Toxicological Response of Chironomus dilutus in Single-Chemical and Binary Mixture Exposure Experiments with 6 Perfluoralkyl Substances.

Few studies have determined the toxicity of perfluoralkyl substances (PFAS) to aquatic invertebrates. We exposed Chironomus dilutus to 6 different PFAS to assess single-chemical toxicity and relative or proportional toxicity among substances. A 10-d range-finding test was conducted to inform 20-d assays for the following PFAS: perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorobutanesulfonic acid (PFBS), perfluorohexanesulfonic acid (PFHxS), and perfluoroheptanoic acid (PFHpA). A 20-d binary mixture study of PFOS+PFHxS followed the single-chemical tests. Measurement endpoints for 20-d tests included larval survival and biomass. Log-logistic concentration response models were used to estimate 10, 20, and 50% effect concentrations (EC20, EC50) for PFOS, PFHxS, and PFOA. Survival EC50s for PFOS, PFHxS, and PFOA were 2.49, 3860, and 192 000 µg/L, respectively, whereas survival EC20s were 1.70, 913, and 119 000 µg/L for PFOS, PFHxS, and PFOA, respectively. Biomass as a combined survival and growth endpoint resulted in EC20s of 1.89, 896, and 137 000 µg/L for PFOS, PFHxS, and PFOA, respectively. Maximum concentrations tested (no-observed-effect concentrations) for PFNA, PFBS, and PFHpA were 2 to 3 orders of magnitude greater than the PFOS EC50s and showed no toxicity to C. dilutus, even at exposure concentrations well above what would be considered environmentally relevant. The binary mixture of 2.5 µg/L PFOS+1000 µg/L PFHxS showed reduced survival compared to controls and some indication of potential additive or synergistic interaction between PFOS and PFHxS. Overall, the present study supports previous studies showing PFOS to be the most toxic PFAS to aquatic life and suggests that PFOS could be more toxic to the freshwater midge than previously reported. Environ Toxicol Chem 2021;40:2319-2333. © 2021 SETAC.

Impact of Motor-Evoked Potential Monitoring on Facial Nerve Outcomes after Vestibular Schwannoma Resection.

OBJECTIVES:: Assess the utility of intraoperative transcranial facial motor-evoked potential (FMEP) monitoring in predicting and improving facial function after vestibular schwannoma (VS) resection. STUDY DESIGN:: Retrospective chart review. METHODS:: Data were obtained from 82 consecutive VS resections meeting inclusion criteria. Sixty-two cases were performed without FMEP and 20 with FMEP. Degradation of FMEP response was defined as a final-to-baseline amplitude ratio of 0.5 or less. House-Brackmann (HB) grade was assessed preoperatively, postoperatively, at follow-up assessments, and it was compared between pre- and post-FMEP cohorts. Positive predictive value (PPV) and negative predictive value (NPV), sensitivity, and specificity of FMEP degradation in predicting facial weakness were calculated. RESULTS:: In the pre-FMEP group, at length of follow-up (LOF) ⩾9 months, 83.9% (52/62) of patients exhibited HB 1-2 outcome. In the post-FMEP cohort, 75.0% (15/20) exhibited HB 1-2 function at LOF ⩾9 months. There was no difference in rates of HB 1-2 outcomes between groups in the immediate postoperative period ( P = .35) or at long-term follow-up ( P = 1.0). With respect to predicting immediate postoperative facial function, FMEP demonstrated high specificity (88.9%) and moderate sensitivity (54.5%). The PPV and NPV for immediate postoperative facial function were 85.7% and 61.5%, respectively. With respect to long-term (⩾9 months LOF) facial function, intraoperative FMEP was moderately sensitive (71.4%) and highly specific (84.6%); PPV was moderate (71.4%), and NPV was high (84.6%). CONCLUSIONS:: Intraoperative FMEP is highly specific and moderately sensitive in predicting postoperative facial function for patients undergoing VS resection, but its use may not be associated with improved facial nerve outcomes. LEVEL OF EVIDENCE:: 4.

Population Pharmacogenomics for Precision Public Health in Colombia.

While genomic approaches to precision medicine hold great promise, they remain prohibitively expensive for developing countries. The precision public health paradigm, whereby healthcare decisions are made at the level of populations as opposed to individuals, provides one way for the genomics revolution to directly impact health outcomes in the developing world. Genomic approaches to precision public health require a deep understanding of local population genomics, which is still missing for many developing countries. We are investigating the population genomics of genetic variants that mediate drug response in an effort to inform healthcare decisions in Colombia. Our work focuses on two neighboring populations with distinct ancestry profiles: Antioquia and Chocó. Antioquia has primarily European genetic ancestry followed by Native American and African components, whereas Chocó shows mainly African ancestry with lower levels of Native American and European admixture. We performed a survey of the global distribution of pharmacogenomic variants followed by a more focused study of pharmacogenomic allele frequency differences between the two Colombian populations. Worldwide, we found pharmacogenomic variants to have both unusually high minor allele frequencies and high levels of population differentiation. A number of these pharmacogenomic variants also show anomalous effect allele frequencies within and between the two Colombian populations, and these differences were found to be associated with their distinct genetic ancestry profiles. For example, the C allele of the single nucleotide polymorphism (SNP) rs4149056 [Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1)∗5], which is associated with an increased risk of toxicity to a commonly prescribed statin, is found at relatively high frequency in Antioquia and is associated with European ancestry. In addition to pharmacogenomic alleles related to increased toxicity risk, we also have evidence that alleles related to dosage and metabolism have large frequency differences between the two populations, which are associated with their specific ancestries. Using these findings, we have developed and validated an inexpensive allele-specific PCR assay to test for the presence of such population-enriched pharmacogenomic SNPs in Colombia. These results serve as an example of how population-centered approaches to pharmacogenomics can help to realize the promise of precision medicine in resource-limited settings.

Transcatheter Aortic Valve-in-Valve Replacement for Degenerated Stentless Bioprosthetic Aortic Valves: Results of a Multicenter Retrospective Analysis.

OBJECTIVES: The purpose of this study was to evaluate the safety and efficacy of valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) for stentless bioprosthetic aortic valves (SBAVs) and to identify predictors of adverse events. BACKGROUND: ViV TAVR in SBAVs is associated with unique technical challenges and risks. METHODS: Clinical records and computer tomographic scans were retrospectively reviewed for procedural complications, predictors of coronary obstruction, mortality, and echocardiographic results. RESULTS: Among 66 SBAV patients undergoing ViV TAVR, mortality was 2 of 66 patients (3.0%) at 30 days and 5 of 52 patients (9.6%) at 1 year. At 1 year, left ventricular end-systolic dimension was decreased versus baseline (median [interquartile range (IQR)]: 3.0 [2.6 to 3.6] cm vs. 3.7 [3.2 to 4.4] cm; p < 0.001). Coronary occlusion in 6 of 66 procedures (9.1%) resulted in myocardial infarction in 2 of 66 procedures (3.0%). Predictors of coronary occlusion included subcoronary implant technique compared with full root replacement (6 of 31, 19.4% vs. 0 of 28, 0%; p = 0.01), short simulated radial valve-to-coronary distance (median [IQR]: 3.4 [0.0 to 4.6] mm vs. 4.6 [3.2 to 6.2] mm; p = 0.016), and low coronary height (7.8 [5.8 to 10.0] mm vs. 11.6 [8.7 to 13.9] mm; p = 0.003). Coronary arteries originated <10 mm above the valve leaflets in 34 of 97 unobstructed coronary arteries (35.1%). CONCLUSIONS: TAVR in SBAVs is frequently associated with high-risk coronary anatomy but can be performed with a low risk of death and myocardial infarction, resulting in favorable ventricular remodeling. A subcoronary surgical approach is associated with an increased risk of coronary obstruction.

Conditional targeting: inducible deletion by Cre recombinase.

Tissue specific gene knockouts using Cre recombinase can have broad applicability in murine disease models of cardiovascular disease. The Cre system has been shown to have broad experimental versatility for both temporal and spatial control of gene deletion. By and large this is achieved by first generating mice with an inducible tissue specific promoter for expression of Cre. These mice can then be crossed with a second line of mice where the gene of interest in 'knocked in' flanked by Cre recognition sequences Lox-P sites. The double transgenic lines are then induced, through administration of an exogenous agent, to allow tissue specific, i.e. cardiac, knockout of the gene of interest at the desired time. An experimental protocol delineating this technique is described in the chapter.

Sensitivity and Specificity of Intraoperative Neuromonitoring for Identifying Safety and Duration of Temporary Aneurysm Clipping Based on Vascular Territory, a Multimodal Strategy.

BACKGROUND: Patients who undergo clipping of cerebral aneurysms face an inherent risk for new postoperative neurologic deficits. Intraoperative neuromonitoring (IONM) is used often for early detection of ischemic changes, while it is still potentially reversible. However, the value, safety, and efficacy of temporary clipping and multimodal IONM to minimize risks are debated. Our retrospective series examined the sensitivity and specificity of IONM using transcranial motor evoked potentials and somatosensory evoked potentials and quantified the safety of temporary clipping by duration and vascular territory. METHODS: Our prospectively collected database (2010-2013) included 123 consecutive patients who underwent clipping of 133 cerebral aneurysms with use of IONM. We determined postoperative deficit rate and sensitivity and specificity of monitoring to predict these changes intraoperatively. The rate of permanent deficit after temporary clipping was correlated with duration, vascular territory, and IONM findings. RESULTS: Of 133 clipped aneurysms, 15 instances of IONM changes occurred, including 12 temporary without new postoperative deficit and 3 permanent with new postoperative deficit. Somatosensory evoked potential monitoring predicted one of the permanent deficits and transcranial motor evoked potentials predicted the other 2 deficits. CONCLUSIONS: Multimodal IONM was highly specific and sensitive for detecting new deficits. Three patients with new deficits had temporary clipping, including 2 patients with IONM changes not temporally associated with clip placement. Our 1.1% rate of permanent neurologic deficit attributed to temporary clipping support its safety. Differences in patterns of IONM changes among vascular territories warrant further investigation.

Comparison of procedural complications with versus without interventional cardiology fellows-in-training during contemporary percutaneous coronary intervention.

Despite increasing complexity of contemporary procedures at tertiary care hospitals, the relationship between interventional cardiology fellows-in-training (ICFITs) and complications of percutaneous coronary intervention (PCI) has not been reported. We compiled logbooks of 6 ICFITs at an academic hospital and evaluated patient and procedural characteristics of PCIs performed with and without presence of an ICFIT. The primary end point was the composite of all in-hospital PCI complications defined by the American College of Cardiology's National Cardiovascular Data Registry: (1) catheterization laboratory events such as no-reflow and dissection/perforation, (2) general clinical events such as stroke or cardiogenic shock, (3) vascular and bleeding complications, and (4) miscellaneous complications such as peak troponin or creatinine levels. Logistic regression adjusted for differences in measured confounders between patients treated with and without presence of an ICFIT. All analyses were repeated after excluding PCI for ST-elevation myocardial infarction. Of 2,605 PCI procedures at the academic hospital between July 2007 and April 2010, an ICFIT was present for 1,638 procedures (63%). Despite having worse clinical and procedural characteristics, patients in the ICFIT group experienced similar rates of the composite end point (12.9% vs 14.5% without ICFIT, p = 0.27). Longer mean fluoroscopy times and greater number of stents were noted in the ICFIT group; however, hospital length of stay was shorter and no individual adverse events were increased in the ICFIT procedures. Presence of an ICFIT remained unrelated to the composite end point after multivariable adjustment (odds ratio 0.92, 95% confidence interval 0.71 to 1.20; p = 0.53), and findings were similar after excluding PCI for ST-elevation myocardial infarction. In conclusion, in contemporary practice at a large academic medical center, PCI complication rates were not adversely affected by the presence of an ICFIT.