Transcatheter Aortic-Valve Replacement in Low-Risk Patients at Five Years.

BACKGROUND: A previous analysis in this trial showed that among patients with severe, symptomatic aortic stenosis who were at low surgical risk, the rate of the composite end point of death, stroke, or rehospitalization at 1 year was significantly lower with transcatheter aortic-valve replacement (TAVR) than with surgical aortic-valve replacement. Longer-term outcomes are unknown. METHODS: We randomly assigned patients with severe, symptomatic aortic stenosis and low surgical risk to undergo either TAVR or surgery. The first primary end point was a composite of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure. The second primary end point was a hierarchical composite that included death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis. Clinical, echocardiographic, and health-status outcomes were assessed through 5 years. RESULTS: A total of 1000 patients underwent randomization: 503 patients were assigned to undergo TAVR, and 497 to undergo surgery. A component of the first primary end point occurred in 111 of 496 patients in the TAVR group and in 117 of 454 patients in the surgery group (Kaplan-Meier estimates, 22.8% in the TAVR group and 27.2% in the surgery group; difference, -4.3 percentage points; 95% confidence interval [CI], -9.9 to 1.3; P = 0.07). The win ratio for the second primary end point was 1.17 (95% CI, 0.90 to 1.51; P = 0.25). The Kaplan-Meier estimates for the components of the first primary end point were as follows: death, 10.0% in the TAVR group and 8.2% in the surgery group; stroke, 5.8% and 6.4%, respectively; and rehospitalization, 13.7% and 17.4%. The hemodynamic performance of the valve, assessed according to the mean (±SD) valve gradient, was 12.8±6.5 mm Hg in the TAVR group and 11.7±5.6 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group. CONCLUSIONS: Among low-risk patients with severe, symptomatic aortic stenosis who underwent TAVR or surgery, there was no significant between-group difference in the two primary composite outcomes. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).

DMRT1-mediated regulation of TOX3 modulates expansion of the gonadal steroidogenic cell lineage in the chicken embryo.

During gonadal sex determination, the supporting cell lineage differentiates into Sertoli cells in males and pre-granulosa cells in females. Recently, single cell RNA-seq data have indicated that chicken steroidogenic cells are derived from differentiated supporting cells. This differentiation process is achieved by a sequential upregulation of steroidogenic genes and downregulation of supporting cell markers. The exact mechanism regulating this differentiation process remains unknown. We have identified TOX3 as a previously unreported transcription factor expressed in embryonic Sertoli cells of the chicken testis. TOX3 knockdown in males resulted in increased CYP17A1-positive Leydig cells. TOX3 overexpression in male and female gonads resulted in a significant decline in CYP17A1-positive steroidogenic cells. In ovo knockdown of the testis determinant DMRT1 in male gonads resulted in a downregulation of TOX3 expression. Conversely, DMRT1 overexpression caused an increase in TOX3 expression. Taken together, these data indicate that DMRT1-mediated regulation of TOX3 modulates expansion of the steroidogenic lineage, either directly, via cell lineage allocation, or indirectly, via signaling from the supporting to steroidogenic cell populations.

Cell lineage specification and signalling pathway use during development of the lateral plate mesoderm and forelimb mesenchyme.

The lateral plate mesoderm (LPM) is a transient tissue that produces a diverse range of differentiated structures, including the limbs. However, the molecular mechanisms that drive early LPM specification and development are poorly understood. In this study, we use single-cell transcriptomics to define the cell-fate decisions directing LPM specification, subdivision and early initiation of the forelimb mesenchyme in chicken embryos. We establish a transcriptional atlas and global cell-cell signalling interactions in progenitor, transitional and mature cell types throughout the developing forelimb field. During LPM subdivision, somatic and splanchnic LPM fate is achieved through activation of lineage-specific gene modules. During the earliest stages of limb initiation, we identify activation of TWIST1 in the somatic LPM as a putative driver of limb bud epithelial-to-mesenchymal transition. Furthermore, we define a new role for BMP signalling during early limb development, revealing that it is necessary for inducing a somatic LPM fate and initiation of limb outgrowth, potentially through activation of TBX5. Together, these findings provide new insights into the mechanisms underlying LPM development, somatic LPM fate choice and early initiation of the vertebrate limb.

Resolving the mechanisms underlying epithelial-to-mesenchymal transition of the lateral plate mesoderm.

Formation of the vertebrate limb buds begins with a localized epithelial-to-mesenchymal transition (EMT) of the somatic lateral plate mesoderm (LPM). While the processes that drive proliferation and outgrowth of the limb mesenchyme are well established, the fundamental mechanisms that precede this process and initiate EMT are less understood. In this review, we outline putative drivers of EMT of the LPM, drawing from analyses across a range of vertebrates and developmental models. We detail the expression patterns of key EMT transcriptional regulators in the somatic LPM of the presumptive limb fields, and their potential role in producing a mesenchymal cell fate. These include a putative cooperative role between the EMT inducers PRRX1 and TWIST1, supported by evidence in zebrafish and chicken models but unconfirmed data from mice. As such, additional functional data are required to definitively determine the mechanisms that initiate and drive EMT of the somatic LPM, a critical transition preceding formation of the limb bud mesenchyme.

Bed rest impairs the vestibular control of balance.

Prolonged bed rest impairs standing balance but the underlying mechanisms are uncertain. Previous research suggests strength loss is not the cause, leaving impaired sensorimotor control as an alternative. Here we examine vestibular control of posture in 18 male volunteers before and after 60 days of bed rest. Stochastic vestibular stimulation (SVS) was used to evoke sway responses before, 1 and 6 days after bed rest under different head yaw orientations. The directional accuracy and precision of these responses were calculated from ground reaction force vectors. Bed rest caused up to 63% increases in spontaneous standing sway and 31% reductions in leg strength, changes which were uncorrelated. The increase in sway was exacerbated when the eyes were closed. Mean directions of SVS-evoked sway responses were unaffected, being directed towards the anodal ear and rotating in line with head orientation in the same way before and after bed rest. However, individual trial analysis revealed 25%-30% increases in directional variability, which were significantly correlated with the increase in spontaneous sway (r = 0.48-0.71; P ≤ 0.044) and were still elevated on day 6 post-bed rest. This reveals that individual sway responses may be inappropriately oriented, a finding masked by the averaging process. Our results confirm that impaired balance following prolonged bedrest is not related to loss of strength. Rather, they demonstrate that the sensorimotor transformation process which converts vestibular feedback into appropriately directed balance responses is impaired. KEY POINTS: Prolonged inactivity impairs balance but previous research suggests this is not caused by loss of strength. Here we investigated vestibular control of balance before and after 60 days of bed rest using electrical vestibular stimulation (EVS) to evoke sway responses. Spontaneous sway significantly increased and muscle strength reduced following bed rest, but, in keeping with previous research, these two effects were not correlated. While the overall accuracy of EVS-evoked sway responses was unaffected, their directional variability significantly increased following bed rest, and this was correlated with the increases in spontaneous sway. We have shown that the ability to transform head-centred vestibular feedback into an appropriately directed body sway response is negatively affected by prolonged inactivity; this may contribute to the impaired balance commonly observed following bed rest.

Economic Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients with Severe Aortic Stenosis and Low Surgical Risk: Results from the PARTNER 3 Trial.

BACKGROUND: In patients with severe symptomatic aortic stenosis at low surgical risk, transfemoral transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve has been shown to reduce the composite of death, stroke, or rehospitalization at 2-year follow-up compared with surgical aortic valve replacement (SAVR). Whether TAVR is cost-effective compared with SAVR for low-risk patients remains uncertain. METHODS: Between 2016 and 2017, 1000 low-risk patients with aortic stenosis were randomly assigned to TAVR with the SAPIEN 3 valve or SAVR in the PARTNER 3 trial (Placement of Aortic Transcatheter Valves). Of these patients, 929 underwent valve replacement, were enrolled in the United States, and were included in the economic substudy. Procedural costs were estimated using measured resource use. Other costs were determined by linkage with Medicare claims or by regression models when linkage was not feasible. Health utilities were estimated using the EuroQOL 5-item questionnaire. With the use of a Markov model informed by in-trial data, lifetime cost-effectiveness from the perspective of the US health care system was estimated in terms of cost per quality-adjusted life-year gained. RESULTS: Although procedural costs were nearly $19 000 higher with TAVR, total index hospitalization costs were only $591 more with TAVR compared with SAVR. Follow-up costs were lower with TAVR such that TAVR led to 2-year cost savings of $2030/patient compared with SAVR (95% CI, -$6222 to $1816) and a gain of 0.05 quality-adjusted life-years (95% CI, -0.003 to 0.102). In our base-case analysis, TAVR was projected to be an economically dominant strategy with a 95% probability that the incremental cost-effectiveness ratio for TAVR would be <$50 000/quality-adjusted life-year gained (consistent with high economic value from a US health care perspective). These findings were sensitive to differences in long-term survival, however, such that a modest long-term survival advantage with SAVR would render SAVR cost-effective (although not cost saving) compared with TAVR. CONCLUSIONS: For patients with severe aortic stenosis and low surgical risk similar to those enrolled in the PARTNER 3 trial, transfemoral TAVR with the SAPIEN 3 valve is cost saving compared with SAVR at 2 years and is projected to be economically attractive in the long run as long as there are no substantial differences in late death between the 2 strategies. Long-term follow-up will be critical to ultimately determine the preferred treatment strategy for low-risk patients from both a clinical and economic perspective.

The Curious Case of Avian Sex Determination.

Ioannidis and colleagues show that the gene DMRT1 is the master regulator of testis development in the chicken. Yet, remarkably, when this gene is deleted in genetic males and gonads form ovaries, the body remains male. This debunks the notion that somatic sex is driven primarily by hormones in birds.

The homeobox gene TGIF1 is required for chicken ovarian cortical development and generation of the juxtacortical medulla.

During early embryogenesis in amniotic vertebrates, the gonads differentiate into either ovaries or testes. The first cell lineage to differentiate gives rise to the supporting cells: Sertoli cells in males and pre-granulosa cells in females. These key cell types direct the differentiation of the other cell types in the gonad, including steroidogenic cells. The gonadal surface epithelium and the interstitial cell populations are less well studied, and little is known about their sexual differentiation programs. Here, we show the requirement of the homeobox transcription factor gene TGIF1 for ovarian development in the chicken embryo. TGIF1 is expressed in the two principal ovarian somatic cell populations: the cortex and the pre-granulosa cells of the medulla. TGIF1 expression is associated with an ovarian phenotype in estrogen-mediated sex reversal experiments. Targeted misexpression and gene knockdown indicate that TGIF1 is required, but not sufficient, for proper ovarian cortex formation. In addition, TGIF1 is identified as the first known regulator of juxtacortical medulla development. These findings provide new insights into chicken ovarian differentiation and development, specifically cortical and juxtacortical medulla formation.

Robust thrombolytic and anti-inflammatory action of a constitutively active ADAMTS13 variant in murine stroke models.

Advances in our understanding of ADAMTS13 structure, and the conformation changes required for full activity, have rejuvenated the possibility of its use as a thrombolytic therapy. We have tested a novel Ala1144Val ADAMTS13 variant (constitutively active [ca] ADAMTS13) that exhibits constitutive activity, characterized using in vitro assays of ADAMTS13 activity, and greatly enhanced thrombolytic activity in 2 murine models of ischemic stroke, the distal FeCl3 middle cerebral artery occlusion (MCAo) model and transient middle cerebral artery occlusion (tMCAO) with systemic inflammation and ischemia/reperfusion injury. The primary measure of efficacy in both models was restoration of regional cerebral blood flow (rCBF) to the MCA territory, which was determined using laser speckle contrast imaging. The caADAMTS13 variant exhibited a constitutively active conformation and a fivefold enhanced activity against fluorescence resonance energy transfer substrate von Willebrand factor 73 (FRETS-VWF73) compared with wild-type (wt) ADAMTS13. Moreover, caADAMTS13 inhibited VWF-mediated platelet capture at subphysiological concentrations and enhanced t-PA/plasmin lysis of fibrin(ogen), neither of which were observed with wtADAMTS13. Significant restoration of rCBF and reduced lesion volume was observed in animals treated with caADAMTS13. When administered 1 hour after FeCl3 MCAo, the caADAMTS13 variant significantly reduced residual VWF and fibrin deposits in the MCA, platelet aggregate formation, and neutrophil recruitment. When administered 4 hours after reperfusion in the tMCAo model, the caADAMTS13 variant induced a significant dissolution of platelet aggregates and a reduction in the resulting tissue hypoperfusion. The caADAMTS13 variant represents a potentially viable therapeutic option for the treatment of acute ischemic stroke, among other thrombotic indications, due to its enhanced in vitro and in vivo activities that result from its constitutively active conformation.

Females battle to suppress their inner male.

Conventional wisdom holds that the ovary and testis are terminally differentiated organs in adult mammals. However, Uhlenhaut et al. (2009) now report that deletion of a single gene, Foxl2, is sufficient to induce transdifferentiation of ovary into testis in adult mice, suggesting that testicular development is actively repressed throughout the life of females.

Physical activity and circulating inflammatory markers and cytokines during pregnancy: A population-based cohort study.

INTRODUCTION: Physical activity (PA) during pregnancy has numerous benefits, which may be mediated via effects on the immune system. However, supportive evidence is inconsistent and is mainly from studies in high-risk groups. We estimated the effect of PA during pregnancy on systemic inflammatory markers and cytokines in mothers recruited in the Barwon infant study. MATERIAL AND METHODS: The Barwon infant study is a prebirth cohort of 1064 mothers recruited in the Barwon Region of Victoria, Australia. Participants reported their previous week's PA at their 28-week antenatal appointment using the International PA Questionnaire. Women were grouped into low, moderate, and high PA categories based on daily duration and weekly frequency of walking, moderate- or vigorous-intensity PA. Women reporting moderate levels of PA, consistent with current recommendations, served as the comparison group. Markers of systemic inflammation, high-sensitivity C-reactive protein (hsCRP), glycoprotein acetyls (GlycA), and 17 cytokines were measured at 28 weeks gestation and log transformed as appropriate. Regression analyses adjusted for maternal smoking, gestational diabetes mellitus, prepregnancy BMI, and household size were performed. RESULTS: Compared to women in the moderate group (n = 371, 42%), women reporting low PA (n = 436, 50%) had 10.1% higher hsCRP (95% CI (3.7% to 16.6%), p < 0.01) while women in high PA (n = 76, 9%) had a 14% higher hsCRP (95% CI (3.1% to 24.8%), p = 0.01). Women in the high PA category had higher interleukin (IL)-4 (q = 0.03) and IL-9 (q = 0.03) levels compared to those in moderate category. Each vigorous MET minute/week was associated with lower GlycA (ß = -0.004, 95% CI (-0.044 to 0.035); p = 0.03). CONCLUSIONS: Low and high PA are each associated with higher hsCRP than moderate PA, suggesting that undertaking the recommended moderate PA during pregnancy decreases systemic inflammation. High PA affects T cell-associated cytokines during pregnancy. Evidence from our study suggests that PA can modulate the immune responses during pregnancy. Studies are now required to assess whether PA during pregnancy impacts maternal and infant clinical outcomes by modifying inflammatory responses.

Accelerated Measurement of Carotid Plaque Volume Using Artificial Intelligence Enhanced 3D Ultrasound.

BACKGROUND: Carotid plaque volume (CPV) can be measured by 3D ultrasound and may be a better predictor of stroke than stenosis, but analysis time limits clinical utility. This study tested the accuracy, reproducibility, and time saved of using an artificial intelligence (AI) derived semiautomatic software to measure CPV ("auto-CPV"). METHODS: Three-dimensional (3D) ultrasound images for 121 individuals were analyzed by 2 blinded operators to measure auto-CPV. Corresponding endarterectomy specimen volumes were calculated by the validated saline suspension technique. Inter-rater and intrarater agreement plus accuracy compared with the volume of the endarterectomized plaque were calculated. Measurement times were compared with previous manual CPV measurement. RESULTS: The mean difference between auto-CPV and surgical volume was small at (±s.d.) [95% confidence interval [CI]] 0.06 (0.24) [-0.41 to 0.54] cm3. The intraclass correlation (ICC) was strong at 0.91; 95% CI 0.86-0.94. Interobserver and intraobserver error was low with mean difference (±s.d.) [95%CI] 0.01 (0.26) [-0.5 to 0.5] cm3 and 0.03 (0.19) [-0.35 to 0.40] cm3 respectively. Both showed excellent ICC with narrow confidence intervals, ICC = 0.90; 95% CI (0.85-0.94) and ICC = 0.95; 95% CI (0.92-0.96). Auto-CPV measurement took 43% the time of manual planimetry; median (IQR) 05:39 (01:58) minutes compared to 13:05 (04:15) minutes, Wilcoxon rank-sum test, P < 0.01. CONCLUSIONS: Auto-CPV assessment is accurate, reproducible, and significantly faster than manual planimetry. Improved feasibility means that the utility of CPV can be assessed in large population studies to stratify risk in asymptomatic carotid disease or assess response to medical treatment.

Injury patterns and mortality associated with near-hanging in children.

BACKGROUND: The pathophysiology of near-hanging in children is different from that of adults due to anatomic, physiologic, and injury-related mechanisms, with evidence suggesting that blunt cerebrovascular injuries (BCVI) and cervical spine injuries (CSI) are uncommon. We sought to estimate the incidence of secondary injuries and their association with mortality in pediatric near-hanging victims. METHODS: We performed a retrospective observational study of children (≤17 years) with a diagnosis code for hanging between October 1, 2015 and February 28, 2023 who presented to one of 47 geographically diverse US children's hospitals. We evaluated the incidence of the following secondary injuries: cerebral edema, pneumothorax, pulmonary edema, BCVI, and CSI. We performed Fisher's exact test with Bonferroni correction to identify associations between intentionality, sex, age, and secondary injuries with mortality. RESULTS: We included 1929 children, of whom 33.8% underwent neuroimaging, 45.9% underwent neck imaging, and 38.7% underwent neck angiography. The most common injury was cerebral edema (24.0%), followed by pulmonary edema (3.2%) and pneumothorax (2.8%). CSI (2.1%) and BCVI (0.9%) occurred infrequently. Cerebral edema, pneumothorax, pulmonary edema, and younger age (≤12 years) were associated with mortality. CONCLUSIONS: In this multi-center study of pediatric near-hanging victims, BCVI and CSI occurred rarely and were not associated with mortality. While children in our study underwent neck imaging more frequently than head imaging, cerebral edema occurred more often than other injury types and imparted the highest mortality risk. Given the rarity of BCVI and CSI, a selective approach to neck imaging may be warranted in pediatric near-hanging events.

Acetabular "Fleck" Sign: Outcomes of Surgical Repair.

BACKGROUND: Traumatic, posterior hip dislocations in the pediatric population are typically managed by closed reduction to achieve a concentric hip joint. The presence of an acetabular "fleck" sign, despite concentric reduction, has been shown to signify significant hip pathology. The purpose of this study was to evaluate the outcomes of open labral repair through a surgical hip dislocation (SHD) in a consecutive series of patients with an acetabular "fleck" sign associated with a traumatic hip dislocation/subluxation. METHODS: A retrospective review of patients between 2008 and 2022 who presented to a single, level 1 pediatric trauma center with a traumatic posterior hip dislocation/subluxation was performed. Patients were included if they had an acetabular "fleck" sign on advanced imaging and underwent open labral repair through SHD. Medical records were reviewed for sex, age, laterality, mechanism of injury (MOI), and associated orthopaedic injuries. The modified Harris hip score (mHHS) was utilized as the primary clinical outcomes measure. Patients were assessed for the presence of heterotopic ossification (HO) and complications, including implant issues, infection, avascular necrosis (AVN), and post-traumatic dysplasia. RESULTS: Twenty-nine patients (23 male, average age: 13.0±2.7 y; range: 5.2 to 17.3) were identified. Eighteen injuries were sports related, 9 caused by motor vehicle accidents, and 1 pedestrian struck. All patients were found to have an acetabular "fleck" sign on CT (26 patients) or MRI (5 patients). Associated injuries included: femoral head fracture (n=6), pelvic ring injury (n=3), ipsilateral femur fracture (n=2), and ipsilateral PCL avulsion (n=1). At the latest follow-up (2.2±1.4 y), all patients had returned to preinjury activity/sport. Three patients developed asymptomatic, grade 1 HO in the greater trochanter region. There was no incidence of AVN. One patient developed post-traumatic acetabular dysplasia due to early triradiate closure. mHHS scores showed excellent outcomes (n=21, 94.9±7.4, range: 81 to 100.1). CONCLUSIONS: The acetabular "fleck" sign indicates a consistent pattern of osteochondral avulsion of the posterior/superior labrum. Restoring native hip anatomy and stability is likely to improve outcomes. SHD with open labral repair in these patients produces excellent clinical outcomes, with no reported cases of AVN. LEVEL OF EVIDENCE: Level IV-therapeutic.

The impact of libraries and informationists on patient and population care: a mixed-methods study.

Objective: While several studies have examined the effectiveness of librarian interactions with clinicians and impact of librarians on patient care, no studies have explored a library's effects on population care. The goal of this study was to investigate the library's impact on both patient and population care. Methods: Using a sequential exploratory mixed-methods design, we first interviewed a small set of clinicians and researchers active in patient and population care. Based on the themes that we discovered through coding the interviews, we created a survey that was sent to faculty in the health sciences and the health system. Results: We collected data from a representative sample of our population. We discovered that all respondents value the library and informationists, using our services most for teaching, publishing, presenting, and professional development. Conclusion: We now have data to support our value to our population and to show where we can do more work to improve the use of our services. Our study shows the value of doing a mixed-methods sequential exploration in which themes that are important to our user community were identified prior to launching a large-scale survey.

Setting the context for a complex dental intervention of role substitution in care homes: Initial process evaluation findings.

OBJECTIVES: SENIOR (uSing rolE-substitutioN In care homes to improve oRal health) is a randomised controlled trial designed to determine whether role substitution could improve oral health for this population. A parallel process evaluation was undertaken to understand context. This paper reports on the first phase of the process evaluation. BACKGROUND: The oral health and quality-of-life of older adults residing in care homes is poorer than those in the community. Oral health care provision is often unavailable and a concern and challenge for managers. The use of Dental Therapists and Dental Nurses rather than dentists could potentially meet these needs. MATERIALS AND METHODS: Semi-structured interviews were conducted with 21 key stakeholders who either worked or had experience of dependent care settings. Questions were theoretically informed by the: Promoting Action on Research Implementation in Health Services (PAHRIS) framework. The focus was on contextual factors that could influence adoption in practice and the pathway-to-impact. Interviews were fully transcribed and analysed thematically. RESULTS: Three themes (receptive context, culture, and leadership) and 11 codes were generated. Data show the complexity of the setting and contextual factors that may work as barriers and facilitators to intervention delivery. Managers are aware of the issues regarding oral health and seek to provide best care, but face many challenges including staff turnover, time pressures, competing needs, access to services, and financial constraints. Dental professionals recognise the need for improvement and view role substitution as a viable alternative to current practice. CONCLUSION: Although role substitution could potentially meet the needs of this population, an in-depth understanding of contextual factors appeared important in understanding intervention delivery and implementation.

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.

BACKGROUND: There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk. METHODS: We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke. RESULTS: At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P = 0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery. CONCLUSIONS: Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

Prevalence and Characteristics of Diagnostic Error in Pediatric Critical Care: A Multicenter Study.

OBJECTIVES: Effective interventions to prevent diagnostic error among critically ill children should be informed by diagnostic error prevalence and etiologies. We aimed to determine the prevalence and characteristics of diagnostic errors and identify factors associated with error in patients admitted to the PICU. DESIGN: Multicenter retrospective cohort study using structured medical record review by trained clinicians using the Revised Safer Dx instrument to identify diagnostic error (defined as missed opportunities in diagnosis). Cases with potential errors were further reviewed by four pediatric intensivists who made final consensus determinations of diagnostic error occurrence. Demographic, clinical, clinician, and encounter data were also collected. SETTING: Four academic tertiary-referral PICUs. PATIENTS: Eight hundred eighty-two randomly selected patients 0-18 years old who were nonelectively admitted to participating PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 882 patient admissions, 13 (1.5%) had a diagnostic error up to 7 days after PICU admission. Infections (46%) and respiratory conditions (23%) were the most common missed diagnoses. One diagnostic error caused harm with a prolonged hospital stay. Common missed diagnostic opportunities included failure to consider the diagnosis despite a suggestive history (69%) and failure to broaden diagnostic testing (69%). Unadjusted analysis identified more diagnostic errors in patients with atypical presentations (23.1% vs 3.6%, p = 0.011), neurologic chief complaints (46.2% vs 18.8%, p = 0.024), admitting intensivists greater than or equal to 45 years old (92.3% vs 65.1%, p = 0.042), admitting intensivists with more service weeks/year (mean 12.8 vs 10.9 wk, p = 0.031), and diagnostic uncertainty on admission (77% vs 25.1%, p < 0.001). Generalized linear mixed models determined that atypical presentation (odds ratio [OR] 4.58; 95% CI, 0.94-17.1) and diagnostic uncertainty on admission (OR 9.67; 95% CI, 2.86-44.0) were significantly associated with diagnostic error. CONCLUSIONS: Among critically ill children, 1.5% had a diagnostic error up to 7 days after PICU admission. Diagnostic errors were associated with atypical presentations and diagnostic uncertainty on admission, suggesting possible targets for intervention.

Cytokine-inducible SH2 domain containing protein contributes to regulation of adiposity, food intake, and glucose metabolism.

The cytokine-inducible SH2 domain containing protein (CISH) is the founding member of the suppressor of cytokine signaling (SOCS) family of negative feedback regulators and has been shown to be a physiological regulator of signaling in immune cells. This study sought to investigate novel functions for CISH outside of the immune system. Mice deficient in CISH were generated and analyzed using a range of metabolic and other parameters, including in response to a high fat diet and leptin administration. CISH knockout mice possessed decreased body fat and showed resistance to diet-induced obesity. This was associated with reduced food intake, but unaltered energy expenditure and microbiota composition. CISH ablation resulted in reduced basal expression of the orexigenic Agrp gene in the arcuate nucleus (ARC) region of the brain. Cish was basally expressed in the ARC, with evidence of co-expression with the leptin receptor (Lepr) gene in Agrp-positive neurons. CISH-deficient mice also showed enhanced leptin responsiveness, although Cish expression was not itself modulated by leptin. CISH-deficient mice additionally exhibited improved insulin sensitivity on a high-fat diet, but not glucose tolerance despite reduced body weight. These data identify CISH as an important regulator of homeostasis through impacts on appetite control, mediated at least in part by negative regulation of the anorexigenic effects of leptin, and impacts on glucose metabolism.