Antihypertensive medication prescription dispensation among pregnant women in the United States: A cohort study.

IMPORTANCE: Hypertension is increasingly common in pregnancy capable individuals, yet there is limited data on antihypertensive medication dispensation in peripartum individuals. OBJECTIVE: To describe antihypertensive medication dispensation from preconception through the first year postpartum. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used the Truven Health Market Scan administrative data from 2008 to 2014 to identify women in the United States with commercial or government health insurance, aged 15-54, free from heart disease, who experienced a pregnancy and filled at least 1 prescription for an antihypertensive medication between 3 months prior to conception and 12 months after the end of the pregnancy. MAIN OUTCOMES AND MEASURES: We describe antihypertensive dispensation patterns (continuation, initiation, and discontinuation) by medication class during 5 time periods: preconception, first, second, and third trimesters, and the first year postpartum. RESULTS: Of 1,058,521 pregnancies, 108,614 (10.3%) were exposed to at least 1 antihypertensive medication dispensation. The most commonly dispensed medications across all periods combined were adrenergic blockers, calcium channel blockers (CCBs), and diuretics. Renin-angiotensin-aldosterone system (RAAS) inhibitors were the third most dispensed medication class in the preconception period (26.4%), and fills decreased to 5.7% and 1.7% in the second and third trimesters, respectively. Of the women with chronic hypertension who filled at least 1 prescription prior to conception, 8.4% were not dispensed an antihypertensive medication during the first year after delivery. CONCLUSIONS AND RELEVANCE: Antihypertensive prescription dispensation of both preferred and potentially harmful agents is common in pregnancy capable individuals. Patterns of dispensation suggest room for improvement in the treatment of chronic hypertension after a pregnancy.

Reprint of: Self-identified prescriber tendencies in sodium-glucose cotransporter-2 inhibitor outpatient prescribing.

BACKGROUND: Despite expanded indications and demonstrated cardiovascular and renal benefits, prescribing rates of sodium-glucose cotransporter-2 (SGLT-2) inhibitors are low. OBJECTIVES: The study aimed to identify factors impacting prescriber decision-making when prescribing SGLT-2 inhibitors in the outpatient setting and identify differences across specialties in self-identified prescribing patterns. METHODS: An anonymous survey was administered electronically to prescribers in relevant specialties at a large community health system. Descriptive statistics were used to compile results, and subgroup comparisons were conducted utilizing Fisher's exact test. RESULTS: Fifty-one prescribers completed the survey, representing a 25.2% response rate. The highest reported prescribing rates were for type 2 diabetes (92%), and the lowest for HFpEF (20%) and atherosclerotic cardiovascular disease risk reduction (16%). Prescribers without clinic-embedded pharmacist were more likely to report cost and insurance had at least a moderate effect on prescribing compared to prescribers with clinic-embedded pharmacists (95.3% vs. 62.5%, P = 0.0228) and less likely to report hemoglobin A1c less than 6.5% to have at least a moderate effect on prescribing (20.9% vs. 62.5%, P = 0.0317). Compared to specialty providers, primary care prescribers were more likely to report hemoglobin A1c over 9% had at least a moderate effect on prescribing (92.0% vs. 42.9%, P = 0.0082) and less likely to note history of urinary tract infection (22.2% vs. 85.7%, P = 0.0028), history of mycotic infection (38.9% vs. 100%, P = 0.0036), and sex (male: 5.6% vs. 42.9%, P = 0.0242; female: 8.0% vs. 42.9%, P = 0.0447) had at least a moderate effect on prescribing. CONCLUSION: Prescribing hesitancies vary across specialty and when clinic-embedded pharmacists are present. Pharmacists may help improve SGLT-2 inhibitor prescribing rates and use of guideline-directed therapies. Pharmacists can target identified hesitancies through medication-access consultations, education regarding adverse effects, and expanded benefits of the class. Future studies should examine the impact of pharmacist intervention on SGLT-2 inhibitor prescribing rates.

RBD design increases the functional antibody titers elicited by SARS-CoV-2 spike vaccination.

Most COVID-19 vaccines contain the SARS-CoV-2 spike protein as an antigen, but they lose efficacy as neutralizing antibody titers wane and escape variants emerge. Modifying the spike antigen to increase neutralizing antibody titers would help counteract this decrease in titer. We previously used a structure-based computational design method to identify nine amino acid changes in the receptor-binding domain (RBD) of spike that stabilize the RBD and increase the neutralizing antibody titers elicited by vaccination. Here, we introduce those enhancing amino acid changes into a full-length spike (FL-S-2P) ectodomain representative of most approved vaccine antigens. These amino acid changes can be incorporated into the FL-S-2P protein without negatively effecting expression or stability. Furthermore, the amino acid changes improved functional antibody titers in both mice and monkeys following vaccination. These amino acid changes could increase the duration of protection conferred by most COVID-19 vaccines.

Bactericidal effectors of the Stenotrophomonas maltophilia type IV secretion system: functional definition of the nuclease TfdA and structural determination of TfcB.

Stenotrophomonas maltophilia expresses a type IV protein secretion system (T4SS) that promotes contact-dependent killing of other bacteria and does so partly by secreting the effector TfcB. Here, we report the structure of TfcB, comprising an N-terminal domain similar to the catalytic domain of glycosyl hydrolase (GH-19) chitinases and a C-terminal domain for recognition and translocation by the T4SS. Utilizing a two-hybrid assay to measure effector interactions with the T4SS coupling protein VirD4, we documented the existence of five more T4SS substrates. One of these was protein 20845, an annotated nuclease. A S. maltophilia mutant lacking the gene for 20845 was impaired for killing Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Moreover, the cloned 20845 gene conferred robust toxicity, with the recombinant E. coli being rescued when 20845 was co-expressed with its cognate immunity protein. The 20845 effector was an 899 amino-acid protein, comprised of a GHH-nuclease domain in its N-terminus, a large central region of indeterminant function, and a C-terminus for secretion. Engineered variants of the 20845 gene that had mutations in the predicted catalytic site did not impede E. coli, indicating that the antibacterial effect of 20845 involves its nuclease activity. Using flow cytometry with DNA staining, we determined that 20845, but not its mutant variants, confers a loss in DNA content of target bacteria. Database searches revealed that uncharacterized homologs of 20845 occur within a range of bacteria. These data indicate that the S. maltophilia T4SS promotes interbacterial competition through the action of multiple toxic effectors, including a potent, novel DNase.IMPORTANCEStenotrophomonas maltophilia is a multi-drug-resistant, Gram-negative bacterium that is an emerging pathogen of humans. Patients with cystic fibrosis are particularly susceptible to S. maltophilia infection. In hospital water systems and various types of infections, S. maltophilia co-exists with other bacteria, including other pathogens such as Pseudomonas aeruginosa. We previously demonstrated that S. maltophilia has a functional VirB/D4 type VI protein secretion system (T4SS) that promotes contact-dependent killing of other bacteria. Since most work on antibacterial systems involves the type VI secretion system, this observation remains noteworthy. Moreover, S. maltophilia currently stands alone as a model for a human pathogen expressing an antibacterial T4SS. Using biochemical, genetic, and cell biological approaches, we now report both the discovery of a novel antibacterial nuclease (TfdA) and the first structural determination of a bactericidal T4SS effector (TfcB).

Pre-Pandemic Versus Early COVID-19 Perinatal Outcomes at a Military Hospital.

PURPOSE: The purpose of this study was to examine the impact of the first year of COVID-19 pandemic on maternal and neonatal outcomes at a large military treatment facility in Southern California. STUDY DESIGN AND METHODS: A retrospective review of maternal and neonatal medical records was conducted between January 1, 2019, and December 31, 2020. Outcomes measured included stillbirth rate, neonatal intensive care unit admission, neonatal death, cesarean birth, and postpartum hemorrhage. RESULTS: A total of 4,425 records were analyzed. Rates of stillbirth between the years did not vary. The neonatal death rate decreased more than 50% in 2020 (p = .149). Cesarean births rose by 2.7% in 2020 (p = .046). Rates of postpartum hemorrhage did not vary between years. CLINICAL IMPLICATIONS: The impact of COVID-19 on maternal and neonatal outcomes at a military treatment facility in the first year of the COVID-19 pandemic provides guidance for optimizing perinatal health care. Vertical transmission of COVID-19 is low and routine testing of asymptomatic neonates of positive mothers may not be necessary. COVID-19 infections should not be an indication for cesarean birth and are not associated with neonatal deaths or NICU admission.

Two-Dimensional Cobalt(II) Benzoquinone Frameworks for Putative Kitaev Quantum Spin Liquid Candidates.

The realization and discovery of quantum spin liquid (QSL) candidate materials are crucial for exploring exotic quantum phenomena and applications associated with QSLs. Most existing metal-organic two-dimensional (2D) quantum spin liquid candidates have structures with spins arranged on the triangular or kagome lattices, whereas honeycomb-structured metal-organic compounds with QSL characteristics are rare. Here, we report the use of 2,5-dihydroxy-1,4-benzoquinone (X2dhbq, X = Cl, Br, H) as the linkers to construct cobalt(II) honeycomb lattices (NEt4)2[Co2(X2dhbq)3] as promising Kitaev-type QSL candidate materials. The high-spin d7 Co2+ has pseudospin-1/2 ground-state doublets, and benzoquinone-based linkers not only provide two separate superexchange pathways that create bond-dependent frustrated interactions but also allow for chemical tunability to mediate magnetic coupling. Our magnetization data show antiferromagnetic interactions between neighboring metal centers with Weiss constants from -5.1 to -8.5 K depending on the X functional group in X2dhbq linkers (X = Cl, Br, H). No magnetic transition or spin freezing could be observed down to 2 K. Low-temperature susceptibility (down to 0.3 K) and specific heat (down to 0.055 K) of (NEt4)2[Co2(H2dhbq)3] were further analyzed. Heat capacity measurements confirmed no long-range order down to 0.055 K, evidenced by the broad peak instead of the λ-like anomaly. Our results indicate that these 2D cobalt benzoquinone frameworks are promising Kitaev QSL candidates with chemical tunability through ligands that can vary the magnetic coupling and frustration.

The impact of post-operative enteral nutrition on duodenal injury outcomes: A post hoc analysis of an EAST multicenter trial.

BACKGROUND: Leak following surgical repair of traumatic duodenal injuries results in prolonged hospitalization and oftentimes nil per os(NPO) treatment. Parenteral nutrition(PN) has known morbidity; however, duodenal leak(DL) patients often have complex injuries and hospital courses resulting in barriers to enteral nutrition(EN). We hypothesized EN alone would be associated with 1)shorter duration until leak closure and 2)less infectious complications and shorter hospital length of stay(HLOS) compared to PN. METHODS: This was a post-hoc analysis of a retrospective, multicenter study from 35 Level-1 trauma centers, including patients >14 years-old who underwent surgery for duodenal injuries(1/2010-12/2020) and endured post-operative DL. The study compared nutrition strategies: EN vs PN vs EN + PN using Chi-Square and Kruskal-Wallis tests; if significance was found pairwise comparison or Dunn's test were performed. RESULTS: There were 113 patients with DL: 43 EN, 22 PN, and 48 EN + PN. Patients were young(median age 28 years-old) males(83.2%) with penetrating injuries(81.4%). There was no difference in injury severity or critical illness among the groups, however there were more pancreatic injuries among PN groups. EN patients had less days NPO compared to both PN groups(12 days[IQR23] vs 40[54] vs 33[32],p = <0.001). Time until leak closure was less in EN patients when comparing the three groups(7 days[IQR14.5] vs 15[20.5] vs 25.5[55.8],p = 0.008). EN patients had less intra-abdominal abscesses, bacteremia, and days with drains than the PN groups(all p < 0.05). HLOS was shorter among EN patients vs both PN groups(27 days[24] vs 44[62] vs 45[31],p = 0.001). When controlling for predictors of leak, regression analysis demonstrated EN was associated with shorter HLOS(ß -24.9, 95%CI -39.0 to -10.7,p < 0.001). CONCLUSION: EN was associated with a shorter duration until leak closure, less infectious complications, and shorter length of stay. Contrary to some conventional thought, PN was not associated with decreased time until leak closure. We therefore suggest EN should be the preferred choice of nutrition in patients with duodenal leaks whenever feasible. LEVEL OF EVIDENCE: IV.

Extraordinary Thermoelectric Properties of Topological Surface States in Quantum-Confined Cd3As2 Thin Films.

Topological insulators and semimetals have been shown to possess intriguing thermoelectric properties promising for energy harvesting and cooling applications. However, thermoelectric transport associated with the Fermi arc topological surface states on topological Dirac semimetals remains less explored. This work systematically examines thermoelectric transport in a series of topological Dirac semimetal Cd3As2 thin films grown by molecular beam epitaxy. Surprisingly, significantly enhanced Seebeck effect and anomalous Nernst effect are found at cryogenic temperatures when the Cd3As2 layer is thin. In particular, a peak Seebeck coefficient of nearly 500 µV K-1 and a corresponding thermoelectric power factor over 30 mW K-2 m-1 are observed at 5 K in a 25-nm-thick sample. Combining angle-dependent quantum oscillation analysis, magnetothermoelectric measurement, transport modeling, and first-principles simulation, the contributions from bulk and surface conducting channels are isolated and the unusual thermoelectric properties are attributed to the topological surface states. The analysis showcases the rich thermoelectric transport physics in quantum-confined topological Dirac semimetal thin films and suggests new routes to achieving high thermoelectric performance at cryogenic temperatures.

Levels of the HtrA1 Protein in Serum and Vitreous Humor Are Independent of Genetic Risk for Age-Related Macular Degeneration at the 10q26 Locus.

Purpose: The purpose of this study was to determine if levels of the HtrA1 protein in serum or vitreous humor are influenced by genetic risk for age-related macular degeneration (AMD) at the 10q26 locus, age, sex, AMD status, and/or AMD disease severity, and, therefore, to determine the contribution of systemic and ocular HtrA1 to the AMD disease process. Methods: A custom-made sandwich ELISA assay (SCTM ELISA) for detection of the HtrA1 protein was designed and compared with three commercial assays (R&D Systems, MyBiosource 1 and MyBiosource 2) using 65 serum samples. Concentrations of HtrA1 were thereafter determined in serum and vitreous samples collected from 248 individuals and 145 human donor eyes, respectively. Results: The SCTM ELISA demonstrated high specificity, good recovery, and parallelism within its linear detection range and performed comparably to the R&D Systems assay. In contrast, we were unable to demonstrate the specificity of the two assays from MyBioSource using either recombinant or native HtrA1. Analyses of concentrations obtained using the validated SCTM assay revealed that genetic risk at the 10q26 locus, age, sex, or AMD status are not significantly associated with altered levels of the HtrA1 protein in serum or in vitreous humor (P > 0.05). Conclusions: HtrA1 levels in serum and vitreous do not reflect the risk for AMD associated with the 10q26 locus or disease status. Localized alteration in HTRA1 expression in the retinal pigment epithelium, rather than systemic changes in HtrA1, is the most likely driver of elevated risk for developing AMD among individuals with risk variants at the 10q26 locus.

Self-identified prescriber tendencies in sodium-glucose cotransporter-2 inhibitor outpatient prescribing.

BACKGROUND: Despite expanded indications and demonstrated cardiovascular and renal benefits, prescribing rates of sodium-glucose cotransporter-2 (SGLT-2) inhibitors are low. OBJECTIVES: The study aimed to identify factors impacting prescriber decision-making when prescribing SGLT-2 inhibitors in the outpatient setting and identify differences across specialties in self-identified prescribing patterns. METHODS: An anonymous survey was administered electronically to prescribers in relevant specialties at a large community health system. Descriptive statistics were used to compile results, and subgroup comparisons were conducted utilizing Fisher's exact test. RESULTS: Fifty-one prescribers completed the survey, representing a 25.2% response rate. The highest reported prescribing rates were for type 2 diabetes (92%), and the lowest for HFpEF (20%) and ASCVD risk reduction (16%). Prescribers without clinic-embedded pharmacist were more likely to report cost and insurance had at least a moderate effect on prescribing compared to prescribers with clinic-embedded pharmacists (95.3% vs. 62.5%, P = 0.0228) and less likely to report hemoglobin A1c less than 6.5% to have at least a moderate effect on prescribing (20.9% vs. 62.5%, P = 0.0317). Compared to specialty providers, primary care prescribers were more likely to report hemoglobin A1c over 9% had at least a moderate effect on prescribing (92.0% vs. 42.9%, P = 0.0082) and less likely to note history of urinary tract infection (22.2% vs. 85.7%, P = 0.0028), history of mycotic infection (38.9% vs. 100%, P = 0.0036), and sex (male: 5.6% vs. 42.9%, P = 0.0242; female: 8.0% vs. 42.9%, P = 0.0447) had at least a moderate effect on prescribing. CONCLUSION: Prescribing hesitancies vary across specialty and when clinic-embedded pharmacists are present. Pharmacists may help improve SGLT-2 inhibitor prescribing rates and use of guideline-directed therapies. Pharmacists can target identified hesitancies through medication-access consultations, education regarding adverse effects, and expanded benefits of the class. Future studies should examine the impact of pharmacist intervention on SGLT-2 inhibitor prescribing rates.

Clozapine metabolism and cardiotoxicity: A prospective longitudinal study.

BACKGROUND: Clozapine-induced myocarditis and cardiomyopathy are difficult to detect clinically and may be fatal if not detected early. The current/routine biomarkers for clozapine-induced myocarditis are non-specific indicators of inflammation (C-reactive protein) or cardiomyocyte damage (troponins I and T) that lack sensitivity, and for which changes often arise too late to be clinically useful. METHODS: The Clozapine Safety Study was a prospective, longitudinal, observational study to determine what, if any, the plasma concentrations of clozapine, N-desmethylclozapine, and clozapine-N-oxide in patients contribute to cardiotoxicity. Samples were collected and analysed using liquid chromatography mass spectrometry over a 41-month period from patients in the Auckland District Health Board. RESULTS: Sixty-seven patients were included. Six patients were diagnosed with myocarditis; none were diagnosed with cardiomyopathy in the study period. In patients not undergoing dose titration, clozapine biotransformation may shift to the N-oxide pathway rather than the N-desmethyl pathway with increasing dose. During dose titration, the timeframe in which myocarditis occurs, the rate of increase in the plasma concentration of clozapine-N-oxide, as well as the ratio of N-oxidation relative to N-desmethylation, were significantly higher in patients diagnosed with myocarditis. CONCLUSIONS: The assessment of clozapine-N-oxide formation, and N-oxidation relative to N-desmethylation ratios during treatment, may help identify a biomarker to aid the early detection of patients at risk of developing clozapine-induced cardiotoxicity.

CYP-catalysed cycling of clozapine and clozapine-N-oxide promotes the generation of reactive oxygen species in vitro.

Clozapine is an effective atypical antipsychotic indicated for treatment-resistant schizophrenia, but is under-prescribed due to the risk of severe adverse drug reactions such as myocarditis.A mechanistic understanding of clozapine cardiotoxicity remains elusive.This study aimed to investigate the contribution of selected CYP isoforms to cycling between clozapine and its major circulating metabolites, N-desmethylclozapine and clozapine-N-oxide, with the potential for reactive species production.CYP supersome™-based in vitro techniques were utilised to quantify specific enzyme activity associated with clozapine, clozapine-N-oxide and N-desmethylclozapine metabolism.The formation of reactive species within each incubation were quantified, and known intermediates detected.CYP3A4 predominately catalysed clozapine-N-oxide formation from clozapine and was associated with concentration-dependent reactive species production, whereas isoforms favouring the N-desmethylclozapine pathway (CYP2C19 and CYP1A2) did not produce reactive species.Extrahepatic isoforms CYP2J2 and CYP1B1 were also associated with the formation of clozapine-N-oxide and N-desmethylclozapine but did not favour one metabolic pathway over another.Unique to this investigation is that various CYP isoforms catalyse clozapine-N-oxide reduction to clozapine.This process was associated with the concentration-dependent formation of reactive species with CYP3A4, CYP1B1 and CYP1A1 that did not correlate with known reactive intermediates, implicating metabolite cycling and reactive oxygen species in the mechanism of clozapine-induced toxicity.

NLRP12 downregulates the Wnt/ß-catenin pathway via interaction with STK38 to suppress colorectal cancer.

Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-mesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/ß-catenin pathway, but not NF-κB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates ß-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of ß-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3ß, leading to the degradation of ß-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3ß and ß-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/ß-catenin pathway, and the NLRP12/STK38/GSK3ß signaling axis could be a promising therapeutic target for CRC.

DNA Extraction of Bone Through Demineralization.

In the field of forensic science, the DNA extraction of bone is utilized in investigations involving mass disasters, unidentified remains, and missing persons. However, bone samples can be challenging samples due to their exposure to extreme environmental conditions over long periods of time. The use of an effective DNA extraction method to properly isolate and purify the DNA is essential for bone samples. This chapter describes the DNA extraction of bone samples through a total demineralization protocol, which aims to entirely dissolve the bone matrix in order to access the DNA molecules.

Variation in assessments of suitability and number of contributors for DNA mixtures.

The interpretation of a DNA mixture (a sample that contains DNA from two or more people) depends on a laboratory/analyst's assessment of the suitability of the sample for comparison/analysis, and an assessment of the number of contributors (NoC) present in the sample. In this study, 134 participants from 67 forensic laboratories provided a total of 2272 assessments of 29 DNA mixtures (provided as electropherograms). The laboratories' responses were evaluated in terms of the variability of suitability assessments, and the accuracy and variability of NoC assessments. Policies and procedures related to suitability and NoC varied notably among labs. We observed notable variation in whether labs would assess a given mixture as suitable or not, predominantly due to differences in lab policies: if two labs following their standard operating procedures (SOPs) were given the same mixture, they agreed on whether the mixture was suitable for comparison 66% of the time. Differences in suitability assessments have a direct effect on variability in interpretations among labs, since mixtures assessed as not suitable would not result in reported interpretations. For labs following their SOPs, 79% of assessments of NoC were correct. When two different labs provided NoC responses, 63% of the time both labs were correct, and 7% of the time both labs were incorrect. Incorrect NoC assessments have been shown to affect statistical analyses in some cases, but do not necessarily imply inaccurate interpretations or conclusions. Most incorrect NoC estimates were overestimates, which previous research has shown have less of an effect on likelihood ratios than underestimates.

Evidence-Based Medicine and Pharmacotherapy Content Alignment.

OBJECTIVE: When effectively executed, content alignment can aid student performance in associated courses. Limited research exists for content alignment of evidence-based medicine (EBM) and pharmacotherapy courses. This study assesses the impact of EBM and pharmacotherapy course alignment on student performance. METHODS: Content alignment included assignment of 6 landmark trials in EBM coursework. The articles were identified by pharmacotherapy instructors as "landmark" to management of associated diseases in the aligned pharmacotherapy semester. Articles were the basis for quizzes over skills taught in the EBM course and were referenced during pharmacotherapy lectures. RESULTS: During the alignment semester, students were more likely to cite specific guidelines and/or primary literature to rationalize pharmacotherapeutic plans on examinations compared with the prealignment period (54% vs 34%). Overall, pharmacotherapy case performance and plan rationale scores were significantly higher in the alignment semester compared with prealignment. Student performance on the Assessing Competency in Evidence-Based Medicine tool improved from the start of the semester (8.64, SD 1.66) to the end (9.5, SD 1.49; mean score +0.86). Comfort in applying EBM analysis to primary literature increased significantly between the first and final assignments, with 6.7% and 71.7% of students self-reporting a high degree of confidence, respectively. Students (73%) reported an enhanced understanding of pharmacotherapy due to alignment compared with a previous semester of pharmacotherapy without alignment. CONCLUSION: The use of landmark trial assignments to align EBM and pharmacotherapy coursework demonstrated a positive impact on student rationale for clinical decision-making and student confidence in evaluating primary literature.

Outcomes among trauma patients with duodenal leak following primary versus complex repair of duodenal injuries: An Eastern Association for the Surgery of Trauma multicenter trial.

BACKGROUND: Duodenal leak is a feared complication of repair, and innovative complex repairs with adjunctive measures (CRAM) were developed to decrease both leak occurrence and severity when leaks occur. Data on the association of CRAM and duodenal leak are sparse, and its impact on duodenal leak outcomes is nonexistent. We hypothesized that primary repair alone (PRA) would be associated with decreased duodenal leak rates; however, CRAM would be associated with improved recovery and outcomes when leaks do occur. METHODS: A retrospective, multicenter analysis from 35 Level 1 trauma centers included patients older than 14 years with operative, traumatic duodenal injuries (January 2010 to December 2020). The study sample compared duodenal operative repair strategy: PRA versus CRAM (any repair plus pyloric exclusion, gastrojejunostomy, triple tube drainage, duodenectomy). RESULTS: The sample (N = 861) was primarily young (33 years) men (84%) with penetrating injuries (77%); 523 underwent PRA and 338 underwent CRAM. Complex repairs with adjunctive measures were more critically injured than PRA and had higher leak rates (CRAM 21% vs. PRA 8%, p < 0.001). Adverse outcomes were more common after CRAM with more interventional radiology drains, prolonged nothing by mouth and length of stay, greater mortality, and more readmissions than PRA (all p < 0.05). Importantly, CRAM had no positive impact on leak recovery; there was no difference in number of operations, drain duration, nothing by mouth duration, need for interventional radiology drainage, hospital length of stay, or mortality between PRA leak versus CRAM leak patients (all p > 0.05). Furthermore, CRAM leaks had longer antibiotic duration, more gastrointestinal complications, and longer duration until leak resolution (all p < 0.05). Primary repair alone was associated with 60% lower odds of leak, whereas injury grades II to IV, damage control, and body mass index had higher odds of leak (all p < 0.05). There were no leaks among patients with grades IV and V injuries repaired by PRA. CONCLUSION: Complex repairs with adjunctive measures did not prevent duodenal leaks and, moreover, did not reduce adverse sequelae when leaks did occur. Our results suggest that CRAM is not a protective operative duodenal repair strategy, and PRA should be pursued for all injury grades when feasible. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Electric field-dependent phonon spectrum and heat conduction in ferroelectrics.

This article shows experimentally that an external electric field affects the velocity of the longitudinal acoustic phonons (vLA), thermal conductivity (κ), and diffusivity (D) in a bulk lead zirconium titanate-based ferroelectric. Phonon conduction dominates κ, and the observations are due to changes in the phonon dispersion, not in the phonon scattering. This gives insight into the nature of the thermal fluctuations in ferroelectrics, namely, phonons labeled ferrons that carry heat and polarization. It also opens the way for phonon-based electrically driven all-solid-state heat switches, an enabling technology for solid-state heat engines. A quantitative theoretical model combining piezoelectric strain and phonon anharmonicity explains the field dependence of vLA, κ, and D without any adjustable parameters, thus connecting thermodynamic equilibrium properties with transport properties. The effect is four times larger than previously reported effects, which were ascribed to field-dependent scattering of phonons.

Large Common Mitochondrial DNA Deletions Are Associated with a Mitochondrial SNP T14798C Near the 3' Breakpoints.

Introduction: Large somatic deletions of mitochondrial DNA (mtDNA) accumulate with aging in metabolically active tissues such as the brain. We have cataloged the breakpoints and frequencies of large mtDNA deletions in the human brain. Methods: We quantified 112 high-frequency mtDNA somatic deletions across four human brain regions with the Splice-Break2 pipeline. In addition, we utilized PLINK/Seq to test the association of mitochondrial genotypes with the abundance of these high-frequency mtDNA deletions. A conservative p value threshold of 5E-08 was used to find the significant loci. Results: One mtDNA SNP (T14798C) was significantly associated with mtDNA deletions in two brain regions, the dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus. Since the DLPFC showed the most robust association between T14798C and two deletion breakpoints (7816-14807 and 5462-14807), this association was tested in the DLPFC of a replication sample and validated the first results. Incorporating the C allele at 14,798 bp increased the perfect/imperfect length of the repeat at the 3' breakpoint of the two associated deletions. Conclusion: This is the first study to identify the association of mtDNA SNP with large mtDNA deletions in the human brain. The T14798C allele located in the MT-CYB gene is a common polymorphism that occurs in several mitochondrial haplogroups. We hypothesize that the T14798C association with two deletions occurs by extending the repeat length around the 3' deletion breakpoints. This simple mechanism suggests that mtDNA SNPs can affect the mitochondrial genome structure, especially in brain where high levels of reactive oxygen species lead to deletion accumulation with aging.

Developing a quality measure to assess use of antibiotic medications for respiratory conditions.

Objective: Antibiotics are essential medications for treating life-threatening infections. However, incorrect prescribing can lead to adverse events and contribute to antibiotic resistance. We sought to develop a utilization quality measure that could be used by health insurance plans to track overall prescribing for respiratory conditions. Design: A consensus-based process that included evidence review, testing, and stakeholder input was used to develop a measure and assess its usefulness for the Healthcare Effectiveness Data and Information Set (HEDIS), a national quality measurement tool. Methods: Guidelines and literature were reviewed to establish the rationale for the measure. The measure was tested in claims data for commercial, Medicaid and Medicare Advantage enrollees to assess feasibility of collecting and reporting needed information. The measure was vetted with multistakeholder advisory panels and posted for public comment to solicit wide input on relevance and usability. Results: Respiratory conditions are frequent reasons for outpatient care in the data assessed. On average, across all lines of business, the measure revealed that approximately one-third of outpatient visits for respiratory conditions are followed by antibiotics. Stakeholders supported the measure as a tool for monitoring antibiotic prescribing across health plans alongside existing measures that assess inappropriate prescribing for specific conditions. The final measure assesses the number of antibiotic prescriptions dispensed across all outpatient respiratory-related encounters at a health-plan level. Conclusions: The measure on antibiotic prescribing for respiratory conditions was relevant, feasible, and useful. Stakeholders strongly supported the newly developed measure and recommended its integration into HEDIS.