Early Death Research Articles

Silver-Russell syndrome-like features in a child with recombinant chromosome 11 derived from maternal pericentric inversion.

Silver-Russell syndrome (SRS) is a well-known syndrome but with heterogeneous etiologies. We present the case of a child with severe SRS-like features resulting from a complex rearrangement of chromosome 11 inherited from his mother. We studied the index case with karyotyping, MS-MLPA and molecular karyotyping. The mother was studied with karyotyping and subtelomeric FISH. We found a child with marked developmental delay and fatal outcome due to failure to thrive, carrying an 11p15 duplication and an 11q25 deletion of maternal origin. We discovered that the mother was a carrier of a pericentric inversion of chromosome 11, with a history of recurrence in other family members who had severe growth retardation and early death. To our knowledge, no similar SRS-like cases have been described in the literature. This report supports the importance of identification the causative genetic mechanism in SRS-like individuals with duplication in 11p15 region due to high risk of recurrence and to provide an appropriate genetic counseling to the family.

Association of Antenatal Corticosteroids with Neonatal Outcomes among Very Preterm Infants Born to Mothers with Clinical Chorioamnionitis: A Multicenter Cohort Study.

The objective of this study was to assess the relationship of ACS with neonatal outcomes among very preterm infants born to mothers with clinical chorioamnionitis in China. This was a multicenter retrospective cohort study. Study participants included infants born at <32 weeks' gestation with clinical chorioamnionitis and registered in the Chinese Neonatal Network from 1 January 2019 to 31 December 2020. Infants were divided into two groups: any amount of ACS or no administration of ACS. Multivariable generalized linear models using generalized estimating equations were used to assess the association between ACS and neonatal outcomes among the study population. We identified 2193 infants eligible for this study; 1966 (89.6%) infants had received ACS therapy, and 227 (10.4%) had not received any ACS therapy. Among very preterm infants born to mothers with clinical chorioamnionitis, any ACS usage was significantly associated with decreased risks of early death (aRR 0.56, 95% CI 0.32, 0.99) and severe ROP (aRR 0.51, 95% CI 0.28, 0.93) after adjustment for maternal hypertension, gestational age at birth, Caesarean section, being inborn, and administration of systemic antibiotics to the mother within 24 h before birth. In addition, out of the 2193 infants, the placentas of 1931 infants underwent pathological examination with recorded results. Subsequently, 1490 of these cases (77.2%) were diagnosed with histological chorioamnionitis. In 1490 cases of histologic chorioamnionitis, any ACS usage was significantly related to decreased risks of overall mortality (aRR 0.52, 95% CI 0.31, 0.87), severe ROP (aRR 0.47, 95% CI 0.25, 0.97), and respiratory distress syndrome (aRR 0.52, 95% CI 0.31, 0.87). We concluded that any ACS was associated with reduced risks for neonatal early death and severe ROP among very preterm infants born to mothers with clinical chorioamnionitis.

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies have stratified outcomes by class I obesity, class II obesity, and class III obesity, and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n = 729). Class III obesity was associated with an increased rate of early death (p = 0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

Disparities in frontline treatment and overall survival in the era of targeted tyrosine kinase inhibitor therapy for chronic myeloid leukemia: 2004-2021.

11187 Background: The treatment of chronic myeloid leukemia (CML) was revolutionized in 2001 with the introduction of the BCR::ABL tyrosine kinase inhibitor (TKI), imatinib. In 2006, dasatinib was approved, followed by nilotinib in 2007. Two other TKIs, bosutinib &amp; ponatinib were approved in 2012, followed by the allosteric ABL myristoyl inhibitor asciminib in 2021, providing multiple options for patients (pts) who have refractory disease. In this study we examine how survival has improved in CML pts with the availability of multiple TKI’s and identify disadvantaged socioeconomic &amp; demographic groups which continue to have disparate survival. Methods: The National Cancer Database was used to identify CML pts diagnosed (dx) from 2004-2021. Demographic, treatment, &amp; overall survival (OS) were compared by era of TKI availability, with pts dx from 2004-2005 considered to be treated in the imatinib era, 2006-2011 for dasatinib &amp; nilotinib, 2012-2020 with access to bosutinib &amp; ponatinib, and 2021 for asciminib. Results: Of 44,993 CML pts identified, 55.8% were male &amp; 82.5% were White, with median age of 58 years. The portion of pts who were untreated (due to contraindication or early death) decreased by each time period, from 17.8% in the imatinib era to only 7.8% in 2021. The rate of upfront transplant decreased from 2.5% from 2004-2005, to 0.8% in 2021. For dx 2004-2005 median OS was 11.5 yrs (95% CI 10.6-12.5). This increased to 13.6 yrs (CI 13.1-14.1), with age-adjusted hazard ratio (HR) of 0.86 (CI 0.81-0.91) for pts dx 2006-2011, with median OS unreached for 2012-2020, HR 0.67 (CI 0.63-0.71, p&lt;0.001); referenced to 2004-2006. Survival at 1-, 5- &amp; 10-yrs was improved for each subsequent time period of dx, with 5-yr OS of 65%, 71%, &amp; 76%, respectively, p&lt;0.001. On multivariate cox regression adjusted for yr of dx, features associated with reduced OS included age (HR 1.06 [95% CI 1.05-1.06], p&lt;0.001 for each yr), Black race (HR 1.11 [95% CI 1.05-1.18], p&lt;0.001), increased comorbidity index (HR 1.94 [95% CI 1.84-2.04], p&lt;0.001 for index ≥2), uninsured (HR 2.20 [95% CI 2.01-2.41], p&lt;0.001), or insured through Medicaid (HR 2.40 [95% CI 2.23-2.58], p&lt;0.001). Conclusions: Survival for CML pts has significantly improved during the last 20 yrs with the availability of each additional TKI, likely related to increased treatment options for pts with resistance or intolerance. Additional TKI options, particularly approval of ponatinib for patients with T315I mutation, have a secondary benefit of decreasing the utilization of allogenic transplant. Though survival has improved for all pts, pts from traditionally underserved populations, including pts who are underinsured or from racial minority groups, have reduced OS. Continued advances in treatment &amp; efforts to improve access to care for underserved populations is vital to achieve equitable survival outcomes in CML.

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

Phytofabrication of biocompatible zinc oxide nanoparticle using Gymnema sylvestre and its potent in vitro antibacterial, antibiofilm, and cytotoxicity against human breast cancer cells (MDA-MB-231).

The increasing incidence of breast cancer and bacterial biofilm in medical devices significantly heightens global mortality and morbidity, challenging synthetic drugs. Consequently, greener-synthesized nanomaterials have emerged as a versatile alternative for various biomedical applications, offering new therapeutic avenues. This study explores the synthesis of biocompatible zinc oxide (ZnONPs) nanoparticles using Gymnema sylvestre and its antibacterial, antibiofilm, and cytotoxic properties. Characterization of ZnONPs inferred that UV-Vis spectra exhibited a sharp peak at 370nm. Fourier transform infrared spectroscopical analysis revealed the presence of active functional groups such as aldehyde, alkyne, cyclic alkene, sulfate, alkyl aryl ether, and Zn-O bonds. X-ray diffraction analysis results confirmed the crystalline nature of the nanoparticle. Scanning electron microscope analysis evidenced hexagonal morphology, and energy-dispersive X-ray analysis confirmed zinc content. High-resolution transmission electron microscope analysis showed hexagonal and rod-shaped ZnONPs with a size of 5nm. Zeta potential results affirmed the stability of nanoparticles. The ZnONPs effectively inhibited gram-positive (18-20mm) than gram-negative (12-18mm) bacterial pathogens with lower bacteriostatic and higher bactericidal values. Biofilm inhibitory property inferred ZnONPs were more effective against gram-positive (38-94%) than gram-negative bacteria (27-86%). The concentration of ZnONPs to exert 50% biofilm-inhibitory is lower against gram-positive bacteria (179.26-203.95μg/mL) than gram-negative bacteria (201.46-236.19μg/mL). Microscopic visualization inferred that at 250μg/mL, ZnONPs strongly disrupted biofilm formation, as evidenced by decreased biofilm density and altered architecture. The cytotoxicity of ZnONPs against breast cancer cells showed a dose-dependent reduction in cell viability with an IC50 value of 19.4µg/mL. AO/EB staining indicated early and late apoptotic cell death of breast cancer cells under fluorescence microscopy. The results of hemolytic activity validated the biocompatibility of the ZnONPs. Thus, the unique properties of the green-synthesized ZnONPs suggest their potential as effective drug carriers for targeted delivery in cancer therapy and the treatment of biofilm-related infections.

Musashi-2 induces cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing cluh and smyd1 mRNA

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work is funded by Ramalingaswami Re-entry Fellowship (BT/RLF/re-entry/14/2019) from the Department of Biotechnology, Government of India Background Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 are known to control RNA stability and translation with a well-characterized role in the hematopoietic system, gut and cancer. However, the functions of Musashi in the heart is not explored. Purpose Despite the expression of MSI2 in the heart, its role remains largely unknown. In our study, we endeavor to understand the cardiac function of MSI2. Methods RNA-seq analysis, adeno-associated virus (AAV), lentivirus, echocardiography, histopathology, proteomics, electron microscopy, luciferase assay, ROS measurement, TMRE red staining, seahorse assay, MSI2 pooldown, and H3K4me3 ChIP assay were used to elucidate the function of Msi2 in cardiomyocytes. Results Among the two Musashi members, the heart expresses only Msi2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 is significantly enriched in the heart cardiomyocytee fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4 and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure,and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assys, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream target of Msi2. Overexpression of Cluh and Smyd1 inhbited Msi2-induced cardiac mitochondrial dysfunction. Collectively, we show that Msi2 inducs hypertrophy, mitochondrial dysfunction, and heart failure. Conclusion We here show that Msi2 has a pro-hypertrophic function in cardiomyocytes leading to heart failure and death in mice. AAV9 mediated overexpression of Msi2 promoted degradation of Cluh and Smyd1 and thus led to mitochondrial dysfunction. Overexpression of Cluh and Smyd1 inhibits the pro-hypertrophic and mitochondrial dysfunction induced by Msi2.

Mortality Risk Among Women With Premenstrual Disorders in Sweden

Premenstrual disorders (PMDs) adversely affect the quality of life of millions of women worldwide, yet research on the long-term consequences of PMDs is limited, and the risk of mortality has not been explored. To estimate the associations of PMDs with overall and cause-specific mortality. This nationwide, population-based, matched cohort study used data from population and health registers in Sweden. Participants included women of reproductive age with a first diagnosis of PMDs between January 1, 2001, and December 31, 2018. Data analysis was performed from September 2022 to April 2023. PMDs were identified through inpatient and outpatient diagnoses and drug dispensing. Dates of death and underlying causes were ascertained from the National Cause of Death Register. Conditional Cox regression was used to estimate the hazard ratios (HRs) of overall and cause-specific death (eg, death due to natural or nonnatural cause, suicide, or cardiovascular events), adjusting for age, socioeconomic status, and somatic and psychiatric comorbidities; in a separate sibling comparison, models were also adjusted for all factors that sisters share. A total of 67 748 women with clinically diagnosed PMDs and 338 740 matched unaffected women were included, for a total of 406 488 women. Women with PMDs received a diagnosis at a mean (SD) age of 35.8 (8.2) years. During a mean (SD) follow-up of 6.2 (4.6) years (range, 1-18 years), 367 deaths were observed among women with PMDs (rate, 8.4 deaths per 10 000 person-years; 95% CI, 7.6-9.3 deaths per 10 000 person-years), and 1958 deaths were observed among women without PMDs (rate, 9.1 deaths per 10 000 person-years; 95% CI, 8.7-9.6 deaths per 10 000 person-years). Compared with unaffected women, women with PMDs had increased risk of death due to nonnatural causes (HR, 1.59; 95% CI, 1.25-2.04), particularly suicide (HR, 1.92; 95% CI, 1.43-2.60), but they did not have increased risk of overall mortality (adjusted HR, 0.91; 95% CI, 0.82-1.02). Notably, women who received a diagnosis before the age of 25 years experienced higher all-cause mortality (HR, 2.51; 95% CI, 1.42-4.42) and death from both suicide (HR, 3.84; 95% CI, 1.18-12.45) and natural causes (HR, 2.59; 95% CI, 1.21-5.54). The findings of this matched cohort study suggest that women with PMDs are not at increased risk of early death overall. However, the risk was elevated among young women and for death by suicide. This supports the importance of careful follow-up for young patients and highlights the need to develop suicide prevention strategies for all women with PMDs.

Long-term outcomes of repair in children with total anomalous pulmonary venous connection.

The clinical data of patients with total anomalous pulmonary venous connection who underwent repair in our centre in the past 13 years were reviewed. In this study, we systemically reviewed our experience in the optimal surgical strategy for patients with total anomalous pulmonary venous connection, aiming to provide evidence for clinical decision-making. From January 1, 2009, to December 31, 2021, 122 patients undergoing surgical treatment for total anomalous pulmonary venous connection in our hospital were enrolled. Among them, 18 patients with single ventricle repair were excluded from the study. Multivariate analysis was used to determine the risk factors for early and late death and the risk factors for pulmonary vein obstruction. There were 64 males and 40 females. The median age at surgery was 107 days (range, 25 days-788 days), the median weight at surgery was 4.8 kg (range, 3 kg-22 kg), and the median follow-up was 59 months (range, 0-150 months). Seven patients died early after surgery and six died late after discharge. Multivariable analysis indicated that prolonged cardiopulmonary bypass time was the only independent risk factor for early postoperative mortality. Multivariate analysis did not identify risk factors for late death. Emergency surgery, preoperative moderate and severe pulmonary hypertension, and prolonged cardiopulmonary bypass time were independent risk factors for postoperative pulmonary vein obstruction. Early and long-term late outcomes of repair in patients with total anomalous pulmonary venous connection have been encouraging. Postoperative pulmonary vein obstruction remains a major problem for specialists worldwide. Pulmonary vein obstruction should be considered in children with preoperative emergency surgery, moderate to severe pulmonary hypertension and prolonged cardiopulmonary bypass time, and regular follow-up is necessary.

Treatment outcomes of pediatrics acute myeloid leukemia (AML) and associated factors in the country’s tertiary referral hospital, Ethiopia

BackgroundPediatric Acute Myeloid Leukemia (AML) is a major cause of morbidity and mortality in children with cancer in Africa and other developing continents. Systemic chemotherapy and effective supportive care have significantly contributed to increased survival rates of pediatric AML in developed countries reaching approximately 70%. There is a paucity of contextual data regarding overall and event-free survival outcomes in children with acute myeloid leukemia in developing countries and most centers in Africa provide palliative care. The objective of this study was to assess the overall survival, event-free survival, and associated factors in pediatric AML patients treated in Ethiopia.MethodsThis retrospective study was conducted on Pediatric AML patients treated at Tikur Anbessa Hospital between January 1, 2015, and May 30, 2022. The socio-demographic profile of patients, the clinical characteristics, the biochemical and morphological subtypes of AML were analyzed using SPSS version 25. The Kaplan–Meier survival curve was used to estimate the probabilities of overall and event-free survival. Statistical significance was set at p < 0.05.ResultsA total of 92 children with AML were included in this study. The median age at diagnosis was 7 years (interquartile range: 5–10 years) with a slight male predominance. The median duration of symptoms was one month. Neutropenic fever (56, 86.2%) was the most common complication during treatment. About 29.3% of the patients succumbed to early death. The corresponding 1-year and 3-year OS probabilities were 28.2% and 23% respectively. The median event-free survival time for all pediatric AML patients was one-month (95% CI: 0.77–1.23). The determinants of poorer survival outcomes were FAB subtype, type of protocol used, and signs of CNS involvement (p < 0.05).ConclusionThe survival rates of children from AML were low in the study setting. More than 25% of AML patients succumbed to early death, and febrile neutropenia was the most common complication. Effective supportive and therapeutic measures should be taken to manage febrile neutropenia and to prevent early death in AML patients.

Prevalence of obstructive sleep apnea in whole spectrum chronic kidney disease patients: A systematic review and meta-analysis

BackgroundObstructive sleep apnea (OSA) is a common sleep disorder among chronic kidney disease (CKD) patients, associated with considerable morbidity. Various studies from around the globe have reported different prevalence rates. ObjectiveThis systematic review and meta-analysis aimed to determine the prevalence of OSA and quantify the relationship between OSA and mortality risk in patients with CKD. MethodsFour databases were systematically searched, and additional references to relevant articles were manually searched. The prevalence of OSA and the mortality risk based on random-effects models were assessed using percentages and hazard ratio (HR) with a 95 % confidence interval (95 % CI). In addition, the heterogeneity between studies was assessed using I2 statistics. ResultsA total of 44 literature (47 studies with 223,967 participants) met the eligibility criteria for the meta-analysis. The results showed that the prevalence of OSA in CKD patients was reported to be 39.3 % (95 % CI, 32.3–46.7). Among study participants in different age groups, the highest prevalence of OSA was found in CKD respondents aged 60 years or older, at 47.1 % (95 % CI 34.4–60.3). Of the eight literature (10 cohorts) that provided survival data, the pooled estimates indicated a 26.5 % (HR: 1.265; 95 % CI 1.021–1.568) higher mortality risk in subjects with OSA than CKD patients without OSA. ConclusionsThis systematic review and meta-analysis found that more than 1/3 of CKD patients have comorbid OSA, which increases the risk of early death in CKD patients. These results should help policymakers to provide adequate healthcare for this population. Prospero registration idCRD42023465497.

Proof-of-concept for an automatable mortality prediction scoring in hospitalised older adults

IntroductionIt is challenging to prognosticate hospitalised older adults. Delayed recognition of end-of-life leads to failure in delivering appropriate palliative care and increases healthcare utilisation. Most mortality prediction tools specific for older adults require additional manual input, resulting in poor uptake. By leveraging on electronic health records, we aim to create an automatable mortality prediction tool for hospitalised older adults.MethodsWe retrospectively reviewed electronic records of general medicine patients ≥75 years at a tertiary hospital between April–September 2021. Demographics, comorbidities, ICD-codes, age-adjusted Charlson Comorbidity Index (CCI), Hospital Frailty Risk Score, mortality and resource utilization were collected. We defined early deaths, late deaths and survivors as patients who died within 30 days, 1 year, and lived beyond 1 year of admission, respectively. Multivariate logistic regression analyses were adjusted for age, gender, race, frailty, and CCI. The final prediction model was created using a stepwise logistic regression.ResultsOf 1,224 patients, 168 (13.7%) died early and 370 (30.2%) died late. From adjusted multivariate regression, risk of early death was significantly associated with ≥85 years, intermediate or high frail risk, CCI &amp;gt; 6, cardiovascular risk factors, AMI and pneumonia. For late death, risk factors included ≥85 years, intermediate frail risk, CCI &amp;gt;6, delirium, diabetes, AMI and pneumonia. Our mortality prediction tool which scores 1 point each for age, pneumonia and AMI had an AUC of 0.752 for early death and 0.691 for late death.ConclusionOur mortality prediction model is a proof-of-concept demonstrating the potential for automated medical alerts to guide physicians towards personalised care for hospitalised older adults.

#2459 Matching-adjusted indirect comparison of eGFR in patients with immunoglobulin A nephropathy treated with Nefecon (TRF budesonide) or sparsentan

Abstract Background and Aims Primary immunoglobulin A nephropathy (IgAN) is an immune-mediated disease that can lead to kidney failure, need for dialysis and kidney transplantation, and early death. IgAN is the most common type of primary glomerulonephritis globally, with an estimated worldwide incidence of 2.5 per 100 000 individuals per year. Estimated glomerular filtration rate (eGFR) is a measure of renal function and is accepted as a surrogate endpoint for clinical trials evaluating kidney function deterioration. In December 2023, the US Food and Drug Administration (FDA) granted full approval to Nefecon (marketed as Tarpeyo® by Calliditas Therapeutics), a targeted-release formulation of budesonide, to reduce the loss of kidney function in adults with IgAN at risk of disease progression, based on the Phase 3 NefIgArd clinical trial. In February 2023, sparsentan (marketed as Filspari™ by Travere Therapeutics) was granted accelerated approval by the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein–creatinine ratio (UPCR) ≥1.5 g/g, based on the Phase 3 PROTECT study. Matching-adjusted indirect comparison (MAIC) is a widely accepted and relevant methodology for comparing treatments across trials in the absence of head-to-head comparisons. In this analysis, we aimed to compare the effects of Nefecon and sparsentan on kidney function deterioration in patients with IgAN, as assessed by eGFR. Method An anchored MAIC was performed to estimate the relative effect of Nefecon and sparsentan on the absolute eGFR change from baseline at 9, 12 and 24 months, with common comparators of optimized renin–angiotensin system inhibition for NefIgArd and irbesartan for PROTECT. Patient-level data from NefIgArd were used to select a population matched to PROTECT, and the following baseline characteristics were used to determine the weights: mean age (years), sex (% male), race (% white), mean eGFR (mL/min/1.73 m2), mean UPCR (g/g), urine albumin–creatinine ratio (UACR) (% with UACR &amp;gt;1.1 g/g), and urinary protein excretion (% with urinary protein excretion &amp;gt;1.8 g/day). Absolute change in eGFR was analyzed using a mixed model for repeated measures (MMRM) method, including baseline, 3-, 6-, 9-, 12-, 18- and 24-month data, baseline eGFR, baseline eGFR-by-time interaction, treatment, and treatment-by-time interaction. The MAIC weights were incorporated into the MMRM. A Bayesian fixed-effects network meta-analysis was performed on the relative effect from PROTECT and the weighted relative effect from NefIgArd, measured by the estimated absolute change from baseline in eGFR. Results The matching-adjustment of the NefIgArd patient population to the PROTECT population is shown in Table 1. The weighted NefIgArd population exhibits very similar baseline characteristics to the PROTECT population. The effective sample size of the weighted NefIgArd population is 208. Results from the anchored MAIC showed statistically and clinically significant favorable effects of Nefecon versus sparsentan on eGFR for all time points analyzed (Fig. 1). Mean differences in the absolute change in eGFR of 5.68 mL/min/1.73 m2 (95% credible interval [Crl] 3.14, 8.20; p &amp;lt; 0.001), 3.48 mL/min/1.73 m2 (95% Crl 0.97, 5.97; p = 0.006) and 3.28 mL/min/1.73 m2 (95% Crl 0.02, 6.51; p = 0.048) were observed when comparing Nefecon with sparsentan at 9 months vs 36 weeks, 12 months vs 48 weeks, and 24 months vs 106 weeks, respectively. Conclusion After accounting for differences in the patient populations from the NefIgArd and PROTECT trials, the anchored MAIC showed that treatment with Nefecon 16 mg/day for 9 months was associated with greater eGFR benefit compared with continuous treatment with sparsentan 400 mg/day over 2 years, with significant differences observed as early as 9 months after treatment initiation and sustained up to 2-years of follow-up.

A History of Teen Pregnancy Is Associated with Early Death in Women.

Adverse childhood experiences are likely risk factors.

Interleukin-41: a novel serum marker for the diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma.

For the lack of effective serum markers for hepatocellular carcinoma(HCC) diagnosis, it is difficult to detect liver cancer and identify its recurrence early. Databases were used to analyze the genes potentially associated with alpha-fetoprotein(AFP). ELISA assay was used to detect the serum IL-41 in HCC, liver metastases, hepatitis, and healthy people. Immunohistochemical staining was used to analyze the relative quantification of IL-41 in HCC and paracancer tissues. Various survival curves were plotted according to clinical pathological data and helped us draw the ROC curve of IL-41 diagnosis of HCC. The serum expression of IL-41 was highest in AFP negative HCC patients and significantly higher than that in AFP positive HCC and metastatic cancer patients. There was a significant negative correlation between elevated serum IL-41 and AFP(<1500ng/ml). The clinicopathological features suggested that the serum IL-41 level was significantly correlated with capsule invasion, low differentiation and AFP. High serum expression of IL-41 suggests poorer survival and earlier recurrence after resection, and IL-41 upregulated in patients with early recurrence and death. The expression of IL-41 was higher in HCC tissues of patients with multiple tumors or microvascular invasion. The ROC curve showed that serum IL-41 had a sensitivity of 90.17 for HCC and a sensitivity of 96.63 for AFP-negative HCC, while the specificity was higher than 61%. IL-41 in serum and tissue suggests poor prognosis and postoperative recurrence in HCC patients and could be a new serum diagnostic marker for AFP negative patients.

Epidemiological profile of congenital syphilis in the state of Mato Grosso do Sul, Brazil

Introduction: When syphilis is not treated during pregnancy, it results in a considerable proportion of early fetal and neonatal deaths, with a high probability of vertical transmission, and when this occurs, Congenital Syphilis (CS) develops. Aim: To evaluate the epidemiological profile of SC in the state of Mato Grosso do Sul, from 2012 to 2021. Design: A cross sectional, descriptive, retrospective, qualitative and quantitative study was carried out, limited to the years 2012 to 2021, with secondary data and the variables: child's age, final diagnosis, mother's age range, race, or color, having undergone prenatal care, time of diagnosis of maternal syphilis, maternal treatment regimen and deaths due to CS in children under one year of age. Results: 2,932 cases of CS were reported during the period. In the state, 88.1% of cases were in children less than 7 days old. 71.4% of mothers reported receiving prenatal care. Given the information about the mother's therapeutic regimen, 39.1% were inadequate, 28.8% did not receive treatment and in only 3.2% the treatment was adequate. Implications: The CS incidence rate in the State remained above the established national parameter, which is why it is necessary to invest more in epidemiological surveillance, as this is the first step to controlling the disease.

Distinct clinical endpoints of Staphylococcus aureus bacteraemia complicate assessment of outcome.

We aimed to test the hypothesis that development of metastatic infection represents a distinct clinical endpoint from death due to SAB. We conducted a retrospective observational study of adults with SAB between 20/12/2019 and 23/08/2022 (n=464). Simple logistic regression, odds ratios, and z-scores were used to compare host, clinical and microbiologic features. Co-occurrence of attributable mortality and metastatic infection was infrequent. Charlson Comorbidity Index and age were strongly associated with attributable mortality, but not metastatic infection. We compared patients with fatal SAB (without clinically-apparent metastatic complications, 14·4% of cohort), metastatic SAB (without attributable mortality, 22·2%), neither complication (56·7%), and overlapping fatal/metastatic SAB (6·7%). Compared to SAB without complications, fatal SAB was specifically associated with older age and multi-morbidity. Metastatic SAB was specifically associated with community acquisition, persistent fever, persistent bacteraemia, and recurrence. Endocarditis was over-represented in the fatal/metastatic SAB overlap group, which shared patient characteristics with fatal SAB. In contrast to other (predominantly musculoskeletal) metastatic complications, endocarditis was associated with increased mortality, with death occurring in older multi-morbid patients later after SAB onset. Patients with SAB experience distinct clinical endpoints: (i) early death, associated with multi-morbidity and age; (ii) metastatic (predominantly musculoskeletal) SAB; (iii) endocarditis, associated with late death occurring in older people with multi-morbidity, and (iv) bacteraemia without complications. These distinctions could be important for selecting appropriate outcomes in clinical trials: different interventions might be required to reduce mortality vs. improve clinical response in patients with metastatic SAB.

The Connection Between Anatomical Substrate and Clinical Severity in Fetal Ebstein Anomaly.

Ebstein anomaly (EA) is a rare congenital heart defect characterized by abnormal development of the tricuspid valve (TV) and right ventricular myocardium. This study documents 2 dramatic cases of fetal EA characterized by hydrops and cardiomegaly, leading to intrauterine or early neonatal death. These clinical outcomes were associated with morphological abnormalities including severe tricuspid regurgitation, unguarded TV orifice, pulmonary atresia, and flattened right ventricular myocardium. This study highlights that these adverse anatomical features may result in unfavorable clinical outcomes in fetal EA. While timely identification of such features by prenatal ultrasound is crucial for providing accurate prognostic stratification and guiding treatment decisions, fetopsy may be necessary to discern EA among the spectrum of right-heart anomalies.

Trends in Survival After First Myocardial Infarction in People With Diabetes.

The aim of this study was to investigate temporal trends in survival and subsequent cardiovascular events in a nationwide myocardial infarction population with and without diabetes. Between 2006 and 2020, we identified 2527 individuals with type 1 diabetes, 48 321 individuals with type 2 diabetes and 243 170 individuals without diabetes with first myocardial infarction in national health care registries. Outcomes were trends in all-cause death after 30 and 365 days, cardiovascular death and major adverse cardiovascular events (ie, nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and heart failure hospitalization). Pseudo-observations were used to estimate the mortality risk, with 95% CIs, using linear regression, adjusted for age and sex. Individuals with type 1 diabetes were younger (62±12.2 years) and more often women (43.6%) compared with individuals with type 2 diabetes (75±10.8 years; women, 38.1%), and individuals without diabetes (73±13.2 years; women, 38.4%). Early death decreased in people without diabetes from 23.1% to 17.5%, (annual change -0.48% [95% CI, -0.52% to -0.44%]) and in people with type 2 diabetes from 22.6% to 19.3% (annual change, -0.33% [95% CI, -0.43% to -0.24%]), with no such significant trend in people with type 1 diabetes from 23.8% to 21.7% (annual change, -0.18% [95% CI, -0.53% to 0.17%]). Similar trends were observed with regard to 1-year death, cardiovascular death, and major adverse cardiovascular events. During the past 15 years, the trend in survival and major adverse cardiovascular events in people with first myocardial infarction without diabetes and with type 2 diabetes have improved significantly. In contrast, a similar improvement was not seen in people with type 1 diabetes.

Ventilatory Assistance Before Umbilical Cord Clamping in Extremely Preterm Infants

Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants. To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death. This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth. After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs. Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort. This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight. ClinicalTrials.gov Identifier: NCT02742454.