Low Probability Research Articles

Can the APACHE II score be used to assess the risk of mortality in the elderly with hip fractures?

<p><strong>Aim </strong>Various predictive models have been developed to help identify patients with hip fractures with greater or lower probability of survival. The aim of this study was to establish the capacity of the APACHE II score to predict the survival of patients with hip fracture, in people aged over 65 years, and compare it with the existing score used to predict the survival of these patients. </p> <p><strong>Methods </strong>This was a prospective, cohort study conducted in a tertiary care teaching hospital including 410 consecutive patients with hip fracture aged ≥65 years. As part of the preoperative preparation, general health of the patients was classified according to the ASA score. The Charlson Comorbidity Index (CCI), the Nottingham Hip Fracture Score (NHFS), the POSSUM-P and the APACHE II scores were analysed. </p> <p><strong>Results </strong>The sensitivity and specificity of the P-POSSUM score were 78.3 and 73.0, respectively, which was better than the APACHE II whose sensitivity and specificity were 56.6 and 89.7. The area beneath the ROC curve for P-POSSUM was 0.809, and for APACHE II, 0.803. However, there was no statistically significant difference between the APACHE II and P-POSSUM scores. The P-POSSUM and APACHE II scores were statistically significantly better than ASA, the Nottingham score and CCI. </p> <p><strong>Conclusion </strong>This study showed that POSSUM-P and APACHE II can be used to predict mortality in elderly people with hip fractures. </p>

Home Health Care and Place of Death in Medicare Beneficiaries With and Without Dementia.

Home health care supports patient goals for aging in place. Our objective was to determine if home health care use in the last 3 years of life reduces the risk of inpatient death without hospice. We analyzed the characteristics of 2,065,300 Medicare beneficiaries who died in 2019 and conducted multinomial logistic regression analyses to evaluate the association between the use and timing of home health care, dementia diagnosis, and place of death. Receiving any home health care in the last 3 years of life was associated with a lower probability of inpatient death without hospice (Pr 23.3% vs 31.5%, p < .001), and this effect was stronger when home health care began prior to versus during the last year of life (Pr 22.5% vs 24.3%, p < .001). Among all decedents, the probability of death at home with hospice compared to inpatient death with hospice was greater when any home health care was used (Pr 46.0% vs 36.5%, p < .001), and this association was strongest among beneficiaries with dementia who started home health care at least 1 year prior to death (Pr 55.6%, p < .001). Use of home health care during the last 3 years of life was associated with reduced rates of inpatient death without hospice, and increased rates of home death with hospice. Increasing affordable access to home health care can positively affect end-of-life care outcomes for older Americans and their family caregivers, especially those with dementia.

Patient Preferences for Surgical Treatments for Benign Prostatic Hyperplasia: A Discrete Choice Experiment

Purpose: When symptoms of benign prostatic hyperplasia cannot or can no longer be treated by conservative treatment options adequately, various surgical treatment options are available. Different risks and benefits are associated with each type of surgery; the optimal choice depends on the patient's preference. This study analyzes patients' preferences and investigates patient characteristics that might influence patient preferences in Germany. Materials and Methods: We conducted an online discrete choice experiment based on 9 treatment attributes related to risks (probability of ejaculatory dysfunction, permanent incontinence, needing surgery again, and erectile dysfunction) and efficacy (frequency of daytime and nighttime urination, urgency and duration of urination, and time until symptoms improve) of surgeries. To estimate preferences, we applied a mixed-logit model. Subgroup analyses based on patients' characteristics were conducted. Results: Three hundred thirty participants completed the discrete choice experiment. Overall, participants preferred a lower risk of ejaculatory dysfunction, lower urgency and duration of urination, lower probability of permanent incontinence, lower frequency of nighttime and daytime urination, and lower probability of needing another surgery. Moreover, a faster onset of overall symptom reduction was preferred. Several patient characteristics especially characteristics related to a patient's sexual life seem to influence patients' preferences. Conclusions: Significant preference heterogeneity could be observed in this study, and subgroup analyses suggest differences in preferences in relation to patients' characteristics. These findings highlight the need for individualized treatment decisions. Physicians should evaluate patients' clinical but also inquire about a patient's personal situation and preferences to select the optimal treatment in collaboration with the individual patient.

Platelet to erythrocyte ratio and mortality in massively transfused trauma patients.

BackgroundThe optimal transfusion ratio of platelets (PLT), plasma and red blood cells (RBC) in trauma patients with massive haemorrhage is still a subject of discussion. The objective of this study is to assess the effect of platelet transfusion on mortality in trauma patients who received massive transfusion. MethodsData were collected from four Dutch level-1 trauma centres. All trauma patients aged ≥ 16 years who received ≥ 6 RBC / 6 hours from the time of injury were included. Patients were divided based on PLT:RBC ratio (no platelets, low (<1:5) and high (≥1:5)). Primary outcome measure was 6-hour mortality and secondary outcomes included mortality at other time points and transfusion characteristics. ResultsA total of 292 patients were included. Patients in the high PLT ratio group had lower mortality rates at six and 12 hours as compared to the low PLT ratio and no PLT group. In the high PLT group mortality as a result of exsanguination (12%) was significantly lower as compared to the low PLT group (23%). High PLT ratio had lower probability for 6-hour mortality multivariable analysis. Higher plasma:RBC ratios were associated with lower mortality at all time points. ConclusionsAlthough the optimal patient specific transfusion strategy in patients with traumatic haemorrhage is still not resolved, these results show that higher PLT to RBC ratios are associated with lower early mortality.

Environmental orientation, regional innovation, and equity crowdfunding campaigns’ outcomes: Evidence from two Italian platforms

The purpose of this paper is to examine how the crowdfunding campaigns success and long-term corporate failure are affected by the campaigns and firms’ environmental orientation, as well as by the regional innovation level. This study reveals that environmental orientations (of both campaigns and firms) are linked with higher campaign success, while only firm environmental orientation is linked with a lower probability of long-term corporate failure. Additionally, we find that regional levels of innovation are negatively linked with the probability of campaign success.

Acclimation and size influence predation, growth, and survival of sexually produced Diploria labyrinthiformis used in restoration

Stony coral tissue loss disease (SCTLD) has swept through Florida reefs and caused mass mortality of numerous coral species. In the wake of these losses, efforts are underway to propagate coral species impacted by SCTLD and promote population recovery. However, numerous knowledge gaps must be addressed to effectively grow, outplant, and restore populations of the slower growing, massive species that were lost. Here, we used sexual recruits of Diploria labyrinthiformis spawned in captivity to understand how conditioning, coral size, and nutritional status at outplanting affect coral survivorship, growth, and susceptibility to predation. We found that ex situ conditioning with supplemental feeding increased coral growth rates, resulting in larger sized corals at the time of outplanting. In turn, these corals had higher growth rates in the field and a lower probability of being removed by predators than outplants that were conditioned in in situ nurseries. Additionally, we found that coral size was an important predictor of survivorship, suggesting that hastening the speed at which young corals grow and outplanting larger juveniles can improve restoration outcomes. Taken together, our results suggest that providing supplemental food to corals at ex situ facilities confers benefits that could help restore populations of massive coral species impacted by SCTLD.

СИСТЕМАТИЗАЦИЯ СОВРЕМЕННОГО МЯСОРЕЗАТЕЛЬНОГО ОБОРУДОВАНИЯ И ОЦЕНКА НЕИСПРАВНОСТЕЙ ПРОМЫШЛЕННЫХ ВОЛЧКОВ

Based on the analysis of the designs of modern meat cutting equipment used by processing plants, their great diversity has been established, justified by the design and technological requirements for this type of machines. (Objective of the study) To establish the features characterizing industrial grinders, compile their classification, determine the main faults and the degree of their influence on the operability of industrial grinders. (Materials and methods) Design and technological requirements for industrial grinders have been determined. An analysis has been carried out and the main causes of malfunctions of industrial grinders have been identified. Structural parameters characterizing the technical condition of industrial grinders have been established. A priori ranking technique has been selected based on an expert assessment by specialists of the main faults of industrial grinder units. (Results and discussion) The features characterizing industrial grinders have been established, based on this, their classification has been compiled. A structural diagram of the "Industrial grinder" technical system is presented. The main faults and the degree of their influence on the loss of operability of the devices under consideration during operation have been determined. The entire set of industrial grinding machine malfunctions is grouped relative to three subsystems: cutting, feeding and driving. During the malfunction analysis, 10 most important of them were identified, affecting the grinder operability and its technological process performance. (Conclusions) The entire set of presented industrial grinding machine malfunctions was ranked by weight. A 10-point system was used for their assessment and points were assigned in accordance with complexity within the range from 1 to 10. The first group included malfunctions with ranks higher than 238 (malfunctions with a higher probability of occurrence). The second group included malfunctions with a rank value lower than 150 (malfunctions with a lower probability of occurrence). It was found that the maximum weight has malfunctions designated as n6, n10, n9. They characterize the technical condition of the cutting and feeding subsystems. Priority for maintenance and control should be given to these subsystems

COVID-19 and severe cutaneous allergic reactions to sulfonamides.

Background: Sulfonamides are associated with severe cutaneous adverse reactions (SCARs). Coronavirus disease 2019 (COVID-19) triggers an immune response, which may increase the likelihood of developing a hypersensitivity reaction. Objectives: We sought to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the probability of developing SCARs and/or erythema multiforme (EM) reactions to sulfonamides. Methods: In the propensity score-matched cohort study by using the de-identified TriNetX Research data base, patients who had an exposure to antibiotic or non-antibiotic sulfonamides between March 1, 2020, and January 1, 2023, were divided into two groups based on the presence or absence of a previous COVID-19 infection within 6 months of starting the sulfonamide agent. The outcomes studied were the 30-day risk of developing SCARs or EM (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, or EM) within 3 months of sulfonamide exposure. Cohorts were matched based on baseline demographics; malignant lymphoid neoplasms; human immunodeficiency virus; systemic lupus erythematosus; bone marrow transplantation; diabetes; psoriasis; seizures; gout; solid organ or stem cell transplantation; COVID-19 vaccination; and exposure to risk medications, including allopurinol, levetiracetam, carbamazepine, lamotrigine, oxcarbazepine, phenytoin, phenobarbital, abacavir, nevirapine, piroxicam, tenoxicam, or mexiletine. Results: When comparing 345,119 patients on sulfonamides and with previous COVID-19 to an equal number of sulfonamides users without a previous COVID-19, patients with COVID-19 had a lower risk of developing any form of SCARs (relative risk 0.39 [95% confidence interval, 0.26, 0.58]; p < 0.001). Conclusion: Previous SARS-CoV-2 infection seems to be associated with a lower probability of developing SCARs or EM among patients using sulfonamides.

PUFA stabilizes a conductive state of the selectivity filter in IKs channels.

In cardiomyocytes, the KCNQ1/KCNE1 channel complex mediates the slow delayed-rectifier current (IKs), pivotal during the repolarization phase of the ventricular action potential. Mutations in IKs cause long QT syndrome (LQTS), a syndrome with a prolonged QT interval on the ECG, which increases the risk of ventricular arrhythmia and sudden cardiac death. One potential therapeutical intervention for LQTS is based on targeting IKs channels to restore channel function and/or the physiological QT interval. Polyunsaturated fatty acids (PUFAs) are potent activators of KCNQ1 channels and activate IKs channels by binding to two different sites, one in the voltage sensor domain - which shifts the voltage dependence to more negative voltages - and the other in the pore domain - which increases the maximal conductance of the channels (Gmax). However, the mechanism by which PUFAs increase the Gmax of the IKs channels is still poorly understood. In addition, it is unclear why IKs channels have a very small single-channel conductance and a low open probability or whether PUFAs affect any of these properties of IKs channels. Our results suggest that the selectivity filter in KCNQ1 is normally unstable, contributing to the low open probability, and that the PUFA-induced increase in Gmax is caused by a stabilization of the selectivity filter in an open-conductive state.

PUFA stabilizes a conductive state of the selectivity filter in IKs channels

In cardiomyocytes, the KCNQ1/KCNE1 channel complex mediates the slow delayed-rectifier current (IKs), pivotal during the repolarization phase of the ventricular action potential. Mutations in IKs cause long QT syndrome (LQTS), a syndrome with a prolonged QT interval on the ECG, which increases the risk of ventricular arrhythmia and sudden cardiac death. One potential therapeutical intervention for LQTS is based on targeting IKs channels to restore channel function and/or the physiological QT interval. Polyunsaturated fatty acids (PUFAs) are potent activators of KCNQ1 channels and activate IKs channels by binding to two different sites, one in the voltage sensor domain – which shifts the voltage dependence to more negative voltages – and the other in the pore domain – which increases the maximal conductance of the channels (Gmax). However, the mechanism by which PUFAs increase the Gmax of the IKs channels is still poorly understood. In addition, it is unclear why IKs channels have a very small single-channel conductance and a low open probability or whether PUFAs affect any of these properties of IKs channels. Our results suggest that the selectivity filter in KCNQ1 is normally unstable, contributing to the low open probability, and that the PUFA-induced increase in Gmax is caused by a stabilization of the selectivity filter in an open-conductive state.

Does regression of skin thickening predict improvement of internal organ involvement and survival in patients with diffuse cutaneous systemic sclerosis? A EUSTAR analysis

ObjectivePatients with diffuse cutaneous systemic sclerosis (dcSSc) frequently show spontaneous improvement of skin fibrosis. Our aim was to examine whether an improvement in skin fibrosis predicts lower likelihood of visceral organ progression and better survival.MethodsPatients from the European Scleroderma Trials and Research (EUSTAR) cohort with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, and valid mRSS at 12±3 months follow up were included. Regression/progression of skin fibrosis was defined as a decrease/increase in mRSS >5 points and≥25% from baseline to follow up. The outcomes included progression of lung, renal, cardiac and gastrointestinal manifestations using consensus derived definitions and all-cause death. Regressive, stable and progressive patients were compared by univariate, Kaplan-Meier survival curve and Cox regression analysis.ResultsOf 1257 included patients, 883 (70.2%) were stable, 282 (22.4%) regressive, and 92 (7.3%) progressive. Regressive patients, adjusted for baseline mRSS, baseline immunosuppression, baseline FVC, and disease duration, showed a significantly lower probability of FVC decline ≥10% than progressive patients (p=0.00003), lower probability of all-cause mortality during follow up (p=0.035) compared to progressive patients. .Improvement of skin fibrosis was not associated with progression of other organ manifestations.ConclusionWe found that regression of skin fibrosis is associated with a lower probability of lung progression and better survival at follow up. The link between the disease course of skin and lung fibrosis in SSc can help to better stratify patients in clinical practice and enrich for ILD progressive patients in clinical trials.

Оцінка інформативності клініко-інструментальних та лабораторних показників у виявленні активності патогенетичних факторів, асоційованих зі змінами перебігу інфаркту міокарда в період воєнного стану

The aim – to establish markers of clinical and functional state development in patients with acute myocardial infarction inherent in wartime.Materials and methods. A cohort of 133 STEMI patients was examined (77.4 % men, 61.7±0.9 years). Part of the patients (group 1) was hospitalized from February to May 2019 (n=87), while the other part of them (group 2) was hospitalized in the period from February 24, 2022 to May 2023 (n=46) within the first 24 hours from the development of symptoms (average time of admission 5.2±0.4 hours). In order to eliminate discrepancies in indicators, which with a low probability are related to the action of wartime factors, comparable samples were made from groups 1 and 2 (52 patients and 17 patients, respectively). Comparison of groups was carried out based on clinical and anamnestic and laboratory parameters of the first day.Results and discussion. At the admission to the hospital, markers of a specific clinical and functional state in patients with STEMI due to the influence of wartime factors are: level of leukocytes &gt; 13.0 · 109/L, monocytes &gt; 0.5 · 109/L, lymphocytes &gt; 1.2 . 109/L, triglycerides &gt; 1.63 mmol/L, heart rate &gt; 76 beats/min, as well as criteria made up of these indicators (in particular, products of the level of monocytes or lymphocytes, the level of triglycerides and heart rate, as well as the 7-component scale, which takes into account heart rate, ESR, glucose and triglyceride levels, as well as the number of monocytes, lymphocytes and platelets). Moreover, the increase in the number of monocytes is not associated with hospital complications in these patients. Instead, the level of triglycerides, the number of lymphocytes and platelets are directly related both to the influence of wartime factors and to the complicated hospital course of STEMI.Conclusions. The influence of wartime factors in patients with STEMI is combined with the response to myocardial damage. It leads to an increase in the risk of a complicated course of the hospital stage, as well as to specific clinical and laboratory changes. These changes make it possible to recognize the impact of wartime factors and patients at high risk of hospital course of myocardial infarction.

Modeling Cs-137 Migration in Groundwater due to Low Probability Event of Leaching from Near Surface Disposal Facility for Low Level Solid Radioactive Waste

In this paper, we present impact of Cesium-137 (Cs-137) disposal in a Near Surface Disposal Facility (NSDF) with respect to groundwater migration and its consumption for drinking. We employ the Multiple Area Source Model for simulating the fate of radionuclide in groundwater to evaluate its potential contamination due to extremely low probability event of leaching from the NSDF. The assessment conservatively assumes direct interaction between disposal trenches and the underlying aquifer neglecting the barrier provided by the unsaturated zone. Temporal profiles of concentration of Cs-137 at different down flow distances in groundwater are obtained over a period extending several years post-disposal. The results indicate that even under such a worst-case conservative scenario and for an annual disposal rate of 3 TBq/y for a period of 50y, the maximum Cs-137 concentration in groundwater remains significantly below the safe drinking water threshold of 10 Bq/L recommended by the World Health Organization. It is found that amount of Cs-137 generally disposed in NSDF is significantly lower than the allowable disposal limit corresponding to concentration defined for safe drinking water limit.

Multidimensional employment trajectories and dynamic links with mental health: Evidence from the UK Household Longitudinal Study.

Low-quality and precarious employment have been associated with adverse mental health and wellbeing. More evidence is needed on how the quality of employment trajectories - including transitions in and out of unemployment, inactivity, and employment of varying quality - are associated with individuals' mental health over time. This paper aimed to derive a typology of multidimensional employment trajectories and assess associations with mental health in the UK. Data from waves 1-9 of the UK Household Longitudinal Study were used (2009-2019). Individuals aged 30-40 at baseline were included (N=1603). Using multichannel sequence and clustering analyses, we derived a typology of employment trajectories across employment statuses and four employment quality indicators. We assessed associations with subsequent psychological distress, accounting for baseline mental health. Changes in average General Health Questionnaire scores are described. A typology of five trajectory clusters highlighted stable and secure and precarious/low-quality trajectories for both men and women. Women who reported being economically inactive at most waves had higher odds of experiencing psychological distress than did women in 'standard' trajectories, regardless of baseline mental health. Women's scores of psychological distress in the 'precarious' group on average increased along their trajectories characterized by instability and transitions in/out of unemployment, before a move into employment. Men who likely moved in and out of unemployment and economic inactivity, with low probability of paid employment, reported increased psychological distress at the end of follow-up. This may partly be due to pre-existing mental ill-health. This paper shows the importance of high-quality employment for individuals' mental health over time. Researchers need to consider dynamic associations between employment quality and mental health across the life-course.

The effectiveness of a mobile mammography units in breast cancer screening

Breast cancer remains the leading cause of death in the female population. Screening studies are conducted in order to detect the disease at an early stage. At the same time, domestic authors emphasize the lack of alternatives to preventive mammography in breast cancer screening and the prospects of using mobile mammographs for early diagnosis of breast cancer and precancerous breast diseases.Aim. To evaluat the results of the use of mobile mammography units for active and early detection of breast cancer.Materials and methods. The research uses methods of content analysis, information and analytical materials of Russian and foreign researchers, and forms of federal statistical observation. Statistical research methods were used to analyze the data obtained.Results. Regression analysis with a very low probability of error (p = 0.001) showed that the larger the total volume of mammographic studies with preventive purposes in the subjects of the Russian Federation, the higher the proportion of cases of active detection of breast cancer, although this relationship is rather weak. Taking into account the obtained value of R2 (0.192), only 19.2% of the increase in the proportion of breast cancer cases detected actively can be explained by an increase in the volume of preventive mammograms. The correlation analysis showed that the volumes of preventive mammograms performed using mobile devices in the subjects of the Russian Federation were not associated with either the proportion of breast cancer cases detected actively or with the proportion of breast cancer cases detected in the early stages. At the same time, it is worth noting that the obtained value of p ≥ 0.5 indicates a statistically insignificant result of evaluating the relationship between variables, the interpretation of which should be performed with caution.Conclusion. Despite the high cost of mobile mammography units, the increase in their number in the subjects of the Russian Federation and the growth in their activities, the contribution of these diagnostic devices to solving the problem of early and active diagnosis of breast cancer remains uncertain. More promising are personalized approaches to the timely detection of cancers, including breast cancer, based on an assessment of the individual risk of their occurrence.

Sociodemographic Disparities in 1-Year Outcomes of Children With Community-Acquired Acute Kidney Injury

Racial disparities have been identified in pediatric community-acquired acute kidney injury (CA-AKI), and they are associated with increased risk of child mortality, morbidity, and progression of kidney disease. To assess clinical outcomes at 1 year among children with CA-AKI, stratified by age, race, and ethnicity. This retrospective cohort study is a population-based analysis of deidentified, aggregated electronic health record data collected by 61 large health care organizations from 2003 to 2023 and accessed through the TriNetX platform. Outcomes were assessed at 1 year after a CA-AKI episode. Participants included pediatric patients (aged <18 years) with AKI. Data were accessed in January 2024. A diagnosis of CA-AKI and sociodemographic factors such as race, ethnicity, and age, as reported in electronic health records. The primary end point of this study was to assess differences in clinical outcomes within 1 year of an episode of CA-AKI, including all-cause emergency department (ED) visits, intensive care unit (ICU) admissions, mechanical intubation and ventilation, and mortality. Risk was compared between White children and Asian (including Asian, Native Hawaiian, and Other Pacific Islander), Black, and Hispanic children, stratified by age group. Measures of association, Cox proportional hazard analyses, and Kaplan-Meier survival curves were performed within the TriNetX Advanced Analytics Platform between racial and ethnic groups for each analysis. From the total sample of 18 152 children, those with hospital-acquired AKI, chronic kidney disease, end-stage kidney failure, or dialysis dependence were excluded, leaving a final cohort of 17 125 children (mean [SD] age, 11.2 [5.2] years; 9424 male [55.3%]). Eligible patients were divided into racial and ethnic groups as follows: non-Hispanic Asian, 1169 children (6.5%); non-Hispanic Black, 4636 children (27.3%); Hispanic, 1786 children (10.2%); and non-Hispanic White, 9534 children (55.9%). Patients were further subdivided into groups aged 0 to 9 years (546 Asian children, 1675 Black children, 689 Hispanic children, and 3340 White children) and 10 to 18 years (623 Asian children, 2961 Black children, 1091 Hispanic children, and 6104 White children). Within 1 year of CA-AKI diagnosis, compared with White children, Black children experienced greater rates of ED visits (hazard ratio [HR], 1.53; 95% CI, 1.40-1.67), ICU admissions (HR, 1.31; 95% CI, 1.16-1.47), mechanical ventilation (HR, 1.33; 95% CI, 1.13-1.56), and all-cause mortality (HR, 1.27; 95% CI, 1.09-1.48), as well as the greatest risk for composite outcomes (HR, 1.43; 95% CI, 1.33-1.53). Hispanic children experienced greater rates of ED visits (HR, 1.40; 95% CI, 1.21-1.62) and the greatest risk of all-cause mortality (HR, 1.66; 95% CI, 1.31-2.09), whereas Asian children experienced greater rates of mechanical ventilation (HR, 1.69; 95% CI, 1.26-2.27), compared with White children. Black and Hispanic children aged 0 to 9 years were at greatest risk of experiencing poor clinical outcomes. Black children had a 11.41% lower survival probability and Hispanic children had a 7.14% lower survival probability compared with White children after an initial ED encounter. Among children with an identified episode of CA-AKI diagnosed in an ED, within 1 year, Black and Hispanic children had a poorer survival probability compared with White children. Future studies are needed to understand these disparities and improve awareness and follow-up after emergency care.

A probabilistic evaluation method on temperature and time-dependent stress intensity limit St in creep assessment of components at elevated temperatures

Abstract Creep is an important damage mode of components at elevated temperatures, and the temperature and time-dependent stress intensity limit St is an essential indicator in creep assessment of components. In general, the safety factors are directly applied to three criteria in stress intensity limit St in ASME code, but a quantitative evaluation on the failure probability covered in this indicator is rarely reported. Based on this, a probabilistic evaluation method on stress intensity limit St is proposed by correlating each criterion with mean creep rupture life data. The failure probability of three criteria in stress intensity limit St of 316 and 304 stainless steels is calculated, and the effect of safety factors on failure probability results is discussed. A probabilistic evaluation on stress intensity limit St is conducted. Results indicate that the stress intensity limit St presents a low failure probability or high conservativeness, and the minimum stress to creep rupture is the governing role in stress intensity limit St for cases involved. The failure probability of stress intensity limit St of 316 stainless steel is much lower than that of 304 stainless steel, attributed to the differences of creep deformation features and data scatter of the two stainless steels.

Intranasal M2SR and BM2SR Vaccine Viruses Do Not Shed or Transmit in Ferrets

Background/Objectives: Live influenza vaccines are considered to stimulate better overall immune responses but are associated with safety concerns regarding shedding and the potential for transmission or reassortment with wild-type influenza viruses. Intranasal M2SR and BM2SR (M2- and BM2-deficient single replication), intranasal influenza viruses, have shown promise as broadly cross-reactive next-generation influenza vaccines. The replication deficiency, shedding, and transmissibility of M2SR/BM2SR viruses were evaluated in a ferret model. Methods: Wild-type influenza A and B control viruses replicated in upper respiratory organs and transmitted to both direct and aerosol contact ferrets, whereas M2SR and BM2SR influenza vaccine viruses were not detected in any tissues or in nasal washes after inoculation and were not recovered from any direct or aerosol contact ferrets. Mice were simultaneously infected with wild-type influenza A and M2SR viruses to assess reassortment potential. Sequence and PCR analyses of the genome recovered from individual virus plaques isolated from lung homogenates identified the origin of the segments as exclusively from the replicating wild-type virus. Results: These results indicate that M2SR and BM2SR influenza vaccine viruses are attenuated, do not shed or transmit, and have a low probability for reassortment after coinfection. Absence of shedding was further demonstrated in nasal swabs taken from subjects who were inoculated with H3N2 M2SR in a previously described Phase 1 clinical study. Conclusions: These results indicate that M2SR/BM2SR viruses have the potential to be used in a broader population range than current live influenza vaccines.

Cardiovascular Disease Pathogenicity Predictor (CVD-PP): A Tissue-Specific In Silico Tool for Discriminating Pathogenicity of Variants of Unknown Significance in Cardiovascular Disease Genes.

Interpretation of variants of uncertain significance (VUSs) remains a challenge in the care of patients with inherited cardiovascular diseases (CVDs); 56% of variants within CVD risk genes are VUS, and machine learning algorithms trained upon large data resources can stratify VUS into higher versus lower probability of contributing to a CVD phenotype. We used ClinVar pathogenic/likely pathogenic and benign/likely benign variants from 47 CVD genes to build a predictive model of variant pathogenicity utilizing measures of evolutionary constraint, deleteriousness, splicogenicity, local pathogenicity, cardiac-specific expression, and population allele frequency. Performance was validated using variants for which the ClinVar pathogenicity assignment changed. Functional validation was assessed using prior studies in >900 identified VUS. The model utility was demonstrated using the Catheterization Genetics cohort. We identified a top-ranked model that accurately prioritized variants for which ClinVar clinical significance had changed (n=663; precision-recall area under the curve, 0.97) and performed well compared with conventional in silico methods. This model (CVD pathogenicity predictor) also had high accuracy in prioritizing VUS with functional effects in vivo (precision-recall area under the curve, 0.58). In Catheterization Genetics, there was a greater burden of higher CVD pathogenicity predictor scored VUS in individuals with dilated cardiomyopathy compared with controls (P=8.2×10-15). Of individuals in Catheterization Genetics who harbored highly ranked CVD pathogenicity predictor VUS meeting clinical pathogenicity criteria, 27.6% had clinical evidence of disease. Variant prioritization using this model increased genetic diagnosis in Catheterization Genetics participants with a known clinical diagnosis of hypertrophic cardiomyopathy (7.8%-27.2%). We present a cardiac-specific model for prioritizing variants underlying CVD syndromes with high performance in discriminating the pathogenicity of VUS in CVD genes. Variant review and phenotyping of individuals carrying VUS of pathogenic interest support the clinical utility of this model. This model could also have utility in filtering variants as part of large-scale genomic sequencing studies.

Echocaridographic assessment of pulmonary hypertension: improving the probability

Abstract Introduction Pulmonary hypertension (PH) is a cardio-pulmonary disorder characterised by raised pulmonary artery pressure (mPAP &amp;gt;20mmHg) leading to right ventricular failure, and death if left untreated. Transthoracic echocardiography (TTE) assessment of PH uses a probability-based approach, combining peak tricuspid regurgitant velocity with other supporting signs. We evaluated the latest ESC TTE PH guidelines in a real-world UK dataset and identified markers that may improve the sensitivity of the existing algorithm. Method Retrospective analysis of 447 patients referred for initial PH assessment. This was a select population of patients who underwent both TTE and right heart catheter (RHC) (mean time to RHC = 40±30 days). In addition to current TTE PH probability markers we analysed right ventricular free wall strain (RVFWS). Measurements were made by a single operator using Tomtec Arena 2020. Crosstabulation, ROC curve analysis and T-tests were used to compare variables between PH and no PH. Results Mean sample age was 64±15 yrs (61% female). 6.9% (n=4) of the no PH group had pulmonary mid-systolic notching, which may be due to pseudo-notching attributable to incomplete Doppler envelope. Sensitivity and specificity of current ESC TTE probability guidelines were 83%, and 65% respectively (95% C.I.). However, within the low probability group (i.e. those felt to be less likely to have PH) 62% (n=63) had confirmed PH at RHC (mPAP = 28±9). The addition of RVFWS as an additional marker to the existing supporting signs of PH (Table 1) resulted in an improvement of the sensitivity of the algorithm to 92% with a mild reduction in specificity (63%). The number of false negatives were reduced by 51%. Of these, the majority were in the low TTE probability group (n = 32). Conclusions Using current PH TTE probability algorithms classifies a significant proportion of those with PH as having a low TTE PH probability. The addition of RVFWS improves the sensitivity of the existing algorithm to 92% and reduces false negatives by 51%.