Early Mortality Research Articles

Real-world treatment outcomes for Hodgkin lymphoma in South Africa: a prospective observational study

BackgroundProspective data from sub-Saharan Africa suggests that treatment outcomes for people living with HIV (PWH) with Hodgkin lymphoma (HL) are similar to those without HIV. However, real-world data from high-resource settings and retrospective studies from sub-Saharan Africa, suggest inferior outcomes. We set out to evaluate the real-world treatment outcomes for HL in South Africa to better understand the disparate outcomes.MethodsWe established a prospective, observational cohort of newly diagnosed, adult (≥ 18 years) HL cases recruited from Chris Hani Baragwanath Academic and Netcare Olivedale Hospitals in Johannesburg, South Africa between March 2021 and March 2023. Participants were followed for up to 18 months after enrollment with data censored on December 23rd, 2023. The primary endpoint was 1-year overall survival.ResultsWe enrolled 47 participants with HL including 31 PWH and 16 HIV-negative. Advanced stage disease and B symptoms were common at time of diagnosis irrespective of HIV status. Bone marrow biopsy, performed during the work-up and evaluation of cytopenias, provided the initial diagnosis of HL in 16/31 (52%) PWH. HIV status and bone marrow involvement were associated with early mortality (within 3 months of diagnosis) and a poorer 1-year overall survival from diagnosis (HIV: 55% vs. 88%; p = 0.03; bone marrow involvement: 50% vs. 80%; p = 0.02). Among evaluable participants, those that received at least 6 cycles of chemotherapy and underwent response assessment, there was no difference between those with and without HIV.ConclusionTraditional laboratory markers of poor prognosis including anemia, lymphopenia and hypoalbuminemia were more common among PWH and those with bone marrow involvement and suggest high risk disease. A better understanding of the drivers of these aggressive presentations is warranted to ensure more PWH are able to tolerate chemotherapy.

The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome.

Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.

Effect of surgical fixation timing on in-hospital mortality and morbidity of distal femur fractures

IntroductionThe literature lacks a large-scale study investigating the effect of surgical fixation timing on early mortality and morbidity outcomes in distal femur fractures. The aims of this study were to determine the effect of fixation timing on in-hospital mortality and morbidity outcomes for operatively treated distal femur fractures retrospectively using large database data. MethodsThis study is a retrospective analysis using data from the National Trauma Data Bank. Patients were stratified into a fragility cohort (age ≥ 60, ISS < 16) and polytrauma cohort (age < 60, ISS ≥16), with both cohorts analyzed separately. Within each cohort, patients were split into three fixation timing groups: within 24 h, between 24 and 48 h, and greater than 48 h from presentation to the hospital. Fixation-timing groups were compared based on the primary outcome of in-hospital mortality rate. Secondary outcomes included hospital length of stay (LOS), ICU length of stay (ICU LOS), days on a ventilator, and complications. ResultsThe fragility and polytrauma cohorts included 22,045 and 5,905 patients, respectively. The in-hospital mortality rate was 1.23 % in the fragility cohort and 2.56 % in the polytrauma cohort. Multivariate analysis of the fragility cohort showed that fixation greater than 48 h from time of presentation was associated with increased mortality compared to fixation within 24 h (OR 1.89, CI: 1.26–2.83, p=0.002) and between 24 and 48 h (OR 1.63, CI: 1.23–2.15, p<0.001). In the polytrauma cohort, multivariate analysis showed no significant mortality differences between fixation timing groups. Multivariate analysis of morbidity outcomes in both cohorts showed that fixation greater than 48 h was associated with increased LOS, ICU LOS, ventilator days, and complications compared to fixation within 24 h. In the polytrauma cohort, fixation between 24 and 48 h was associated with decreased LOS, ICU LOS, and complications compared to the other two timing groups. ConclusionsFixation of distal femur fractures before 48 h from presentation may lead to improved mortality and morbidity in older, lower injury severity patients. No significant mortality benefit was observed in younger, polytrauma fractures. Further prospective work is needed to validate these findings.

Comparing NEWS2, TRISS, RTS, SI, GAP, and MGAP in predicting early and total mortality rates in trauma patients based on emergency department data set: A diagnostic study

IntroductionIn the global context, trauma remains a significant cause of mortality, particularly among individuals under 50 years old with mortality and morbidity. Timely assessment, efficient triage, and appropriate post-trauma care can help mitigate long-term mortality and morbidity risks. While the trauma and injury severity score (TRISS) is considered accurate, its complexity limits clinical utility, prompting the development of new tools like the National Early Warning Score 2 (NEWS2) and others. Thus, this study aims to evaluate the predictive abilities of NEWS2, RTS (revised trauma score), TRISS, SI (shock index), GAP (Glasgow coma score, age, and systolic blood pressure), and MGAP (mechanism of injury, Glasgow coma score, age, and systolic blood pressure) scoring systems in trauma patient care to enhance outcomes and reduce mortality and morbidity rates. MethodsThis retrospective diagnostic study included a total of 6894 trauma patients with data collected from the emergency department. Patient information, including vital signs and demographic data, was recorded on datasheets completed by ED staff. Ethical guidelines were followed, and patient consent forms were not required due to the study's retrospective nature. Scoring systems such as NEWS2, RTS, TRISS, SI, GAP, and MGAP were calculated and interpreted based on specific formulas and scoring charts. ResultsOf 6894 patients, 2.83% died during hospitalization, and 0.72% within the first 24 hours. Factors associated with mortality included age, cause of injury, duration of hospitalization, and various physiological parameters. The majority of scoring systems are reliable in predicting mortality, except for the sock index (SI), with NEWS2 demonstrating the highest sensitivity and accuracy for predicting mortality rates, while TRISS and RTS were the most specific. GAP was also the most competent predictor of overall mortality. ConclusionMost scoring systems effectively predict mortality, with TRISS and NEWS2 demonstrating high sensitivity and specificity together in forecasting in-hospital mortality. NEWS2 stands out as a precise tool for mortality prediction in the emergency department due to its simplicity and quick application. However, further research is needed to identify the most effective predictive system in trauma patients.

Analysis of Echocardiography Indicators Depending on the Type of Surgical Correction of the Mitral Valve in Patients with Ischemic Heart Disease

The aim. To study the influence of echocardiography indicators on the choice of surgical intervention on the mitral valve in patients with mitral insufficiency and coronary heart disease. Materials and methods. The study included patients with mitral insufficiency who underwent myocardial revascularization and mitral valve reconstruction (plasty or replacement). The mean age of the study participants was 65.9 ± 4.0 years. The material for analysis was data from the primary medical records: medical history, clinical and instrumental examination data and protocols of operations. The division into study groups was performed retrospectively, according to the mitral valve operation performed: plasty (experimental group) or replacement (control group). Results. We identified the features of the main echocardiographic data that guide the cardiologist when choosing the tactics of surgical correction of the mitral valve. It was established that in patients of the research group, the following was reliably significant: moderate degree of mitral insufficiency (p = 0.02; χ2 = 9.38), decrease in the systolic function of the left ventricle (p = 0.001; χ2 = 10.75); it was found that calcium deposits on the fibrous ring of the mitral valve were insignificant. When analyzing the morphological changes in patients of the experimental group, we found a significantly lower frequency of anterior leaflet prolapse (p = 0.04; χ2 = 4.21) and in general the frequency of all prolapses of any type, while in the control group the frequency of all prolapses was significantly higher (p = 0.04; χ2 = 4.0). In patients of the control group, a significantly higher frequency of akinesis (p = 0.04; χ2 = 4.21) and hypokinesis zones of the posterior-inferior-lateral wall (p = 0.001; χ2 = 19.76) was established, which is an additional sign of involvement of the chordal-muscular apparatus of the mitral valve in pathological process. Conclusions. As a result of the study, echocardiographic differences in the structure of the mitral valve were established, which influenced the selection of the intervention volume. It was found that in patients of the experimental group, the early postoperative mortality and the duration of inpatient treatment were significantly higher than in patients of the control group, which indicates the imperfection of the criteria used by cardiac surgeons when choosing the tactics of surgical correction of the mitral valve in an attempt to perform organ-preserving surgery.

Liquid Chromatography Mass Spectrometric Method and a Fluorometric 96 Well Plate Assay for Determination of Thiamine in Salmonid Eggs.

Thiamine deficiency is a large contributor to reduced reproduction success among salmonids throughout the northern hemisphere. In Scandinavia, this reproduction disorder is known as M74; while in North America, it is known as early mortality syndrome (EMS). The disorder fluctuates in magnitude from year to year. During years with high prevalence of the disorder, salmonid hatcheries that stock various aquatic systems to maintain the population size experience difficulties filling their quotas without thiamine treatment of alevins. The disorder is monitored both by observing the survival rate and by measuring the thiamine content of prefertilized eggs in the hatcheries. Here, a simple extraction procedure is presented, which allows for quantitative determination of the various phosphorylated forms of thiamine using liquid chromatography mass spectrometry but also allows for extraction in 96 deep-well plates and measurement of the total thiamine content using fluorescence monitoring with a plate reader, following oxidation of thiamine to thiochrome. The latter procedure could also be integrated into a highly portal system where the thiochrome is determined using the DeNovix QFX analyzer. The newly developed extraction procedure and cleanup method for fluorescence measurement represent the most versatile and simple methods to date for monitoring of thiamine in salmonid eggs. The methods produced accurate and precise data with quantification limits below the limit where the deficiency causes 100% lethality.

Increased cardiovascular morbidity and reduced life expectancy in a large Italian cohort of patients with resistance to thyroid hormone β (RTHβ).

Decreased survival and higher cardiovascular morbidity have been recently reported in a UK cohort of 61 RTHβ patients, but there is no evidence from other countries. Retrospective cohort study from an historical group of 284 Italian RTHβ patients, diagnosed between 1984 and 2023. We collected data on diagnosis of 284 cases and longitudinal data of 249 RTHβ who carried heterozygous pathogenic variants in the THRB gene. We studied how thyroid function and recognized risk factors for cardiovascular disease, such as hypertension and diabetes, affected overall mortality and major cardiovascular events. The cumulative prevalence of sinus/supraventricular tachycardia and atrial fibrillation was 40% and 18%, respectively. FT4 values 57% higher than the upper limit of normal were associated with premature cardiovascular manifestations. Major cardiovascular events (MACEs) occurred in RTHβ patients at a median age (IQR) of 59.4 years (50.4-66.4) and early mortality resulted in a mean of 11 years of life lost. While at univariable analysis hypertension, dyslipidemia, high fasting glucose/diabetes were also associated with MACEs, at multivariable analysis only age at diagnosis, increased fT4 levels, and male gender remained significantly associated with MACEs and age at diagnosis and higher fT4 levels with mortality. Previous thyroidectomy or radioiodine therapy had no statistically significant effect in the prevention of major cardiovascular events or all-cause mortality. These data should raise the general awareness on the cardiovascular risk and prompt a proactive cardiovascular monitoring in RTHβ, especially in men and those with fT4 levels above 30 pmol/L.

Operations for increasing the pulmonary blood flow in newborns with cyanotic congenital heart defects: results and features of outpatient postoperative monitoring

Background. In patients with cyanotic congenital heart defects, pulmonary blood flow is maintained by a functio­ning patent ductus arteriosus (PDA). Most patients with complex ductal-dependent cyanotic defects require intermediate staged treatment before radical correction of the defect. Timely and comprehensive outpatient monitoring by a pediatrician and pediatric cardiologist are important for patient survival following palliative treatment, along with determining optimal timing for consultations at specialized cardiac surgical centers. Objective: to present the outcomes of using two methods for increasing pulmonary blood flow (systemic-to-pulmonary artery shunt (SPAS) and PDA sten­ting), as well as the features of outpatient cardiological observation and treatment in these patients. Materials and methods. From 2000 to February 2024, 22 patients underwent SPAS, and 25 — PDA stenting at the State Institution “Scientific and Practical Medical Center of Pediatric Cardiology and Cardiac Surgery” of the Ministry of Health of Ukraine. Results. After interventions, the mean arterial oxygen saturation (SatO2) increased in both groups, significantly higher in the PDA stenting group (p &lt; 0.05). The ave­rage length of stay in the intensive care unit in the SPAS group was 19.6 ± 11.1 (range: 5 to 91) days compared to 12.8 ± 6.3 (range: 4 to 37) days in those with PDA stenting (p = 0.05). The duration of artificial lung ventilation in the SPAS group was 290.3 ± 215.3 (range: 63 to 751) hours, and in the PDA stenting group, it was shorter, 151.8 ± 75.5 (range: 39 to 549) hours (p &lt; 0.05). Early (30-day) postoperative mortality in the SPAS group was 13.6 % (3/22 patients), with a late mortality of 18 % (4/22). In contrast, there was not early (30-day) postoperative mortality in the PDA stenting group, and late mortality was 8 % (2/25). Before the subsequent stage of surgical correction, sufficient growth of pulmonary artery branches was noted (Nakata index increased from 156.9 ± 33.3 mm2/m2 to 277.0 ± 35.9 mm2/m2 in the SPAS group and from 142.7 ± 55.2 mm2/m2 to 289.1 ± 149.2 mm2/m2 in the PDA stenting group), and the left ventricular end-diastolic index has increased (from 51.2 ± 32.4 mm2/m2 to 67.5 ± 15.5 mm2/m2 in the SPAS group and from 50.8 ± 24.9 mm2/m2 to 56.7 ± 28.5 mm2/m2 in the PDA stenting group). Thirteen patients in the SPAS group underwent the next stage of surgical correction (Glenn shunt or total repair of the congenital heart defect), while in the PDA stenting group — 17 patients. Conclusions. For cyanotic congenital heart defects, which have ductus-dependent pulmonary blood flow, both described methods are quite effective.

Biomarkers as Predictors of Mortality in Sepsis and Septic Shock for Patients Admitted to Emergency Department: Who Is the Winner? A Prospective Study

Background/Objectives: Sepsis and septic shock remain significant contributors to high early mortality rates among patients admitted to the emergency department (ED). The objective of this study was to identify among newer biomarkers those with the highest sensitivity in early mortality prediction. Methods: This prospective, unicentric, observational study enrolled 47 adult patients admitted to the ED between November 2020 and December 2022. This study monitored the kinetics of the older and newer biomarkers, including azurocidin (AZU1), soluble triggering receptor expressed on myeloid cells (sTREM), soluble urokinase-type plasminogen activator receptor (suPAR), high-sensitivity C-reactive protein (hsCRP), procalcitonin (PCT), and interleukin-6 (IL-6), and their capacity in predicting mortality. Results: SuPAR showed the most significant predictive utility for early prognosis of mortality in the ED, with an area under the curve (AUC) of 0.813 (95% CI: 0.672 to 0.912), a cutoff value &gt; 8168 ng/mL, sensitivity of 75%, and specificity of 81.48% (p &lt; 0.001). IL-6 and PCT showed comparable prognostic accuracy, whereas hsCRP and AZU1 demonstrated lower predictive performance. Conclusions: In our study, suPAR, IL-6, and PCT showed good predictive value for short-term mortality in sepsis and septic shock patients.

Centralisation of extremely preterm births and decreased early postnatal mortality in Sweden, 2004-2007 versus 2014-2016.

We evaluated the increased centralisation of extremely preterm (EPT) births in Sweden in relation to the changes in mortality and morbidity. Population-based data covering Swedish live births from 22 + 0 to 26 + 6 weeks of gestation during 2004-2007 and 2014-2016 were analysed for associations between time-period, birth within (inborn) or outside (outborn) regional centres, and outcomes. Among 1626 liveborn infants, 703 were born in 2004-2007 and 923 in 2014-2016. Birth outside (vs. within) regional centres was associated with a higher infant mortality even after adjustment for birth cohort, gestational age, birthweight standard deviation score and infant sex (adjusted odds ratio 2.01, 95% confidence interval 1.31-3.07, p = 0.001). The higher 1-yearmortality in outborn infants was mainly due to more deaths within 24 h after birth. Outborn infants had a higher incidence of intraventricular haemorrhage grade 3-4 than inborn infants (22% vs. 14% in 2004-2007, and 22% vs. 13% in 2014-2016, both p < 0.05). While survival to 1 year without major morbidity increased in inborn infants (33%-40%, p = 0.008), it remained unchanged in outborn infants (29% vs. 30%, p = 0.88). Centralisation of EPT births contributed to a lower 1-year mortality in 2014-2016 than that in 2004-2007, attributed to a decrease in deaths before 24 h among inborn infants.

Development of an antigen-based approach to noninvasively image CAR T cells in real time and as a predictive tool.

CAR T cell therapy has revolutionized the treatment of a spectrum of blood-related malignancies. However, treatment responses vary among cancer types and patients. Accurate monitoring of CAR T cell dynamics is crucial for understanding and evaluating treatment efficacy. Positron emission tomography (PET) offers a comprehensive view of CAR T cell homing, especially in critical organs such as lymphoid structures and bone marrow. This information will help assess treatment response and predict relapse risk. Current PET imaging methods for CAR T require genetic modifications, limiting clinical use. To overcome this, we developed an antigen-based imaging approach enabling whole-body CAR T cell imaging. The probe detects CAR T cells in vivo without affecting their function. In an immunocompetent B cell leukemia model, CAR-PET signal in the spleen predicted early mortality risk. The antigen-based CAR-PET approach allows assessment of CAR T therapy responses without altering established clinical protocols. It seamlessly integrates with FDA-approved and future CAR T cell generations, facilitating broader clinical application.

Interactions between broiler parent stock age and egg pre-incubation duration: effects on embryo development, hatchability, day-old chick weight, and yolk sac weight

Egg storage is a common practice in commercial hatcheries, but prolonged storage can negatively impact hatchability, causing a significant problem for the poultry industry. Repeated pre-incubation could mitigate the decline depending on the age of the parent stock. The study investigated the interactions between parent stock age (30, 45, and 58 weeks) and repeated pre-incubation on the hatchability and embryo development of 15-day stored eggs from Ross 308 parent stock. Three different pre-incubation durations were employed during storage: no pre-incubation and twice at the 5th and 10th days of egg storage for either 4 or 8 h. For each parent stock age, 3 600 eggs collected on the same day from the same parent stock were used for hatchability assessment. The duration of pre-incubation was determined as the eggshell temperature increased from 28 °C to a maximum of 35 °C and then cooled to 28 °C; the persistency at 35 °C was either 1 or 4 h for the total pre-incubation period. The hatchability of both set and fertile eggs and early, middle, and late embryonic mortality depended on the parent stock’s age (P < 0.001). Pre-incubation alone did not have any impact on hatchability. Conversely, a significant interaction was observed between parent stock age and pre-incubation duration on the hatchability of fertile eggs (P = 0.001). At 30 weeks of parent stock age, both durations of pre-incubation positively influenced the hatchability. At 45 weeks of parent stock age, pre-incubation length had no effect on hatchability. At 58 weeks of parent stock age, a longer pre-incubation period, 2 × 8 h, was associated with decreased hatchability. Early embryonic mortality was not influenced by pre-incubation. However, a significant interaction was observed (P = 0.003). At 30 weeks of parent stock age, both short and long lengths of pre-incubation were associated with a decrease in early embryonic mortality. However, at 45 and 58 weeks, pre-incubation did not significantly affect early embryonic mortality. Additionally, longer pre-incubation periods significantly increased middle mortality compared to untreated eggs (P = 0.035). The median of embryo development for untreated eggs was the same across all ages (stage 10). In the older parent stock (45 and 58 weeks), repeated pre-incubation increased variability in embryo development, while in the younger parent stock, repeated pre-incubation decreased variability in embryo development. In conclusion, the duration and the frequency of pre-incubation should be specified based on the age of the parent stock.

Black Americans With Sickle Cell Disease (SCD) Demonstrate Accelerated Epigenetic Pace of Aging Compared to Black Americans Without SCD.

Sickle cell disease (SCD) is a chronic medical condition characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, and subsequently, end-organ damage and reduced survival. Because of this significant pathophysiology and early mortality, we hypothesized that patients with SCD are experiencing accelerated biological aging compared with individuals without SCD. We utilized the DunedinPACE measure to compare the epigenetic pace of aging in 131 Black Americans with SCD to 1391 Black American veterans without SCD. SCD patients displayed a significantly accelerated pace of aging (DunedinPACE mean difference of 0.057 points) compared with the veterans without SCD, whereby SCD patients were aging ≈0.7 months more per year than those without SCD (p = 4.49 × 10-8). This was true, even though the SCD patients were significantly younger according to chronological age than the individuals without SCD, making the epigenetic aging discrepancy even more apparent. This association became stronger when we removed individuals with posttraumatic stress disorder from the non-SCD group (p = 2.18 × 10-9), and stronger still when we restricted the SCD patients to those with hemoglobin SS and Sβ0 thalassemia genotypes (p = 1.61 × 10-10). These data support our hypothesis that individuals with SCD experience accelerated biological aging as measured by global epigenetic variation. The assessment of epigenetic measures of biological aging may prove useful to identify which SCD patients would most benefit from clinical interventions to reduce mortality.

The HCV-Melanoma Paradox: First Multi-Cohort and Molecular Net-Work Analysis Reveals Lower Incidence but Worse Outcomes-Integrating Clinical, Real-World, and In Silico Data.

Background and Objectives: The relationship between hepatitis C virus (HCV) infection and melanoma remains poorly understood. This study aimed to investigate the association between HCV and melanoma, assess outcomes in patients with both conditions, and explore potential molecular mechanisms connecting the two diseases. Materials and Methods: We conducted a retrospective cohort study of 142 melanoma patients, including 29 with HCV-related cirrhosis, and analyzed their clinical outcomes. For external validation, we used the TriNetX Global Collaborative Network database, comprising 219,960 propensity-matched patients per group. An in silico analysis was performed to identify the molecular pathways linking HCV and melanoma. Results: In the retrospective cohort, HCV-positive melanoma patients showed an increased risk of early relapse (41.4% vs. 18.6%, p = 0.014), recurrence (65.5% vs. 39.8%, p = 0.020), and mortality (65.5% vs. 23.0%, p < 0.001) compared to HCV-negative patients. TriNetX data analysis revealed that HCV-positive patients had a 53% lower risk of developing melanoma (RR = 0.470, 95% CI: 0.443-0.498, p < 0.001). However, HCV-positive melanoma patients had higher all-cause mortality (HR = 1.360, 95% CI: 1.189-1.556, p < 0.001). An in silico analysis identified key molecular players, including IL-6 and CTLA4, in the HCV-melanoma network. Conclusions: While HCV infection may be associated with a lower risk of melanoma development, HCV-positive patients who develop melanoma have poorer outcomes. The identified molecular pathways provide potential targets for future research and therapeutic interventions.

Considerations in Premature Menopause: A Review.

Premature menopause impacts 1% of women under the age of 40. The women are at risk of premature death, ischemicdisease of the heart, neurological conditions, mood disturbances, psychosexual problems, osteoporosis, and subfertility. There is an imperative for less complicated protocols and enhanced approaches for oocyte donation togetpregnantand achievemotherhood in at-risk women. A review of the pertinent literature on premature ovarian insufficiency and selected references was done.A comprehensive review was undertaken by searching the databases PubMed, Scopus, EMBASE, Web of Science, and Science Direct. Pregnancy in women with prematuremenopause was formerly uncommon, but because ofrecent advances in oocyte donation, women with premature menopause can now aspire to have a child. Hormone replacement treatment is useful in treating the negative effects of premature ovarian insufficiency. Women who experience early menopause are at risk for early mortality, ischemic heart disease, neurological conditions, mood problems, psychosexual disorder, osteoporosis, and subfertility. Public awareness and education are critical tools for saving womenat peril.

Health-Related Quality-of-Life Utility Values in Adults With Late-Onset Pompe Disease: Analyses of EQ-5D Data From the PROPEL Clinical Trial

Background: Pompe disease is a rare lysosomal storage disorder, leading to accumulation of glycogen characterized by muscle weakness, fatigue, pain, and, in the longer term, a requirement for ventilatory and ambulatory support, and early mortality if untreated. Clinical evidence suggests that enzyme replacement therapy improves health outcomes for adults with late-onset Pompe disease (LOPD). PROPEL was a Phase 3, double-blind, randomized controlled trial, which evaluated cipaglucosidase alfa plus miglustat, vs alglucosidase alfa plus placebo in 123 adult patients with LOPD (clinicaltrials.gov: NCT03729362). Objectives: To analyze EQ-5D health-related quality of life (HRQoL) utility data from PROPEL. Methods: Multilevel modeling techniques (mixed regression methods) were used to analyze PROPEL EQ-5D-3L estimates and predict utility values for 7 health states previously identified in an economic evaluation for LOPD. In PROPEL, EQ-5D-5L values were assessed at screening and at weeks 12, 26, 38, and 52. EQ-5D-5L utility values were mapped to EQ-5D-3L values using the van Hout algorithm as recommended by the EuroQoL and the National Institute of Health and Care Excellence position statement at time of analysis. UK population tariffs were applied for all EQ-5D utility valuations. Utility values were predicted according to 6-minute walk distance (6MWD) and percent predicted sitting forced vital capacity. Results: The mixed model predicted that EQ-5D-3L utility values for patients who could walk &gt;75 m with LOPD ranged between 0.55 and 0.67 according to patient 6MWD and respiratory function. In this analysis, patients with a 6MWD ≤75 m, consistent with a health state requiring wheelchair support in the economic analysis, had a predicted utility value of 0.49. There were few patients in PROPEL who could walk ≤75 m at any time point in the study, hence, these utility estimates should be interpreted with caution. EQ-5D-3L utility estimates from PROPEL were consistent with previously reported EQ-5D-3L values in LOPD. Conclusions: Overall, the results from our analysis indicate that important HRQoL losses are associated with reductions in mobility and respiratory function for patients with Pompe disease. The study provides important evidence of HRQoL utility values for patients with advanced LOPD, a population for whom published data are limited.

Health-Related Quality-of-Life Utility Values in Adults With Late-Onset Pompe Disease: Analyses of EQ-5D Data From the PROPEL Clinical Trial.

Background: Pompe disease is a rare lysosomal storage disorder, leading to accumulation of glycogen characterized by muscle weakness, fatigue, pain, and, in the longer term, a requirement for ventilatory and ambulatory support, and early mortality if untreated. Clinical evidence suggests that enzyme replacement therapy improves health outcomes for adults with late-onset Pompe disease (LOPD). PROPEL was a Phase 3, double-blind, randomized controlled trial, which evaluated cipaglucosidase alfa plus miglustat, vs alglucosidase alfa plus placebo in 123 adult patients with LOPD (clinicaltrials.gov: NCT03729362). Objectives: To analyze EQ-5D health-related quality of life (HRQoL) utility data from PROPEL. Methods: Multilevel modeling techniques (mixed regression methods) were used to analyze PROPEL EQ-5D-3L estimates and predict utility values for 7 health states previously identified in an economic evaluation for LOPD. In PROPEL, EQ-5D-5L values were assessed at screening and at weeks 12, 26, 38, and 52. EQ-5D-5L utility values were mapped to EQ-5D-3L values using the van Hout algorithm as recommended by the EuroQoL and the National Institute of Health and Care Excellence position statement at time of analysis. UK population tariffs were applied for all EQ-5D utility valuations. Utility values were predicted according to 6-minute walk distance (6MWD) and percent predicted sitting forced vital capacity. Results: The mixed model predicted that EQ-5D-3L utility values for patients who could walk >75 m with LOPD ranged between 0.55 and 0.67 according to patient 6MWD and respiratory function. In this analysis, patients with a 6MWD ≤75 m, consistent with a health state requiring wheelchair support in the economic analysis, had a predicted utility value of 0.49. There were few patients in PROPEL who could walk ≤75 m at any time point in the study, hence, these utility estimates should be interpreted with caution. EQ-5D-3L utility estimates from PROPEL were consistent with previously reported EQ-5D-3L values in LOPD. Conclusions: Overall, the results from our analysis indicate that important HRQoL losses are associated with reductions in mobility and respiratory function for patients with Pompe disease. The study provides important evidence of HRQoL utility values for patients with advanced LOPD, a population for whom published data are limited.

Clinical Care for Cardiovascular Disease in Patients With Williams-Beuren Syndrome.

Williams-Beuren syndrome (WBS) is a congenital multisystem disorder affecting the cardiovascular, central nervous, and musculoskeletal systems. Cardiovascular abnormalities, which consist principally of vascular stenoses, occur in approximately 80% of people with WBS and are the predominant cause of early morbidity and mortality. Supravalvar aortic stenosis and peripheral pulmonary artery stenosis are the most common stenotic lesions in WBS, though other stenoses often occur, including stenoses of the coronary arteries. Approximately one-third of people with WBS undergo cardiovascular interventions. The risk of sudden cardiac death is markedly higher than the general population, with most events occurring in the periprocedural period. Because of the rarity of WBS and the often-complex nature of the cardiovascular abnormalities, most physicians, including cardiologists, have limited experience in caring for patients with WBS. Further, heretofore, clinical cardiovascular management guidelines based on international expert consensus have not been available. This state-of-the-art review provides a comprehensive synopsis of the cardiovascular abnormalities in WBS and presents clinical management guidelines based on the authors' expert consensus.

Association between red blood cell distribution width and 30-day mortality in critically ill septic patients: a propensity score-matched study

BackgroundSepsis is the leading cause of death worldwide, and a number of biomarkers have been developed for early mortality risk stratification. Red blood cell distribution width (RDW) is a routinely available hematological data and has been found to be associated with mortality in a number of diseases; therefore, we aim to address the association between RDW and mortality in critically ill patients with sepsis.MethodsWe analyzed data of critically ill adult patients with sepsis on the TriNetX platform, excluding those with hematologic malignancies, thalassemia, and iron deficiency anemia. Propensity score-matching (PSM) (1:1) was used to mitigate confounding effects, and hazard ratio (HR) with 95% confidence (CI) was calculated to determine the association between RDW and 30-day mortality. We further conducted sensitivity analyses through using distinct cut-points of RDW and severities of sepsis.ResultsA total of 256,387 critically ill septic patients were included in the analysis, and 40.0% of them had RDW equal to or higher than 16%. After PSM, we found that high RDW was associated with an increased 30-day mortality rate (HR: 1.887, 95% CI 1.847–1.928). The associations were consistent using distinct cut-points of RDW, with the strength of association using cut-points of 12%, 14%, 16%, 18% and 20% were 2.098, 2.204, 1.887, 1.809 and 1.932, respectively. Furthermore, we found consistent associations among critically ill septic patients with distinct severities, with the association among those with shock, receiving mechanical ventilation, bacteremia and requirement of hemodialysis being 1.731, 1.735, 2.380 and 1.979, respectively.ConclusionWe found that RDW was associated with 30-day mortality in critically ill septic patients, underscoring the potential as a prognostic marker in sepsis. More studies are needed to explore the underlying mechanisms.

Protective potential of Bacillus subtilis (NMCC-path-14) against extraarticular manifestations during acute and sub-acute phase of arthritis using mice model

Extra-articular manifestations (EAM), which are associated with rheumatoid arthritis (RA), affect the quality of life of patients and are one of the critical causes of early mortality. This study was aimed at investigating whether Bacillus subtilis NMCC-path-14 (1 × 108 CFU/animal/day) could serve as a valuable therapeutic agent in managing EAM using complete Freund's adjuvant (CFA) induced arthritis during acute and sub-acute phases. Arthritis was induced using intra-dermal administration of CFA in the right hind paw of mice on day 1. Dexamethasone (Dexa) (5 mg/kg/day/animal) was used as a standard treatment. Animals in Dexa and Bacillus subtilis concurrent treatment (BS-CT) received treatments on day 1. The Bacillus subtilis pre-treatment (BS-PT) group received a probiotic dose 7 days before arthritis induction. Parameters like body weight, relative organ weight, colon length, hematology, serum biochemistry, antioxidant capacity, and histopathology of liver, kidney, spleen, colon, stress-related behavioral changes, and cortisol levels were evaluated on days 7 (acute) and 14 (sub-acute). Dexa failed to manage the EAM in arthritic mice and instead exacerbated them. On the other hand, B. subtilis NMCC-path-14 significantly declined EAM with no notable side effects, highlighting its safety and effectiveness. The current data show that B. subtilis NMCC-path-14 may be an alternative option for arthritis treatment that can reduce systemic symptoms associated with arthritis. More studies are required to comprehend the underlying mechanisms of mitigating the EAM by B. subtilis NMCC-path-14.