An aggregated mitochondrial distribution in preimplantation embryos disrupts nuclear morphology, function, and developmental potential.

A dispersed cytoplasmic distribution of mitochondria is a hallmark of normal cellular organization. Here, we have utilized the expression of exogenous Trak2 in mouse oocytes and embryos to disrupt the dispersed distribution of mitochondria by driving them into a large cytoplasmic aggregate. Our findings reveal that aggregated mitochondria have minimal impact on asymmetric meiotic cell divisions of the oocyte. In contrast, aggregated mitochondria during the first mitotic division result in daughter cells with unequal sizes and increased micronuclei. Further, in two-cell embryos, microtubule-mediated centering properties of the mitochondrial aggregate prevent nuclear centration, distort nuclear shape, and inhibit DNA synthesis and the onset of embryonic transcription. These findings demonstrate the motor protein-mediated distribution of mitochondria throughout the cytoplasm is highly regulated and is an essential feature of cytoplasmic organization to ensure optimal cell function.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Maturation of cardioventilatory physiological trajectories in extremely preterm infants.

BACKGROUND: In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life. METHODS: The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation. RESULTS: Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8-12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3-4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31-33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing. CONCLUSIONS: Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. IMPACT: Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms.

High parasite prevalence in an ecosystem engineer correlated with both local- and landscape-level factors.

Spatial variation in parasitic infection may have many physical and biological drivers. Uncovering these drivers may be especially important for parasites of ecosystem engineers because the engineers are foundational to their communities. Oysters are an important coastal ecosystem engineer that have declined drastically worldwide, in part due to enhanced cases of lethal oyster diseases, such as Dermo and MSX, caused by the protozoan parasites Perkinsus marinus and Haplosporidium nelsoni, respectively. Besides water quality and hydrodynamics, there is little information on how other variables influence the prevalence and intensity of these pathogens in oysters across a regional scale. To examine drivers of spatial variation in these oyster parasites-including host size, local reef properties, and landscape properties-we sampled 24 reefs systematically spread along the coast of Georgia, USA. Across sites, we found universally high prevalence of oysters with at least one of these parasites (91.02% ± 8.89, mean ± SD). Not only are high levels of parasite prevalence potentially problematic for a pivotal ecosystem engineer, but also low spatial variability may limit the explanatory power of variables across a regional scale. Our statistical models explained between 18 and 42% of the variation in spatial patterns of prevalence and intensity of these microparasites. Interestingly, landscape context was a positive predictor of P. marinus, but a negative predictor of H. nelsoni. Overall, our findings suggest that factors driving parasite prevalence and intensity operate across multiple spatial scales, and the same factor can both facilitate and hinder different parasites within the same host species.

Quantitative and Qualitative Changes in Peripheral Chemoreceptor Activity in Preterm Infants.

Rationale: Preterm infants are at risk for ventilatory control instability that may be due to aberrant peripheral chemoreceptor activity. Although term infants have increasing peripheral chemoreceptor contribution to overall ventilatory drive with increasing postnatal age, how peripheral chemoreceptor contribution changes in preterm infants with increasing postmenstrual age is not known. Objectives: To evaluate peripheral chemoreceptor activity between 32 and 52 weeks postmenstrual age in preterm infants, using both quantitative and qualitative measures. Methods: Fifty-five infants born between 24 weeks, 0 days gestation and 28 weeks, 6 days gestation underwent hyperoxic testing at one to four time points between 32 and 52 weeks postmenstrual age. Quantitative [Formula: see text] decreases were calculated, and qualitative responses were categorized as apnea, continued breathing with a clear reduction in [Formula: see text], sigh breaths, and no response. Measurements and Main Results: A total of 280 hyperoxic tests were analyzed (2.2 ± 0.3 tests per infant at each time point). Mean peripheral chemoreceptor contribution to ventilatory drive was 85.2 ± 20.0% at 32 weeks and 64.1 ± 22.0% at 52 weeks. Apneic responses were more frequent at earlier postmenstrual ages. Conclusions: Among preterm infants, the peripheral chemoreceptor contribution to ventilatory drive was greater at earlier postmenstrual ages. Apnea was a frequent response to hyperoxic testing at earlier postmenstrual ages, suggesting high peripheral chemoreceptor activity. A clearer description of how peripheral chemoreceptor activity changes over time in preterm infants may help explain how ventilatory control instability contributes to apnea and sleep-disordered breathing later in childhood. Clinical trial registered with www.clinicaltrials.gov (NCT03464396).

Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Distinct type I collagen alterations cause intrinsic lung and respiratory defects of variable severity in mouse models of osteogenesis imperfecta.

Type I collagen alterations cause osteogenesis imperfecta (OI), a connective tissue disorder characterized by severe bone fragility. Patients with OI can suffer from significant pulmonary manifestations including severe respiratory distress in the neonatal period and a progressive decline in respiratory function in adulthood. We and others have shown intrinsic lung defects in some mouse models of OI. In this large study, we performed histological, histomorphometric, microcomputed tomography and invasive studies on oim/+, Col1a2+/G610C , CrtapKO and oim/oim mice, mimicking mild to moderate to severe OI, with the overall goal of determining the extent of their pulmonary and respiratory mechanics defects and whether these defects correlate with the skeletal disease severity and affect each sex equally. Although with variable severity, OI lung histology consistently showed alveolar simplification with enlarged acinar airspace and reduced alveolar surface. Numerous respiratory mechanics parameters, including respiratory system resistance and elastance, tissue damping, inspiratory capacity, total lung capacity, and others, were significantly and similarly impacted in CrtapKO and oim/oim but not in oim/+ or Col1a2+/G610C compared to control mice. Our data indicate that the impact of type I collagen alterations and OI on lung morphology and function positively correlate with the severity of the extracellular matrix deficiency. Moreover, the respiratory defects were more pronounced in male compared to female mice. It will be important to determine whether our observations in mice translate to OI patients and to dissect the respective contribution of intrinsic lung defects vs. extrinsic skeletal defects to impaired lung function in OI. KEY POINTS: Different type I collagen alterations in mouse models of osteogenesis imperfecta (OI) cause similar abnormal lung histology, with alveolar simplification and reduced alveolar surface, reminiscent of emphysema. Several respiratory mechanics parameters are altered in mouse models of OI. The impact of type I collagen alterations and OI on lung morphology and function positively correlate with the severity of the extracellular matrix deficiency. Respiratory defects were more pronounced in male compared to female mice. It will be important to determine whether our observations in mice translate to OI patients and to dissect the respective contribution of intrinsic lung defects vs. extrinsic skeletal defects to impaired lung function in OI.

Three-year outcomes for transcatheter repair in patients with mitral regurgitation from the CLASP study.

BACKGROUND: Mitral valve transcatheter edge-to-edge repair (M-TEER) is an effective option for treatment of mitral regurgitation (MR). We previously reported favorable 2-year outcomes for the PASCAL transcatheter valve repair system. OBJECTIVES: We report 3-year outcomes from the multinational, prospective, single-arm CLASP study with analysis by functional MR (FMR) and degenerative MR (DMR). METHODS: Patients with core-lab determined MR ≥ 3+ were deemed candidates for M-TEER by the local heart team. Major adverse events were assessed by an independent clinical events committee to 1 year and by sites thereafter. Echocardiographic outcomes were evaluated by the core laboratory to 3 years. RESULTS: The study enrolled 124 patients, 69% FMR; 31% DMR (60% NYHA class III-IVa, 100% MR ≥ 3+). The 3-year Kaplan-Meier estimate for survival was 75% (66% FMR; 92% DMR) and freedom from heart failure hospitalization (HFH) was 73% (64% FMR; 91% DMR), with 85% reduction in annualized HFH rate (81% FMR; 96% DMR) (p < 0.001). MR ≤ 2+ was achieved and maintained in 93% of patients (93% FMR; 94% DMR) and MR ≤ 1+ in 70% of patients (71% FMR; 67% DMR) (p < 0.001). The mean left ventricular end-diastolic volume (181 mL at baseline) decreased progressively by 28 mL [p < 0.001]. NYHA class I/II was achieved in 89% of patients (p < 0.001). CONCLUSIONS: The 3-year results from the CLASP study demonstrated favorable and durable outcomes with the PASCAL transcatheter valve repair system in patients with clinically significant MR. These results add to the growing body of evidence establishing the PASCAL system as a valuable therapy for patients with significant symptomatic MR.

Should All Patients with Barrett's Esophagus Receive Ablation?

PURPOSE OF REVIEW: The aim of this paper is to review and assess the appropriateness of eradication of nondysplastic Barrett's esophagus. Dysplasia in Barrett's esophagus is a known predictor for the development of esophageal cancer, and is currently the best marker in aiding the decision making regarding treatment options. Current data supports endoscopic eradication therapy for most patients with dysplastic Barrett's. The controversy, however, lies in the management of nondysplastic Barrett's and when to recommend ablation versus ongoing surveillance. RECENT FINDINGS: There have been increasing efforts to identify factors that can help predict which patients with nondysplastic Barrett's esophagus are at increased risk for cancer progression, and to quantify that risk. While there is currently varying data and literature supporting this, a more objective risk score is likely to soon become available and accepted, in an effort to differentiate between low and high risk nondysplastic Barrett's, and better aid in decision making regarding surveillance versus endoscopic eradication. This article reviews the current data on Barrett's esophagus and its risk for cancer progression, and it outlines several factors which impact progression that should be considered in the management approach to nondysplastic Barrett's esophagus.

When Pinocchio becomes a real boy: Capability and felicity in AI and interactive depictions.

Clark and Fischer analyze social robots as interactive depictions, presenting characters that people can interact with in social settings. Unlike other types of depictions, the props for social robot depictions depend on emerging interactive technologies. This raises questions about how such depictions depict: They conflate character and prop in ways that delight, confuse, mistreat, and may become ordinary human-technology interactions.

Amplatzer Amulet Left Atrial Appendage Occluder Versus Watchman Device for Stroke Prophylaxis (Amulet IDE): A Randomized, Controlled Trial.

BACKGROUND: Percutaneous closure of the left atrial appendage (LAA) is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amulet IDE trial (Amplatzer Amulet Left Atrial Appendage Occluder IDE Trial) was designed to evaluate the safety and effectiveness of the dual-seal mechanism of the Amulet LAA occluder compared with the Watchman device. METHODS: Patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned (1:1) to undergo percutaneous implantation of a LAA occluder with the Amulet occluder or Watchman device. The primary end points included safety (composite of procedure-related complications, all-cause death, or major bleeding at 12 months), effectiveness (composite of ischemic stroke or systemic embolism at 18 months), and the rate of LAA occlusion at 45 days. Prespecified secondary end points included a composite of all stroke, systemic embolism, or cardiovascular/unexplained death at 18 months, major bleeding at 18 months, and superiority test of the 3 primary end points. RESULTS: A total of 1878 patients were enrolled. The Amulet occluder was noninferior to the Watchman device for the primary safety end point (14.5% versus 14.7%; difference=-0.14 [95% CI, -3.42 to 3.13]; P<0.001 for noninferiority). Major bleeding and all-cause death were similar between groups (10.6% versus 10.0% and 3.9% versus 5.1%, respectively). Procedure-related complications were higher for the Amulet occluder (4.5% versus 2.5%), largely related to more frequent pericardial effusion and device embolization. The Amulet occluder was noninferior to the Watchman device for the primary effectiveness end point (2.8% versus 2.8%; difference=0.00 [95% CI, -1.55 to 1.55]; P<0.001 for noninferiority), and the composite of stroke, systemic embolism, or cardiovascular/unexplained death (5.6% versus 7.7%, difference=-2.12 [95% CI, -4.45 to 0.21]; P<0.001 for noninferiority). The rate of major bleeding was similar between groups (11.6% versus 12.3%; difference=-0.71 [95% CI, -3.72 to 2.31]; P=0.32 for superiority). LAA occlusion was higher for the Amulet occluder than for the Watchman device (98.9% versus 96.8%; difference=2.03 [95% CI, 0.41-3.66]; P<0.001 for noninferiority; P=0.003 for superiority). CONCLUSIONS: The Amulet occluder was noninferior for safety and effectiveness of stroke prevention for nonvalvular atrial fibrillation compared with the Watchman device and superior for LAA occlusion. Procedure-related complications were higher with the Amulet occluder and decreased with operator experience. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02879448.

Composite Metric for Benchmarking Site Performance in Transcatheter Aortic Valve Replacement: Results From the STS/ACC TVT Registry.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a transformative therapy for aortic stenosis. Despite rapid improvements in technology and techniques, serious complications remain relatively common and are not well described by single outcome measures. The purpose of this study was to determine whether there is site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. METHODS: We performed a retrospective cohort study using data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry to develop a novel ranked composite performance measure that incorporates mortality and serious complications. The selection and rank order of the complications for the composite was determined by their adjusted association with 1-year outcomes. Sites with risk-adjusted outcomes significantly more or less frequent than the national average based on a 95% probability interval were classified as performing worse or better than expected. RESULTS: The development cohort consisted of 52 561 patients who underwent TAVR between January 1, 2015, and December 31, 2017. Based on associations with 1-year risk-adjusted mortality and health status, we identified 4 periprocedural complications to include in the composite risk model in addition to mortality. Ranked empirically according to severity, these included stroke, major, life-threatening or disabling bleeding, stage III acute kidney injury, and moderate or severe perivalvular regurgitation. Based on these ranked outcomes, we found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better than expected site performance was observed in 25/301 (8%) sites, performance as expected was observed in 242/301 sites (80%), and worse than expected performance was observed in 34/301 (11%) sites. Thirty-day mortality; stroke; major, life-threatening, or disabling bleeding; and moderate or severe perivalvular leak were each substantially more common in sites with worse than expected performance as compared with other sites. There was good aggregate reliability of the model. CONCLUSIONS: There are substantial variations in the quality of TAVR care received in the United States and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine structural, process-related, and technical factors associated with high- and low-performing sites.

Changes in subcellular structures and states of pumilio 1 regulate the translation of target Mad2 and cyclin B1 mRNAs.

Temporal and spatial control of mRNA translation has emerged as a major mechanism for promoting diverse biological processes. However, the molecular nature of temporal and spatial control of translation remains unclear. In oocytes, many mRNAs are deposited as a translationally repressed form and are translated at appropriate times to promote the progression of meiosis and development. Here, we show that changes in subcellular structures and states of the RNA-binding protein pumilio 1 (Pum1) regulate the translation of target mRNAs and progression of oocyte maturation. Pum1 was shown to bind to Mad2 (also known as Mad2l1) and cyclin B1 mRNAs, assemble highly clustered aggregates, and surround Mad2 and cyclin B1 RNA granules in mouse oocytes. These Pum1 aggregates were dissolved prior to the translational activation of target mRNAs, possibly through phosphorylation. Stabilization of Pum1 aggregates prevented the translational activation of target mRNAs and progression of oocyte maturation. Together, our results provide an aggregation-dissolution model for the temporal and spatial control of translation.

Procedural Volume and Outcomes for Transcatheter Aortic-Valve Replacement.

BACKGROUND: During the introduction of transcatheter aortic-valve replacement (TAVR) in the United States, requirements regarding procedural volume were mandated by the Centers for Medicare and Medicaid Services as a condition of reimbursement. A better understanding of the relationship between hospital volume of TAVR procedures and patient outcomes could inform policy decisions. METHODS: We analyzed data from the Transcatheter Valve Therapy Registry regarding procedural volumes and outcomes from 2015 through 2017. The primary analyses examined the association between hospital procedural volume as a continuous variable and risk-adjusted mortality at 30 days after transfemoral TAVR. Secondary analysis included risk-adjusted mortality according to quartile of hospital procedural volume. A sensitivity analysis was performed after exclusion of the first 12 months of transfemoral TAVR procedures at each hospital. RESULTS: Of 113,662 TAVR procedures performed at 555 hospitals by 2960 operators, 96,256 (84.7%) involved a transfemoral approach. There was a significant inverse association between annualized volume of transfemoral TAVR procedures and mortality. Adjusted 30-day mortality was higher and more variable at hospitals in the lowest-volume quartile (3.19%; 95% confidence interval [CI], 2.78 to 3.67) than at hospitals in the highest-volume quartile (2.66%; 95% CI, 2.48 to 2.85) (odds ratio, 1.21; P = 0.02). The difference in adjusted mortality between a mean annualized volume of 27 procedures in the lowest-volume quartile and 143 procedures in the highest-volume quartile was a relative reduction of 19.45% (95% CI, 8.63 to 30.26). After the exclusion of the first 12 months of TAVR procedures at each hospital, 30-day mortality remained higher in the lowest-volume quartile than in the highest-volume quartile (3.10% vs. 2.61%; odds ratio, 1.19; 95% CI, 1.01 to 1.40). CONCLUSIONS: An inverse volume-mortality association was observed for transfemoral TAVR procedures from 2015 through 2017. Mortality at 30 days was higher and more variable at hospitals with a low procedural volume than at hospitals with a high procedural volume. (Funded by the American College of Cardiology Foundation National Cardiovascular Data Registry and the Society of Thoracic Surgeons.).

Oocyte mitochondria-key regulators of oocyte function and potential therapeutic targets for improving fertility.

The development of oocytes and early embryos is dependent on mitochondrial ATP production. This reliance on mitochondrial activity, together with the exclusively maternal inheritance of mitochondria in development, places mitochondria as central regulators of both fertility and transgenerational inheritance mechanisms. Mitochondrial mass and mtDNA content massively increase during oocyte growth. They are highly dynamic organelles and oocyte maturation is accompanied by mitochondrial trafficking around subcellular compartments. Due to their key roles in generation of ATP and reactive oxygen species (ROS), oocyte mitochondrial defects have largely been linked with energy deficiency and oxidative stress. Pharmacological treatments and mitochondrial supplementation have been proposed to improve oocyte quality and fertility by enhancing ATP generation and reducing ROS levels. More recently, the role of mitochondria-derived metabolites in controlling epigenetic modifiers has provided a mechanistic basis for mitochondria-nuclear crosstalk, allowing adaptation of gene expression to specific metabolic states. Here, we discuss the multi-faceted mechanisms by which mitochondrial function influence oocyte quality, as well as longer-term developmental events within and across generations.

Long-term outcomes of endoscopic mucosal resection for early-stage esophageal adenocarcinoma.

BACKGROUND: With growing application of endoscopic therapy for early-stage esophageal cancer, we sought to review our experience of endoscopic mucosal resections (EMRs). The aim of our study was to understand the natural course of these patients, especially with positive margins. METHODS: A prospectively maintained database of all patients undergoing endoscopic therapies at Georgetown University Hospital for esophageal cancer was used for the analysis between 2010 and 2020. RESULTS: Of 80 patients in the EMR database, 35 were performed as index cases for esophageal adenocarcinoma. Majority (74.3%) had a pre-treatment ultrasound confirming absence of regional adenopathy. There were no post-EMR bleeding or perforation events requiring re-intervention. Complete R0 resection was achieved in 22/35 (62.9%) after initial EMR. Thirteen patients had positive margins. Of these 13 patients, only 7 patients underwent repeat endoscopic resection, 2 underwent subsequent esophagectomy, 2 received definitive radiation given poor surgical candidacy, and 2 were lost to follow-up. Overall and 5-year survival of all patients undergoing EMR was 67.9 months and 85%, respectively. Subset analysis of the 13 patients with R1 resection demonstrated an overall survival of 49.2 months and 60% 5-year survival vs overall survival of 78.9 months and 93% 5-year survival for R0 resection. At a median follow-up of 60.5 months, cancer recurrence occurred in 3 patients. All of them were successfully managed with repeat EMR. CONCLUSIONS: Endoscopic resections represent a safe and effective treatment for early-stage esophageal cancer. Patients with high-risk features should be counseled to undergo an esophagectomy if they are operable candidates.

Design and Evaluation Challenges of Conversational Agents in Health Care and Well-being: Selective Review Study.

BACKGROUND: Health care and well-being are 2 main interconnected application areas of conversational agents (CAs). There is a significant increase in research, development, and commercial implementations in this area. In parallel to the increasing interest, new challenges in designing and evaluating CAs have emerged. OBJECTIVE: This study aims to identify key design, development, and evaluation challenges of CAs in health care and well-being research. The focus is on the very recent projects with their emerging challenges. METHODS: A review study was conducted with 17 invited studies, most of which were presented at the ACM (Association for Computing Machinery) CHI 2020 conference workshop on CAs for health and well-being. Eligibility criteria required the studies to involve a CA applied to a health or well-being project (ongoing or recently finished). The participating studies were asked to report on their projects' design and evaluation challenges. We used thematic analysis to review the studies. RESULTS: The findings include a range of topics from primary care to caring for older adults to health coaching. We identified 4 major themes: (1) Domain Information and Integration, (2) User-System Interaction and Partnership, (3) Evaluation, and (4) Conversational Competence. CONCLUSIONS: CAs proved their worth during the pandemic as health screening tools, and are expected to stay to further support various health care domains, especially personal health care. Growth in investment in CAs also shows the value as a personal assistant. Our study shows that while some challenges are shared with other CA application areas, safety and privacy remain the major challenges in the health care and well-being domains. An increased level of collaboration across different institutions and entities may be a promising direction to address some of the major challenges that otherwise would be too complex to be addressed by the projects with their limited scope and budget.

European position paper on the management of patients with patent foramen ovale. Part II - Decompression sickness, migraine, arterial deoxygenation syndromes and select high-risk clinical conditions.

Patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions but to date only one official position paper related to left circulation thromboembolism has been published. This interdisciplinary paper, prepared with the involvement of eight European scientific societies, reviews the available evidence and proposes a rationale for decision making for other PFO-related clinical conditions. In order to guarantee a strict evidence-based process, we used a modified grading of recommendations, assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements were weighed and graded according to predefined scales. Despite being based on limited and observational or low-certainty randomised data, a number of position statements were made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognising the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thromboembolism and strongly stresses the need for fresh high-quality evidence on these topics.

HENMT1 is involved in the maintenance of normal female fertility in the mouse.

PIWI-interacting small RNAs (piRNAs) maintain genome stability in animal germ cells, with a predominant role in silencing transposable elements. Mutations in the piRNA pathway in the mouse uniformly lead to failed spermatogenesis and male sterility. By contrast, mutant females are fertile. In keeping with this paradigm, we previously reported male sterility and female fertility associated with loss of the enzyme HENMT1, which is responsible for stabilising piRNAs through the catalysation of 3'-terminal 2'-O-methylation. However, the Henmt1 mutant females were poor breeders, suggesting they could be subfertile. Therefore, we investigated oogenesis and female fertility in these mice in greater detail. Here, we show that mutant females indeed have a 3- to 4-fold reduction in follicle number and reduced litter sizes. In addition, meiosis-II mutant oocytes display various spindle abnormalities and have a dramatically altered transcriptome which includes a down-regulation of transcripts required for microtubule function. This down-regulation could explain the spindle defects observed with consequent reductions in litter size. We suggest these various effects on oogenesis could be exacerbated by asynapsis, an apparently universal feature of piRNA mutants of both sexes. Our findings reveal that loss of the piRNA pathway in females has significant functional consequences.