The interaction of sex,height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individual‐patient data meta‐analysis

Aims

To explore possible associations that may explain the greater benefit from cardiac resynchronization therapy (CRT) reported amongst women.

Methods and results

In an individual‐patient data meta‐analysis of five randomized controlled trials, all‐cause mortality and the composite of all‐cause mortality or first hospitalization for heart failure (HF) were compared among 794 women and 2702 men assigned to CRT or a control group. Multivariable analyses were performed to assess the impact of sex, QRS duration, HF aetiology, left ventricular end‐diastolic diameter (LVEDD), and height on outcome. Women were shorter, had smaller LVEDD, more often left bundle branch block, and less often ischaemic heart disease, but QRS duration was similar between sexes. Women tended to obtain greater benefit from CRT but sex was not an independent predictor of either outcome. For all‐cause mortality, QRS duration was the only independent predictor of CRT benefit. For the composite outcome, height and QRS duration, but not sex, were independent predictors of CRT benefit. Further analysis suggested increasing benefit with increasing QRS duration amongst shorter patients, of whom a great proportion were women.

Conclusions

In this individual‐patient data meta‐analysis, CRT benefit was greater in shorter patients, which may explain reports of enhanced CRT benefit among women. Further analyses are required to determine whether recommendations on the QRS threshold for CRT should be adjusted for height. ( ClinicalTrials.gov numbers: NCT00170300, NCT00271154, NCT00251251).

     

Association of the -159 C --> T polymorphism in the CD14 promoter with variations in serum lipoproteins in healthy subjects.

The CD14-159 C --> T polymorphism, a single nucleotide polymorphism (SNP) at position -159 in the promoter region of the gene encoding the pattern recognition receptor CD14, has been associated with elevated plasma concentrations of soluble CD14, lowered serum immunoglobulin E, increased risk for myocardial infarction, and decreased risk for allergy and asthma. In the present study, the CD14-159 C --> T polymorphism has been investigated in order to determine its frequency and association with proinflammatory variables and lipid profile traits of 117 volunteers. The frequency of the CD14 promoter genotype as determined by polymerase chain reaction amplification-restriction fragment length polymorphism analysis was 35.0% (CC), 44.4% (CT), and 20.5% (TT), and the T allele frequency was 42.7%. Compared with the other genotypes, notably CC homozygotes, TT homozygotes were associated with lower total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B-100 (P < 0.01) concentrations in serum. However, no association was found between the investigated SNP and inflammatory mediators such as fibrinogen, interleukin-6, tumor necrosis factor-alpha, tissue factor, C-reactive protein, plasminogen activator inhibitor-1, leukotriene B4, or thromboxane B2. In conclusion, the CD14-159 C --> T polymorphism may be an important genetic trait, related to the ability of CD14 to bind and transport lipids, such as cholesterol.     

Imatinib mesylate in idiopathic and postpolycythemic myelofibrosis

Imatinib mesylate targets the adenosine triphosphate (ATP)-binding sites of the protein tyrosine kinase domains associated with Bcr-abl, the platelet-derived growth factor (PDGF) and c-kit. In idiopathic myelofibrosis (IMF) PDGF is considered to be one of the growth factors responsible for the development of bone marrow fibrosis. Recently, it has been shown that imatinib has antifibrogenic effect on bone marrow fibrosis in chronic myelogenous leukemia. Treatment with imatinib alone in IMF has been associated with significant side effects. In this study, the safety and efficacy of imatinib therapy in IMF, either administered as a single agent or in combination with hydroxyurea (HU) and/or alpha-interferon (IFN-alpha) are evaluated. Eleven patients (median age, 63 years; range, 33-82 years) with IMF (n = 8) or postpolycythemic myelofibrosis (PPMF) (n = 3) were studied All patients had been treated with HU (n = 9) and/or IFN (n = 7) before study entry. In all but one patient, treatment with these agents was discontinued when imatinib therapy was instituted. One patient continued IFN when treatment with imatinib was started. Imatinib was given at a dose of 400 mg/day. Nine patients were in an advanced disease phase. The patients have been followed for a median period of 2 months (range, 0.5-12 months). Treatment with imatinib has been stopped in six patients (55%), because of overt side effects (n = 4), recurrence of transitory dizziness and visual defects owing to a rising platelet count (n = 1), or the occurrence of an acute subdural hemorrhage that was evacuated without neurological deficits (n = 1). In nine patients imatinib treatment was followed by a rise in leukocyte and platelet counts that required combination with HU or IFN. The combined treatment modalities were followed by a rapid decrease in cell counts and were well tolerated apart from IFN side effects. A beneficial effect of imatinib was documented in three patients. It is concluded that leukocytosis and thrombocytosis are seen in most patients with myelofibrosis during treatment with imatinib. Combination therapy with HU or IFN seems safe and well tolerated and followed by a decrease in disease activity. A subgroup of patients in an early disease phase might benefit from imatinib therapy alone.     

Left atrial far-field sensing by left ventricular leads: a potential hazard in cardiac resynchronisation therapy.

BACKGROUND: Cardiac resynchronisation therapy (CRT) requires a lead advanced through the coronary sinus (CS) to pace the left ventricle (LV). Left atrial far-field signals (LAFFS) may be sensed by the LV lead at the time of implant or after lead dislodgement, and may inhibit ventricular pacing. OBJECTIVE: To assess the incidence of detection of LAFFS > 2 mV and its correlation with the CS lead position. METHODS: Data from the first 75 consecutive patients enrolled in the InSync III multicentre study were analysed. The position of the LV lead was recorded at implant. During follow-up, pacing was temporarily inhibited and the LV channel electrogram was recorded. The amplitude of LAFFS observed before discharge from the hospital and at 1 month of follow-up was retrospectively analysed. A LAFFS > 2 mV was considered clinically significant. RESULTS: CRT systems were successfully implanted in 71 of 75 patients. A LAFFS > 2 mV was recorded by the LV lead channel in six of 71 patients (8.5%). This phenomenon developed between hospital discharge and 1 month of follow-up in two of these patients and in one case disappeared within 1 month. It was observed in all CS tributaries except the anterior and mid-cardiac veins. CONCLUSIONS: Left atrial far-field signals sensed by the LV lead were not rare. Implanting physicians should be aware of this phenomenon in order to prevent potentially serious complications.     

Nordic OCD & Related Disorders Consortium: Rationale,design, and methods

Obsessive‐compulsive disorder (OCD) is a debilitating psychiatric disorder, yet its etiology is unknown and treatment outcomes could be improved if biological targets could be identified. Unfortunately, genetic findings for OCD are lagging behind other psychiatric disorders. Thus, there is a pressing need to understand the causal mechanisms implicated in OCD in order to improve clinical outcomes and to reduce morbidity and societal costs. Specifically, there is a need for a large‐scale, etiologically informative genetic study integrating genetic and environmental factors that presumably interact to cause the condition. The Nordic countries provide fertile ground for such a study, given their detailed population registers, national healthcare systems and active specialist clinics for OCD. We thus formed the Nordic OCD and Related Disorders Consortium (NORDiC, www.crowleylab.org/nordic ), and with the support of NIMH and the Swedish Research Council, have begun to collect a large, richly phenotyped and genotyped sample of OCD cases. Our specific aims are geared toward answering a number of key questions regarding the biology, etiology, and treatment of OCD. This article describes and discusses the rationale, design, and methodology of NORDiC, including details on clinical measures and planned genomic analyses.     

Clinical value of CD133 and nestin in patients with glioma: a population-based study

Cancer stem cell-related (CSC) markers have been suggested to have promising potentials as novel types of prognostic and predictive markers in gliomas. However no single CSC-related marker is currently used in clinical decisions. The aim of this study was to investigate the prognostic value of CD133 and nestin separately and in combination using a novel quantitative approach in a well-characterized population-based cohort of glioma patients. The expression of CD133 and nestin was measured by systematic random sampling in stained paraffin sections from 239 glioma patients diagnosed between 2005 and 2009. We found that the expression of CD133 did not correlate with WHO grade, and there was no association with overall survival (OS). The level of nestin correlated positively with WHO grade. In patients with WHO grade II tumors, a high level of nestin was associated with short progression-free survival (PFS) in multivariate analysis. High levels of co-localization were associated with poor PFS in patients with WHO grade II tumors, but not with OS. We conclude that CD133 was not an independent prognostic factor, but a high level of nestin was associated with poor PFS in patients with WHO grade II tumors. The combination of double-immunofluorescence and automated analysis seems to be a feasible and reproducible approach for investigation of the prognostic potential of biomarkers.     

Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma

Tumors could escape an immune attack by inducing peripheral T cell tolerance. To test this, T cell receptor (TCR)-transgenic mice were injected with plasmacytoma cells secreting a highly tumor-specific antigen, a monoclonal immunglobulin (Ig), for which the transgene-encoded TCR is specific. The TCR recognizes a third hypervariable region idiotypic (Id) peptide of the Ig, presented by a class II molecule on host antigen-presenting cells. The TCR-transgenic mice have previously been shown to be protected against an Id⁺ plasmacytoma challenge. In the present experiments, the protection was deliberately overwhelmed by subcutaneous injection of large numbers of plasmacytoma cells. Such tumor mice, chronically exposed to increasing amounts of monoclonal Ig, delete Id-specific CD4⁺ T cells in their peripheral lymphoid organs and in the tumor. The residual CD4⁺ cells express endogenous, rather than transgene-encoded TCR α chains. Peripheral deletion, functional T cell unresponsiveness, and thymocyte deletion are all first detected at the same serum concentration of monoclonal Ig, ∼50 μg/ml (0.3 μM), and become more and more profound as the tumor burden increases. The results suggest that peripheral T cell tolerance to Id could be a tumor escape mechanism in patients with B cell malignancies. In addition, the findings have implications for T cell tolerance to Ig V regions in normal individuals.     

Combining H-Adaptivity with the Element Splitting Method for Crack Simulation in Large Structures

H-adaptivity is an effective tool to introduce local mesh refinement in the FEM-based numerical simulation of crack propagation. The implementation of h-adaptivity could benefit the numerical simulation of fatigue or accidental load scenarios involving large structures, such as ship hulls. Meanwhile, in engineering applications, the element deletion method is frequently used to represent cracks. However, the element deletion method has some drawbacks, such as strong mesh dependency and loss of mass or energy. In order to mitigate this problem, the element splitting method could be applied. In this study, a numerical method called ‘h-adaptive element splitting’ (h-AES) is introduced. The h-AES method is applied in FEM programs by combining h-adaptivity with the element splitting method. Two examples using the h-AES method to simulate cracks in large structures under linear-elastic fracture mechanics scenario are presented. The numerical results are verified against analytical solutions. Based on the examples, the h-AES method is proven to be able to introduce mesh refinement in large-scale numerical models that mostly consist of structured coarse meshes, which is also beneficial to the reduction of computational resources. By employing the h-AES method, very small cracks are well represented in large structures without any deletions of elements.     

The global prevalence of headache: an update,with analysis of the influences of methodological factors on prevalence estimates

BackgroundAccording to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimates.Our first aim was to update the documentation of headache epidemiological studies, summarizing global prevalence estimates for all headache, migraine, tension-type headache (TTH) and headache on ≥15 days/month (H15+), comparing these with GBD estimates and exploring time trends and geographical variations. Our second aim was to analyse how methodological factors influenced prevalence estimates.MethodsIn a narrative review, all prevalence studies published until 2020, excluding those of clinic populations, were identified through a literature search. Prevalence data were extracted, along with those related to methodology, world region and publication year. Bivariate analyses (correlations or comparisons of means) and multiple linear regression (MLR) analyses were performed.ResultsFrom 357 publications, the vast majority from high-income countries, the estimated global prevalence of active headache disorder was 52.0% (95%CI 48.9–55.4), of migraine 14.0% (12.9–15.2), of TTH 26.0% (22.7–29.5) and of H15+ 4.6% (3.9–5.5). These estimates were comparable with those of migraine and TTH in GBD2019, the most recent iteration, but higher for headache overall. Each day, 15.8% of the world’s population had headache. MLR analyses explained less than 30% of the variation. Methodological factors contributing to variation, were publication year, sample size, inclusion of probable diagnoses, sub-population sampling (e.g., of health-care personnel), sampling method (random or not), screening question (neutral, or qualified in severity or presumed cause) and scope of enquiry (headache disorders only or multiple other conditions). With these taken into account, migraine prevalence estimates increased over the years, while estimates for all headache types varied between world regions.ConclusionThe review confirms GBD in finding that headache disorders remain highly prevalent worldwide, and it identifies methodological factors explaining some of the large variation between study findings. These variations render uncertain both the increase in migraine prevalence estimates over time, and the geographical differences. More and better studies are needed in low- and middle-income countries.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01402-2.