. Gene therapy for sickle cell disease has shown early success and would be one of the first gene therapies available for a relatively large population.To estimate the budget impact and affordability of a gene therapy for severe sickle cell disease from the perspective of US Medicaid programs with the highest prevalence of sickle cell disease while exploring the impact of an annuity payment model.A budget impact analysis was performed from January 1 to May 31, 2020, for a sickle cell disease gene therapy from the perspective of 10 state Medicaid plans with a 5-year time horizon, using state-level disease prevalence data from 2012. Disease prevalence, Medicaid enrollment, and expenditures were derived from the available literature. The eligible population was based on modified clinical trial inclusion criteria including individuals aged 13 to 45 years with severe disease.The gene therapy was assumed to be administered to 7% of the eligible population annually and was curative (no subsequent disease-related expenditures). The gene therapy price was $1.85 million in the base case, and baseline disease-related expenditures were $42 200 per year.The main outcomes were total budget impact and budget impact per member per month in years 1 through 5. One-way sensitivity analysis was used to evaluate uncertainty of market diffusion, size of eligible population, price of therapy, and cost of routine care.An estimated 5464 Medicaid enrollees would be eligible for the gene therapy nationally, with 2315 individuals in the 10 Medicaid programs of interest (16 per 100 000 enrollees). The model projected a mean 1-year budget impact of $29.96 million per state Medicaid program in the sample ($1.91 per member per month). A 5-year annuity payment reduced the short-term budget impact.This study suggests that a gene therapy for severe sickle cell disease is likely to produce a considerable budget impact for many Medicaid plans while potentially offering substantial benefit to patients. Payers may need to take steps to ensure affordability and access. Gene therapy for sickle cell disease is likely to provide an early demonstration of the unique financial challenges associated with this emerging drug class.

Objective To examine the effect of the 2010 Affordable Care Act (ACA) extended dependent coverage and no cost-sharing provisions on human papillomavirus (HPV) vaccination in relation to sexual orientation identity among U.S. women. Data sources 2006-2010 and 2011-2015 National Survey of Family Growth. Study design We used an interrupted time series design and multivariable Poisson regression to assess differences in HPV vaccination initiation before (2007-2010) and after (2011-2015) the 2010 ACA provisions among heterosexual, bisexual, and lesbian U.S. women aged 15-25 years (N = 7033), adjusting for temporal trends and demographic factors. Data collection Computer-assisted personal interview and audio computer-assisted self-interview questionnaires. Principal findings The adjusted prevalence of HPV vaccination initiation was significantly higher among lesbian and bisexual women after compared to before the 2010 ACA-at 19.1 (95% confidence interval [CI]: 5.4, 32.9) and 15.7 (95% CI: 4.4, 27.1) percentage points in 2015 compared to 2007-2010, respectively. We observed no association between the 2010 ACA provisions and HPV vaccination initiation among heterosexual women after adjusting for temporal trends and demographic factors. Conclusions The 2010 ACA provisions may have improved HPV vaccination initiation among lesbian and bisexual women. Policies and programs that increase access to health insurance and provide HPV vaccines at no cost to patients may facilitate HPV vaccine uptake in these marginalized populations.

The treat-to-target approach for serum uric acid is the recommended model in gout management according to the 2012 American College of Rheumatology (ACR) guidelines. Adherence to urate-lowering therapy (ULT) can be difficult for patients due to barriers, which include medication burden, financial hardship, and lack of medical literacy. Our aim was to create a pharmacist-managed referral for the titration of ULT to target serum uric acid (sUA) levels in a complex patient population. We utilized a clinical database to query patients seen at a rheumatology clinic over a 12-month period with an ICD-10 diagnosis for gout. The referral criteria were indications for ULT per the 2012 ACR guidelines. Rheumatology providers, consisting of attendings, fellows, and a physician assistant, were asked to refer the identified patients to the pharmacist-managed titration program. The intervention group consisted of 19 referred patients and the control group consisted of 28 non-referred patients. The baseline sUA (median (IQR)) at the time of referral was 8.8 (2) mg/dL for the intervention group and 7.6 (2.8) mg/dL for the control group (p = 0.2). At the end of the study period, the sUA was 6.1 (1.4) mg/dL for the intervention group and 6.8 (3.2) mg/dL for the control group (p = 0.08). At the end of the study period, 6 of 19 (32%) intervention group and 7 of 28 (25%) control group were at goal (p = 0.3). A newly instituted pharmacist-managed titration program was able to achieve lower average sUA levels in referred patients compared to demographically similar individuals who received standard gout management.

BACKGROUND: Inadequate diagnostic evaluations of breast lumps and rectal bleeding in primary care are an important source of medical errors. Delays appear particularly common in evaluation of rectal bleeding. Comparing pursuit and completion of diagnostic testing for these two conditions within the same practice settings could help highlight barriers and inform interventions. OBJECTIVES: To examine processes undertaken for diagnostic evaluations of breast lumps and rectal bleeding within the same practices and to compare them with regard to (a) the likelihood that diagnostic tests are ordered according to guidelines and (b) the timeliness of order placement and completion. DESIGN: A retrospective cohort study using explicit chart abstraction methods. PARTICIPANTS: Three hundred women aged 30–80 presenting with breast lumps and 300 men and women aged 40–80 years presenting with rectal bleeding to 15 academically affiliated primary care practices, 2012–2016. MAIN MEASURES: Rates and timing of test ordering and completion and patterns of visits and communications. KEY RESULTS: At initial presentation, physicians ordered recommended imaging or procedures at higher rates for patients with breast lumps compared to those with rectal bleeding (97% vs. 86% of patients recommended to receive imaging or endoscopy; p

SETTING The tuberculous infection control strategy, FAST (Find cases Actively, Separate safely and Treat effectively), recommends prompt initiation of likely effective anti-tuberculosis treatment informed by Xpert® MTB/RIF results.OBJECTIVE: To describe FAST implementation at Quang Nam Provincial TB and Lung Disease Hospital (QNH), Tam Ky, Viet Nam, using time to initiation of effective TB treatment as a process measure. DESIGN Hospital logs were used to calculate the time to likely effective treatment in patients with pulmonary TB (PTB) hospitalised during the study period. RESULTS Between 1 January and 31 December 2016, of 858 patients treated for PTB, 493 (57.5%) received likely effective treatment. The median time to likely effective treatment was 3 days (interquartile range 2.0-6.0), with 213 (43.2%) patients receiving likely effective treatment within 2 days. Of 81 patients receiving likely effective treatment for drug-susceptible TB with a positive Xpert result as their initial in-patient diagnostic test, 64 (79.0%) received likely effective treatment within 2 days compared with 10 (5.7%) who were initially smear-negative then found to be Xpert-positive (P < 0.0001). CONCLUSIONS A 'time to' process measure of the FAST tuberculous infection control strategy indicates delays in the initiation of likely effective anti-tuberculosis treatment in a resource-limited hospital. Expanding access to Xpert may speed time to likely effective treatment.

Objectives Caffeine has well-documented benefits on endurance athletic performance. Because of caffeine’s ergogenic effects of reducing perceived fatigue, it is hypothesized that as duration of athletic event increases, so will the effect size of caffeine upon performance. This study aims to examine the relationship between duration of endurance athletic event and the effect size of caffeine compared to placebo for athletic performance. Design A systematic review and meta-analysis of placebo-controlled trials assessing the effects of caffeine in adults performing endurance athletic events. Methods We searched MedLine, Web of Science, and review article references published through March 2016. We performed meta-analyses on placebo-controlled trials to determine the effect of the duration of an endurance athletic event on the standardized mean difference (Cohen’s d) between the caffeine and placebo groups for athletic performance. Results Forty articles including 56 unique comparison groups were included. Pooled results showed a Cohen’s d of 0.33 (95% CI = 0.21, 0.45; p = 1.00; I2 = 0%). The effect of the duration of athletic event was significantly associated with Cohen’s d (Relative Risk: 0.005; 95% CI = 0.001, 0.009; p = 0.024). For a 30 min increase in duration of the athletic event, Cohen’s d will increase by 0.150. Conclusions This study is the first to report on the statistical finding that the effect size of caffeine increases along with the increasing duration of the time trial event. Endurance athletes may especially benefit from caffeine for performance enhancement.