•Several studies have previously assessed echocardiographic parameters in CKD patients, but findings vary, and frequently cited data date back decades.•In this study of 825 patients with CKD and ...relatively low prevalence of diabetes, we found considerably lower prevalence of hypertrophy, averaging 9% and ranging from 2.4% at stage G1 and G2 (eGFR > 60 ml/min/1.73 m²) to 14.0% at stage G4 and G5 (eGFR <30 ml/min/1.73 m²). Previous studies have reported prevalence of hypertrophy in patients with CKD ranging from 23% to 74%. Prevalence of hypertrophy may vary in different CKD populations and depend on comorbidities, demographic factors, renal pathology and treatment modalities.•Patients with eGFR > 60 ml/min/1.73 m² were similar to healthy controls (n=175), but patients with lower GFR had higher LV mass, lower LVEF and more often impaired GLS.•Patients at stage G3 (eGFR 30 to 60 ml/min/1.73 m²) had lower LV volumes, but similar GLS, LVEF and prevalence of diastolic dysfunction as patients with lower eGFR.
Echocardiographic findings in chronic kidney disease (CKD) vary. We sought to estimate the prevalence of abnormal cardiac structure and function in patients with CKD and their association to estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (UACR).
We prospectively enrolled 825 outpatients with non-dialysis-dependent CKD, mean age 58± 13 yrs, and 175 matched healthy controls, mean age 60±12 yrs. Echocardiography included assessment of left ventricular (LV) hypertrophy, LV ejection fraction (LVEF), global longitudinal strain (GLS) and diastolic dysfunction according to ASE/EACVI guidelines.
LV hypertrophy was found in 9% of patients vs. 1.7% of controls (p=0.005) was independently associated with UACR (p=0.002). Median LVEF was 59.4% (IQR 55.2, 62.8) in patients vs. 60.8% (57.7, 64.1) in controls (p=0.002). GLS was decreased in patients with eGFR <60ml/min/1.73m² (-17.6%±3.1%) vs. patients with higher eGFR (19.0%±2.2%, p<0.001), who were similar to controls. Diastolic dysfunction was detected in 55% of patients and in 34% of controls.
Non-random sampling, cross-sectional analysis.
We report lower prevalence of hypertrophy than previous studies, but similar measurements of systolic and diastolic function. Cardiac remodeling in CKD may be influenced by treatment modalities, demographics, comorbidities and renal pathology.
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The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an ...adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults.BACKGROUNDThe same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults.This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732).METHODSThis randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732).Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events.FINDINGSBetween July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events.V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20.INTERPRETATIONV116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20.Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).FUNDINGMerck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).
Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin α(M) (complement component 3 ...receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.
The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.
The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88×10(-10) and OR(meta)=1.67, 95% CI 1.55 to 1.79; p=3.32×10(-46), respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10(-5)).
These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE.
Today, coastal cities worldwide are facing major changes
resulting from climate change and anthropogenic forcing, which requires
adaptation and mitigation strategies to be established. In this ...context,
sedimentological archives in many Mediterranean cities record a
multi-millennial history of environmental dynamics and human adaptation,
revealing a long-lasting resilience. Founded by the Phoenicians around 3000 years ago, Cádiz (south-western Spain) is a key example of a coastal
resilient city. This urban centre is considered to be one of the first
cities of western Europe and has experienced major natural hazards during its
long history, such as coastal erosion, storms, and also tsunamis (like the
one in 1755 CE following the destructive Lisbon earthquake). In the framework of an international, joint archaeological and
geoarchaeological project, three cores have been drilled in a marine
palaeochannel that ran through the ancient city of Cádiz. These
cores reveal a ≥50 m thick Holocene sedimentary sequence. Importantly,
most of the deposits date from the 1st millennium BCE to the 1st
millennium CE. This exceptional sedimentary archive will allow our
scientific team to achieve its research goals, which are (1) to reconstruct
the palaeogeographical evolution of this specific coastal area; (2) to trace
the intensity of activities of the city of Cádiz based on archaeological
data, as well as geochemical and palaeoecological indicators; and (3) to
identify and date high-energy event deposits such as storms and tsunamis.
•The NCCN recommends first-line re-challenge for relapsed SCLC with CTFI ≥ 180 days.•This recommendation is based on data from small trials from the 1980s.•Lurbinectedin has remarkable activity and ...acceptable safety in second-line SCLC.•ORR was 60.0 % in a preplanned subset of patients with CTFI ≥ 180 days.•Lurbinectedin can be a valuable alternative to re-treatment with first-line therapy.
The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days.
Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1.
ORR was 60.0 % (95 %CI, 36.1−86.9), with a median duration of response of 5.5 months (95 %CI, 2.9−11.2) and disease control rate of 95.0 % (95 %CI, 75.1−99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6−7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported.
Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge.
To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other ...independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).
We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc.
IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10(-3), OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10(-4), OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF- (p=0.025, OR=1.26, 95% CI 1.03 to 1.55).
Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.
Lateral mass screws are routinely placed throughout the subaxial cervical spine in adults, but there are few clinical or radiographic studies regarding lateral mass fixation in children. The ...morphology of pediatric cervical lateral masses may be associated with greater difficulty in obtaining adequate purchase. The authors examined the lateral masses of the subaxial cervical spine in pediatric patients to define morphometric differences compared with adults, establish guidelines for lateral mass instrumentation in children, and define potential limitations of this technique in the pediatric age group.
Morphometric analysis was performed on CT of the lateral masses of C3-7 in 56 boys and 14 girls. Measurements were obtained in the axial, coronal, and sagittal planes.
For most levels and measurements, results in boys and girls did not differ significantly; the few values that were significantly different are not likely to be clinically significant. On the other hand, younger (< 8 years of age) and older children (≥ 8 years of age) differed significantly at every level and measurement except for facet angularity. Sagittal diagonal, a measurement that closely estimates screw length, was found to increase at each successive caudal level from C-3 to C-7, similar to the adult population. A screw acceptance analysis found that all patients ≥ 4 years of age could accept at least a 3.5 × 10 mm lateral mass screw.
Lateral mass screw fixation is feasible in the pediatric cervical spine, particularly in children age 4 years old or older. Lateral mass screw fixation is feasible even at the C-7 level, where pedicle screw placement has been advised in lieu of lateral mass screws because of the small size and steep trajectory of the C-7 lateral mass. Nonetheless, all pediatric patients should undergo high-resolution, thin-slice CT preoperatively to assess suitability for lateral mass screw fixation.
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