The Society for Obstetric Anesthesia and Perinatology Coronavirus Disease 2019 Registry: An Analysis of Outcomes Among Pregnant Women Delivering During the Initial Severe Acute Respiratory Syndrome Coronavirus-2 Outbreak in the United States
BACKGROUND: Early reports associating severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection with adverse pregnancy outcomes were biased by including only women with severe disease without controls. The Society for Obstetric Anesthesia and Perinatology (SOAP) coronavirus disease 2019 (COVID-19) registry was created to compare peripartum outcomes and anesthetic utilization in women with and without SARS-CoV-2 infection delivering at institutions with widespread testing. METHODS: Deliveries from 14 US medical centers, from March 19 to May 31, 2020, were included. Peripartum infection was defined as a positive SARS-CoV-2 polymerase chain reaction test within 14 days of delivery. Consecutive SARS-CoV-2–infected patients with randomly selected control patients were sampled (1:2 ratio) with controls delivering during the same day without a positive test. Outcomes were obstetric (eg, delivery mode, hypertensive disorders of pregnancy, and delivery <37 weeks), an adverse neonatal outcome composite measure (primary), and anesthetic utilization (eg, neuraxial labor analgesia and anesthesia). Outcomes were analyzed using generalized estimating equations to account for clustering within centers. Sensitivity analyses compared symptomatic and asymptomatic patients to controls. RESULTS: One thousand four hundred fifty four peripartum women were included: 490 with SARS-CoV-2 infection (176 [35.9%] symptomatic) and 964 were controls. SARS-CoV-2 patients were slightly younger, more likely nonnulliparous, nonwhite, and Hispanic than controls. They were more likely to have diabetes, obesity, or cardiac disease and less likely to have autoimmune disease. After adjustment for confounders, individuals experiencing SARS-CoV-2 infection exhibited an increased risk for delivery <37 weeks of gestation compared to controls, 73 (14.8%) vs 98 (10.2%) (adjusted odds ratio [aOR], 1.47; 95% confidence interval [CI], 1.03–2.09). Effect estimates for other obstetric outcomes and the neonatal composite outcome measure were not meaningfully different between SARS-CoV-2 patients versus controls. In sensitivity analyses, compared to controls, symptomatic SARS-CoV-2 patients exhibited increases in cesarean delivery (aOR, 1.57; 95% CI, 1.09–2.27), postpartum length of stay (aOR, 1.89; 95% CI, 1.18–2.60), and delivery <37 weeks of gestation (aOR, 2.08; 95% CI, 1.29–3.36). These adverse outcomes were not found in asymptomatic women versus controls. SARS-CoV-2 patients (asymptomatic and symptomatic) were less likely to receive neuraxial labor analgesia (aOR, 0.52; 95% CI, 0.35–0.75) and more likely to receive general anesthesia for cesarean delivery (aOR, 3.69; 95% CI, 1.40–9.74) due to maternal respiratory failure. CONCLUSIONS: In this large, multicenter US cohort study of women with and without peripartum SARS-CoV-2 infection, differences in obstetric and neonatal outcomes seem to be mostly driven by symptomatic patients. Lower utilization of neuraxial analgesia in laboring patients with asymptomatic or symptomatic infection compared to patients without infection requires further investigation.
Metric Development for the Multicenter Improving Pediatric Sepsis Outcomes (IPSO) Collaborative
BACKGROUND: A 56 US hospital collaborative, Improving Pediatric Sepsis Outcomes, has developed variables, metrics and a data analysis plan to track quality improvement (QI)–based patient outcomes over time. Improving Pediatric Sepsis Outcomes expands on previous pediatric sepsis QI efforts by improving electronic data capture and uniformity across sites. METHODS: An expert panel developed metrics and corresponding variables to assess improvements across the care delivery spectrum, including the emergency department, acute care units, hematology and oncology, and the ICU. Outcome, process, and balancing measures were represented. Variables and statistical process control charts were mapped to each metric, elucidating progress over time and informing plan-do-study-act cycles. Electronic health record (EHR) abstraction feasibility was prioritized. Time 0 was defined as time of earliest sepsis recognition (determined electronically), or as a clinically derived time 0 (manually abstracted), identifying earliest physiologic onset of sepsis. RESULTS: Twenty-four evidence-based metrics reflected timely and appropriate interventions for a uniformly defined sepsis cohort. Metrics mapped to statistical process control charts with 44 final variables; 40 could be abstracted automatically from multiple EHRs. Variables, including high-risk conditions and bedside huddle time, were challenging to abstract (reported in <80% of encounters). Size or type of hospital, method of data abstraction, and previous QI collaboration participation did not influence hospitals’ abilities to contribute data. To date, 90% of data have been submitted, representing 200 007 sepsis episodes. CONCLUSIONS: A comprehensive data dictionary was developed for the largest pediatric sepsis QI collaborative, optimizing automation and ensuring sustainable reporting. These approaches can be used in other large-scale sepsis QI projects in which researchers seek to leverage EHR data abstraction.
Assessment of Children With Hearing Loss and Co-Occurring Medical Disorders: Challenging Cases
Purpose Assessing children with hearing loss and co-occurring medical disorders can be challenging. The purpose of this clinical focus article is to highlight multidisciplinary decision making and evaluation considerations when assessing communication skills of children with hearing loss and co-occurring disorders: velopharyngeal insufficiency, childhood apraxia of speech, and autism spectrum disorder. Method Case examples are described to illustrate multidisciplinary decision-making processes for assessing the communication skills of children with hearing loss who have co-occurring velopharyngeal insufficiency, childhood apraxia of speech, or autism spectrum disorder. Conclusions Clinicians must have knowledge of speech sound development, language development, and social communication for differential diagnosis and treatment planning for children with hearing loss and co-occurring disorders. A team-based approach is recommended when assessing and treating children with hearing loss. Speech-language pathologists and audiologists should feel comfortable recommending other professionals to help with differential diagnosis and treatment considerations when appropriate. Continued assessment and monitoring by a multidisciplinary team for individuals with hearing loss is recommended across the life-span.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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Abstract Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.
Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer
The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.
The Impact of Amyloid Burden and
APOE
on Rates of Cognitive Impairment in Late Life Depression
Background: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls ( H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I ( p = 0.044), Logical Memory II ( p = 0.011), and Trail Making Test –B ( p = 0.032), and APOE ɛ4 genotype was associated with worse performance on Logical Memory I ( p = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.
The Society for Obstetric Anesthesia and Perinatology Interdisciplinary Consensus Statement on Neuraxial Procedures in Obstetric Patients With Thrombocytopenia
Because up to 12% of obstetric patients meet criteria for the diagnosis of thrombocytopenia in pregnancy, it is not infrequent that the anesthesiologist must decide whether to proceed with a neuraxial procedure in an affected patient. Given the potential morbidity associated with general anesthesia for cesarean delivery, thoughtful consideration of which patients with thrombocytopenia are likely to have an increased risk of spinal epidural hematoma with neuraxial procedures, and when these risks outweigh the relative benefits is important to consider and to inform shared decision making with patients. Because there are substantial risks associated with withholding a neuraxial analgesic/anesthetic procedure in obstetric patients, every effort should be made to perform a bleeding history assessment and determine the thrombocytopenia etiology before admission for delivery. Whereas multiple other professional societies (obstetric, interventional pain, and hematologic) have published guidelines addressing platelet thresholds for safe neuraxial procedures, the US anesthesia professional societies have been silent on this topic. Despite a paucity of high-quality data, there are now meta-analyses that provide better estimations of risks. An interdisciplinary taskforce was convened to unite the relevant professional societies, synthesize the data, and provide a practical decision algorithm to help inform risk-benefit discussions and shared decision making with patients. Through a systematic review and modified Delphi process, the taskforce concluded that the best available evidence indicates the risk of spinal epidural hematoma associated with a platelet count ≥70,000 × 10 6 /L is likely to be very low in obstetric patients with thrombocytopenia secondary to gestational thrombocytopenia, immune thrombocytopenia (ITP), and hypertensive disorders of pregnancy in the absence of other risk factors. Ultimately, the decision of whether to proceed with a neuraxial procedure in an obstetric patient with thrombocytopenia occurs within a clinical context. Potentially relevant factors include, but are not limited to, patient comorbidities, obstetric risk factors, airway examination, available airway equipment, risk of general anesthesia, and patient preference.
A phase II study of atezolizumab (ATEZO) and bevacizumab (Bev) in combination with Y90 TARE in patients (Pts) with hepatocellular carcinoma (HCC).
TPS358 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC. The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks, and a second tumor biopsy at 4 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.
A 2020 Banff Antibody‐mediatedInjury Working Group examination of international practices for diagnosing antibody‐mediated rejection in kidney transplantation – a cohort study