A fast bootstrap algorithm for causal inference with large data.

Estimating causal effects from large experimental and observational data has become increasingly prevalent in both industry and research. The bootstrap is an intuitive and powerful technique used to construct standard errors and confidence intervals of estimators. Its application however can be prohibitively demanding in settings involving large data. In addition, modern causal inference estimators based on machine learning and optimization techniques exacerbate the computational burden of the bootstrap. The bag of little bootstraps has been proposed in non-causal settings for large data but has not yet been applied to evaluate the properties of estimators of causal effects. In this article, we introduce a new bootstrap algorithm called causal bag of little bootstraps for causal inference with large data. The new algorithm significantly improves the computational efficiency of the traditional bootstrap while providing consistent estimates and desirable confidence interval coverage. We describe its properties, provide practical considerations, and evaluate the performance of the proposed algorithm in terms of bias, coverage of the true 95% confidence intervals, and computational time in a simulation study. We apply it in the evaluation of the effect of hormone therapy on the average time to coronary heart disease using a large observational data set from the Women's Health Initiative.

Neurological Events Reported after COVID-19 Vaccines: An Analysis of VAERS.

OBJECTIVE: To identify the rates of neurological events following administration of mRNA (Pfizer, Moderna) or adenovirus vector (Janssen) vaccines in the U.S.. METHODS: We utilized publicly available data from the U.S. Vaccine Adverse Event Reporting System (VAERS) collected between January 1, 2021-June 14, 2021. All free text symptoms that were reported within 42 days of vaccine administration were manually reviewed and grouped into 36 individual neurological diagnostic categories. Post-vaccination neurological event rates were compared between vaccine types and to age-matched baseline incidence rates in the U.S. and rates of neurological events following COVID. RESULTS: Of 306,907,697 COVID vaccine doses administered during the study timeframe, 314,610 (0.1%) people reported any adverse event and 105,214 (0.03%) reported neurological adverse events in a median of 1 day (IQR0-3) from inoculation. Guillain-Barre Syndrome (GBS), and cerebral venous thrombosis (CVT) occurred in fewer than 1 per 1,000,000 doses. Significantly more neurological adverse events were reported following Janssen (Ad26.COV2.S) vaccination compared to either Pfizer-BioNtech (BNT162b2) or Moderna (mRNA-1273; 0.15% versus 0.03% versus 0.03% of doses, respectively,P<0.0001). The observed-to-expected ratios for GBS, CVT and seizure following Janssen vaccination were ≥1.5-fold higher than background rates. However, the rate of neurological events after acute SARS-CoV-2 infection was up to 617-fold higher than after COVID vaccination. INTERPRETATION: Reports of serious neurological events following COVID vaccination are rare. GBS, CVT and seizure may occur at higher than background rates following Janssen vaccination. Despite this, rates of neurological complications following acute SARS-CoV-2 infection are up to 617-fold higher than after COVID vaccination. This article is protected by copyright. All rights reserved.

Timing of headache after COVID-19 vaccines and its association with cerebrovascular events: An analysis of 41,700 VAERS reports.

BACKGROUND: Delayed-onset of headache seems a specific feature of cerebrovascular events after COVID-19 vaccines. METHODS: All consecutive events reported to the United States Vaccine Adverse Reporting System following COVID-19 vaccines (1 January to 24 June 2021), were assessed. The timing of headache onset post-vaccination in subjects with and without concomitant cerebrovascular events, including cerebral venous thrombosis, ischemic stroke, and intracranial haemorrhage was analysed. The diagnostic accuracy in predicting concurrent cerebrovascular events of the guideline- proposed threshold of three-days from vaccination to headache onset was evaluated. RESULTS: There were 314,610 events following 306,907,697 COVID-19 vaccine doses, including 41,700 headaches, and 178/41,700 (0.4%) cerebrovascular events. The median time between the vaccination and the headache onset was shorter in isolated headache (1 day vs. 4 (in cerebral venous thrombosis), 3 (in ischemic stroke), or 10 (in intracranial hemorrhage) days, all P < 0.001). Delayed onset of headache had an area under the curve of 0.83 (95% CI: 0.75-0.97) for cerebral venous thrombosis, 0.70 (95% CI: 0.63-76) for ischemic stroke and 0.76 (95% CI: 0.67-84) for intracranial hemorrhage, and >99% negative predictive value. CONCLUSION: Headache following COVID-19 vaccination occurs within 1 day and is rarely associated with cerebrovascular events. Delayed onset of headache 3 days post-vaccination was an accurate diagnostic biomarker for the occurrence of a concomitant cerebrovascular events.

More robust estimation of average treatment effects using kernel optimal matching in an observational study of spine surgical interventions.

Inverse probability of treatment weighting (IPTW), which has been used to estimate average treatment effects (ATE) using observational data, tenuously relies on the positivity assumption and the correct specification of the treatment assignment model, both of which are problematic assumptions in many observational studies. Various methods have been proposed to overcome these challenges, including truncation, covariate-balancing propensity scores, and stable balancing weights. Motivated by an observational study in spine surgery, in which positivity is violated and the true treatment assignment model is unknown, we present the use of optimal balancing by kernel optimal matching (KOM) to estimate ATE. By uniformly controlling the conditional mean squared error of a weighted estimator over a class of models, KOM simultaneously mitigates issues of possible misspecification of the treatment assignment model and is able to handle practical violations of the positivity assumption, as shown in our simulation study. Using data from a clinical registry, we apply KOM to compare two spine surgical interventions and demonstrate how the result matches the conclusions of clinical trials that IPTW estimates spuriously refute.

Does state malpractice environment affect outcomes following spinal fusions? A robust statistical and machine learning analysis of 549,775 discharges following spinal fusion surgery in the United States.

OBJECTIVE: Spine surgery is especially susceptible to malpractice claims. Critics of the US medical liability system argue that it drives up costs, whereas proponents argue it deters negligence. Here, the authors study the relationship between malpractice claim density and outcomes. METHODS: The following methods were used: 1) the National Practitioner Data Bank was used to determine the number of malpractice claims per 100 physicians, by state, between 2005 and 2010; 2) the Nationwide Inpatient Sample was queried for spinal fusion patients; and 3) the Area Resource File was queried to determine the density of physicians, by state. States were categorized into 4 quartiles regarding the frequency of malpractice claims per 100 physicians. To evaluate the association between malpractice claims and death, discharge disposition, length of stay (LOS), and total costs, an inverse-probability-weighted regression-adjustment estimator was used. The authors controlled for patient and hospital characteristics. Covariates were used to train machine learning models to predict death, discharge disposition not to home, LOS, and total costs. RESULTS: Overall, 549,775 discharges following spinal fusions were identified, with 495,640 yielding state-level information about medical malpractice claim frequency per 100 physicians. Of these, 124,425 (25.1%), 132,613 (26.8%), 130,929 (26.4%), and 107,673 (21.7%) were from the lowest, second-lowest, second-highest, and highest quartile states, respectively, for malpractice claims per 100 physicians. Compared to the states with the fewest claims (lowest quartile), surgeries in states with the most claims (highest quartile) showed a statistically significantly higher odds of a nonhome discharge (OR 1.169, 95% CI 1.139-1.200), longer LOS (mean difference 0.304, 95% CI 0.256-0.352), and higher total charges (mean difference [log scale] 0.288, 95% CI 0.281-0.295) with no significant associations for mortality. For the machine learning models-which included medical malpractice claim density as a covariate-the areas under the curve for death and discharge disposition were 0.94 and 0.87, and the R2 values for LOS and total charge were 0.55 and 0.60, respectively. CONCLUSIONS: Spinal fusion procedures from states with a higher frequency of malpractice claims were associated with an increased odds of nonhome discharge, longer LOS, and higher total charges. This suggests that medicolegal climate may potentially alter practice patterns for a given spine surgeon and may have important implications for medical liability reform. Machine learning models that included medical malpractice claim density as a feature were satisfactory in prediction and may be helpful for patients, surgeons, hospitals, and payers.

Optimal probability weights for estimating causal effects of time-varying treatments with marginal structural Cox models.

Marginal structural Cox models have been used to estimate the causal effect of a time-varying treatment on a survival outcome in the presence of time-dependent confounders. These methods rely on the positivity assumption, which states that the propensity scores are bounded away from zero and one. Practical violations of this assumption are common in longitudinal studies, resulting in extreme weights that may yield erroneous inferences. Truncation, which consists of replacing outlying weights with less extreme ones, is the most common approach to control for extreme weights to date. While truncation reduces the variability in the weights and the consequent sampling variability of the estimator, it can also introduce bias. Instead of truncated weights, we propose using optimal probability weights, defined as those that have a specified variance and the smallest Euclidean distance from the original, untruncated weights. The set of optimal weights is obtained by solving a constrained quadratic optimization problem. The proposed weights are evaluated in a simulation study and applied to the assessment of the effect of treatment on time to death among people in Sweden who live with human immunodeficiency virus and inject drugs.

Risk behaviour determinants among people who inject drugs in Stockholm, Sweden over a 10-year period, from 2002 to 2012.

BACKGROUND: People who inject drugs (PWID) frequently engage in injection risk behaviours exposing them to blood-borne infections. Understanding the underlying causes that drive various types and levels of risk behaviours is important to better target preventive interventions. METHODS: A total of 2150 PWID in Swedish remand prisons were interviewed between 2002 and 2012. Questions on socio-demographic and drug-related variables were asked in relation to the following outcomes: Having shared injection drug solution and having lent out or having received already used drug injection equipment within a 12 month recall period. RESULTS: Women shared solutions more than men (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.03; 2.21). Those who had begun to inject drugs before age 17 had a higher risk (OR 1.43, 95% CI 0.99; 2.08) of having received used equipment compared to 17-19 year olds. Amphetamine-injectors shared solutions more than those injecting heroin (OR 2.43, 95% CI 1.64; 3.62). A housing contract lowered the risk of unsafe injection by 37-59% compared to being homeless. CONCLUSIONS: Women, early drug debut, amphetamine users and homeless people had a significantly higher level of injection risk behaviour and need special attention and tailored prevention to successfully combat hepatitis C and HIV transmission among PWID. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02234167.

Impact of peer support on virologic failure in HIV-infected patients on antiretroviral therapy - a cluster randomized controlled trial in Vietnam.

BACKGROUND: The effect of peer support on virologic and immunologic treatment outcomes among HIVinfected patients receiving antiretroviral therapy (ART) was assessed in a cluster randomized controlled trial in Vietnam. METHODS: Seventy-one clusters (communes) were randomized in intervention or control, and a total of 640 patients initiating ART were enrolled. The intervention group received peer support with weekly home-visits. Both groups received first-line ART regimens according to the National Treatment Guidelines. Viral load (VL) (ExaVir™ Load) and CD4 counts were analyzed every 6 months. The primary endpoint was virologic failure (VL >1000 copies/ml). Patients were followed up for 24 months. Intention-to-treat analysis was used. Cluster longitudinal and survival analyses were used to study time to virologic failure and CD4 trends. RESULTS: Of 640 patients, 71% were males, mean age 32 years, 83% started with stavudine/lamivudine/nevirapine regimen. After a mean of 20.8 months, 78% completed the study, and the median CD4 increase was 286 cells/µl. Cumulative virologic failure risk was 7.2%. There was no significant difference between intervention and control groups in risk for and time to virologic failure and in CD4 trends. Risk factors for virologic failure were ART-non-naïve status [aHR 6.9;(95% CI 3.2-14.6); p < 0.01]; baseline VL ≥100,000 copies/ml [aHR 2.3;(95% CI 1.2-4.3); p < 0.05] and incomplete adherence (self-reported missing more than one dose during 24 months) [aHR 3.1;(95% CI 1.1-8.9); p < 0.05]. Risk factors associated with slower increase of CD4 counts were: baseline VL ≥100,000 copies/ml [adj.sq.Coeff (95% CI): -0.9 (-1.5;-0.3); p < 0.01] and baseline CD4 count <100 cells/µl [adj.sq.Coeff (95% CI): -5.7 (-6.3;-5.4); p < 0.01]. Having an HIV-infected family member was also significantly associated with gain in CD4 counts [adj.sq.Coeff (95% CI): 1.3 (0.8;1.9); p < 0.01]. CONCLUSION: There was a low virologic failure risk during the first 2 years of ART follow-up in a rural low-income setting in Vietnam. Peer support did not show any impact on virologic and immunologic outcomes after 2 years of follow up. TRIAL REGISTRATION: NCT01433601 .

Patient Characteristics Impacting Adherence to Serial Observation for Vestibular Schwannomas.

OBJECTIVE: To examine patient characteristics that impact serial observation adherence among vestibular schwannoma (VS) patients. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary care center. METHODS: We selected for VS patients from 201 to 2020 who elected for serial observation as initial management. Patients under 18, with previous management, bilateral or intralabyrinthine VS, and neurofibromatosis type 2 were excluded. Demographics, tumor characteristics, and follow-up status were extracted. Single and multiple logistic regression was used to identify patient characteristics impacting follow-up. RESULTS: We identified 507 VS patients who chose serial observation as initial management. Most were female (56.0%), white (73.0%), and married (72.8%). The mean age was 59.3 and most had private insurance (56.4%). Median Charlson Comorbidity Index was 2.00. Mean pure tone audiometry (PTA) average was 41.7 Hz. Average tumor size was 9.04 mm. Of 507 patients, 358 (70.6%) returned for at least one follow-up. On multiple logistic regression analysis, patients with private insurance (odds ratio [OR]: 0.39, confidence interval [CI]: 0.22-0.68; P = .001), racial minority background (OR: 0.54, CI: 0.35-0.83; P = .005), worse PTA averages (OR: 0.99, CI: 0.98-1.00; P = .044), and older age at diagnosis (OR: 0.97, CI: 0.95-1.00; P = .038) were less likely to follow-up. CONCLUSION: Private health insurance, racial minority background, worse PTA average, and older age were associated with decreased follow-up among adult VS patients electing serial observation. Patients with these characteristics may require additional support to ensure serial observation adherence.

Comparison of four ventilation tubes commonly used in the pediatric population: A retrospective cohort study.

Objective: To assess differences in otorrhea, tympanic membrane perforation, and time to extrusion in children receiving one of four commonly used, short-term ventilation tubes for the first time. Methods: Retrospective chart review of 2 years of postoperative follow-up to analyze patient outcomes after insertion of either a Paparella type-I Activent, Armstrong Beveled, Modified Armstrong, or Armstrong Microgel ventilation tube. Incidence of complications was determined by reviewing provider notes. Adjusted multivariate logistic regression models were used to determine odds ratios of complications among the four tube types. Results: A total of 387 patients were reviewed. The mean age was 2.4 years and 35.9% were female. Armstrong beveled tubes had the highest odds of otorrhea. Paparella type-I tube had the shortest time to extrusion of about 9 months, while Armstrong Beveled had the longest, at almost 19 months. When evaluating episodes of otorrhea each child experienced on average, per month, Armstrong beveled tubes had the highest monthly rate of otorrhea and Paparella type-I the least. No significant differences were found regarding tympanic membrane perforation. Conclusions: This retrospective chart review showed that no tube was clinically superior across all complications. The findings from this study may give otolaryngologists an opportunity to consider choosing a specific type of tube according to the clinical situation. The large variations in extrusion times should be considered in terms of patient age, seasonality, and desired duration of tube placement. Level of Evidence: 4.

Adjuvant Radiotherapy in Moderately Advanced (T3) Oral Cavity Cancers.

OBJECTIVE: To investigate the impact of adjuvant radiotherapy in isolated locally advanced oral cavity cancers (pT3N0M0) without adverse features. METHODS: We selected all patients from the National Cancer Database (2004-2019) who underwent surgical treatment where the final pathology was T3N0M0 with negative margins. Demographics, details of treatment, and outcomes were abstracted. The impact of radiotherapy on survival was assessed with univariable, multivariable, and propensity score-matched analyses. RESULTS: We identified 571 patients in our survival cohort. Most were male (348, 60.9%), and median age was 65. Less than one-third (176, 30.8%) received adjuvant radiotherapy. The median length of follow-up was 29 months. Overall, adjuvant radiotherapy was associated with improved survival (87.2% vs. 77.7%, at 2 years, p < 0.01). On multivariable analysis controlling for age and comorbidities, this survival difference persisted (HR: 0.62, 95% CI: 0.43-0.90, p = 0.01). In a propensity score-matched population of 278 patients matched on age and comorbidities, adjuvant radiotherapy was still associated with longer survival (87.4% vs. 78.5%, p = 0.014). CONCLUSION: In our study, adjuvant radiotherapy was associated with improved survival in completely excised locally advanced oral cavity tumors (T3N0M0). However, a significant proportion of patients do not receive adjuvant radiotherapy. These findings highlight the need for continued efforts to promote guideline-recommended care. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2236-2242, 2024.

Acute Effects of Steroids on Vocal Fold Epithelium Post-injury in a Preclinical Model.

INTRODUCTION: Glucocorticoids (GCs) are commonly prescribed for laryngeal indications due to their potent anti-inflammatory properties. However, GCs effect on vocal fold (VF) epithelial morphology and barrier function following injury is overlooked and may be key to efficacy. In this study, the effects of GCs on epithelial morphology and barrier function were quantified in injured VFs. We seek to increase our understanding of biochemical processes underlying GC mechanisms to refine therapeutic strategies. METHODS: Microflap injury was induced in 65 rabbits. Seven days after injury, animals received bilateral 20 µL intracordal injections of saline, dexamethasone, methylprednisolone, or triamcinolone (n = 15 per condition). Five rabbits in each condition were euthanized 1, 7, or 60 days following treatment. An additional five animals served as non-injured/untreated controls. To quantify transepithelial electrical resistance (TEER), 1 mm epithelial biopsies were placed in an Ussing chamber. The contralateral VF was processed for transmission electron microscopy and epithelial depth analysis. RESULTS: At 60 days, GC treatment maintained TEER levels similar to non-injured/untreated controls. However, triamcinolone reduced TEER compared with saline-treated conditions. Acutely, epithelial hyperplasia typically persisted in all injured VFs. At 60 days, only dexamethasone and triamcinolone increased epithelial depth in injured VFs; all GCs increased epithelial depth compared with non-injured/untreated controls. CONCLUSION: Acutely, GCs did not alter TEER. Additionally, GCs did not alter epithelial depth compared with saline treatment, indicating alignment with natural healing responses. At 60 days, GCs exhibited varying degrees of TEER restoration and epithelial hyperplasia, possibly due to distinct pharmacodynamic profiles. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Clinical prediction for surgical versus nonsurgical interventions in patients with vertebral osteomyelitis and discitis.

Background: Vertebral osteomyelitis and discitis (VOD), an infection of intervertebral discs, often requires spine surgical intervention and timely management to prevent adverse outcomes. Our study aims to develop a machine learning (ML) model to predict the indication for surgical intervention (during the same hospital stay) versus nonsurgical management in patients with VOD. Methods: This retrospective study included adult patients (≥18 years) with VOD (ICD-10 diagnosis codes M46.2,3,4,5) treated at a single institution between 01/01/2015 and 12/31/2019. The primary outcome studied was surgery. Candidate predictors were age, sex, race, Elixhauser comorbidity index, first-recorded lab values, first-recorded vital signs, and admit diagnosis. After splitting the dataset, XGBoost, logistic regression, and K-neighbor classifier algorithms were trained and tested for model development. Results: A total of 1,111 patients were included in this study, among which 30% (n=339) of patients underwent surgical intervention. Age and sex did not significantly differ between the two groups; however, race did significantly differ (P<0.0001), with the surgical group having a higher percentage of white patients. The top ten model features for the best-performing model (XGBoost) were as follows (in descending order of importance): admit diagnosis of fever, negative culture, Staphylococcus aureus culture, partial pressure of arterial oxygen to fractional inspired oxygen ratio (PaO2:FiO2), admit diagnosis of intraspinal abscess and granuloma, admit diagnosis of sepsis, race, troponin I, acid-fast bacillus culture, and alveolar-arterial gradient (A-a gradient). XGBoost model metrics were as follows: accuracy =0.7534, sensitivity =0.7436, specificity =0.7586, and area under the curve (AUC) =0.8210. Conclusions: The XGBoost model reliably predicts the indication for surgical intervention based on several readily available patient demographic information and clinical features. The interpretability of a supervised ML model provides robust insight into patient outcomes. Furthermore, it paves the way for the development of an efficient hospital resource allocation instrument, designed to guide clinical suggestions.

Reducing Length of Stay in Reconstructive Head and Neck Surgery Patients: A Quality Improvement Initiative.

OBJECTIVE: To investigate whether a new preoperative education and discharge planning protocol reduced unexpected discharge delays for patients undergoing reconstructive surgery for head and neck cancer. METHODS: A quality improvement (QI) intervention was implemented in January 2021 with several components to address historically prolonged observed lengths of stay (LOS) with head and neck cancer patients. The intervention added a preoperative educational visit with a head and neck cancer advanced practice provider, a standardized preoperative speech and swallow assessment, a personalized patient care plan document, discussion of inpatient hospital stay expectations, and early discharge planning. The intervention group included patients who underwent the preoperative education protocol from February to December 2021. For comparison, an age and sex-matched control group was constructed from inpatients who had been admitted for similar procedures in the 2 years prior to the QI intervention (2019-2020) and received standard of care counseling. RESULTS: Our study demonstrated a significant reduction in observed to expected LOS ratio after implementation of the intervention (1.24 ± 0.74 control, 0.95 ± 0.52 intervention; P = .012). DISCUSSION: We discuss a preoperative education QI intervention at our institution. Our findings demonstrate that our intervention was associated with decreased LOS for patients undergoing head and neck reconstructive surgeries. IMPLICATIONS FOR PRACTICE: This QI study shows the benefit of a new standardized preoperative education and discharge planning protocol for patients undergoing head and neck reconstructive surgeries.

Anti-spike antibody responses to SARS-CoV-2 mRNA vaccines in people with schizophrenia and schizoaffective disorder.

Importance: Individuals with schizophrenia are at higher risk for severe COVID-19 illness and severe breakthrough infection following vaccination. It is unclear whether immune response to vaccination differs in this population. Objective: To assess whether anti-SARS-CoV-2 spike antibody titers after vaccination differ in people with a diagnosis of schizophrenia or schizoaffective disorder (SZ) compared to controls without a psychiatric disorder. Design: This cohort study assessed antibody response following the first and second dose of mRNA vaccines at longitudinal timepoints, up to 7 weeks following the first dose of vaccine. Setting: A multi-center study including psychiatric healthcare settings in the United States and Europe. Participants: 205 adults with no history of COVID-19 infection, including 106 individuals with SZ and 99 controls without a psychiatric disorder, who received their first dose of SARS-CoV-2 mRNA vaccine between December 20, 2020 and May 27, 2021. Main outcomes and measures: Mean SARS-CoV-2 anti-Spike IgG antibody levels within 7 weeks after the first dose of vaccination. Results: A total of 205 individuals (mean [SD] age, 44.7 [12.0] years; 90 [43.9%] male) were included, of which 106 (51.7%) were diagnosed with SZ. SZ was associated with lower mean log antibody levels (-0.15; 95% CI, -0.27 to -0.03, P = 0.016) after adjusting for age, sex, body mass index, smoking, days since vaccination, and vaccine manufacturer. In secondary analyses of dose-specific responses, SZ was associated with a lower mean log antibody level after the second dose of vaccine (-0.23; 95% CI -0.39 to -0.06, P = 0.006), but not the first dose of vaccine (0.00; 95% CI -0.18- 0.19, P = 0.96). Conclusions and Relevance: In this cohort study of individuals with SZ and a control group without psychiatric disorders, SZ was associated with lower SARS-CoV-2 anti-spike antibody levels following 2 doses of SARS-CoV-2 mRNA vaccination. This highlights the need for further studies assessing vaccine immunogenicity in individuals with schizophrenia.

Robust weights that optimally balance confounders for estimating marginal hazard ratios.

Covariate balance is crucial in obtaining unbiased estimates of treatment effects in observational studies. Methods that target covariate balance have been successfully proposed and largely applied to estimate treatment effects on continuous outcomes. However, in many medical and epidemiological applications, the interest lies in estimating treatment effects on time-to-event outcomes. With this type of data, one of the most common estimands of interest is the marginal hazard ratio of the Cox proportional hazards model. In this article, we start by presenting robust orthogonality weights, a set of weights obtained by solving a quadratic constrained optimization problem that maximizes precision while constraining covariate balance defined as the correlation between confounders and treatment. By doing so, robust orthogonality weights optimally deal with both binary and continuous treatments. We then evaluate the performance of the proposed weights in estimating marginal hazard ratios of binary and continuous treatments with time-to-event outcomes in a simulation study. We finally apply robust orthogonality weights in the evaluation of the effect of hormone therapy on time to coronary heart disease and on the effect of red meat consumption on time to colon cancer among 24,069 postmenopausal women enrolled in the Women's Health Initiative observational study.

Point-of-Care Chemistry-Guided Dialysate Adjustment to Reduce Arrhythmias: A Pilot Trial.

Introduction: Excessive dialytic potassium (K) and acid removal are risk factors for arrhythmias; however, treatment-to-treatment dialysate modification is rarely performed. We conducted a multicenter, pilot randomized study to test the safety, feasibility, and efficacy of 4 point-of-care (POC) chemistry-guided protocols to adjust dialysate K and bicarbonate (HCO3) in outpatient hemodialysis (HD) clinics. Methods: Participants received implantable cardiac loop monitors and crossed over to four 4-week periods with adjustment of dialysate K or HCO3 at each treatment according to pre-HD POC values: (i) K-removal minimization, (ii) K-removal maximization, (iii) Acidosis avoidance, and (iv) Alkalosis avoidance. The primary end point was percentage of treatments adhering to the intervention algorithm. Secondary endpoints included pre-HD K and HCO variability, adverse events, and rates of clinically significant arrhythmias (CSAs). Results: Nineteen subjects were enrolled in the study. HD staff completed POC testing and correctly adjusted the dialysate in 604 of 708 (85%) of available HD treatments. There was 1 K ≤3, 29 HCO3 <20 and 2 HCO3 >32 mEq/l and no serious adverse events related to study interventions. Although there were no significant differences between POC results and conventional laboratory measures drawn concurrently, intertreatment K and HCO3 variability was high. There were 45 CSA events; most were transient atrial fibrillation (AF), with numerically fewer events during the alkalosis avoidance period (8) and K-removal maximization period (3) compared to other intervention periods (17). There were no significant differences in CSA duration among interventions. Conclusion: Algorithm-guided K/HCO3 adjustment based on POC testing is feasible. The variability of intertreatment K and HCO3 suggests that a POC-laboratory-guided algorithm could markedly alter dialysate-serum chemistry gradients. Definitive end point-powered trials should be considered.

Acceptance and Benefit of Electroacoustic Stimulation in Children.

OBJECTIVE: Children with high-frequency severe-to-profound hearing loss and low-frequency residual hearing who do not derive significant benefit from hearing aids are now being considered for cochlear implantation. Previous research shows that hearing preservation is possible and may be desirable for the use of electroacoustic stimulation (EAS) in adults, but this topic remains underexplored in children. The goal of this study was to explore factors relating to hearing preservation, acceptance, and benefits of EAS for children. STUDY DESIGN: Retrospective review. SETTING: Tertiary academic medical center. PATIENTS: Forty children (48 ears) with preoperative low-frequency pure-tone averages of 75 dB HL or less at 250 and 500 Hz (n = 48). INTERVENTION: All patients underwent cochlear implantation with a standard-length electrode. MAIN OUTCOME MEASURE: Low-frequency audiometric thresholds, speech perception, and EAS usage were measured at initial stimulation, and 3 and 12 months postoperatively. Outcomes were compared between children with and without hearing preservation, and between EAS users and nonusers. RESULTS: Hearing was preserved at similar rates as adults but worse for children with an enlarged vestibular aqueduct. Fewer than half of children who qualified to use EAS chose to do so, citing a variety of audiologic and nonaudiologic reasons. No differences were detected in speech perception scores across the groups for words, sentences, or sentences in noise tests. CONCLUSIONS: Neither hearing preservation nor EAS use resulted in superior speech perception in children with preoperative residual hearing; rather, all children performed well after implantation.

Cochlear Implantation Outcomes in Patients With Retrocochlear Pathology: A Systematic Review and Pooled Analysis.

OBJECTIVE: To review the current literature regarding cochlear implantation in patients with retrocochlear pathologies and extract speech perception scores between 6 months and 1 year after surgery. DATABASES REVIEWED: PubMed/MEDLINE, Embase and Cochrane CENTRAL via Ovid, CINAHL Complete via Ebsco, and Web of Science. METHODS: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Search strategies included keywords and subject headings to maximize retrieval and reflect cochlear implants and retrocochlear pathologies. Patients with previously resected vestibular schwannoma (VS) were excluded. RESULTS: There were 2,524 abstracts screened against inclusion criteria, and 53 studies were included, with individual data available for 171 adult patients. Pathologies included were either observed or irradiated VS (previously operated tumors were excluded) (n = 99, 57.9%), superficial siderosis (n = 39, 22.8%), neurosarcoidosis (n = 11, 6.4%), and previous central nervous system or skull base radiation (n = 22, 12.9%). Mean (standard deviation) postoperative consonant-nucleus-consonant (CNC) word scores were 45.4% (24.2) for observed VS, 44.4% (20.8) for irradiated VS, 43.6% (21.0) for superficial siderosis, 89.5% (3.0) for neurosarcoidosis, and 30.0% (30.2) in patients with previous central nervous system or skull base irradiation. Irradiated compared with observed VS had similar postoperative CNC word scores (effect size, 0.06; p = 0.71). Age, sex, maximal tumor dimension, and neurofibromatosis type 2 status did not significantly impact cochlear implant performance in patients with VS. Eighty-two percent of patients with reported device usage were daily users, and overall, 82% of cases benefitted from cochlear implantation. CONCLUSION: Cochlear implantation in patients with concomitant retrocochlear pathology generally results in improved speech discrimination scores sustained over time.