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Volume and quality benchmarks for open abdominal aortic surgery and particularly open aortic aneurysm repair (OAR) in the endovascular era are guided by the Society for Vascular Surgery guidelines, but the Vascular Quality Initiative (VQI) OAR module fails to capture the full spectrum of complex OAR. We hypothesized that VQI-ineligible complex OAR would be the dominant form of open repairs performed at a VQI-participating tertiary center.All OAR cases performed at a single tertiary care center from 2007 to 2020 were reviewed. The VQI OAR criteria were applied with exclusions (non-VQI) defined as concomitant renal bypass, clamping above the superior mesenteric artery or celiac artery, repairs performed for trauma, anastomotic aneurysm, isolated iliac aneurysm, or infected aneurysms. Linear regression was used to assess temporal trends.Among a total of 481 open abdominal aortic operations, 355 (74%) were OAR. The average annual OAR volume remained stable over 14 years (25 ± 6; P = .46). Non-VQI OAR comprised 54% of all cases and persisted over time (RComplex OAR comprises a majority of OAR cases in a contemporary tertiary referral hospital, yet these cases are not accounted for in the VQI. Creation of a "complex OAR" VQI module would capture these cases in a quality-driven national registry and help to better inform benchmarks for volume and outcomes in aortic surgery.

Addition of NO to a nonheme dithiolate-ligated iron(II) complex, Fe

Мета. Визначити ступінь кореляційних зв’язків між цінними для проведення екологічної селекції кількісними ознаками гібридів F1 кабачка: величинами гідротермічного коефіцієнту (ГТК) за роками досліджень та ознаками гібридів F1, що є структурними компонентами урожайності; показником “Ступінь розвитку хвороби”, який належить до вірусу жовтої мозаїки кабачка (ZYMV) та аналогічними показниками, які належать до ступеня розвитку борошнистої роси, бактеріозу та інших вірусних інфекцій, якими уражувалися гібриди F1 кабачка у польових умовах. Методи. Польові, лабораторні, аналітично-вимірювальні. Результати. Селекційну роботу проводили з 18 гібридами F1 кабачка іноземного походження. Проведено кореляційний аналіз між реакцією гібридних зразків на ураження вірусом ZYMV у лабораторних умовах та проявом інших хвороб, які зустрічалися у польових умовах. Встановлено, що найвищий рівень кореляційного зв’язку простежується у випадку порівняння ступеня розвитку польових вірусних хвороб та симптомів ураження вірусом жовтої мозаїки (15 статистично підтверджених значень коефіцієнта парної кореляції або 80,33 %). Виділися 8 гібридів F1 кабачка, у яких за всіма парами ознак відмічені статистично достовірні кореляційні зв’язки. Серед них, Alfresco F1, Rimini F1, Eight Ball F1, Firenze F1, Tuscany F1, Parador F1, Gold Rush F1, Cronos F1 (-0,50 < rp < 0,95). Низьку залежність від гідротермічних умов вирощування продемонстрували три гібриди – Mikinos F1, Jaguar F1 і Best of British F1. Перші два гібриди по суті не мали лінійного кореляційного зв’язку з ГТК (rp < 0,1) за проявом 3 кількісних ознак: “Загальна урожайність”, “Товарна урожайність” та “Загальна продуктивність однієї рослини”. У гібрида Best of British F1 спостерігалися слабкі кореляційні зв’язки (0,1 < rp < 0,3) між ГТК та трьома ознаками “Загальна урожайність”, “Загальна продуктивність однієї рослини” та “Середня маса товарного плоду”. Інші гібриди F1 мали високу залежність від гідротермічних умов вирощування, оскільки за проявом більшості кількісних ознак, що є структурними компонентами урожайності відзначилися помірними, сильними або дуже сильними кореляційними зв’язками p ГТК (0,5 < rp < 0,99). Висновки. Проведений аналіз кореляційних зв’язків виявив досить складну генетичну організацію кількісних ознак та їх взаємодію з біотичними й абіотичними факторами навколишнього середовища. Одержані дані дозволять у подальшій селекційній роботі значно полегшити роботу з прогнозу адаптивного потенціалу за проаналізованим комплексом кількісних ознак у проміжних форм кабачка, створених на основі вивчених гібридних генотипів,які виявили стабільну фенотипову реакцію на застосовані умови вирощування.

Supplemental Tables 1-3

Perspective on this Article from Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar Alterations in p53, ras, and HER-2/neu

Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24–5.47), prostate (OR, 2.58; 95% CI, 1.93–3.44), gastric (OR, 2.97; 95% CI, 1.66–5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89–2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76–5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61–2.02), male breast cancer (OR, 1.72; 95% CI, 1.08–2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35–1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24–1.79), and melanoma (OR, 1.46; 95% CI, 1.18–1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection.Prevention Relevance:This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.

Purpose: Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival.Experimental Design: Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC50). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets.Results: Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively).Conclusion: The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target. Clin Cancer Res; 17(19); 6356–66. ©2011 AACR.

Supplementary Figure 1 from Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk

Purpose: Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer–related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence.Experimental Design: Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1-8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNP). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HR) and 95% confidence intervals (CI), adjusting for known prognostic factors.Results: Variation within angiogenesis was most strongly associated with survival time overall (P = 0.03) and among patients with serous cancer (P = 0.05), particularly for EIF2B5 rs4912474 (all patients HR, 0.69; 95% CI, 0.54-0.89; P = 0.004), VEGFC rs17697305 (serous subtype HR, 2.29; 95% CI, 1.34-3.92; P = 0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, P = 0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up.Conclusion: An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain. Clin Cancer Res; 16(3); 995–1007

Supplemental Figure 3 - Box and whisker plots of the dominant bacteria in enterotype clusters 1, 2, or 3. Black dots are the means. Sum refers to the sum of the Pyramidobacter, Oscillibacter and Dethiosulfitibacter in Cluster 3.

Supplementary Tables S1-S3 from Microarray Analysis of Early Stage Serous Ovarian Cancers Shows Profiles Predictive of Favorable Outcome

Purpose: Although few women with advanced serous ovarian cancer are cured, detection of the disease at an early stage is associated with a much higher likelihood of survival. We previously used gene expression array analysis to distinguish subsets of advanced cancers based on disease outcome. In the present study, we report on gene expression of early-stage cancers and validate our prognostic model for advanced-stage cancers.Experimental Design: Frozen specimens from 39 stage I/II, 42 stage III/IV, and 20 low malignant potential cancers were obtained from four different sites. A linear discriminant model was used to predict survival based upon array data.Results: We validated the late-stage survival model and show that three of the most differentially expressed genes continue to be predictive of outcome. Most early-stage cancers (38 of 39 invasive, 15 of 20 low malignant potential) were classified as long-term survivors (median probabilities 0.97 and 0.86). MAL, the most differentially expressed gene, was further validated at the protein level and found to be an independent predictor of poor survival in an unselected group of advanced serous cancers (P = 0.0004).Conclusions: These data suggest that serous ovarian cancers detected at an early stage generally have a favorable underlying biology similar to advanced-stage cases that are long-term survivors. Conversely, most late-stage ovarian cancers seem to have a more virulent biology. This insight suggests that if screening approaches are to succeed it will be necessary to develop approaches that are able to detect these virulent cancers at an early stage.

PDF file - 3931KB, Genes/probe sets.

Supplemental Figure 1 - The distribution of the dominant genera across samples from 115 premenopausal women.

Supplemental Figure 2 - Silhouette width for clusters.

Supplementary Tables S1-S7 & Figure S1

PDF file - 103KB, SUPPLEMENTARY EXPERIMENTAL PROCEDURES AND SUPPLEMENTAL REFERENCES.

Supplemental Figure Legends

Supplementary Table 2 from Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk

Background: Lignans in plant foods are metabolized by gut bacteria to the enterolignans, enterodiol (END) and enterolactone (ENL). Enterolignans have biologic activities important to the prevention of cancer and chronic diseases. We examined the composition of the gut microbial community (GMC) as a contributor to human enterolignan exposure.Methods: We evaluated the association between the GMC in stool, urinary enterolignan excretion, and diet from a 3-day food record in 115 premenopausal (ages 40–45 years) women in the United States. Urinary enterolignans were measured using gas chromatography–mass spectroscopy. The GMC was evaluated using 454 pyrosequencing of the 16S rRNA gene. Sequences were aligned in SILVA (www.arb-silva.de). Operational taxonomic units were identified at 97% sequence similarity. Taxonomic classification was performed and alpha and beta diversity in relationship to ENL production were assessed. Multivariate analysis and regression were used to model the association between enterolignan excretion and the GMC. Bacteria associated with ENL production were identified using univariate analysis and ridge regression.Results: After adjusting for dietary fiber intake and adiposity, we found a significant positive association between ENL excretion and either the GMC (P = 0.0007), or the diversity of the GMC (P = 0.01). The GMC associated with high ENL production was distinct (UNIFRAC, P < 0.003, MRPP) and enriched in Moryella spp., Acetanaerobacterium spp., Fastidiosipila spp., and Streptobacillus spp.Conclusion: Diversity and composition of the GMC are associated with increased human exposure to enterolignans.Impact: Differences in gut microbial diversity and composition explain variation in gut metabolic processes that affect environmental exposures and influence human health. Cancer Epidemiol Biomarkers Prev; 24(3); 546–54. ©2014 AACR.

PDF file - 450KB, Genes/probe sets in patient samples.

PDF file - 65KB, BAD pathway signature genes: probe sets representing 47 unique genes comprising a BAD-pathway signature.

Background: Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility.Methods: Through a multicenter study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 nuclear-encoded SNPs localized to 138 genes involved in mitochondrial biogenesis (BIO, n = 35), steroid hormone metabolism (HOR, n = 13), and oxidative phosphorylation (OXP, n = 90) pathways. Unconditional logistic regression was used to estimate OR and 95% CI between genotype and case status. Overall significance of each gene and pathway was evaluated by using Fisher's method to combine SNP-level evidence. At the SNP level, we investigated whether lifetime ovulation, hormone replacement therapy (HRT), and cigarette smoking were confounders or modifiers of associations.Results: Interindividual variation involving BIO was most strongly associated with EOC risk (empirical P = 0.050), especially for NRF1, MTERF, PPARGC1A, ESRRA, and CAMK2D. Several SNP-level associations strengthened after adjustment for nongenetic factors, particularly for MTERF. Statistical interactions with cigarette smoking and HRT use were observed with MTERF and CAMK2D SNPs, respectively. Overall variation within mtDNA, HOR, and OXP was not statistically significant (empirical P > 0.10).Conclusion: We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility.Impact: A deeper understanding of the complex mechanisms implicated in mitochondrial biogenesis and oxidative stress may aid in developing strategies to reduce morbidity and mortality from EOC. Cancer Epidemiol Biomarkers Prev; 20(6); 1131–45. ©2011 AACR.

PDF file - 76KB, Diagram of dosing schedules.

Purpose:Prognostic molecular assays may aid in treatment decisions for women with estrogen receptor (ER)-positive, HER2-negative breast cancer. The prognostic value of a 12-gene expression assay (EndoPredict) was reevaluated in the combined ABCSG-6/8 cohorts with longer clinical follow-up.Experimental Design:EndoPredict (EP; molecular score, EPclin score) was evaluated in women with ER-positive, HER2-negative node-positive and node-negative breast cancer who received 5 years of endocrine therapy only (median follow-up, 9.6 years; N = 1,702). Distant recurrence-free rate (DRFR; 95% confidence interval) was assessed 10 and 15 years after diagnosis.Results:Overall, 62.6% of patients had low-risk EPclin scores with significantly improved DRFR relative to high-risk patients (HR, 4.77; 95% CI, 3.37–6.67; P < 0.0001). Ten-year DRFR (0–10 years) was improved among patients with low-risk versus high-risk EPclin scores in the full cohort [95.5% (94.1%–97.0%) vs. 80.3% (76.9%–83.9%)] as well as for patients with node-negative disease [95.5% (94.0%–97.1%) vs. 87.0% (82.6%–91.7%)] or with 1 to 3 positive nodes [95.6% (92.2%–99.1%) vs. 80.9% (75.9%–86.1%)]. The molecular and EPclin scores were significant predictors of DRFR after adjusting for clinical variables, regardless of nodal status. Similar results were observed for late recurrence (5–15 years; HR, 4.52; 95% CI, 2.65–7.72; P < 0.0001). The EPclin score significantly added prognostic information to a late metastasis nomogram (CTS5 score; P < 0.001).Conclusions:This study demonstrates that EPclin can identify patients at low risk for early or late recurrence who may safely forgo adjuvant chemotherapy or extended endocrine therapy, respectively, regardless of nodal status.

Supplemental Methods

Supplementary Table 1 from Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk

Supplementary Table S1 from LIN28B Polymorphisms Influence Susceptibility to Epithelial Ovarian Cancer

Supplemental Methods. Includes more detailed methods for the main manuscript and additional supplemental methods including Cell Culture, Sources of drugs/radioactive tracers,Targets/functions of metabolic drugs and antioxidants, Preparation of protein lysates, Nutrient metabolism assays, qPCR primer sequences, Cytotoxicity assays, Cell doubling times, Cellular ATP levels, ROS assays, Mass spectrometry of Acetyl-CoA and Pyruvylated-CoA, and Supplemental References.

Supplementary Figure S1 from LIN28B Polymorphisms Influence Susceptibility to Epithelial Ovarian Cancer

Supplementary Table S4 from LIN28B Polymorphisms Influence Susceptibility to Epithelial Ovarian Cancer

Supplementary Table S3 from LIN28B Polymorphisms Influence Susceptibility to Epithelial Ovarian Cancer

Whole genome regions with copy number gain/loss were included ; All genes with CNA affecting candidate pathway genes and statistically significant positive correlation (p-value ; Gene expression signature predictive of complete response (CR) versus incomplete response (IR) using the CNA-Correlated-Pathway (CCP) gene subset ; Differentially methylated genes between the CR and IR groups ; Differentially expressed miRNA between the CR and IR groups ; Differentially expressed genes (CR versus IR) from the 1,772 genes identified to have TF binding sites within the CNA-Correlated-Pathway (CCP) gene subset ; 422 significant genes included in the final model or signature ; Pathways and biological processes identified with the software for enrichment analysis GeneGo. These pathways were overrepresented in cluster #1 of the NMF consensus clustering ; Pathways and biological processes identified with the software for enrichment analysis GeneGo. These pathways overrepresented in cluster #2 of the NMF consensus clustering .

Supplemental Figures S1-8. Figure S1: Protein expression in human endometrial tissue. Figure S2: GLUT6 expression in human endometrial tissue Figure S3: Correlation between metabolic protein expression and metabolism in endometrial cells. Figure S4: GLUT6 knockdown in endometrial cancer cells induces cell death. Figure S5: Correlation analyses for drug sensitivity. Figure S6: Precursor Ion Scan of Pyruvylated-CoA. Figure S7: Antioxidants (without thiol groups) could not protect against 3-bromopyruvate-mediated cell death. Figure S8: ATP levels and cell death induced by 3-bromopyruvate.

Supplementary Table S2 from LIN28B Polymorphisms Influence Susceptibility to Epithelial Ovarian Cancer

SCS pincer ligands have an interesting combination of strong-field and weak-field donors, a coordination environment that is also present in the nitrogenase active site. Here, we explore the electronic structures of iron(II) and iron(III) complexes with such a pincer ligand, bearing a monodentate phosphine, thiolate S donor, amide N donor, ammonia, or CO. The ligand scaffold features a proton-responsive thioamide site, and the protonation state of the ligand greatly influences the reduction potential of iron in the phosphine complex. The N–H bond dissociation free energy, derived from a square scheme, is 56 ± 2 kcal/mol. EPR spectroscopy and SQUID magnetometry measurements show that the iron(III) complexes with S and N as the fourth donors have an intermediate spin (S = 3/2) ground state with large zero field splitting, and X-ray absorption spectra show high Fe–S covalency. The Mössbauer spectrum changes drastically with the position of a nearby alkali metal cation in the iron(III) amido complex, and DFT calculations explain this phenomenon through a change between having the doubly-occupied orbital as d(z)2 or d(yz), as the former is more influenced by the nearby positive charge.

Objective Contemporary data on the natural history of large abdominal aortic aneurysms (AAAs) in patients undergoing delayed or no repair are lacking. In this study, we examine the impact of large AAA size on the incidence of rupture and mortality. Methods From a prospectively maintained aneurysm surveillance registry, patients with an unrepaired, large AAA (≥5.5 cm in men and ≥5.0 cm in women) at baseline (ie, index imaging) or who progressed to a large size from 2003 to 2017 were included, with follow-up through March 2020. Outcomes of interest obtained by manual chart review included rupture (confirmed by imaging/autopsy), probable rupture (timing/findings consistent with rupture without more likely cause of death), repair, reasons for either no or delayed (>1 year after diagnosis of large AAA) repair and total mortality. Cumulative incidence of rupture was calculated using a nonparametric cumulative incidence function, accounting for the competing events of death and aneurysm repair and was stratified by patient sex. Results Of the 3248 eligible patients (mean age, 83.6 ± 9.1 years; 71.2% male; 78.1% white; and 32.0% current smokers), 1423 (43.8%) had large AAAs at index imaging, and 1825 progressed to large AAAs during the follow-up period, with a mean time to qualifying size of 4.3 ± 3.4 years. In total, 2215 (68%) patients underwent repair, of which 332 were delayed >1 year; 1033 (32%) did not undergo repair. The most common reasons for delayed repair were discrepancy in AAA measurement between surgeon and radiologist (34%) and comorbidity (20%), whereas the most common reasons for no repair were patient preference (48%) and comorbidity (30%). Among patients with delayed repair (mean time to repair, 2.6 ± 1.8 years), nine (2.7%) developed symptomatic aneurysms, and an additional 11 (3.3%) ruptured. Of patients with no repair, 94 (9.1%) ruptured. The 3-year cumulative incidence of rupture was 3.4% for initial AAA size 5.0 to 5.4 cm (women only), 2.2% for 5.5 to 6.0 cm, 6.0% for 6.1 to 7.0 cm, and 18.4% for >7.0 cm. Women with AAA size 6.1 to 7.0 cm had a 3-year cumulative incidence of rupture of 12.8% (95% confidence interval, 7.5%-19.6%) compared with 4.5% (95% confidence interval, 3.0%-6.5%) in men (P = .002). Conclusions In this large cohort of AAA registry patients over 17 years, annual rupture rates for large AAAs were lower than previously reported, with possible increased risk in women. Further analyses are ongoing to identify those at increased risk for aneurysm rupture and may provide targeted surveillance regimens and improve patient counseling.

The quest for homoleptic Cr TEMPO species has led to the preparation of pseudo-pentagonal planar (η2-TEMPO)2CrX (X = Cl, TEMPO), with perturbations from TEMPO(−) lone pairs at roughly 0°, 90°, 135°, 225° and 270°.

Background Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. Methods A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV®) under emergency compassionate use. Objective were to describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. Results Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) outcomes data are reported from 64 patients. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV treatment was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment reverse transcription–polymerase chain reaction (RT-PCR) results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) and 8 (72.7%) patients reporting a negative RT-PCR within 5 days and 21 days of treatment, respectively. Ten of 85 patients (11.8%) experienced serious adverse events; only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported; neither were attributed to REGEN-COV. Conclusions In this retrospective analysis of immunodeficient patients granted REGEN-COV under emergency compassionate use, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with longstanding COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients’ concurrent medical conditions.

BACKGROUND: Altered functional brain connectivity has been proposed as an intermediate phenotype between genetic risk loci and clinical expression of schizophrenia. Genetic high-risk groups of healthy subjects are particularly suited for the investigation of this proposition because they can be tested in the absence of medication or other secondary effects of schizophrenia. METHODS: Here, we applied dynamic functional connectivity analysis to functional magnetic resonance imaging data to reveal the reconfiguration of brain networks during a cognitive task. We recruited healthy carriers of common risk variants using the recall-by-genotype design. We assessed 197 individuals: 99 individuals (52 female, 47 male) with low polygenic risk scores (schizophrenia risk profile scores [SCZ-PRSs]) and 98 individuals (52 female, 46 male) with high SCZ-PRSs from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents and Children (N = 8169). We compared groups both on conventional brain activation profiles, using the general linear model of the experiment, and on the neural flexibility index, which quantifies how frequent a brain region's community affiliation changes over experimental time. RESULTS: Behavioral performance and standard brain activation profiles did not differ significantly between groups. High SCZ-PRS was associated with reduced flexibility index and network modularity across n-back levels. The whole-brain flexibility index and that of the frontoparietal working memory network was associated with n-back performance. We identified a dynamic network phenotype related to high SCZ-PRS. CONCLUSIONS: Such neurophysiological markers can become important for the elucidation of biological mechanisms of schizophrenia and, particularly, the associated cognitive deficit.

The electronic structures and contrasting reactivity of [Cu(CF3)4]− and [Cu(CF3)3(CH3)]− were probed using coupled cluster and ab initio valence bond calculations.

Homodimers are the most abundant type of enzyme in cells and as such, they represent the most elemental system for studying the phenomenon of allostery. In these systems, in which the allosteric features are manifest by the effect of the first binding event on the similar event at the second site, the most informative state is the asymmetric single bound (lig(1)) form, yet it tends to be elusive thermodynamically. Here we obtain milligram quantities of lig(1) of the allosteric homodimer, chorismate mutase, in the form of a mixed isotopically labeled dimer stabilized by Cu((I)-)catalyzed azide–alkyne cycloaddition (CuAAC) between the subunits. Below, we outline several critical steps required to generate high yields of both types of unnatural amino acid-containing proteins, and overcome multiple pitfalls intrinsic to CuAAC to obtain high yields of highly purified, fully intact, active mixed labeled dimer, which provides the first glimpse of the lig(1) intermediate. These data not only will make possible NMR-based investigations of allostery envisioned by us but should also facilitate other structural applications where specific linkage of proteins is helpful.

PURPOSE Screening and prevention decisions for women at increased risk of developing breast cancer depend on genetic and clinical factors to estimate risk and select appropriate interventions. Integration of polygenic risk into clinical breast cancer risk estimators can improve discrimination. However, correlated genetic effects must be incorporated carefully to avoid overestimation of risk. MATERIALS AND METHODS A novel Fixed-Stratified method was developed that accounts for confounding when adding a new factor to an established risk model. A combined risk score (CRS) of an 86–single-nucleotide polymorphism polygenic risk score and the Tyrer-Cuzick v7.02 clinical risk estimator was generated with attenuation for confounding by family history. Calibration and discriminatory accuracy of the CRS were evaluated in two independent validation cohorts of women of European ancestry (N = 1,615 and N = 518). Discrimination for remaining lifetime risk was examined by age-adjusted logistic regression. Risk stratification with a 20% risk threshold was compared between CRS and Tyrer-Cuzick in an independent clinical cohort (N = 32,576). RESULTS Simulation studies confirmed that the Fixed-Stratified method produced accurate risk estimation across patients with different family history. In both validation studies, CRS and Tyrer-Cuzick were significantly associated with breast cancer. In an analysis with both CRS and Tyrer-Cuzick as predictors of breast cancer, CRS added significant discrimination independent of that captured by Tyrer-Cuzick ( P < 10−11 in validation 1; P < 10−7 in validation 2). In an independent cohort, 18% of women shifted breast cancer risk categories from their Tyrer-Cuzick–based risk compared with risk estimates by CRS. CONCLUSION Integrating clinical and polygenic factors into a risk model offers more effective risk stratification and supports a personalized genomic approach to breast cancer screening and prevention.

Conjugated microporous polymers (CMPs) are porous organic materials that display (semi)conducting behavior due to their highly π-conjugated structures. As such, they are promising next-generation m...