Behavioural and neuropsychological outcomes in children exposed in utero to maternal labour epidural analgesia.

BACKGROUND: Recent studies report conflicting results regarding the relationship between labour epidural analgesia (LEA) in mothers and neurodevelopmental disorders in their offspring. We evaluated behavioural and neuropsychological test scores in children of mothers who used LEA. METHODS: Children enrolled in the Raine Study from Western Australia and delivered vaginally from a singleton pregnancy between 1989 and 1992 were evaluated. Children exposed to LEA were compared with unexposed children. The primary outcome was the parent-reported Child Behaviour Checklist (CBCL) reporting total, internalising, and externalising behavioural problem scores at age 10 yr. Score differences, an increased risk of clinical deficit, and a dose-response based on the duration of LEA exposure were assessed. Secondary outcomes included language, motor function, cognition, and autistic traits. RESULTS: Of 2180 children, 850 (39.0%) were exposed to LEA. After adjustment for covariates, exposed children had minimally increased CBCL total scores (+1.41 points; 95% confidence interval [CI] 0.09 to 2.73; P=0.037), but not internalising (+1.13 points; 95% CI -0.08 to 2.34; P=0.066) or externalising (+1.08 points; 95% CI -0.08 to 2.24; P=0.068) subscale subscores. Increased risk of clinical deficit was not observed for any CBCL score. For secondary outcomes, score differences were inconsistently observed in motor function and cognition. Increased exposure duration was not associated with worse scores in any outcomes. CONCLUSIONS: Although LEA exposure was associated with slightly higher total behavioural scores, there was no difference in subscores, increased risk of clinical deficits, or dose-response relationship. These results argue against LEA exposure being associated with consistent, clinically significant neurodevelopmental deficits in children.

Mode of delivery and behavioral and neuropsychological outcomes in children at 10 years of age.

OBJECTIVES: Previous studies have reported that mode of delivery, particularly cesarean delivery (CD), is associated with neurodevelopmental outcomes in children. This study evaluates behavioral and neuropsychological test scores in children based on mode of delivery. METHODS: Children enrolled in the Raine Study from Western Australia, born between 1989 and 1992 by instrumental vaginal delivery (IVD), elective CD, and non-elective CD, were compared to those with spontaneous vaginal delivery (SVD). The primary outcome was the Child Behavior Checklist (CBCL) administered at age 10. Secondary outcomes included evaluations of language, motor function, cognition, and autistic traits. Multivariable linear regression was used to evaluate score differences by mode of delivery adjusted for sociodemographic and clinical characteristics, and Poisson regression was used to evaluate for increased risk of clinical deficit. RESULTS: Of 2,855 children, 1770 (62.0 %) were delivered via SVD, 480 (16.8 %) via IVD, 346 (12.1 %) via elective CD, and 259 (9.1 %) via non-elective CD. Non-elective CD was associated with higher (worse) CBCL Internalizing (+2.09; 95 % CI 0.49, 3.96; p=0.01) scores, and elective CD was associated with lower (worse) McCarron Assessment of Neuromuscular Development (MAND) (-3.48; 95 % CI -5.61, -1.35; p=0.001) scores. Differences were not seen in other outcomes, and increased risk of clinical deficit was not observed with either the CBCL Internalizing or MAND scores. CONCLUSIONS: Differences in behavior and motor function were observed in children delivered by CD, but given that score differences were not associated with increased incidence of clinical deficit, clinical significance may be limited.

Intraoperative Blood Pressure and Long-Term Neurodevelopmental Function in Children Undergoing Ambulatory Surgery.

BACKGROUND: Some studies have found surgery and anesthesia in children to be associated with neurodevelopmental deficits, but specific reasons for this association have not been fully explored. This study evaluates intraoperative mean arterial pressure (MAP) during a single ambulatory procedure in children and subsequent mental disorder diagnoses. METHODS: A retrospective observational study was performed including children ≥28 days and <18 years of age with intraoperative electronic anesthetic records between January 1, 2009, and April 30, 2017, at our institution. Eligible children were categorized based on their mean intraoperative MAP relative to other children of the same sex and similar age: category 1 (very low): children with mean intraoperative MAP values below the 10th percentile, category 2 (low): mean MAP value ≥10th and <25th percentiles, category 3 (reference): mean MAP value ≥25th and <75th percentiles, category 4 (high): mean MAP value ≥75th and <90th percentile, and category 5 (very high): mean MAP value ≥90th percentile. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) and ICD, Tenth Revision, Clinical Modification (ICD-10)-coded mental disorders were identified in hospital and outpatient claims, with a median duration of follow-up after surgery of 120 days (interquartile range [IQR], 8-774.5 days). Cox proportional hazards models evaluated the hazard ratio (HR) of time to first mental disorder diagnosis associated with intraoperative blood pressure category between the end of surgery and censoring, with the primary analysis adjusting for demographic, anesthetic, comorbidity, and procedure-type variables as potential confounders. RESULTS: A total of 14,724 eligible children who received general anesthesia for a single ambulatory surgical procedure were identified. After adjusting for all available potential confounders, when compared to the reference, there were no statistically significant differences in mental disorder diagnosis risk based on intraoperative mean MAP category. Compared to reference, children in the very low and low blood pressure categories reported HRs of 1.00 (95% confidence interval [CI], 0.74-1.35) and 1.10 (95% CI, 0.87-1.41) for a mental disorder diagnosis, respectively, and children in the high and very high categories reported HRs of 0.87 (95% CI, 0.68-1.12) and 0.76 (95% CI, 0.57-1.03), respectively. CONCLUSIONS: Presence in a predefined mean intraoperative MAP category was not associated with subsequent mental disorder diagnoses within our follow-up period. However, the limitations of this study, including uncertainty regarding what constitutes an adequate blood pressure in children, may limit the ability to form definitive conclusions.

Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit.

BACKGROUND: Exposure to surgery and anesthesia in early childhood has been found to be associated with an increased risk of behavioral deficits. While the US Food and Drug Administration (FDA) has warned against prenatal exposure to anesthetic drugs, little clinical evidence exists to support this recommendation. This study evaluates the association between prenatal exposure to general anesthesia due to maternal procedures during pregnancy and neuropsychological and behavioral outcome scores at age 10. METHODS: This is an observational cohort study of children born in Perth, Western Australia, with 2 generations of participants contributing data to the Raine Study. In the Raine Study, the first generation (Gen1) are mothers enrolled during pregnancy, and the second generation (Gen2) are the children born to these mothers from 1989 to 1992 with neuropsychological and behavioral tests at age 10 (n=2024). In the primary analysis, 6 neuropsychological and behavioral tests were evaluated at age 10: Raven's Colored Progressive Matrices (CPM), McCarron Assessment of Neuromuscular Development (MAND), Peabody Picture Vocabulary Test (PPVT), Symbol Digit Modality Test (SDMT) with written and oral scores, Clinical Evaluation of Language Fundamentals (CELF) with Expressive, Receptive, and Total language scores, and Child Behavior Checklist (CBCL) with Internalizing, Externalizing, and Total behavior scores. Outcome scores of children prenatally exposed to general anesthesia were compared to children without prenatal exposure using multivariable linear regression models adjusting for demographic and clinical covariates (sex, race, income, and maternal education, alcohol or tobacco use, and clinical diagnoses: diabetes, epilepsy, hypertension, psychiatric disorders, or thyroid dysfunction). Bonferroni adjustment was used for the 6 independent tests in the primary analysis, so a corrected P value <.0083 (P = .05 divided by 6 tests, or a 99.17% confidence interval [CI]) was required for statistical significance. RESULTS: Among 2024 children with available outcome scores, 22 (1.1%) were prenatally exposed to general anesthesia. Prenatally exposed children had higher CBCL Externalizing behavioral scores (score difference of 6.1 [99.17% CI, 0.2-12.0]; P = .006) than unexposed children. Of 6 tests including 11 scores and subscores, only CBCL Externalizing behavioral scores remained significant after multiple comparisons adjustment with no significant differences found in any other score. CONCLUSIONS: Prenatal exposure to general anesthetics is associated with increased externalizing behavioral problems in childhood. However, given the limitations of this study and that avoiding necessary surgery during pregnancy can have significant detrimental effects on the mother and the child, further studies are needed before changes to clinical practice are made.

Long-Term Increases in Mental Disorder Diagnoses After Invasive Mechanical Ventilation for Severe Childhood Respiratory Disease: A Propensity Matched Observational Cohort Study.

OBJECTIVES: To evaluate neurodevelopmental and mental disorders after PICU hospitalization in children requiring invasive mechanical ventilation for severe respiratory illness. DESIGN: Retrospective longitudinal observational cohort. SETTING: Texas Medicaid Analytic eXtract data from 1999 to 2012. PATIENTS: Texas Medicaid-enrolled children greater than or equal to 28 days old to less than 18 years old hospitalized for a primary respiratory illness, without major chronic conditions predictive of abnormal neurodevelopment. INTERVENTIONS: We examined rates of International Classification of Diseases, 9th revision-coded mental disorder diagnoses and psychotropic medication use following discharge among children requiring invasive mechanical ventilation for severe respiratory illness, compared with general hospital patients propensity score matched on sociodemographic and clinical characteristics prior to admission. Children admitted to the PICU for respiratory illness not necessitating invasive mechanical ventilation were also compared with matched general hospital patients as a negative control exposure. MEASUREMENTS AND MAIN RESULTS: Of 115,335 eligible children, 1,351 required invasive mechanical ventilation and were matched to 6,755 general hospital patients. Compared with general hospital patients, children requiring invasive mechanical ventilation had increased mental disorder diagnoses (hazard ratio, 1.43 [95% CI, 1.26-1.64]; p < 0.0001) and psychotropic medication use (hazard ratio, 1.67 [1.34-2.08]; p < 0.0001) following discharge. Seven-thousand seven-hundred eighty children admitted to the PICU without invasive mechanical ventilation were matched to 38,900 general hospital patients and had increased mental disorder diagnoses (hazard ratio, 1.08 [1.02-1.15]; p = 0.01) and psychotropic medication use (hazard ratio, 1.11 [1.00-1.22]; p = 0.049). CONCLUSIONS: Children without major comorbidity requiring invasive mechanical ventilation for severe respiratory illness had a 43% higher incidence of subsequent mental disorder diagnoses and a 67% higher incidence of psychotropic medication use. Both increases were substantially higher than in PICU patients with respiratory illness not necessitating invasive mechanical ventilation. Invasive mechanical ventilation is a life-saving therapy, and its application is interwoven with underlying health, illness severity, and PICU management decisions. Further research is required to determine which factors related to invasive mechanical ventilation and severe respiratory illness are associated with abnormal neurodevelopment. Given the increased risk in these children, identification of strategies for prevention, neurodevelopmental surveillance, and intervention after discharge may be warranted.

Causal inference when counterfactuals depend on the proportion of all subjects exposed.

The assumption that no subject's exposure affects another subject's outcome, known as the no-interference assumption, has long held a foundational position in the study of causal inference. However, this assumption may be violated in many settings, and in recent years has been relaxed considerably. Often this has been achieved with either the aid of a known underlying network, or the assumption that the population can be partitioned into separate groups, between which there is no interference, and within which each subject's outcome may be affected by all the other subjects in the group via the proportion exposed (the stratified interference assumption). In this article, we instead consider a complete interference setting, in which each subject affects every other subject's outcome. In particular, we make the stratified interference assumption for a single group consisting of the entire sample. We show that a targeted maximum likelihood estimator for the i.i.d. setting can be used to estimate a class of causal parameters that includes direct effects and overall effects under certain interventions. This estimator remains doubly-robust, semiparametric efficient, and continues to allow for incorporation of machine learning under our model. We conduct a simulation study, and present results from a data application where we study the effect of a nurse-based triage system on the outcomes of patients receiving HIV care in Kenyan health clinics.

A class of semiparametric tests of treatment effect robust to confounder measurement error.

When assessing the presence of an exposure causal effect on a given outcome, measurement error of a confounder can inflate the type I error rate of a treatment effect in even the simplest of settings. In this paper, we develop a large class of semiparametric test statistics of an exposure causal effect, which are completely robust to additive unbiased measurement error of a subset of confounders. A unique and appealing feature of our proposed methodology is that it requires no external information such as validation data or replicates of error-prone confounders. We present a doubly robust form of this test that requires the exposure mean model to be linear in the mismeasured confounders, and only one of two models involving error-free confounders to be correctly specified for the resulting test statistic to have correct type I error rate. We demonstrate validity within our class of test statistics through simulation studies. We apply the methods to a multi-US-city time-series data set to test for an effect of temperature on mortality while adjusting for atmospheric particulate matter with diameter of 2.5 micrometres or less, which is known to be measured with error.

Sex differences in the relationship between body composition and cardiac structure and function.

AIMS: The purpose of this study was to characterize sex differences in the relationship between body composition and cardiac structure and function. In secondary analyses, we explored pathophysiologic mediators of these relationships. METHODS AND RESULTS: In a cross-sectional analysis of 25,063 UK Biobank participants (54% female, median age 55 years), the sex-specific associations of visceral adipose tissue volume (VAT), appendicular lean mass (ALM), and muscle fat infiltration (MFI) with cardiac magnetic resonance (CMR) measures of cardiac structure and function were assessed using linear regression models. Using causal mediation analysis, 10 biomarkers were explored as mediators of the relationship between adipose depots and cardiac parameters. VAT was associated with increased left ventricular mass (LVM; ßwomen = 0.54, ßmen = 0.00, pint = 0.01) and wall thickness (ßwomen = 0.12, ßmen = 0.08, pint<0.001) in women only. A similar sex-specific pattern was observed for MFI effects on LVM (ßwomen = 0.44, ßmen = 0.03, pint<0.001). ALM was associated with increased LVM and LV volumes in both women and men. In mediation analyses, insulin resistance as measured by triglycerides/high density lipoprotein ratio was a potential partial mediator of VAT effects on chamber dimensions. CONCLUSIONS: In the largest and most rigorous analyses of body composition and cardiac parameters to date, we demonstrated that VAT is associated with increased LVM and wall thickness in women but not in men. MFI association with cardiac parameters was similar to VAT, significant in women but not in men.

Longitudinal Changes in the Operative Experience for Junior Urology Residents.

OBJECTIVE: To evaluate longitudinal trends in surgical case volume among junior urology residents. There is growing perception that urology residents are not prepared for independent practice, which may be linked to decreased exposure to major cases early in residency. METHODS: Retrospective review of deidentified case logs from urology residency graduates from 12 academic medical centers in the United States from 2010 to 2017. The primary outcome was the change in major case volume for first-year urology (URO1) residents (after surgery internship), measured using negative binomial regression. RESULTS: A total of 391,399 total cases were logged by 244 residency graduates. Residents performed a median of 509 major cases, 487 minor cases, and 503 endoscopic cases. From 2010 to 2017, the median number of major cases performed by URO1 residents decreased from 64 to 49 (annual incidence rate ratio 0.90, P < .001). This trend was limited to oncology cases, with no change in reconstructive or pediatric cases. The number of major cases decreased more for URO1 residents than for residents at other levels (P-values for interaction <.05). The median number of endoscopic cases performed by URO1 residents increased from 85 to 194 (annual incidence rate ratio 1.09, P < .001), which was also disproportionate to other levels of residency (P-values for interaction <.05). CONCLUSION: There has been a shift in case distribution among URO1 residents, with progressively less exposure to major cases and an increased focus on endoscopic surgery. Further investigation is needed to determine if this trend has implications on the surgical proficiency of residency graduates.

Effects of race and socioeconomic status on treatment for localized renal masses in New York City.

INTRODUCTION: Partial nephrectomy (PN) is the preferred treatment for localized renal masses (LRM), however its use is not uniform across patient socioeconomic (SES) factors. Our hypothesis is that the effect of increased SES on surgical management of LRMs in New York City (NYC) will not be the same for Black and White patients. PATIENTS AND METHODS: Patients were identified from the New York State Cancer Registry (NYSPACED) treated for LRMs with PN or radical nephrectomy from 2004 to 2016. We identified patients' home neighborhoods through Public Use Microdata Areas (PUMA) in NYSCAPED and used a US Census SES index. Logistic regression was used to determine the association of race and SES on receipt of PN, controlling for age, ethnicity, gender, and diagnosis year. RESULTS: On unadjusted analyses, patients from higher PUMA SES quartiles were more likely to receive PN (OR = 1.07, P < 0.05), while Black patients were less likely to receive PN as compared to White patients (OR = 0.66, P < 0.001). Multivariable analysis showed a significant interaction between race and SES quartile (interaction P = 0.005) such that the effect of PUMA SES on receipt of PN was modified by race. PN receipt for Black vs. White patients was significantly different within the highest SES quartile (OR = 0.44, P < 0.001), but not within the lowest. CONCLUSION: In NYC, patients from higher SES quartile neighborhoods had significantly increased odds for receipt of PN for LRMs. As neighborhood SES quartile increased, White patients were significantly more likely to receive PN, while Black patients were not.

Predicting Sepsis in Patients with Ureteral Stones in the Emergency Department.

Background: In the absence of overt infection signs, clinical criteria for early intervention in patients with ureteral stones are poorly defined. We aimed to develop a model that can identify patients who are at risk for developing sepsis if discharged home from the emergency department (ED). Materials and Methods: We retrospectively reviewed patients between January 2010 and December 2019 who were discharged from the ED after diagnosis of ureteral stones. The primary outcome was sepsis requiring urgent surgical decompression. We used multivariable logistic regression to identify predictors of sepsis. We refined the model using backward stepwise regression with a threshold p-value of 0.05. Results: We identified 1331 patients who were discharged from the ED with ureteral stones. Of these patients, 22 (2%) subsequently developed sepsis requiring urgent decompression. In the initial multivariable model, female gender (odds ratio [OR]: 2.82, p = 0.039) and urine white blood cells (WBCs) (OR: 1.02 per cell count, p < 0.001) were predictive of sepsis. After performing backward stepwise regression, female gender, urine WBCs, and leukocytosis (WBCs >15,000/mm3) met criteria for inclusion in the model. A logistic model including these variables predicted sepsis with an internally cross-validated area under the curve (AUC) of 0.79. Among patients with urine cultures completed in the ED, rates of sepsis were 9% in patients with positive cultures and 1% in patients with negative cultures (p < 0.001). Antibiotic usage was not protective against developing sepsis. Conclusions: Sepsis is a rare complication among patients with ureteral stones selected for conservative management. The presence of elevated urine WBCs and female gender can help identify patients who are at risk of developing sepsis. Patients with risk factors should be managed with an increased index of suspicion for infection and may benefit from early intervention to reduce the risk of sepsis. Sepsis is more common in patients with positive urine cultures.

Impact of an Acute Care Urology Service on Timelines and Quality of Care in the Management of Nephrolithiasis.

Background: The acute care surgery model has led to improved outcomes for emergent surgical conditions, but similar models of care have not been implemented in urology. Our department implemented an acute care urology (ACU) service in 2015, and the service evolved in 2018. We aimed to evaluate the impact of the ACU model on the management of nephrolithiasis. Materials and Methods: We conducted a retrospective review of all patients with urology consults in the emergency department for nephrolithiasis, who required surgical intervention from 2013 to 2019. Patients were divided into three cohorts based on date of consultation: Pre-ACU (2013-2014), Phase 1 (2015-2017), and Phase 2 (2018-2019). Results: We identified 733 patients with nephrolithiasis requiring intervention (162 pre-ACU, 334 Phase 1, and 237 Phase 2). Before ACU implementation, median time from consult to definitive intervention was 36 days. After ACU implementation, median time to intervention decreased to 22 days in Phase 1 (p < 0.001) and 15 days in Phase 2 (p < 0.001). On multivariable Cox regression, the hazard of definitive intervention improved in Phase 1 (hazard ratio [HR] 1.90, p < 0.001) and in Phase 2 (HR 1.80, p < 0.001). Rates of primary definitive intervention without initial decompression and loss to follow-up were also significantly improved, compared to the pre-ACU cohort. Conclusions: Implementation of a structured ACU service was associated with improved time to treatment for patients with acute nephrolithiasis, as well as increased primary definitive intervention and improved follow-up care. This model of care has potential to improve patient outcomes for nephrolithiasis and other acute urological conditions.

Neighborhood social cohesion, religious participation and sexual risk behaviors among cisgender black sexual minority men in the southern United States.

BACKGROUND: Few studies have examined associations between neighborhood social cohesion and sexual risk behaviors among gay, bisexual, and other sexual minority men (SMM), and none have among Black SMM in the southern U.S. The purpose of the current study is to examine associations between neighborhood social cohesion and sexual risk behaviors among Black SMM in the southern U.S., a population heavily impacted by HIV. We also examined whether these relationships are modified by religious participation for Black SMM in the southern U.S. METHODS: Data was obtained from the MARI Study, a sample of Black SMM ages 18-66 years, recruited from the Jackson, MS and Atlanta, GA metropolitan areas (n = 354). Neighborhood social cohesion was assessed with a validated 5-item scale. We conducted multivariable regression analyses to examine the association between neighborhood social cohesion with each of the sexual risk behaviors (e.g., condomless sex and drug use before or during sex), controlling for key confounders. We then performed moderation analysis by religious participation (religious attendance and private religiosity). RESULTS: Compared to Black SMM with higher perceived neighborhood social cohesion, Black SMM with lower neighborhood social cohesion had increased odds of alcohol use before or during sex (aPR = 1.56; 95% CI = 1.16-2.11) and condomless anal sex with casual partners (aPR = 1.55; 1.03-2.32). However, the magnitude of these associations varied by religious attendance and private religiosity. Black SMM with low religious service attendance had higher risk of alcohol use in the context of sex when perceived neighborhood social cohesion was low; those with high private religiosity had elevated alcohol use in the context of sex when perceived neighborhood social cohesion was low. DISCUSSION: Interventions that target connectedness among neighborhood members through community education or mobilization efforts, including the involvement of religious organizations, should be considered for HIV prevention focused on alcohol and condomless sex among Black SMM.

Telemedicine in management of genitourinary malignancies: Patient and physician perspectives.

PURPOSE: The rapid expansion of telemedicine has presented a challenge for the care of patients with genitourinary malignancies. We sought to assess patient and physician perspectives on the use of telemedicine for genitourinary cancer care. METHODS: We conducted a prospective cross-sectional study of patients who had telemedicine visits with urology, medical oncology, or radiation oncology for management of genitourinary malignancies from July-August 2020. Patients and physicians each received a questionnaire regarding the telemedicine experience. Responses were scored on a 5-point Likert scale. The primary outcomes of the study were patient and physician satisfaction. RESULTS: Of the 115 patients who enrolled, we received 96 patient responses and 46 physician responses. Overall, 77% of patients and 70% of physicians reported being "extremely satisfied" with the telemedicine encounter. Satisfaction was high among all components of the encounter including patient-physician communication, counseling, shared decision making, time spent, timeliness and efficiency, and convenience. Additionally, 78% of patients and 85% of physicians "strongly agreed" that they were able to discuss sensitive topics about cancer care as well as they could at an in-person visit. Nine telemedicine visits (9%) encountered technological barriers. Technological barriers were associated with lower overall satisfaction scores among both patients and physicians (p ≤ 0.01). CONCLUSION: We observed high levels of patient and physician satisfaction for telemedicine visits for management of genitourinary malignancies. Technological barriers were encountered by 9% of patients and were associated with decreased satisfaction.

Quantifying an Adherence Path-Specific Effect of Antiretroviral Therapy in the Nigeria PEPFAR Program.

Since the early 2000s, evidence has accumulated for a significant differential effect of first-line antiretroviral therapy (ART) regimens on human immunodeficiency virus (HIV) viral load suppression. This finding was replicated in our data from the Harvard President's Emergency Plan for AIDS Relief (PEPFAR) program in Nigeria. Investigators were interested in finding the source of these differences, i.e., understanding the mechanisms through which one regimen outperforms another, particularly via adherence. This question can be naturally formulated via mediation analysis with adherence playing the role of a mediator. Existing mediation analysis results, however, have relied on an assumption of no exposure-induced confounding of the intermediate variable, and generally require an assumption of no unmeasured confounding for nonparametric identification. Both assumptions are violated by the presence of drug toxicity. In this paper, we relax these assumptions and show that certain path-specific effects remain identified under weaker conditions. We focus on the path-specific effect solely mediated by adherence and not by toxicity and propose an estimator for this effect. We illustrate with simulations and present results from a study applying the methodology to the Harvard PEPFAR data. Supplementary materials are available online.