Characteristics and outcomes of pregnancies in the Maternal Outcomes Masterset real-world database.

PURPOSE: Describe patient characteristics and pregnancy outcomes among all pregnant patients, and additionally describe infant outcomes among the subset with linked infants in the Maternal Outcomes Masterset (MOM). METHODS: We used closed claims within the MOM data to identify publicly and privately insured patients at the first record of pregnancy January 1, 2018-December 1, 2021, with ≥180 days baseline enrollment. We described characteristics during baseline and follow-up (until an observed pregnancy endpoint, disenrollment, or 42-week maximum). We described maternal and infant characteristics overall and by infant linkage and contextualized them within national statistics. RESULTS: Among the 1 438 861 pregnant patients meeting the study criteria, the most common pregnancy endpoint recorded was live birth (42%) followed by spontaneous abortion (14%). Among 602 721 patients with a live birth, 99% had a week-specific gestational age recorded and 35% had at least one linked infant. Patients with infant linkage and sufficient follow-up (N = 155 621) had similar baseline comorbidities, pregnancy complications, and gestational age at delivery as those without any linkage. However, more patients with linkage had commercial coverage (70% vs. 31%), and were therefore older (50% vs. 31% aged ≥30 years) and more likely to have an unknown race (57% vs. 34%). CONCLUSIONS: In this large sample of pregnant patients, maternal and infant characteristics generally align with national statistics, providing confidence in the use of this data source for pregnancy research. Further, confirmation that the subset of patients with infant linkage is similar to the overall pregnancy cohort provides assurance that this subset can be considered representative.

High-fidelity KKH variant of Staphylococcus aureus Cas9 nucleases with improved base mismatch discrimination.

The Cas9 nuclease from Staphylococcus aureus (SaCas9) holds great potential for use in gene therapy, and variants with increased fidelity have been engineered. However, we find that existing variants have not reached the greatest accuracy to discriminate base mismatches and exhibited much reduced activity when their mutations were grafted onto the KKH mutant of SaCas9 for editing an expanded set of DNA targets. We performed structure-guided combinatorial mutagenesis to re-engineer KKH-SaCas9 with enhanced accuracy. We uncover that introducing a Y239H mutation on KKH-SaCas9's REC domain substantially reduces off-target edits while retaining high on-target activity when added to a set of mutations on REC and RuvC domains that lessen its interactions with the target DNA strand. The Y239H mutation is modelled to have removed an interaction from the REC domain with the guide RNA backbone in the guide RNA-DNA heteroduplex structure. We further confirmed the greatly improved genome-wide editing accuracy and single-base mismatch discrimination of our engineered variants, named KKH-SaCas9-SAV1 and SAV2, in human cells. In addition to generating broadly useful KKH-SaCas9 variants with unprecedented accuracy, our findings demonstrate the feasibility for multi-domain combinatorial mutagenesis on SaCas9's DNA- and guide RNA- interacting residues to optimize its editing fidelity.

The Isorhamnetin-Containing Fraction of Philippine Honey Produced by the Stingless Bee Tetragonula biroi Is an Antibiotic against Multidrug-Resistant Staphylococcus aureus.

Honey exhibits antibacterial and antioxidant activities that are ascribed to its diverse secondary metabolites. In the Philippines, the antibacterial and antioxidant activities, as well as the bioactive metabolite contents of the honey, have not been thoroughly described. In this report, we investigated the in vitro antibacterial and antioxidant activities of honey from Apis mellifera and Tetragonula biroi, identified the compound responsible for the antibacterial activity, and compared the observed bioactivities and metabolite profiles to that of Manuka honey, which is recognized for its antibacterial and antioxidant properties. The secondary metabolite contents of honey were extracted using a nonionic polymeric resin followed by antibacterial and antioxidant assays, and then spectroscopic analyses of the phenolic and flavonoid contents. Results showed that honey extracts produced by T. biroi exhibits antibiotic activity against Staphylococcal pathogens as well as high antioxidant activity, which are correlated to its high flavonoid and phenolic content as compared to honey produced by A. mellifera. The bioassay-guided fractionation paired with Liquid Chromatography Mass Spectrometry (LCMS) and tandem MS analyses found the presence of the flavonoid isorhamnetin (3-methylquercetin) in T. biroi honey extract, which was demonstrated as one of the compounds with inhibitory activity against multidrug-resistant Staphylococcus aureus ATCC BAA-44. Our findings suggest that Philippine honey produced by T. biroi is a potential nutraceutical that possesses antibiotic and antioxidant activities.

Sterile Compounding Needs Risk Management: Access, Reconstitution Or Preparation, and Administration.

Appropriate risk management strategies must be employed for compounding and administering sterile products. We review the new credentialing, regulatory, and related legal aspects of gaining and maintaining compliance for these processes.

Underwater endoscopic mucosal resection is associated with fewer recurrences and earlier curative resections compared to conventional endoscopic mucosal resection for large colorectal polyps.

BACKGROUND: Studies comparing the efficacy and safety of conventional saline-assisted piecemeal endoscopic mucosal resection (EMR) to underwater EMR (UEMR) without submucosal lifting of colorectal polyps are lacking. The objective of this study was to compare the efficacy and safety of EMR to UEMR of large colorectal polyps. METHODS: Two hundred eighty-nine colorectal polyps were removed by a single endoscopist from 7/2007 to 2/2015 using EMR or UEMR. 135 polyps (EMR: 62, UEMR: 73) that measured ≥15 mm and had not undergone prior attempted polypectomy were evaluated for rates of complete macroscopic resection and adverse events. 101 of these polyps (EMR: 46, UEMR: 55) had at least 1 follow-up colonoscopy and were studied for rates of recurrence and the number of procedures required to achieve curative resection. RESULTS: The rate of complete macroscopic resection was higher following UEMR compared to EMR (98.6 vs. 87.1%, p = 0.012). UEMR had a lower recurrence rate at the first follow-up colonoscopy compared to EMR (7.3 vs. 28.3%, OR 5.0 for post-EMR recurrence, 95% CI: [1.5, 16.5], p = 0.008). UEMR required fewer procedures to reach curative resection than EMR (mean of 1.0 vs. 1.3, p = 0.002). There was no significant difference in rates of adverse events. CONCLUSIONS: UEMR appears superior to EMR for the removal of large colorectal polyps in terms of rates of complete macroscopic resection and recurrent (or residual) abnormal tissue. Compared to conventional EMR, UEMR may offer increased procedural effectiveness without compromising safety in the removal of large colorectal polyps without prior attempted resection.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) progress to date and future plans.

The INHAND Proposal (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) has been operational since 2005. A Global Editorial Steering Committee (GESC) manages the overall objectives of the project and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups (OWG), drawing upon experts from North America, Europe and Japan.Great progress has been made with 9 systems published to date - Respiratory, Hepatobiliary, Urinary, Central/Peripheral Nervous Systems, Male Reproductive and Mammary, Zymbals, Clitoral and Preputial Glands in Toxicologic Pathology and the Integument and Soft Tissue and Female Reproductive System in the Journal of Toxicologic Pathology as supplements and on a web site - www.goreni.org. INHAND nomenclature guides offer diagnostic criteria and guidelines for recording lesions observed in rodent toxicity and carcinogenicity studies. The guides provide representative photo-micrographs of morphologic changes, information regarding pathogenesis, and key references. During 2012, INHAND GESC representatives attended meetings with representatives of the FDA Center for Drug Evaluation and Research (CDER), Clinical Data Interchange Standards Consortium (CDISC), and the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) to begin incorporation of INHAND terminology as preferred terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the FDA. The interest in utilizing the INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists, suggests that there will be wide acceptance of this nomenclature. The purpose of this publication is to provide an update on the progress of INHAND.

ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a malignancy with a poor 5-year survival rate (5%-10%). ERCP-directed radiofrequency ablation (RFA) or photodynamic therapy (PDT) can be performed as palliative therapy for unresectable CCA. ERCP with PDT is associated with improved survival compared with stent placement alone. However, ERCP-directed RFA has not been directly compared with PDT in patients with CCA. OBJECTIVE: To compare overall survival in patients with unresectable CCA who underwent palliative ERCP-directed RFA versus PDT. DESIGN: Retrospective cohort study. SETTING: Tertiary-care academic medical center. PATIENTS: Forty-eight patients with unresectable CCA who underwent ERCP-directed ablative therapy for palliation of unresectable CCA. INTERVENTIONS: ERCP-directed RFA or PDT. MAIN OUTCOME MEASUREMENTS: Overall survival by Kaplan-Meier analysis after initial treatment with either RFA or PDT. RESULTS: Patients who underwent RFA (n = 16) demonstrated an overall survival similar to that of those who underwent PDT (n = 32), with a median survival of 9.6 versus 7.5 months, respectively (P = .799). Patient age (P = .45), sex (P = .52), and lead time (P = .59) from presentation to initial RFA or PDT had no significant association with survival. The presence of distant metastasis was inversely associated with survival (hazard ratio 3.55; 95% confidence interval, 1.29-9.77; P = .014). Patients who underwent RFA (compared with PDT) had a lower mean number of plastic stents placed per month (0.45 vs 1.10, P = .001) but also had more episodes of stent occlusion (0.06 vs 0.02, P = .008) and cholangitis (0.13 vs 0.05, P = .008) per month. LIMITATIONS: Retrospective, single-center design. CONCLUSIONS: Survival after ERCP-directed RFA and PDT was not statistically different in patients with unresectable CCA. A randomized, controlled trial is warranted to validate these preliminary results.

Regulatory Forum commentary: through the looking glass--SENDing the pathology data we have INHAND.

During 2011, International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice (INHAND) Global Editorial Steering Committee representatives had discussions with representatives of the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), Clinical Data Interchange Standards Consortium (CDISC), and the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) to examine the potential use of INHAND terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the FDA. The interest in utilizing the INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists, suggests that there will be wide acceptance of INHAND nomenclature. The purpose of this article is 2-fold: (1) to provide a brief historical background on the development of SEND and how it is structured and (2) to discuss the impact of SEND on toxicologic pathology and the role of INHAND.

Underwater endoscopic mucosal resection of colorectal neoplasia is easily learned, efficacious, and safe.

BACKGROUND: Underwater endoscopic mucosal resection (UEMR) without submucosal injection is a novel endoscopic procedure. It is not known if UEMR can be easily taught and learned, and the efficacy and safety of UEMR has not been demonstrated at multiple medical centers. Our aims were to demonstrate that (1) UEMR is a technique that can be easily learned by an endoscopist trained in traditional EMR, (2) endoscopic ultrasound (EUS) may not be required before UEMR, and (3) UEMR is an efficacious and safe method for resection of large or flat neoplastic colorectal lesions. METHODS: An experienced interventional endoscopist began performing UEMR after observing UEMR procedures. Colorectal UEMR was performed using a pediatric colonoscope with a cap, a waterjet, and a 'duck-bill' snare using blended current. Submucosal injection was not used. Patient data were collected prospectively. RESULTS: A total of 21 patients (17 men, mean age 64.9 years, range 51-83) referred for polypectomy of large colorectal lesions underwent UEMR. A total of 43 colorectal lesions with a mean size of 20 mm (range 8-50) were resected by UEMR. Lesions were found in the right colon (N = 16), transverse colon (N = 5), left colon (N = 19), and rectum (N = 3). Pathology demonstrated tubular adenoma (N = 29), tubulovillous adenoma (N = 5), high-grade dysplasia (N = 3), serrated sessile adenoma without dysplasia (N = 3), and non-neoplastic tissue (N = 3). EUS was used in only two cases of rectal neoplasia (4.7 %). Of the UEMRs, 97.7 % were successful with complete resection of colorectal polyps. The only adverse event was one case (2.3 %) of delayed post-UEMR bleeding. CONCLUSIONS: UEMR was easily learned by an endoscopist already skilled in conventional EMR. EUS may not be required prior to most UEMR procedures. UEMR appears to be an efficacious and safe alternative to traditional EMR or ESD for large or flat colorectal neoplasms.

Accurate top protein variant discovery via low-N pick-and-validate machine learning.

A strategy to obtain the greatest number of best-performing variants with least amount of experimental effort over the vast combinatorial mutational landscape would have enormous utility in boosting resource producibility for protein engineering. Toward this goal, we present a simple and effective machine learning-based strategy that outperforms other state-of-the-art methods. Our strategy integrates zero-shot prediction and multi-round sampling to direct active learning via experimenting with only a few predicted top variants. We find that four rounds of low-N pick-and-validate sampling of 12 variants for machine learning yielded the best accuracy of up to 92.6% in selecting the true top 1% variants in combinatorial mutant libraries, whereas two rounds of 24 variants can also be used. We demonstrate our strategy in successfully discovering high-performance protein variants from diverse families including the CRISPR-based genome editors, supporting its generalizable application for solving protein engineering tasks. A record of this paper's transparent peer review process is included in the supplemental information.

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Calcium lignosulphonate: re-evaluation of relevant endpoints to re-confirm validity and NOAEL of a 90-day feeding study in rats.

A 90-day feeding study in Han/Wistar rats with calcium lignosulphonate was evaluated by the EFSA. The study was considered to be inadequate due to potentially impaired health status of the animals based upon a high incidence of minimal lymphoid hyperplasia in mesenteric/mandibular lymph nodes and Peyer's patches, and minimal lymphoid cell infiltration in the liver in all animals. The EFSA Panel further disagreed with the conclusion that the treatment-related observation of foamy histiocytosis in mesenteric lymph nodes was non-adverse and asked whether this observation would progress to something more adverse over time. A PWG was convened to assess the sections of lymph nodes, Peyer's patches and liver. In addition, all lymphoid tissues were re-examined. The clinical pathology and animal colony health screening data were re-evaluated. The question whether the foamy histiocytosis could progress to an adverse finding with increasing exposure duration was addressed by read-across. In conclusion, the animals on the 90-day feeding study were in good health, the study was adequate for safety evaluation, and the foamy histiocytes in the mesenteric lymph nodes were not considered adverse, but rather an adaptive response that was considered unlikely to progress to an adverse condition with time. The NOAEL was re-affirmed to be 2000 mg/kgbw/d.

International harmonization of toxicologic pathology nomenclature: an overview and review of basic principles.

The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice is a global project that is publishing criteria for both proliferative and nonproliferative changes in laboratory animals. This paper presents a set of general suggestions for terminology across systems. These suggestions include the use of diagnostic versus descriptive terms, modifiers, combination terms, and grading systems; and the use of thresholds, synonyms, and terminology for some processes that are common to several organ systems. The purpose of this paper is to help the reader understand some of the basic principles underlying the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice process.

Machine learning-coupled combinatorial mutagenesis enables resource-efficient engineering of CRISPR-Cas9 genome editor activities.

The genome-editing Cas9 protein uses multiple amino-acid residues to bind the target DNA. Considering only the residues in proximity to the target DNA as potential sites to optimise Cas9's activity, the number of combinatorial variants to screen through is too massive for a wet-lab experiment. Here we generate and cross-validate ten in silico and experimental datasets of multi-domain combinatorial mutagenesis libraries for Cas9 engineering, and demonstrate that a machine learning-coupled engineering approach reduces the experimental screening burden by as high as 95% while enriching top-performing variants by ∼7.5-fold in comparison to the null model. Using this approach and followed by structure-guided engineering, we identify the N888R/A889Q variant conferring increased editing activity on the protospacer adjacent motif-relaxed KKH variant of Cas9 nuclease from Staphylococcus aureus (KKH-SaCas9) and its derived base editor in human cells. Our work validates a readily applicable workflow to enable resource-efficient high-throughput engineering of genome editor's activity.

Saying what you don't mean: A cross-cultural study of perceptions of sarcasm.

Sarcasm is widely used, but its complexities are not well understood. Sarcastic utterances can have multiple nuanced meanings depending on individual differences of the speaker, listener, and the sociocultural context. The current study examined the views of 344 adults ages 31-55 in the United States, Mexico, and China. We used an online survey to ask participants to self-report how frequently they used sarcasm, under what circumstances, and for what reasons. They also completed the Hofstede Value Survey Module (HVSM) based on Hofstede's six dimensions of culture: Individualism/Collectivism, Power Distance, Uncertainty Avoidance, Masculinity/Femininity, Long Term Orientation, and Indulgence/Restraint. Respondents from the U.S. and Mexico, countries higher in Individualism and lower in Power Distance, reported more sarcasm use than respondents from China, a country higher in Power Distance and Collectivism. The most common reasons to use sarcasm in all three countries were "to be funny" and "to have fun with friends." (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Endoscopic submucosal dissection with electrosurgical knives in a patient on aspirin therapy (with video).

BACKGROUND: The electrosurgical knives required to perform endoscopic submucosal dissection (ESD) have recently passed the 510(k) premarketing evaluation by the U.S. Food and Drug Administration and are now available for purchase in the United States. Challenges to ESD being more widely performed in the United States include the lack of intensive hands-on training programs and a low incidence of appropriate, highly dysplastic gastric lesions on which an ESD-trained endoscopist can begin performing this procedure in patients. Furthermore, there are no guidelines regarding the safety of continuing antiplatelet therapy in patients undergoing ESD. OBJECTIVE: To report on the first gastric ESD performed in the United States by using recently approved electrosurgical knives on a patient who was maintained on aspirin therapy. DESIGN: Case report. SETTING: Large academic medical center. PATIENT: One patient with a 2-cm high-grade dysplasia (HGD) lesion in the posterior antrum who had indwelling coronary stents and was maintained on aspirin therapy throughout the periprocedural period. INTERVENTIONS: High-definition white-light and narrow-band imaging endoscopy, endosonography, and ESD by using recently approved electrosurgical knives. MAIN OUTCOME MEASUREMENTS: Complete resection of the HGD gastric lesion. RESULTS: En bloc complete resection of the HGD gastric lesion was achieved without any immediate or delayed bleeding or perforation. No residual or recurrent dysplasia was found on 1- or 3-month follow-up endoscopies. LIMITATIONS: Generalizations cannot be made from this single case. CONCLUSIONS: After receiving intensive hands-on training in both ex vivo and in vivo animal models, gastric ESD was successfully performed by 2 U.S. endoscopists by using recently approved electrosurgical knives in a patient maintained on aspirin therapy without any complications.

Meshed capillary vessels found on narrow-band imaging without optical magnification effectively identifies colorectal neoplasia: a North American validation of the Japanese experience.

BACKGROUND: The presence of meshed capillary (MC) vessels is highly sensitive (96%) and specific (92%) for diagnosing colorectal neoplasia on colonoscopy by using narrow-band imaging (NBI) with optical magnification, which is not available in North America. However, the efficacy of NBI to identify an MC pattern without optical magnification has not been determined. OBJECTIVE: To determine the diagnostic capabilities of NBI colonoscopy without optical magnification in differentiating neoplastic from non-neoplastic colorectal polyps by using the MC pattern. DESIGN: Retrospective comparison of prospectively collected colorectal polyp data. SETTING: Large, academic medical center. PATIENTS: This study involved 126 consecutive colorectal polyps (median size 3 mm) that were found in 52 patients (33 men) with a median age of 59.5 years. INTERVENTION: All lesions identified by white-light colonoscopy were prospectively diagnosed in real-time by using the MC pattern as determined on high-definition NBI, with 1.5x zoom but without true optical magnification, and then endoscopically excised. Surgical pathology was used as the criterion standard. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of identifying neoplastic polyps were calculated. RESULTS: NBI without optical magnification was found to have a sensitivity of 93%, specificity of 88%, positive predictive value of 90%, negative predictive value of 91%, and diagnostic accuracy of 91% when all polyp sizes were considered. For lesions < or =5 mm, sensitivity was 87%, specificity was 93%, positive predictive value was 89%, negative predictive value was 91%, and diagnostic accuracy was 90%. LIMITATIONS: Single-center, single-endoscopist experience. CONCLUSION: Use of the MC pattern on NBI colonoscopy without optical magnification effectively distinguishes neoplastic from non-neoplastic colorectal polyps. NBI colonoscopy without optical magnification for neoplastic polyp diagnosis appears to be comparable with NBI with optical magnification when the MC pattern is used. A large, prospective trial is needed for further validation.