Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury.

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.

Quantitative image analysis pipeline for detecting circulating hybrid cells in immunofluorescence images with human-level accuracy.

Circulating hybrid cells (CHCs) are a newly discovered, tumor-derived cell population found in the peripheral blood of cancer patients and are thought to contribute to tumor metastasis. However, identifying CHCs by immunofluorescence (IF) imaging of patient peripheral blood mononuclear cells (PBMCs) is a time-consuming and subjective process that currently relies on manual annotation by laboratory technicians. Additionally, while IF is relatively easy to apply to tissue sections, its application to PBMC smears presents challenges due to the presence of biological and technical artifacts. To address these challenges, we present a robust image analysis pipeline to automate the detection and analysis of CHCs in IF images. The pipeline incorporates quality control to optimize specimen preparation protocols and remove unwanted artifacts, leverages a ß-variational autoencoder (VAE) to learn meaningful latent representations of single-cell images, and employs a support vector machine (SVM) classifier to achieve human-level CHC detection. We created a rigorously labeled IF CHC data set including nine patients and two disease sites with the assistance of 10 annotators to evaluate the pipeline. We examined annotator variation and bias in CHC detection and provided guidelines to optimize the accuracy of CHC annotation. We found that all annotators agreed on CHC identification for only 65% of the cells in the data set and had a tendency to underestimate CHC counts for regions of interest (ROIs) containing relatively large amounts of cells (>50,000) when using the conventional enumeration method. On the other hand, our proposed approach is unbiased to ROI size. The SVM classifier trained on the ß-VAE embeddings achieved an F1 score of 0.80, matching the average performance of human annotators. Our pipeline enables researchers to explore the role of CHCs in cancer progression and assess their potential as a clinical biomarker for metastasis. Further, we demonstrate that the pipeline can identify discrete cellular phenotypes among PBMCs, highlighting its utility beyond CHCs.

Sex-specific neuropsychological correlates of apathy and depression across neurodegenerative disorders.

BACKGROUND: Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships. OBJECTIVES: We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex. DESIGN, SETTING AND PARTICIPANTS: We conducted a cohort analysis of participants in the COMPASS-ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls. MEASUREMENTS: Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates. RESULTS: Groups included depressive symptoms only (n = 70), apathy symptoms only (n = 52), both (n = 68), or neither (n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory (t(312)  = -2.4, p = 0.02 and t(328)  = -3.8, p = 0.001, respectively) and visuospatial reasoning (t(301)  = -2.3, p = 0.02 and t(321)  = -2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex-stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function (t(166)  = 2.4, p = 0.01) and verbal learning (t(167)  = -4.3, p = 0.001) compared to the female neither group. CONCLUSIONS: This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes.

Modifiable Risk Factors Associated With Cognitive Decline in Late Life Depression: Findings From the Canadian Longitudinal Study on Aging: Facteurs de risque modifiables associés au déclin cognitif dans la dépression en fin de vie : constatations de l'Étude longitudinale canadienne sur le vieillissement.

OBJECTIVE: Depression in later life is associated with a two-fold increased risk of dementia. It is not clear to what extent potentially modifiable risk factors account for this association. METHOD: Older adults (age 50 + ) with objective health measures (n = 14,014) from the Canadian Longitudinal Study on Aging were followed for a mean duration of 35 months. Linear regression analyses were used to determine if clinically significant depression (Centre for Epidemiologic Studies Depression scale score (CESD) ≥ 10) was associated with global cognitive decline, assessed with a neuropsychological battery during follow-up, and if modifiable risk factors mediated this association. RESULTS: Depression was associated with an excess of risk factors for cognitive decline including: vascular disease, hypertension, diabetes, apnoea during sleep, higher body mass index, smoking, physical inactivity and lack of social participation. In regression analyses depression remained independently associated with cognitive decline over time (beta -0.060, P = 0.038) as did cerebrovascular disease (beta -0.197, P < 0.001), HbA1C (beta -0.059, P < 0.001), visual impairment (beta -0.070, P = 0.007), hearing impairment (beta -0.098, P < 0.001) and physical inactivity (beta -0.075, P = 0.014). In mediation analyses, we found that cerebrovascular disease (z = -3.525, P < 0.001), HbA1C (z = -4.976, P < 0.001) and physical inactivity (z = -3.998, P < 0.001) partially mediated the association between depression and cognitive decline. CONCLUSIONS: In this large sample of Canadian older adults incorporating several objective health measures, older adults with depression were at increased risk of cognitive decline and had an excess of potentially modifiable risk factors. Clinicians should pay particular attention to control of diabetes, physical inactivity and risk factors for cerebrovascular disease in older adults presenting with depression as they can contribute to accelerated cognitive decline and may be addressed during routine clinical care.

Identifying determinants of varenicline adherence using the Theoretical Domains framework: a rapid review.

BACKGROUND: Adhering to varenicline has been shown to significantly improve the chances of successfully quitting smoking, with studies indicating a twofold increase in 6-month quit rates. However, despite its potential benefits, many individuals struggle with maintaining good adherence to varenicline; thus there is a need to develop scalable strategies to help people adhere. As a first step to inform the development of an intervention to improve adherence to varenicline, we conducted a rapid literature review to identify: 1) modifiable barriers and facilitators to varenicline adherence, and 2) behaviour change techniques associated with increased adherence to varenicline. METHODS: We searched MEDLINE, Embase, APA PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials for relevant studies published between 2006 and 2022. Search terms included "varenicline," "smoking cessation," and "adherence," and their respective subject headings and synonyms. We screened and included studies reporting modifiable determinants of adherence to varenicline and then assessed quality, extracted modifiable determinants and mapped them to the Theoretical Domains Framework version 2 and the Behaviour Change Technique Taxonomy version 1. RESULTS: A total of 1,221 titles were identified through the database searches; 61 met the eligibility criteria. Most of the studies were randomized controlled trials and predominantly focused on barriers to varenicline. Only nine studies explicitly mentioned behaviour change techniques used to help varenicline adherence. Eight domains were identified as barriers to varenicline adherence (behavioural regulation, memory, goals, intentions, beliefs about capabilities, beliefs about consequences, optimism/pessimism, and environmental context) and five as facilitators (knowledge, behavioural regulation, beliefs about capabilities, social influences, and environmental context). CONCLUSIONS: This study identifies barriers and facilitators that should be addressed when developing a complex adherence intervention tailored to patients' needs based on modifiable determinants of medication adherence, some of which are under- used by existing adherence interventions. The findings from this review will inform the design of a theory-based healthbot planned to improve varenicline adherence in people undergoing smoking cessation treatment. SYSTEMATIC REVIEW REGISTRATION: This study was registered with PROSPERO (# CRD42022321838).

Exploratory Analyses of Circulating Neoplastic-Immune Hybrid Cells as Prognostic Biomarkers in Advanced Intrahepatic Cholangiocarcinoma.

Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.

Efficacy of adjunctive octenidine hydrochloride as compared to chlorhexidine and placebo as adjuncts to instrumentation in stage I-II periodontitis: A double-blinded randomized controlled trial.

OBJECTIVES: This randomized, controlled, double-blinded clinical trial aimed to evaluate the efficacy of octenidine hydrochloride and chlorhexidine mouthwashes as adjuncts to instrumentation in stage I-II periodontitis patients. METHODS: Forty-five patients with mild-to-moderate periodontitis were randomly allocated to three groups: 0.1% octenidine dihydrochloride (OCT), placebo, and 0.12% chlorhexidine (CHX) mouthwashes. Patients were instructed to use the mouthwash after instrumentation for twice a day up to 3 weeks. Periodontal parameters such as probing pocket depth (PPD), clinical attachment loss (CAL), O'Leary plaque index (PI), Loe and Silness gingival index (GI), Lobene stain index (SI), and oral soft tissue changes were recorded at baseline and once every week for 3 weeks. The visual analogue scale (VAS) was also recorded as a self-administered questionnaire at the end of the study. The one-way ANOVA was used to compare VAS scores between the groups. The repeated measures ANOVA and post hoc Newman-Keuls tests were used to assess the differences in the periodontal parameters between groups at different time intervals. The Kruskal-Wallis test was used to compare the mean SI. RESULTS: There was a significant reduction in the mean GI of the OCT and CHX groups compared to placebo (p < 0.05). OCT usage resulted in significantly less staining, according to mean SI, when compared to CHX. Furthermore, VAS scores revealed that OCT was significantly the preferred mouthwash (p < 0.01). CONCLUSION: Adjunctive octenidine hydrochloride may be an alternative to chlorhexidine in its ability to control the periodontal parameters in patients with stage I-II periodontitis. Further larger studies are necessary to confirm these findings.

Gastroparesis in pregnancy.

Gastroparesis is a functional gastrointestinal disorder that more commonly affects women, with most cases being diagnosed during childbearing age. However, there is a paucity of data and guidelines to specifically highlight the epidemiology, disease course, maternal and fetal impact, and the management of existing gastroparesis during pregnancy. Apart from metoclopramide, there is no approved therapy specifically indicated for gastroparesis. More importantly, pregnant and breastfeeding women are excluded from clinical trials evaluating pharmacologic agents in the management of gastroparesis. This poses a real challenge to healthcare providers in counseling and managing patients with gastroparesis. In this systematic review, we summarize the current available literature and the knowledge gaps in the impact of pregnancy on gastroparesis and vice versa. We also highlight the efficacy and safety profiles of available pharmacologic and nonpharmacologic therapies in the management of patients with gastroparesis, with emphasis on judicious use of dietary approaches that are deemed relatively safe during pregnancy.

Prevalence of and disparities in adolescents' susceptibility to novel oral nicotine products marketed as "tobacco-free".

Non-therapeutic, novel oral nicotine products are convenient, discreet to use, and flavored, with increasing sales in the United States. It is unclear whether these products appeal predominantly to adolescents already susceptible to inhalable nicotine products, or whether they attract adolescents who would not otherwise use nicotine. This study examined prevalence and correlates of susceptibility to inhalable and oral nicotine product use among adolescents. Ninth- and tenth-grade students from Southern California who had never used any nicotine product (N = 3129) completed an online survey in Fall 2021 assessing susceptibility to inhalable (i.e., cigarettes, e-cigarettes) and oral (e.g., pouches, gum, gummies) nicotine products. Multinomial logistic regression analyses estimated associations of demographic characteristics with odds of susceptibility to oral, inhalable, or both products. Susceptibility was highest for e-cigarettes (19.7%), followed by cigarettes (15.0%) and nicotine gum, lozenges, tablets and/or gummies (15.0%), and nicotine pouches (8.7%). Dual susceptibility to oral and inhalable products (vs. neither product type) was higher in cisgender female and non-cisgender (vs. cisgender male) adolescents (odds ratios [ORs] = 1.36-2.02; ps < 0.05). Hispanic adolescents (vs. Asian) were more susceptible to both products (OR = 1.47; p < .05). Lower-socioeconomic status (SES) and sexual minority adolescents were more susceptible to oral (ORs = 1.76-1.87; ps < 0.05) and both products (ORs = 1.32-1.88; ps < 0.05), compared to higher-SES and heterosexual adolescents. Adolescents in Southern California may be more susceptible to e-cigarettes than other nicotine/tobacco products. However, appreciable numbers may be susceptible to oral nicotine products, including some youth who might not otherwise use nicotine and youth from populations historically impacted by tobacco-related health disparities.

Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal.

The canonical Wnt/ß-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling ß-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/ß-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

Dose-response effects of two nicotine salt formulations on electronic cigarette appeal and sensory attributes.

OBJECTIVES: Various organic acids are used to create nicotine salt formulations, which may improve the appeal and sensory experience of vaping electronic cigarettes (e-cigarettes). This clinical experiment examined the effects of partially and highly protonated forms of two nicotine salt formulations (nicotine lactate and benzoate) versus free-base (no acid additive) on the appeal and sensory attributes of e-cigarettes. METHODS: Current adult tobacco product users (n=116) participated in an online remote double-blind within-subject randomised experiment involving standardised self-administration of e-cigarette solutions varying in nicotine formulation (free-base, 50% nicotine lactate -1:2 lactic acid to nicotine molar ratio, 100% nicotine lactate - 1:1 ratio, 50% nicotine benzoate and 100% nicotine benzoate). Each formulation had equivalent nicotine concentrations (27.0-33.0 mg/mL) and was administered in four flavours in a pod-style device. After each administration, participants rated appeal (liking, disliking and willingness to use again) and sensory attributes (0-100 scale). RESULTS: Compared with free-base nicotine, 50% and 100% nicotine lactate and benzoate yielded higher appeal, smoothness and sweetness and lower harshness and bitterness. Dose-response analyses found 100% vs 50% nicotine salt improved appeal, smoothness, bitterness and harshness for nicotine lactate and sweetness, smoothness and harshness for nicotine benzoate. Solutions with higher pH were associated with worse appeal and sensory attributes across nicotine formulations. Nicotine formulation effects did not differ by tobacco use status and flavours. CONCLUSION: Restricting benzoic acid or lactic acid additives or setting minimal pHs in e-cigarettes merits consideration in regulations designed to reduce vaping among populations deterred from using e-cigarettes with aversive sensory properties. TRIAL REGISTRATION NUMBER: This study was registered under ClinicalTrials.gov Identifier: NCT03742817 under the title 'Effects of e-Cigarettes on Perceptions and Behavior'.

Effects of flavour and modified risk claims on nicotine pouch perceptions and use intentions among young adults who use inhalable nicotine and tobacco products: a randomised controlled trial.

BACKGROUND: Availability of flavours and potential modified risk tobacco product (MRTP) claims may influence young adults' (YAs') perceptions of and intentions to use nicotine pouches ('pouches'). METHODS: YAs aged 21-34 years (N=47, M age=24.5, SD=3.1) with past-month nicotine/tobacco use (10.6% cigarette-only, 51.1% e-cigarette-only, 38.3% dual use) and no intention to quit were randomised to self-administer four Zyn 3 mg nicotine pouches in a 4 (flavour; within-subjects: smooth, mint, menthol, citrus) × 2 (MRTP claim on packaging; between subjects: present or absent) mixed-factorial design. After self-administering each pouch, participants reported appeal, use intentions and perceived harm compared with cigarettes and e-cigarettes. Three mixed-factorial analysis of variances (ANOVAs) examined main and interactive effects of flavour and MRTP claim on appeal, use intentions and comparative harm perceptions. RESULTS: Mint (M=55.9, SD=26.4), menthol (M=49.7, SD=26.8) and citrus (M=46.6, SD=24.8) flavours were significantly more appealing than smooth (M=37.6, SD=25.4; p<0.001). MRTP claim did not significantly affect product appeal (p=0.376). Use intentions were greater for mint (M=2.6, SD=1.3) and menthol (M=2.0, SD=1.1) flavours than smooth (M=1.8, SD=1.0; p=0.002). Flavour did not affect comparative harm perceptions (p values>0.418). MRTP claims increased use intention (p=0.032) and perceptions of pouches as less harmful than cigarettes (p=0.011), but did not affect perceived harm relative to e-cigarettes (p=0.142). Flavour × MRTP claim interactions were not significant. CONCLUSIONS: Flavoured (vs smooth) pouches were more appealing to YAs. MRTP claims reduced perceived harm of pouches compared with cigarettes; however, intentions to switch were low. To protect YAs' health, regulatory restrictions could target flavours and MRTP claims.

Structural analysis of a trimeric assembly of the mitochondrial dynamin-like GTPase Mgm1.

The fusion of inner mitochondrial membranes requires dynamin-like GTPases, Mgm1 in yeast and OPA1 in mammals, but how they mediate membrane fusion is poorly understood. Here, we determined the crystal structure of Saccharomyces cerevisiae short Mgm1 (s-Mgm1) in complex with GDP. It revealed an N-terminal GTPase (G) domain followed by two helix bundles (HB1 and HB2) and a unique C-terminal lipid-interacting stalk (LIS). Dimers can form through antiparallel HB interactions. Head-to-tail trimers are built by intermolecular interactions between the G domain and HB2-LIS. Biochemical and in vivo analyses support the idea that the assembly interfaces observed here are native and critical for Mgm1 function. We also found that s-Mgm1 interacts with negatively charged lipids via both the G domain and LIS. Based on these observations, we propose that membrane targeting via the G domain and LIS facilitates the in cis assembly of Mgm1, potentially generating a highly curved membrane tip to allow inner membrane fusion.

Society for Maternal-Fetal Medicine Special Statement: Commitment to excellence in obstetrical care, research, and education for people with diverse sexual and gender identities.

The Society for Maternal-Fetal Medicine seeks to ensure excellence in obstetrical outcomes for all people who desire or experience pregnancy, including people with diverse sexual and gender identities. The Society commits to the use of practices in clinical and research settings that affirm the sexual and gender identities of all people, encourages the development of undergraduate and graduate medical education curricula and training programs that address diverse pathways to pregnancy and support clinicians with diverse sexual and gender identities, and promotes the use of inclusive language that is accurate and, when possible, specific.

Incorporating personal-device-based point-of-care ultrasound into obstetric care: a validation study.

BACKGROUND: Personal-device-based point-of-care-ultrasound (P-POCUS) probes plug directly into a cell phone or tablet to function as its display, creating the potential to increase access to obstetric ultrasonography in complex healthcare settings (COVID units, low resource settings); however, new technology must be proven to be reliable in the obstetric setting before integrating into practice. OBJECTIVE: To evaluate the intraclass correlation (reliability) of personal-device-based-point-of-care-ultrasound devices as compared with standard ultrasound machines in obstetrics. STUDY DESIGN: This was a prospective, observational study of patients between 19-39 weeks gestation in an urban, prenatal ultrasound diagnosis center. Each patient underwent assessment by an expert sonographer using standard ultrasound machines and personal-device-based-point-of-care-ultrasound devices to determine estimated fetal weight. The statistical reliability and agreement between the estimated fetal weights was assessed through intraclass correlation coefficients, Bland-Altman plots, and Pearson correlation coefficients. RESULTS: 100 paired sets of scans were performed from October 2020 to December 2020. For the estimated fetal weights, there was near-perfect agreement, with an intraclass correlation coefficient of 0.99 (P<.0001). Bland-Altman analysis showed an average difference of 53 grams, with 95% limit of agreement between -178 grams and 283 grams. Pearson correlation showed near-perfect correlation between the measurements (r=0.99, P<.0001). CONCLUSION: personal-device-based point-of-care-ultrasound devices are reliable tools for performing basic obstetrical ultrasound and have the potential to increase access to obstetrical ultrasound worldwide.

Routine Multidisciplinary Review of Severe Maternal Morbidity Is Associated with a Reduction in Preventable Cases of Severe Maternal Morbidity.

OBJECTIVE: Severe maternal morbidity (SMM) has increased by 45% in the United States and is estimated to affect up to 1.5% of all deliveries. Research has not yet been conducted that demonstrates a benefit to multidisciplinary review of SMM. The aim of our study was to determine if standardized, routine review of the cases of SMM by a multidisciplinary committee results in a reduction of potentially preventable cases of SMM. STUDY DESIGN: A retrospective cohort study of all women admitted for delivery at Cedars-Sinai Medical Center from March 1, 2012 to September 30, 2016. Our cohort was separated into two groups: a preintervention group composed of women admitted for delivery prior to the implementation of the obstetric Quality and Peer Review Committee (OBQPRC), and a postintervention group where the committee had been well established. Cases of confirmed SMM were presented to a multidisciplinary research committee, and the committee determined whether opportunities for improvement in care existed. The groups were compared with determine if there was a decreased incidence of preventable SMM following the implementation of the OBQPRC standardized review process. RESULTS: There were 30,319 deliveries during the study period; 13,120 deliveries in the preintervention group; and 13,350 deliveries in the postintervention group (2,649 deliveries during the transition period). There was no difference in the rate of SMM between the preintervention (125; 0.95%) and postintervention (129; 0.97%) groups, (p = 0.91). There was a significantly lower rate of opportunity for the improvement in care in the postintervention group (29.5%) compared with the preintervention group (46%; p = 0.005). CONCLUSION: We demonstrated a significant reduction in the rate of potentially preventable SMM following the implementation of routine review of all SMM suggesting that this process plays an important role in improving maternal care and outcomes. KEY POINTS: · Benefit to routine review of SMM has not been demonstrated.. · Routine review of SMM is associated with 36% reduction in potentially preventable SMM.. · This is the first study to demonstrate the benefit of routine review of SMM..

Applying Automated Machine Learning to Predict Mode of Delivery Using Ongoing Intrapartum Data in Laboring Patients.

OBJECTIVE: This study aimed to develop and validate a machine learning (ML) model to predict the probability of a vaginal delivery (Partometer) using data iteratively obtained during labor from the electronic health record. STUDY DESIGN: A retrospective cohort study of deliveries at an academic, tertiary care hospital was conducted from 2013 to 2019 who had at least two cervical examinations. The population was divided into those delivered by physicians with nulliparous term singleton vertex (NTSV) cesarean delivery rates <23.9% (Partometer cohort) and the remainder (control cohort). The cesarean rate among this population of lower risk patients is a standard metric by which to compare provider rates; <23.9% was the Healthy People 2020 goal. A supervised automated ML approach was applied to generate a model for each population. The primary outcome was accuracy of the model developed on the Partometer cohort at 4 hours from admission to labor and delivery. Secondary outcomes included discrimination ability (receiver operating characteristics-area under the curve [ROC-AUC]), precision-recall AUC, and calibration of the Partometer. To assess generalizability, we compared the performance and clinical predictors identified by the Partometer to the control model. RESULTS: There were 37,932 deliveries during the study period; after exclusions, 9,385 deliveries were included in the Partometer cohort and 19,683 in the control cohort. Accuracy of predicting vaginal delivery at 4 hours was 87.1% for the Partometer (ROC-AUC: 0.82). Clinical predictors of greatest importance in the stacked Intrapartum Partometer Model included the Admission Model prediction and ongoing measures of dilatation and station which mirrored those found in the control population. CONCLUSION: Using automated ML and intrapartum factors improved the accuracy of prediction of probability of a vaginal delivery over both previously published models based on logistic regression. Harnessing real-time data and ML could represent the bridge to generating a truly prescriptive tool to augment clinical decision-making, predict labor outcomes, and reduce maternal and neonatal morbidity. KEY POINTS: · Our ML-based model yielded accurate predictions of mode of delivery early in labor.. · Predictors for models created on populations with high and low cesarean rates were the same.. · A ML-based model may provide meaningful guidance to clinicians managing labor..

Irritable Bowel Syndrome in Pregnancy.

Irritable bowel syndrome (IBS) affects a significant percentage of the general population and is more common in women. A large proportion of women affected with IBS are of childbearing age; however, there is a paucity of studies and guidelines to specifically address the epidemiology, course, maternal/fetal prognosis, or management of IBS in pregnancy. This scarcity of literature on IBS and pregnancy poses significant challenges to healthcare providers in counseling and managing patients. In this comprehensive review, we summarize the current literature and knowledge gaps regarding the effects of pregnancy on IBS and vice versa, along with the efficacy and safety profiles of commonly used IBS diets and medications in pregnancy. The management of pregnant women with IBS should be multidisciplinary, with emphasis on education and judicious use of dietary modifications and pharmacologic options that are deemed relatively safe during pregnancy.

Circulating Hybrid Cells: A Novel Liquid Biomarker of Treatment Response in Gastrointestinal Cancers.

BACKGROUND: Real-time monitoring of treatment response with a liquid biomarker has potential to inform treatment decisions for patients with rectal adenocarcinoma (RAC), esophageal adenocarcinoma (EAC), and colorectal liver metastasis (CRLM). Circulating hybrid cells (CHCs), which have both immune and tumor cell phenotypes, are detectable in the peripheral blood of patients with gastrointestinal cancers, but their potential as an indicator of treatment response is unexplored. METHODS: Peripheral blood specimens were collected from RAC and EAC patients after neoadjuvant therapy (NAT) or longitudinally during therapy and evaluated for CHC levels by immunostaining. Receiver operating characteristics (ROCs) and the Kaplan-Meier method were used to analyze the CHC level as a predictor of pathologic response to NAT and disease-specific survival (DSS), respectively. RESULTS: Patients with RAC (n = 23) and EAC (n = 34) were sampled on the day of resection, and 11 patients (32%) demonstrated a pathologic complete response (pCR) to NAT. On ROC analysis, CHC levels successfully discriminated pCR from non-pCR with an area under the curve of 0.82 (95% confidence interval [CI], 0.71-0.92; P < 0.001). Additionally, CHC levels in the EAC patients correlated with residual nodal involvement (P = 0.026) and 1-year DSS (P = 0.029). The patients with RAC who were followed longitudinally during NAT (n = 2) and hepatic arterial infusion therapy for CRLM (n = 2) had CHC levels that decreased with therapy response and increased before clinical evidence of disease progression. CONCLUSION: Circulating hybrid cells are a novel blood-based biomarker with potential for monitoring treatment response and disease progression to help guide decisions for further systemic therapy, definitive resection, and post-therapy surveillance. Additional validation studies of CHCs are warranted.

Symptomology following mRNA vaccination against SARS-CoV-2.

Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination.