Association between SARS-CoV-2 Infection and Adverse Perinatal Outcomes by Race/Ethnicity in a Large Integrated Health Care System.

OBJECTIVE: Recent studies have reported associations between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection during pregnancy and adverse perinatal outcomes but the extent to which these associations vary by race/ethnicity remains uncertain. Therefore, we examined how the association between prenatal SARS-CoV-2 infection and adverse perinatal outcomes may be modified by race/ethnicity. STUDY DESIGN: A retrospective cohort study was performed using data on 67,986 pregnant women extracted from the Kaiser Permanente Southern California electronic health records between April 6, 2020, and December 31, 2021. Upon admission to labor and delivery, all women were routinely tested for coronavirus disease 2019 (COVID-19) using real-time reverse-transcriptase polymerase chain reaction test. Adjusted odds ratios (aORs) were used to estimate associations. RESULTS: During the study period, COVID-19 was diagnosed in 4,960 (7%) of singleton pregnancies, with the highest rates observed among Hispanics (9.4%) and non-Hispanic Blacks (6.2%). Compared with non-Hispanic Whites, Hispanics (aOR: 1.12, 95% CI: 1.03, 1.21) with SARS-CoV-2 infection had the highest odds of a pregnancy associated with nonreassuring fetal heart rate tracing. Neonates of all races/ethnicities, except for non-Hispanic Blacks, showed significantly increased odds of SARS-CoV-2 infection, with the highest risk observed among Asians/Pacific Islanders (aOR: 10.88, 95% CI: 1.33, 89.04). Non-Hispanic White mothers who tested positive were admitted to intensive care unit (ICU) at a higher rate at delivery and within 7 days of delivery (aOR: 34.77, 95% CI: 11.3, 107.04; aOR: 26.48, 95% CI: 9.55, 73.46, respectively). Hispanics were also at a significantly higher odds of admission to ICU (aOR: 4.62, 95% CI: 2.69, 7.94; aOR: 4.42, 95% CI: 2.58, 7.56, respectively). Non-Hispanic Black, Hispanic, and Asian/Pacific Islander mothers who tested positive for SARS-CoV-2 prenatally, were at increased risk for preeclampsia/eclampsia, and preterm birth as compared to non-Hispanic White mothers. CONCLUSION: The findings highlight racial/ethnic disparities in the association between SARS-CoV-2 infection and adverse perinatal outcomes. The risk of neonatal SARS-CoV-2 infection was highest for Asian/Pacific Islanders. We also observed a remarkably high risk of ICU admission for non-Hispanic White mothers infected with SARS-CoV-2. KEY POINTS: · Race/ethnicity influences perinatal outcomes in pregnancies impacted by SARS-CoV-2.. · The risk of neonatal SARS-CoV-2 infection was highest for Asian/Pacific Islanders.. · White mothers had a notably high risk of ICU admission at delivery following SARS-CoV-2 infection..

Discontinuation of Car Seat Tolerance Screening and Postdischarge Adverse Outcomes in Infants Born Preterm.

OBJECTIVE: To study the association between discontinuing predischarge car seat tolerance screening (CSTS) with 30-day postdischarge adverse outcomes in infants born preterm. STUDY DESIGN: Retrospective cohort study involving all infants born preterm from 2010 through 2021 who survived to discharge to home in a 14-hospital integrated health care system. The exposure was discontinuation of CSTS. The primary outcome was a composite rate of death, 911 call-triggered transports, or readmissions associated with diagnostic codes of respiratory disorders, apnea, apparent life-threatening event, or brief resolved unexplained events within 30 days of discharge. Outcomes of infants born in the periods of CSTS and after discontinuation were compared. RESULTS: Twelve of 14 hospitals initially utilized CSTS and contributed patients to the CSTS period; 71.4% of neonatal intensive care unit (NICU) patients and 26.9% of non-NICU infants were screened. All hospitals participated in the discontinuation period; 0.1% was screened. Rates of the unadjusted primary outcome were 1.02% in infants in the CSTS period (n = 21 122) and 1.06% after discontinuation (n = 20 142) (P = .76). The aOR (95% CI) was 0.95 (0.75, 1.19). Statistically insignificant differences between periods were observed in components of the primary outcome, gestational age strata, NICU admission status groups, and other secondary analyses. CONCLUSIONS: Discontinuation of CSTS in a large integrated health care network was not associated with a change in 30-day postdischarge adverse outcomes. CSTS's value as a standard predischarge assessment deserves further evaluation.

HLA-A*03 and response to immune checkpoint blockade in cancer: an epidemiological biomarker study.

BACKGROUND: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. METHODS: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). FINDINGS: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20-1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05-1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01-1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01-1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16-2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0·76) INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. FUNDING: National Institutes of Health, Merck KGaA, and Pfizer.

Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer's disease.

BACKGROUND: Elevated blood homocysteine levels, termed hyperhomocysteinemia (HHcy), is a prevalent risk factor for Alzheimer's disease (AD) in elderly populations. While dietary supplementation of B-vitamins is a generally effective method to lower homocysteine levels, there is little if any benefit to cognition. In the context of amyloid pathology, dietary-induced HHcy is known to enhance amyloid deposition and certain inflammatory responses. Little is known, however, about whether there is a more specific effect on microglia resulting from combined amyloid and HHcy pathologies. METHODS: The present study used a knock-in mouse model of amyloidosis, aged to 12 months, given 8 weeks of B-vitamin deficiency-induced HHcy to better understand how microglia are affected in this comorbidity context. RESULTS: We found that HHcy-inducing diet increased amyloid plaque burden, altered the neuroinflammatory milieu, and upregulated the expression of multiple damage-associated and "homeostatic" microglial genes. CONCLUSIONS: Taken together, these data indicate complex effects of comorbid pathologies on microglial function that are not driven solely by increased amyloid burden. Given the highly dynamic nature of microglia, their central role in AD pathology, and the frequent occurrence of various comorbidities in AD patients, it is increasingly important to understand how microglia respond to mixed pathological processes.

Universal SARS-Cov-2 Screening in Women Admitted for Delivery in a Large Managed Care Organization.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has created a need for data regarding the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnant women. After implementing universal screening for COVID-19 in women admitted for delivery, we sought to describe the characteristics of COVID-19 in this large cohort of women. STUDY DESIGN: An observational study of women admitted to labor and delivery units in Kaiser Permanente Southern California (KPSC) hospitals between April 6 and May 11, 2020 who were universally offered testing for SARS-CoV-2 infection (n = 3,963). Hospital inpatient and outpatient physician encounter, and laboratory records were used to ascertain universal testing levels, test results, and medical and obstetrical histories. The prevalence of SARS-CoV-2 infection was estimated from the number of women who tested positive during labor per 100 women delivered. RESULTS: Of women delivered during the study period, 3,923 (99.0%) underwent SARS-CoV-2 testing. A total of 17 (0.43%; 95% confidence interval: 0.23-0.63%) women tested positive, and none of them were symptomatic on admission. There was no difference in terms of characteristics between SARS-CoV-2 positive and negative tested women. One woman developed a headache attributed to COVID-19 3 days postpartum. No neonates had a positive test at 24 hours of life. CONCLUSION: The findings suggest that in pregnant women admitted for delivery between April 6 and May 11, 2020 in this large integrated health care system in Southern California, prevalence of SARS-CoV-2 test positive was very low and all patients were asymptomatic on admission. KEY POINTS: · The prevalence of SARS-CoV-2 infection in a large diverse cohort of term pregnant women was 0.43%.. · 99% of women accepted SARS-CoV-2 screening on admission to labor and delivery.. · All women with positive test results were asymptomatic at the time of testing..

Trends in Neonatal Intensive Care Unit Utilization in a Large Integrated Health Care System.

Importance: There are few population-based studies addressing trends in neonatal intensive care unit (NICU) admission and NICU patient-days, especially in the subpopulation that, by gestational age (GA) and birth weight (BW), might otherwise be able to stay in the room with their mothers. Objective: To describe population-based trends in NICU admissions, NICU patient-days, readmissions, and mortality in the birth population of a large integrated health care system. Design, Setting, and Participants: This cohort study was conducted using data extracted from electronic medical records at Kaiser Permanente Southern California (KPSC) health care system. Participants included all women who gave birth at KPSC hospitals and their newborns from January 1, 2010, through December 31, 2018. Data extraction was limited to data entry fields whose contents were either numbers or fixed categorical choices. Rates of NICU admission, NICU patient-days, readmission rates, and mortality rates were measured in the total population, in newborns with GA 35 weeks or greater and BW 2000 g or more (high GA and BW group), and in the remaining newborns (low GA and BW group). Admissions to the NICU and NICU patient-days were risk adjusted with a machine learning model based on demographic and clinical characteristics before NICU admission. Changes in the trends were assessed with 2-sided correlated seasonal Mann-Kendall test. Data analysis was performed in August 2019. Exposures: Admission to the NICU and NICU patient-days among the birth cohort. Main Outcomes and Measures: The primary outcomes were NICU admission and NICU patient-days in the total neonatal population and GA and BW subgroups. The secondary outcomes were readmission and mortality rates. Results: Over the study period there were 320 340 births (mean [SD] age of mothers, 30.1 [5.7] years; mean [SD] gestational age, 38.6 [1.97] weeks; mean [SD] birth weight, 3302 [573] g). The risk-adjusted NICU admission rate decreased from a mean of 14.5% (95% CI, 14.2%-14.7%) to 10.9% (95% CI, 10.7%-11.7%) (P for trend = .002); 92% of the change was associated with changes in the care of newborns in the high GA and BW group. The number of risk-adjusted NICU patient-days per birth decreased from a mean of 1.50 patient-days (95% CI, 1.43-1.54 patient-days) to 1.40 patient-days (95% CI, 1.36-1.48 patient-days) (P for trend = .03); 70% of the change was associated with newborns in the high GA and BW group. The unadjusted 30-day readmission rates and mortality rates did not change. Conclusions and Relevance: Admission rates to the NICU and numbers of NICU patient-days decreased over the study period without an increase in readmissions or mortality. The observed decrease was associated with the high GA and BW newborn population. How much of this decrease is attributable to intercurrent health care systemwide quality improvement initiatives would require further investigation. The remaining unexplained variation suggests that further changes are also possible.

Cerebral patterns of neuropsychological disturbances in hepatitis C patients.

Neuropsychiatric symptoms and cognitive impairment have been consistently reported in patients with hepatitis C virus (HCV) infection. Since the mechanisms behind remain to be established, the present study attempted to assess whether neuropsychological impairments in HCV-infected patients are accompanied by structural alterations in the brain. Therefore, 19 anti-HCV-antibody-positive women with mild liver disease and 16 healthy controls underwent extensive neuropsychological testing and cranial magnetic resonance imaging (MRI) examination. Nine of the patients and five controls were followed up after 6-7 years. Voxel-based morphometry and magnetization transfer imaging were utilized to study HCV-associated structural gray and white matter changes. The HCV-infected patients had significantly worse fatigue and depression scores and significantly poorer performance on attention and memory tests than controls. The patients displayed gray matter (GM) atrophy in the bilateral insula and thalamus and a profound GM volume increases in the cerebellum. Microstructural GM changes in the insula were also evident by a reduced magnetization transfer ratio. Structural white matter changes were observed along several descending and crossing fiber tracts. Follow-up at 7 years revealed increased GM atrophy in the left amygdala and left parahippocampal regions over time. We conclude that our data provide evidence for structural alterations in the brains of patients with chronic HCV infection. Disturbances of cerebellothalamocortical regions and circuits, linking cerebellar projections to the prefrontal cortex through the thalamus, underpin the emotional and cognitive dysfunction characteristically observed in these patients.

Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exacerbates Neuropathology in a Mouse Model of Alzheimer's Disease.

Damage occurring to noradrenergic neurons in the locus coeruleus (LC) contributes to the evolution of neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by conditional unilateral knockout of brain-derived neurotrophic factor (BDNF) in adult mice. To evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored familial mutations for human amyloid precursor protein and presenilin-1. In these mice, BDNF depletion reduced tyrosine hydroxylase staining, a marker of noradrenergic neurons, in the rostral LC. BDNF depletion also reduced noradrenergic innervation in the hippocampus, the frontal cortex, and molecular layer of the cerebellum, assessed by staining for dopamine beta hydroxylase. BDNF depletion led to an increase in cortical amyloid plaque numbers and size but was without effect on plaque numbers in the striatum, a site with minimal innervation from the LC. Interestingly, cortical Iba1 staining for microglia was reduced by BDNF depletion and was correlated with reduced dopamine beta hydroxylase staining. These data demonstrate that reduction of BDNF levels in an LC target region can cause retrograde damage to LC neurons, leading to exacerbation of neuropathology in distinct LC target areas. Methods to reduce BDNF loss or supplement BDNF levels may be of value to reduce neurodegenerative processes normally limited by LC noradrenergic activities.