Correlation of Adenoviral Titers with Severity of Adenoviral Conjunctivitis and Time to Viral Clearance for 21 Days.

SIGNIFICANCE: This investigation reports the correlation of conjunctival viral titers in adenoviral conjunctivitis with patient-reported symptoms and clinician-graded signs for 21 days of follow-up. PURPOSE: Adenoviral conjunctivitis is a highly contagious viral eye infection with significant morbidity and economic impact. This study investigates whether severity of signs and symptoms and time to viral clearance are correlated with conjunctival viral titers at baseline and during 21 days of follow-up. METHODS: The Reducing Adenoviral Patient Infected Days study was a pilot study of the efficacy of a single in-office administration of ophthalmic 5% povidone-iodine. This article outlines longitudinal analyses after the primary outcome report. Of 212 participants screened, 28 participants with quantitative polymerase chain reaction-confirmed adenoviral conjunctivitis were randomized and had follow-up visits on days 1, 2, 4, 7, 14, and 21. At each visit, clinician-graded signs, participant-reported symptoms, and a conjunctival swab for quantitative polymerase chain reaction analysis were obtained. The correlation of viral titers with symptoms and signs was calculated: (1) cross-sectionally at each visit and (2) longitudinally for 21 days using a repeated-measures mixed-effects model. RESULTS: Twenty-five of 28 participants had sufficient data for this report. Higher viral titers for 21 days were correlated with greater severity of symptoms (tearing, matting, and redness, r ≥ 0.70; P < .02) and greater severity of clinical signs (bulbar redness and serous discharge, r ≥ 0.60; P < .01). Eyes with highest baseline viral titers required longer time to viral clearance ( r = 0.59, P = .008). Signs and symptoms persisted in approximately half of the eyes even after viral clearance. CONCLUSIONS: Higher conjunctival viral titers across 21 days were strongly correlated with more severe signs and symptoms and longer time to viral clearance. Our results also indicate that symptoms and signs can persist after viral clearance.

HIMA2: high-dimensional mediation analysis and its application in epigenome-wide DNA methylation data.

Mediation analysis plays a major role in identifying significant mediators in the pathway between environmental exposures and health outcomes. With advanced data collection technology for large-scale studies, there has been growing research interest in developing methodology for high-dimensional mediation analysis. In this paper we present HIMA2, an extension of the HIMA method (Zhang in Bioinformatics 32:3150-3154, 2016). First, the proposed HIMA2 reduces the dimension of mediators to a manageable level based on the sure independence screening (SIS) method (Fan in J R Stat Soc Ser B 70:849-911, 2008). Second, a de-biased Lasso procedure is implemented for estimating regression parameters. Third, we use a multiple-testing procedure to accurately control the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. We demonstrate its practical performance using Monte Carlo simulation studies and apply our method to identify DNA methylation markers which mediate the pathway from smoking to reduced lung function in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Success of Masking 5% Povidone-Iodine Treatment: The Reducing Adenoviral Patient Infected Days Study.

SIGNIFICANCE: The effectiveness of masking is rarely evaluated or reported in single- or double-masked clinical trials. Knowledge of treatment assignment by participants and clinicians can bias the assessment of treatment efficacy. PURPOSE: This study aimed to evaluate the effectiveness of masking in a double-masked trial of 5% povidone-iodine for the treatment of adenoviral conjunctivitis. METHODS: The Reducing Adenoviral Patient Infected Days study is a double-masked, randomized trial comparing a one-time, in-office administration of 5% povidone-iodine with artificial tears for the treatment of adenoviral conjunctivitis. Masking was assessed by asking participants and masked clinicians at designated time points if they believed the treatment administered was povidone-iodine or artificial tears, or if they were unsure. Adequacy of masking was quantified using a modified Bang Blinding Index. RESULTS: Immediately after treatment, 34% of participants who received povidone-iodine and 69% of those who received artificial tears guessed incorrectly or were unsure of their treatment (modified Bang Indices of 0.31 and -0.38, respectively). On day 4, 38% of the povidone-iodine participants and 52% of the artificial tear participants guessed incorrectly or were unsure of their treatment (modified Bang Indices of 0.24 and -0.05, respectively), indicating adequate and ideal masking. On days 1, 4, 7, 14, and 21, masked clinicians guessed incorrectly or were unsure of treatment in 53%, 50%, 40%, 39%, and 42% among povidone-iodine participants compared with 44%, 35%, 38%, 35%, and 39% among artificial tears participants, respectively. The modified Bang Indices for clinician masking in the povidone-iodine group ranged from -0.05 to 0.25 and from 0.13 to 0.29 in the artificial tears group. CONCLUSIONS: Masking of participants and clinicians was adequate. Successful masking increases confidence that subjective measurements are not biased. We recommend quantitative assessment and reporting the effectiveness of masking in ophthalmic clinical trials.

Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious CDK12 Alterations in the Phase 2 IMPACT Trial.

PURPOSE: CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. PATIENTS AND METHODS: Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. RESULTS: PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%-28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden >10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6-11.4) in cohort A and 4.5 months (95% CI, 3.4-13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2-12.3) in cohort A and 13.8 months (95% CI, 3.6-not reached) in cohort C. CONCLUSIONS: There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.

Patterns and trends of medical student research.

BACKGROUND: Our study describes the change in the research output, trends and content of published research involving medical students over the last century. METHODS: Pubmed® and Scopus® were searched for keywords 'Medical Student' in the affiliation field. The search results were combined in Endnote® and duplicate entries removed and the multiple variables described below were assessed. RESULTS: The combined searches after excluding duplicates yielded 416 results and 66 articles were excluded. There was an exponential increase in medical student research from 1980-2010. Medical student was the first author in 170 (48.6%) studies and 55 studies were authored by a single medical student. The 3 most common areas of research in descending order were Psychiatry (n = 26, 7.4%), General Medicine (n = 24, 6.9%) and Medical Education (n = 21, 6%). The commonest type of articles, in descending order were review articles (n = 48, 13.7%), Cross sectional studies (n = 47, 13.4%) and Case reports (n = 43, 12.3. The majority of these articles (n = 207, 59.1%) have never been cited subsequently. The trend of increasing number of articles was seen equally among all article types, fields and countries. CONCLUSIONS: There is an exponential increase in articles by medical students but the majority of articles have not been cited. The numbers of medical student authors per publication have remained static while the total numbers of authors have increased. The proportions in the type of articles, fields of study and country of origin have largely remained static. Publishers and authors should strive to enhance the quality and quantity of data available in indexing services.

Diagnostic accuracy of clinical signs, symptoms and point-of-care testing for early adenoviral conjunctivitis.

CLINICAL RELEVANCE: This study identifies key signs and symptoms of acute conjunctivitis, that when combined with a point-of-care test, can improve clinician accuracy of diagnosing adenoviral conjunctivitis. BACKGROUND: Adenoviral conjunctivitis is a common ocular infection with the potential for high economic impact due to widespread outbreaks and subsequent furloughs from work and school. In this report, we describe clinical signs and participant-reported symptoms that most accurately identify polymerase chain reaction (PCR)-confirmed adenoviral conjunctivitis. METHODS: Adults with 'red eye' symptoms of four days or less were enrolled. Participants rated 10 ocular symptoms from 0 (not bothersome) to 10 (very bothersome), and indicated the presence or absence of systemic flu-like symptoms. Clinicians determined the presence or absence of swollen lymph nodes and rated the severity of eight ocular signs using a 5-point scale. An immunoassay targeting adenovirus antigen was utilised for the point-of-care test, and conjunctival swab samples were obtained for subsequent adenovirus detection by PCR analyses. Univariate and multivariate logistic regression models were used to identify symptoms and signs associated with PCR-confirmed adenoviral conjunctivitis. The diagnostic accuracy of these clinical findings, and the potential benefit of incorporating point-of-care test results, was assessed by calculating areas under the receiver operating characteristic curves (AUC). RESULTS: Clinician-rated bulbar conjunctival redness, participant-rated eyelid swelling and overall ocular discomfort had the best predictive value in the multivariate logistic regression model with an AUC of 0.83. The addition of the point-of-care test results to these three clinical sign/symptom scores improved diagnostic accuracy, increasing the AUC to 0.94. CONCLUSIONS: Conjunctival redness severity and participant-reported eyelid swelling and overall discomfort, along with adenoviral point-of-care test results, were highly predictive in identifying individuals with PCR-confirmed adenoviral conjunctivitis. Improved diagnostic accuracy by clinicians at the initial presenting visit could prevent unnecessary work furloughs and facilitate earlier treatment decisions.

Differential Outcomes Among Survivors of Head and Neck Cancer Belonging to Racial and Ethnic Minority Groups.

Importance: Approximately 1 in 5 new patients with head and neck cancer (HNC) in the US belong to racial and ethnic minority groups, but their survival rates are worse than White individuals. However, because most studies compare Black vs White patients, little is known about survival differences among members of racial and ethnic minority groups. Objective: To describe differential survival and identify nonclinical factors associated with stage of presentation among patients with HNC belonging to racial and ethnic minority groups. Design, Setting, and Participants: This population-based retrospective cohort study used data from the 2007 to 2016 Surveillance, Epidemiology, and End Results (SEER) database and included non-Hispanic Black, Asian Pacific Islander, American Indian/Alaska Native, and Hispanic patients with HNC. The data were analyzed from December 2020 to May 2021. Main Outcomes and Measures: Outcomes were time to event measures: (HNC-specific and all-cause mortality) and stage of presentation. Covariates included nonclinical (age at diagnosis, sex, race and ethnicity, insurance status, marital status, and a composite socioeconomic status [SES]) and clinical factors (stage, cancer site, chemotherapy, radiation, and surgery). A Cox regression model was used to adjust associations of covariates with the hazard of all-cause death, and a Fine and Gray competing risks proportional hazards model was used to estimate associations of covariates with the hazard of HNC-specific death. A proportional log odds ordinal logistic regression identified which nonclinical factors were associated with stage of presentation. Results: There were 21 966 patients with HNC included in the study (mean [SD] age, 56.02 [11.16] years; 6072 women [27.6%]; 9229 [42.0%] non-Hispanic Black, 6893 [31.4%] Hispanic, 5342 [24.3%] Asian/Pacific Islander, and 502 [2.3%] American Indian/Alaska Native individuals). Black patients had highest proportion with very low SES (3482 [37.7%]) and the lowest crude 5-year overall survival (46%). After adjusting for covariates, Hispanic individuals had an 11% lower subdistribution hazard ratio (sdHR) of HNC-specific mortality (sdHR, 0.89; 95% CI, 0.83-0.95), 15% lower risk for Asian/Pacific Islander individuals (sdHR, 0.85; 95% CI, 0.78-0.93), and a trending lower risk for American Indian/Alaska Native individuals (sdHR, 0.85; 95% CI, 0.71-1.01), compared with non-Hispanic Black individuals. Race, sex, insurance, marital status, and SES were consistently associated with all-cause mortality, HNC-specific mortality, and stage of presentation, with non-Hispanic Black individuals faring worse compared with individuals of other racial and ethnic minority groups. Conclusions and Relevance: In this cohort study that included only patients with HNC who were members of racial and ethnic minority groups, Black patients had significantly worse outcomes that were not completely explained by stage of presentation. There may be unexplored multilevel factors that are associated with social determinants of health and disparities in HNC outcomes.

Characteristics of U.S. Acute Care Hospitals That Have Implemented Telemedicine Critical Care.

OBJECTIVES: Telemedicine critical care is associated with improved efficiency, quality, and cost-effectiveness. As of 2010, fewer than 5% of U.S. hospitals had telemedicine critical care, and fewer than 10% of ICU beds were covered. We evaluated recent telemedicine critical care implementation and bed coverage rates in the United States and compared characteristics of hospitals with and without telemedicine critical care. DESIGN: Cross-sectional study of 2018 American Hospital Association Annual Survey Database. SETTING: U.S. hospitals. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We obtained data regarding telemedicine critical care implementation, ICU capability (defined as ≥ 1 ICU bed), other hospital characteristics, and the Herfindahl-Hirschman Index, a measure of ICU market competition based on hospital referral regions. Among 4,396 hospitals (response rate 71%), 788 (17.9%) had telemedicine critical care, providing potential coverage to 27,624 (28% of total) ICU beds. Among 306 hospital referral regions, 197 (64%) had a respondent hospital with telemedicine critical care. Telemedicine critical care implementation was associated with being a nonprofit (odds ratio, 7.75; 95% CI, 5.18-11.58) or public (odds ratio, 4.16 [2.57-6.73]) compared with for-profit hospital; membership in a health system (odds ratio, 3.83 [2.89-5.08]; stroke telemedicine presence (odds ratio, 6.87 [5.35-8.81]); ICU capability (odds ratio, 1.68 [1.25-2.26]); and more competitive ICU markets (odds ratio per 1,000-point decrease in Herfindahl-Hirschman Index 1.11 [1.01-1.22]). Notably, rural critical access hospitals had lower odds of telemedicine critical care implementation (odds ratio, 0.49 [0.34-0.70]). Teaching status, geographic region, and rurality were not associated with telemedicine critical care implementation. CONCLUSIONS: About one fifth of respondent hospitals had telemedicine critical care by 2018, providing potential coverage of nearly one third of reported ICU beds. This represents a substantial increase in telemedicine critical care implementation over the last decade. Future expansion to include more rural hospitals that could benefit most may be aided by addressing hospital financial and market barriers to telemedicine critical care implementation.

Adaptive Multi-task Elastic Net based feature selection from Pharmacogenomics Databases.

Integrating multiple databases of similar tasks is a significant problem in biological data analysis. In this paper, we consider whether feature selection in a single database can benefit from incorporating similar databases. We report that by using adaptive multi-task elastic net for feature selection and Random Forest for prediction, the prediction performance can be improved for pharmacogenomics databases. We also present a simulation study to explain the robust feature selection benefit of adaptive multi task elastic net while dealing with noisy features.

Correlation of three dimensional anorectal manometry and three dimensional endoanal ultrasound findings in primi gravida: a cross sectional study.

BACKGROUND: 3-dimensional anorectal manometry (3DARM) and 3-dimensional endoanal ultrasound (3DEAUS) have not been used to assess the anal sphincter complex (ASC) in primi gravida. This study was conducted to identify any correlation that may exist between 3DARM and 3DEAUS. METHODS: We analyzed 3DARM and 3DEAUS data of 101 consecutive primi mothers assessed in the late second trimester or early 3rd trimester. 3DARM was performed using the Given Imaging(®) Manoscan system and 3DEAUS was performed with the Olympus(®) RU 12M-R1 probe and EU-ME1 ultrasound system. RESULTS: The mean age was 24.7 (SD-5.1) years. All patients had a normal Cleveland Clinic Incontinence Score. The mean resting pressure (RP) was 87.02 (SD-18.43) mmHg and the maximum squeeze pressure (SP) was 179.21 (SD-52.96) mmHg. The mean length of the high pressure zone was 3.67 (SD-0.52) cm. On 3DEAUS, there were three characteristic segments of the ASC that were identified; upper, middle and lower. Mean thicknesses for both internal anal sphincter (IAS) and external anal sphincter (EAS) were identified for primi gravida. IAS was thicker anteriorly and at 9 o' clock positions and EAS was thicker posteriorly. There was good correlation in the length of the ASC at each quadrant between 3DARM and 3DEAUS. There was no correlation between either RP or SP thickness of IAS or EAS at each level and quadrant. CONCLUSION: Correlation is seen only in the length of ASC at each quadrant. No correlation exist between RP or SP and thickness of IAS and EAS.