Glymphatic fluid transport is suppressed by the aquaporin-4 inhibitor AER-271.

The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain.

The Impact of Adjusting for Hysterectomy Prevalence on Cervical Cancer Incidence Rates and Trends Among Women Aged 30 Years and Older - United States, 2001-2019.

Hysterectomy protects against cervical cancer when the cervix is removed. However, measures of cervical cancer incidence often fail to exclude women with a hysterectomy from the population at risk denominator, underestimating and distorting disease burden. In this study, we estimated hysterectomy prevalence from the Behavioral Risk Factor Surveillance System surveys to remove the women who were not at risk of cervical cancer from the denominator and combined these estimates with the United States Cancer Statistics data. From these data, we calculated age-specific and age-standardized incidence rates for women aged >30 years from 2001-2019, adjusted for hysterectomy prevalence. We calculated the difference between unadjusted and adjusted incidence rates and examined trends by histology, age, race and ethnicity, and geographic region using Joinpoint regression. The hysterectomy-adjusted cervical cancer incidence rate from 2001-2019 was 16.7 per 100,000 women-34.6% higher than the unadjusted rate. After adjustment, incidence rates were higher by approximately 55% among Black women, 56% among those living in the East South Central division, and 90% among women aged 70-79 and >80 years. These findings underscore the importance of adjusting for hysterectomy prevalence to avoid underestimating cervical cancer incidence rates and masking disparities by age, race, and geographic region.

Trends in Racial Inequalities in the Administration of Opioid and Non-opioid Pain Medication in US Emergency Departments Across 1999-2020.

BACKGROUND: Despite initiatives to eradicate racial inequalities in pain treatment, there is no clear picture on whether this has translated to changes in clinical practice. OBJECTIVE: To determine whether racial disparities in the receipt of pain medication in the emergency department have diminished over a 22-year period from 1999 to 2020. DESIGN: We used data from the National Hospital Ambulatory Medical Care Survey, an annual, cross-sectional probability sample of visits to emergency departments of non-federal general and short-stay hospitals in the USA. PATIENTS: Pain-related visits to the ED by Black or White patients. MAIN MEASURES: Prescriptions for opioid and non-opioid analgesics. KEY RESULTS: A total of 203,854 of all sampled 625,433 ED visits (35%) by Black or White patients were pain-related, translating to a population-weighted estimate of over 42 million actual visits to US emergency departments for pain annually across 1999-2020. Relative risk regression found visits by White patients were 1.26 (95% CI, 1.22-1.30; p<0.001) times more likely to result in an opioid prescription for pain compared to Black patients (40% vs. 32%). Visits by Black patients were also 1.25 (95% CI, 1.21-1.30; p<0.001) times more likely to result in non-opioid analgesics only being prescribed. Results were not substantively altered after adjusting for insurance status, type and severity of pain, geographical region, and other potential confounders. Spline regression found no evidence of meaningful change in the magnitude of racial disparities in prescribed pain medication over 22 years. CONCLUSIONS: Initiatives to create equitable healthcare do not appear to have resulted in meaningful alleviation of racial disparities in pain treatment in the emergency department.

Racial and Ethnic Disparities in the Prescribing of Pain Medication in US Primary Care Settings, 1999-2019: Where Are We Now?

BACKGROUND: Policy initiatives have attempted to reduce healthcare inequalities in the USA, but evidence on whether these initiatives have reduced racial and ethnic disparities in pain treatment in primary care is lacking. OBJECTIVE: To determine whether racial and ethnic disparities in medication prescribed for pain in primary care settings have diminished over a 21-year period from 1999 to 2019. DESIGN: An annual, representative cross-sectional probability sample of visits to US primary care physicians, taken from the National Ambulatory Medical Care Survey. PATIENTS: Pain-related visits to primary care physicians. MAIN MEASURES: Prescriptions for opioid and non-opioid analgesics. KEY RESULTS: Of 599,293 (16%) sampled visits, 94,422 were pain-related, representing a population-weighted estimate of 143 million visits made annually to primary care physicians for pain. Relative risk analysis controlling for insurance, pain type, and other potential confounds showed no difference in pain medication prescribed between Black and White patients (p = .121). However, White patients were 1.61 (95% CI 1.32-1.97) and Black patients 1.57 (95% CI 1.26-1.95) times more likely to be prescribed opioids than a more underrepresented group consisting of Asian, Native-Hawaiian/Pacific-Islander, and American-Indian/Alaska-Natives (ps < .001). Non-Hispanic/Latino patients were 1.32 (95% CI 1.18-1.45) times more likely to receive opioids for pain than Hispanic/Latino patients (p < .001). Penalized cubic spline regression found no substantive narrowing of disparities over time. CONCLUSIONS: These findings suggest that additional intervention strategies, or better implementation of existing strategies, are needed to eliminate ethnic and racial disparities in pain treatment towards the goal of equitable healthcare.

Integrated Response to Address a Resurgent Syphilis Epidemic in a Rural American Indian Community, Whiteriver, Arizona, January 2022 to June 2023.

BACKGROUND: The United States has seen a significant rise in syphilis over the past 20 years with a disparate impact on American Indian communities. We conducted a thorough review of the local epidemiology that guided an innovative response to curb the epidemic. METHODS: We analyzed syphilis data from a hospital in rural Arizona that serves an American Indian population of more than 18,000. Testing data were extracted from 2017 to 2023 with detailed chart reviews of all reactive results since January 2022. Descriptive and comparative statistics were computed using parametric and nonparametric methods where appropriate. RESULTS: Among 5888 tested persons, 555 (9.4%) had reactive results and 277 (4.7%) represented new infections. Among new cases, 151 (54.5%) were female and 55 (19.9%) were reinfections. The annualized incidence rate was 10.0 cases per 1000 persons with peak annualized incidence among women aged 30 to 34 years of 22.6 infections per 1000 persons. During the observation period and after the implementation of programmatic changes in June 2022, there were statistically significant reductions in median time to treatment (-80%), test positivity (-70%), infections (-60%), and no congenital syphilis cases during the observation period. CONCLUSIONS: We observed significantly elevated syphilis rates in American Indian/Alaska Native persons compared with the general population. Strategic implementation of new policies and practices led to a measurable and meaningful improvement in several epidemic variables, and our experience may serve as a model to other communities.

A comprehensive analysis of neuroblastoma incidence, survival, and racial and ethnic disparities from 2001 to 2019.

BACKGROUND: We characterize the incidence and 5-year survival of children and adolescents with neuroblastoma stratified by demographic and clinical factors based on the comprehensive data from United States Cancer Statistics (USCS) and the National Program of Cancer Registries (NPCR). METHODS: We analyzed the incidence of neuroblastoma from USCS (2003-2019) and survival data from NPCR (2001-2018) for patients less than 20 years old. Incidence trends were calculated by average annual percent change (AAPC) using joinpoint regression. Differences in relative survival were estimated comparing non-overlapping confidence intervals (CI). RESULTS: We identified 11,543 primary neuroblastoma cases in USCS. Age-adjusted incidence was 8.3 per million persons [95% CI: 8.2, 8.5], with an AAPC of 0.4% [95% CI: -0.1, 0.9]. Five-year relative survival from the NPCR dataset (n = 10,676) was 79.7% [95% CI: 78.9, 80.5]. Patients aged less than 1 year had the highest 5-year relative survival (92.5%). Five-year relative survival was higher for non-Hispanic White patients (80.7%) or Hispanic patients (80.8%) compared to non-Hispanic Black patients (72.6%). CONCLUSION: Neuroblastoma incidence was stable during 2003-2019. Differences in relative survival exist by sex, age, race/ethnicity, and stage; patients who were male, older, non-Hispanic Black, or with distant disease had worse survival. Future studies could seek to assess the upstream factors driving disparities in survival, and evaluate interventions to address inequities and improve survival across all groups.

Characteristics and outcomes of a hospitalized cohort with reduced mortality from COVID-19, White Mountain apache tribal lands, April 1 - July 31, 2020.

BACKGROUND: Widespread transmission of COVID-19 continues to threaten public health, particularly of rural, American Indian communities. Although COVID-19 risk factors for severe disease and clinical characteristics are well described in the general population, there has been little shared on hospitalized American Indian populations. METHODS: In this observational study, we performed chart extractions on all persons hospitalized with COVID-19 from April 1 through July 31, 2020 among an exclusively American Indian population living on or near Tribal lands in eastern Arizona. We provide descriptive statistics for the cohort stratified by presentation, comparing those who self-presented or were referred by an outreach program. Exploratory analyses were performed to identify risk factors for morbidity and mortality. RESULTS: During the observation period, 2262 persons were diagnosed with COVID-19 and 490 (22%) were hospitalized. Hospitalized persons had a median age of 54 years; 92% had at least one comorbidity, 72% had greater than one comorbidity, and 60% had a BMI of > 30. Most persons required supplemental oxygen (83%), but the majority (62%) only required nasal cannula and only 11% were intubated. The case fatality rates were 1.7% for the population, 7.1% among hospitalizations, and 9.3% among hospitalized patients 50 years and older. All rates that are significantly lower than those reported nationally during the same period. CONCLUSIONS: We observed a cohort of American Indian patients hospitalized secondary to COVID-19 with greater number of comorbidities compared to the general population but with lower mortality rates. We posit that the primary driver of mortality reduction for this population and the hospitalized cohort was a community-based referral program that led to disproportionately lower fatality rates among the oldest persons.

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease.

SIGNIFICANCE STATEMENT: African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. BACKGROUND: African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. METHODS: We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. RESULTS: In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. CONCLUSIONS: APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.

Relative Effectiveness of Coronavirus Disease 2019 Vaccination and Booster Dose Combinations Among 18.9 Million Vaccinated Adults During the Early Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Period-United States, 1 January 2022 to 31 March 2022.

BACKGROUND: Small sample sizes have limited prior studies' ability to capture severe COVID-19 outcomes, especially among Ad26.COV2.S vaccine recipients. This study of 18.9 million adults aged ≥18 years assessed relative vaccine effectiveness (rVE) in three recipient cohorts: (1) primary Ad26.COV2.S vaccine and Ad26.COV2.S booster (2 Ad26.COV2.S), (2) primary Ad26.COV2.S vaccine and mRNA booster (Ad26.COV2.S+mRNA), (3) two doses of primary mRNA vaccine and mRNA booster (3 mRNA). METHODS: We analyzed two de-identified datasets linked using privacy-preserving record linkage (PPRL): insurance claims and retail pharmacy COVID-19 vaccination data. We assessed the presence of COVID-19 diagnosis during January 1-March 31, 2022 in: (1) any claim, (2) outpatient claim, (3) emergency department (ED) claim, (4) inpatient claim, and (5) inpatient claim with intensive care unit (ICU) admission. rVE for each outcome comparing three recipient cohorts (reference: two Ad26.COV2.S doses) was estimated from adjusted Cox proportional hazards models. RESULTS: Compared with two Ad26.COV2.S doses, Ad26.COV2.S+mRNA and three mRNA doses were more effective against all COVID-19 outcomes, including 57% (95% CI: 52-62) and 62% (95% CI: 58-65) rVE against an ED visit; 44% (95% CI: 34-52) and 54% (95% CI: 48-59) rVE against hospitalization; and 48% (95% CI: 22-66) and 66% (95% CI: 53-75) rVE against ICU admission, respectively. CONCLUSIONS: This study demonstrated that Ad26.COV2.S + mRNA doses were as good as three doses of mRNA, and better than two doses of Ad26.COV2.S. Vaccination continues to be an important preventive measure for reducing the public health impact of COVID-19.

Variation in hysterectomy prevalence and trends among U.S. States and Territories-Behavioral Risk Factor Surveillance System, 2012-2020.

PURPOSE: We estimated up-to-date state- and territory-level hysterectomy prevalence and trends, which can help correct the population at risk denominator and calculate more accurate uterine and cervical cancer rates. METHODS: We analyzed self-reported data for a population-based sample of 1,267,013 U.S. women aged ≥ 18 years who participated in the Behavioral Risk Factor Surveillance System surveys from 2012 to 2020. Estimates were age-standardized and stratified by sociodemographic characteristics and geography. Trends were assessed by testing for any differences in hysterectomy prevalence across years. RESULTS: Hysterectomy prevalence was highest among women aged 70-79 years (46.7%) and ≥ 80 years (48.8%). Prevalence was also higher among women who were non-Hispanic (NH) Black (21.3%), NH American Indian and Alaska Native (21.1%), and from the South (21.1%). Hysterectomy prevalence declined by 1.9 percentage points from 18.9% in 2012 to 17.0% in 2020. CONCLUSIONS: Approximately one in five U.S. women overall and half of U.S. women aged ≥ 70 years reported undergoing a hysterectomy. Our findings reveal large variations in hysterectomy prevalence within and between each of the four census regions and by race and other sociodemographic characteristics, underscoring the importance of adjusting epidemiologic measures of uterine and cervical cancers for hysterectomy status.

Impact of data extraction errors in meta-analyses on the association between depression and peripheral inflammatory biomarkers: an umbrella review.

BACKGROUND: Accumulating evidence suggests that alterations in inflammatory biomarkers are important in depression. However, previous meta-analyses disagree on these associations, and errors in data extraction may account for these discrepancies. METHODS: PubMed/MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched from database inception to 14 January 2020. Meta-analyses of observational studies examining the association between depression and levels of tumor necrosis factor-α (TNF-α), interleukin 1-ß (IL-1ß), interleukin-6 (IL-6), and C-reactive protein (CRP) were eligible. Errors were classified as follows: incorrect sample sizes, incorrectly used standard deviation, incorrect participant inclusion, calculation error, or analysis with insufficient data. We determined their impact on the results after correction thereof. RESULTS: Errors were noted in 14 of the 15 meta-analyses included. Across 521 primary studies, 118 (22.6%) showed the following errors: incorrect sample sizes (20 studies, 16.9%), incorrect use of standard deviation (35 studies, 29.7%), incorrect participant inclusion (7 studies, 5.9%), calculation errors (33 studies, 28.0%), and analysis with insufficient data (23 studies, 19.5%). After correcting these errors, 11 (29.7%) out of 37 pooled effect sizes changed by a magnitude of more than 0.1, ranging from 0.11 to 1.15. The updated meta-analyses showed that elevated levels of TNF- α, IL-6, CRP, but not IL-1ß, are associated with depression. CONCLUSIONS: These findings show that data extraction errors in meta-analyses can impact findings. Efforts to reduce such errors are important in studies of the association between depression and peripheral inflammatory biomarkers, for which high heterogeneity and conflicting results have been continuously reported.

Differential expression of MicroRNAs in Alzheimer's disease: a systematic review and meta-analysis.

Alzheimer's disease (AD) results in progressive cognitive decline owing to the accumulation of amyloid plaques and hyperphosphorylated tau. MicroRNAs (miRNAs) have attracted attention as a putative diagnostic and therapeutic target for neurodegenerative diseases. However, existing meta-analyses on AD and its association with miRNAs have produced inconsistent results. The primary objective of this study is to evaluate the magnitude and consistency of differences in miRNA levels between AD patients, mild cognitive impairment (MCI) patients and healthy controls (HC). Articles investigating miRNA levels in blood, brain tissue, or cerebrospinal fluid (CSF) of AD and MCI patients versus HC were systematically searched in PubMed/Medline from inception to February 16th, 2021. Fixed- and random-effects meta-analyses were complemented with the I2 statistic to measure the heterogeneity, assessment of publication bias, sensitivity subgroup analyses (AD severity, brain region, post-mortem versus ante-mortem specimen for CSF and type of analysis used to quantify miRNA) and functional enrichment pathway analysis. Of the 1512 miRNAs included in 61 articles, 425 meta-analyses were performed on 334 miRNAs. Fifty-six miRNAs were significantly upregulated (n = 40) or downregulated (n = 16) in AD versus HC and all five miRNAs were significantly upregulated in MCI versus HC. Functional enrichment analysis confirmed that pathways related to apoptosis, immune response and inflammation were statistically enriched with upregulated pathways in participants with AD relative to HC. This study confirms that miRNAs' expression is altered in AD and MCI compared to HC. These findings open new diagnostic and therapeutic perspectives for this disorder.

Cancer Distribution Among Asian, Native Hawaiian, and Pacific Islander Subgroups - United States, 2015-2019.

Non-Hispanic Asian (Asian) and non-Hispanic Native Hawaiian and Pacific Islander (NHPI) persons represent growing segments of the U.S. population (1). Epidemiologic cancer studies often aggregate Asian and NHPI persons (2,3); however, because Asian and NHPI persons are culturally, geographically, and linguistically diverse (2,4), subgroup analyses might provide insights into the distribution of health outcomes. To examine the frequency and percentage of new cancer cases among 25 Asian and NHPI subgroups, CDC analyzed the most current 2015-2019 U.S. Cancer Statistics data.* The distribution of new cancer cases among Asian and NHPI subgroups differed by sex, age, cancer type, and stage at diagnosis (for screening-detected cancers). The percentage of cases diagnosed among females ranged from 47.1% to 68.2% and among persons aged <40 years, ranged from 3.1% to 20.2%. Among the 25 subgroups, the most common cancer type varied. For example, although breast cancer was the most common in 18 subgroups, lung cancer was the most common cancer among Chamoru, Micronesian race not otherwise specified (NOS), and Vietnamese persons; colorectal cancer was the most common cancer among Cambodian, Hmong, Laotian, and Papua New Guinean persons. The frequency of late-stage cancer diagnoses among all subgroups ranged from 25.7% to 40.3% (breast), 38.1% to 61.1% (cervical), 52.4% to 64.7% (colorectal), and 70.0% to 78.5% (lung). Subgroup data illustrate health disparities among Asian and NHPI persons, which might be reduced through the design and implementation of culturally and linguistically responsive cancer prevention and control programs, including programs that address social determinants of health.

Ramelteon for delirium prevention in hospitalized patients: An updated meta-analysis and trial sequential analysis of randomized controlled trials.

Although ramelteon has been examined as a relatively new therapeutic option for delirium prevention, current evidence to evaluate its efficacy is limited. We conducted an updated meta-analysis and examine the reliability of existing evidence regarding the effect of ramelteon on delirium prevention in hospitalized patients. Seven major electronic databases were systematically searched to identify randomized controlled trials examining the efficacy of ramelteon in delirium prevention. Data were pooled using a frequentist-restricted maximum-likelihood random-effects model. A trial sequential analysis was performed using relative risk reduction thresholds of 50%. The primary outcome was the incidence of delirium (reported as odds ratio with 95% confidence intervals). The secondary outcomes were the days of delirium, all-cause mortality, and all-cause discontinuation. Of 187 potentially eligible studies identified, 8 placebo-controlled randomized controlled trials (n = 587) were included. This updated meta-analysis showed that ramelteon was associated with lower odds of delirium occurrence than placebo (0.50; 0.29-0.86; I2 = 17.48%). In trial sequential analysis, the effect of ramelteon across the superiority boundary when using a relative risk reduction threshold ranging from 40% to 60%. In subgroup analyses, ramelteon compared with placebo was associated with lower odds of delirium occurrence in the elderly group (k = 5; 0.28; 0.09-0.85; I2 = 27.93%) and multiple dosage group (k = 5; 0.34; 0.14-0.82; I2 = 44.24%) but not in the non-elderly and non-multiple dosage groups. When considering surgical patients and medical patients separately, ramelteon showed a trend in the treatment of delirium prevention in both groups, while these findings were not statistically significant. No significant between-group differences were found in the secondary outcomes. The current meta-analysis provides updated and reliable evidence that ramelteon, in comparison with placebo, reduces the risk of delirium among hospitalized patients.

Up-to-Date Breast, Cervical, and Colorectal Cancer Screening Test Use in the United States, 2021.

INTRODUCTION: We examined national estimates of breast, cervical, and colorectal cancer (CRC) screening test use and compared them with Healthy People 2030 national targets. Test use in 2021 was compared with prepandemic estimates. METHODS: In 2022, we used 2021 National Health Interview Survey (NHIS) data to estimate proportions of adults up to date with US Preventive Services Task Force recommendations for breast (women aged 50-74 y), cervical (women aged 21-65 y), and CRC screening (adults aged 50-75 y) across sociodemographic and health care access variables. We compared age-standardized estimates from the 2021 and 2019 NHIS. RESULTS: Percentages of adults up to date in 2021 were 75.7% (95% CI, 74.4%-76.9%), 75.2% (95% CI, 73.9%-76.4%), and 72.2% (95% CI, 71.2%-73.2%) for breast, cervical, and CRC screening, respectively. Estimates were below 50% among those without a wellness check in 3 years (all screening types), among those without a usual source of care or insurance (aged <65 y) (breast and CRC screening), and among those residing in the US for less than 10 years (CRC screening). Percentages of adults who were up to date with breast and cervical cancer screening and colonoscopy were similar in 2019 and 2021. Fecal occult blood/fecal immunochemical test (FOBT/FIT) use was modestly higher in 2021 (P < .001). CONCLUSIONS: In 2021, approximately 1 in 4 adults of screening age were not up to date with breast, cervical, and CRC screening recommendations, and Healthy People 2030 national targets were not met. Disparities existed across several characteristics, particularly those related to health care access. Breast, cervical, and colonoscopy test use within recommended screening intervals approximated prepandemic levels. FOBT/FIT estimates were modestly higher in 2021.

Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis.

AIM: Many randomized controlled trials (RCTs) have investigated the use of interleukin 6 antagonists for the treatment of coronavirus disease 2019 (COVID-19), yielding inconsistent results. This network meta-analysis (NMA) aimed to identify the source of these inconsistent results by reassessing whether participants treated with standard of care (SoC) plus placebo have different all-cause mortality from those treated with SoC alone and to reevaluate the efficacy of interleukin 6 antagonists in the treatment of COVID-19. METHODS: We conducted a systematic search for relevant RCTs from the inception of electronic databases through 1 September 2022. The primary outcome was all-cause mortality. The secondary outcomes were the incidences of major medical events, secondary infections, all-cause discontinuation, and serious adverse events. RESULTS: The results of NMA of 33 RCTs showed that patients with COVID-19 treated with SoC plus placebo had lower odds of all-cause mortality than those who received SoC alone (OR, 0.75 [95% confidence interval, 0.58-0.97]). This finding remained consistent after excluding studies with no incident deaths. In addition, when we consider the impact of the widely promoted COVID-19 vaccination and newly developed antiviral treatment strategy, the results from the analysis of the RCT published in 2021 and 2022 remained similar. CONCLUSION: These findings suggest the potential influence of placebo effects on the treatment outcomes of COVID-19 in RCTs. When evaluating the efficacy of treatment strategies for COVID-19, it is crucial to consider the use of placebo in the design of clinical trials.

Ethical climate in healthcare: A systematic review and meta-analysis.

BACKGROUND: Ethical climate refers to the shared perception of ethical norms and sets the scope for what is ethical and acceptable behaviour within teams. AIM: This paper sought to explore perceptions of ethical climate amongst healthcare workers as measured by the Ethical Climate Questionnaire (ECQ), the Hospital Ethical Climate Survey (HECS) and the Ethics Environment Questionnaire (EEQ). METHODS: A systematic review and meta-analysis was utilised. PSYCINFO, CINAHL, WEB OF SCIENCE, MEDLINE and EMBASE were searched, and papers were included if they sampled healthcare workers and used the ECQ, HECS or EEQ. ETHICAL CONSIDERATION: Ethical approval was not required. RESULTS: The search returned 1020 results. After screening, 61 papers were included (n = 43 HECS, n = 15 ECQ, n = 3 EEQ). The overall sample size was over 17,000. The pooled mean score for the HECS was 3.60. Mean scores of individual studies ranged from 2.97 to 4.5. For the HECS studies, meta-regression was carried out. No relationship was found between the country of the studies, the study setting (ICU v non-ICU settings) or the mean years of experience that the sample had. For the ECQ, sub-scales had mean scores ranging from 3.41 (instrumental) to 4.34 (law) and were all observed to have significant and substantial heterogeneity. Three studies utilised the EEQ so further analysis was not carried out. CONCLUSIONS: The above results provide insight into the variability of scores as measured by the HECS, ECQ and EEQ. To some extent, this variability is not surprising with studies carried out across 21 countries and in a range of healthcare systems. Results also suggest that it may be that more local and context specific factors are more important when it comes to predicting ethical climate.

Risk of clear-cell adenocarcinoma of the vagina and cervix among US women with potential exposure to diethylstilbestrol in utero.

PURPOSE: Women exposed to diethylstilbestrol (DES) in utero were at elevated risk of clear-cell adenocarcinoma of the vagina and cervix (CCA) as young women. Previous research suggested that this elevated risk of CCA may persist into adulthood. We extended a published analysis to measure CCA risk as these women aged. METHODS: Standardized incidence ratios (SIR) compared CCA risk among women born from 1947 through 1971 (the DES-era) to CCA risk among the comparison group of women born prior to 1947, using registry data that covered the US population. RESULTS: Incidence rates of CCA among both cohorts increased with age. Among the DES-era birth cohort, higher rates of CCA were observed across all age groups except 55-59 years. SIR estimates had wide confidence intervals that often included the null value. CONCLUSIONS: Results are consistent with prior research and suggest an elevated risk of CCA in midlife and at older ages among women exposed in utero to DES. These results highlight unresolved issues regarding cancer risk among aging DES daughters and appropriate screening guidance. The examination of population-based cancer surveillance data may be a useful tool for monitoring trends in the incidence of other rare cancers over time among specific birth cohorts.

A large-scale meta-analytic atlas of mental health problems prevalence during the COVID-19 early pandemic.

The COVID-19 pandemic and related restrictions can impact mental health. To quantify the mental health burden of COVID-19 pandemic, we conducted a systematic review and meta-analysis, searching World Health Organization COVID-19/PsycInfo/PubMed databases (09/29/2020), including observational studies reporting on mental health outcomes in any population affected by COVID-19. Primary outcomes were the prevalence of anxiety, depression, stress, sleep problems, posttraumatic symptoms. Sensitivity analyses were conducted on severe mental health problems, in high-quality studies, and in representative samples. Subgroup analyses were conducted stratified by age, sex, country income level, and COVID-19 infection status. One-hundred-seventy-three studies from February to July 2020 were included (n = 502,261, median sample = 948, age = 34.4 years, females = 63%). Ninety-one percent were cross-sectional studies, and 18.5%/57.2% were of high/moderate quality. The highest prevalence emerged for posttraumatic symptoms in COVID-19 infected people (94%), followed by behavioral problems in those with prior mental disorders (77%), fear in healthcare workers (71%), anxiety in caregivers/family members of people with COVID-19 (42%), general health/social contact/passive coping style in the general population (38%), depression in those with prior somatic disorders (37%), and fear in other-than-healthcare workers (29%). Females and people with COVID-19 infection had higher rates of almost all outcomes; college students/young adults of anxiety, depression, sleep problems, suicidal ideation; adults of fear and posttraumatic symptoms. Anxiety, depression, and posttraumatic symptoms were more prevalent in low-/middle-income countries, sleep problems in high-income countries. The COVID-19 pandemic adversely impacts mental health in a unique manner across population subgroups. Our results inform tailored preventive strategies and interventions to mitigate current, future, and transgenerational adverse mental health of the COVID-19 pandemic.

Can high-intensity interval training improve mental health outcomes in the general population and those with physical illnesses? A systematic review and meta-analysis.

OBJECTIVE: High-intensity interval training (HIIT) is a safe and feasible form of exercise. The aim of this meta-analysis was to investigate the mental health effects of HIIT, in healthy populations and those with physical illnesses, and to compare the mental health effects to non-active controls and other forms of exercise. DESIGN: Random effects meta-analyses were undertaken for randomised controlled trials (RCTs) comparing HIIT with non-active and/or active (exercise) control conditions for the following coprimary outcomes: mental well-being, symptoms of depression, anxiety and psychological stress. Positive and negative affect, distress and sleep outcomes were summarised narratively. DATA SOURCES: Medline, PsycINFO, Embase and CENTRAL databases were searched from inception to 7 July 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: RCTs that investigated HIIT in healthy populations and/or those with physical illnesses and reported change in mental well-being, depression, anxiety, psychological stress, positive/negative affect, distress and/or sleep quality. RESULTS: Fifty-eight RCTs were retrieved. HIIT led to moderate improvements in mental well-being (standardised mean difference (SMD): 0.418; 95% CI: 0.135 to 0.701; n=12 studies), depression severity (SMD: -0.496; 95% CI: -0.973 to -0.020; n=10) and perceived stress (SMD: -0.474; 95% CI: -0.796 to -0.152; n=4) compared with non-active controls, and small improvements in mental well-being compared with active controls (SMD:0.229; 95% CI: 0.054 to 0.403; n=12). There was a suggestion that HIIT may improve sleep and psychological distress compared with non-active controls: however, these findings were based on a small number of RCTs. CONCLUSION: These findings support the use of HIIT for mental health in the general population. LEVEL OF EVIDENCE: The quality of evidence was moderate-to-high according to the Grading of Recommendations Assessment, Development and Evaluation) criteria. PROSPERO REGISTRATION NUMBER: CRD42020182643.