Abstract
Background
As treatment strategies for patients with chronic heart failure (HF) become more sophisticated, identifying patients at high risk of death and predicting mode of death is ...important. The aim of this study was to explore the potential utility of heart rate turbulence (HRT) to identify patients with HF at high risk of death.
Methods and results
In a prospective study, 553 ambulant outpatients age 63 ± 10 with symptoms of HF and evidence of cardiac dysfunction were recruited. All patients underwent 24-h Holter ECG recordings, which were analysed for arrhythmias, heart rate variability and HRT a measurement that is thought to quantify cardiac autonomic regulatory mechanisms. Baseline chest radiograph, biochemistry and 12-lead electrocardiograms were also obtained. In patients with HRT measurements at 5 years follow up, 146 patients had died, 59 due to decompensated HF. Independent predictors of death from decompensated HF at 5-year follow up (Cox proportional hazard model) were HRT slope (HR for 10% increment 0.84, 95% CI 0.77-0.91), serum sodium (HR for 10% increment 0.75, 95% CI 0.62-0.91) and serum creatinine (for 10% increment HR 1.14, 95% CI 1.08-1.19) all P < 0.01. These 3 variables combined had excellent discrimination between patients dying of decompensated HF and other patients, C-statistic = 0.82.
Conclusions
In patients with mild-to-moderate HF, HRT slope is an independent predictor of death due to decompensated HF. HRT may have the potential to help tailor therapy in this patient group.
Abstract Objective To establish the associations and prognostic utility of angiographic, clinical and HRV parameters in a large cohort of patients undergoing diagnostic cardiac catheterisation (CC). ...Methods Patients undergoing CC as elective day cases were enrolled at a single tertiary center from September 2001 to January 2003. Patient data, serum biochemistry, current drug therapy, catheter reports and five minute high resolution electrocardiograph (ECG) recordings were prospectively recorded and validated in an electronic archive. ECG recordings were used to generate time domain (SDNN (standard deviation of NN intervals)) and spectral HRV parameters (low frequency (LF) and high frequency (HF) power). Significant associations between dichotomized HRV variables and covariates were investigated using binary logistic regression. The independent prognostic ability of clinical markers was evaluated using the Cox proportional hazard model. Results 841 consecutive consenting patients of mean age 61 ± 10 years were recruited into the study with a mean follow-up period of 690 ± 436 days. In multivariate analysis decreasing LF spectral power was independently associated with proximal right coronary stenosis OR (odds ratio) = 1.65 (95% CI = 1.16–2.36), P = 0.006 and to all cause mortality OR = 5.01 (95% CI = 1.47–17.01), P = 0.010. Increasing LF power was also independently associated with normal coronary angiograms in patients investigated suspected coronary disease without a confirmed prior history of a coronary ischaemic event OR = 2.16 (95% CI = 1.26–3.73), P = 0.002. Conclusions Reduced LF power independently predicts all cause mortality in a large cohort of patients receiving medical therapy after elective CC. LF power was also independently associated with > 75% proximal RCA stenosis.
Therapies for patients with chronic heart failure caused by left ventricular systolic dysfunction have advanced substantially over recent decades. The cumulative effect of these therapies on ...mortality, mode of death, symptoms, and clinical characteristics has yet to be defined.
This study was a comparison of 2 prospective cohort studies of outpatients with chronic heart failure caused by left ventricular systolic dysfunction performed between 1993 and 1995 (historic cohort: n=281) and 2006 and 2009 (contemporary cohort: n=357). In the historic cohort, 83% were prescribed angiotensin-converting enzyme inhibitors and 8.5% were prescribed β-adrenoceptor antagonists, compared with 89% and 80%, respectively, in the contemporary cohort. Mortality rates over the first year of follow-up declined from 12.5% to 7.8% between eras (P=0.04), and sudden death contributed less to contemporary mortality (33.6% versus 12.7%; P<0.001). New York Heart Association class declined between eras (P<0.001). QTc dispersion across the chest leads declined from 85 ms (SD, 2) to 34 ms (SD, 1) and left ventricular end-diastolic dimensions declined from 65 mm (SD, 0.6) to 59 mm (SD, 0.5) (both P<0.001).
Survival has significantly improved in patients with chronic heart failure caused by left ventricular systolic dysfunction over the past 15 years; furthermore, sudden death makes a much smaller contribution to mortality, and noncardiac mortality is a correspondingly greater contribution. This has been accompanied by an improvement in symptoms and some markers of adverse electric and structural left ventricular remodeling.
Antitumoral immunity requires organized, spatially nuanced interactions between components of the immune tumor microenvironment (iTME). Understanding this coordinated behavior in effective versus ...ineffective tumor control will advance immunotherapies. We re-engineered co-detection by indexing (CODEX) for paraffin-embedded tissue microarrays, enabling simultaneous profiling of 140 tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 protein markers. We identified nine conserved, distinct cellular neighborhoods (CNs)—a collection of components characteristic of the CRC iTME. Enrichment of PD-1+CD4+ T cells only within a granulocyte CN positively correlated with survival in a high-risk patient subset. Coupling of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter-CN communication was associated with inferior outcomes. This study provides a framework for interrogating how complex biological processes, such as antitumoral immunity, occur through concerted actions of cells and spatial domains.
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•FFPE-CODEX multiplexed tissue imaging of 56 markers in 140 tissues of 35 CRC patients•Cellular neighborhoods reveal spatial organization of the tumor microenvironment•Altered organization of tumor and immune components in low- versus high-risk patients•Local enrichment of PD-1+CD4+ T cells correlates with survival in high-risk patients
A multiplexed tissue imaging and computational analysis framework applied to colorectal cancer allows interrogation of how spatial organization of the immune tumor microenvironment is linked to clinical outcomes.
A range of electron-poor and heterocyclic sulfonamides react with phenylacetyl chlorides to produce benzhydryl derivatives in a single step. The reaction proceeds via tandem amide bond ...formation/Dohmori–Smiles rearrangement under the simple conditions of an aqueous base. In the case of o-nosylamides, a further reaction takes place at the nitro group to yield indazoles.
The efficacy of the paraprofessional-delivered Family Spirit home-visiting intervention for young American Indian mothers on maternal knowledge and infant behavior outcomes is supported. ...Participating mothers showed greater knowledge gains compared to non-participating mothers.
Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART).
We conducted an open-label, randomized, noninferiority trial ...comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed.
From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01).
In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).
Dolutegravir-based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised ...concerns about an association between pre-conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub-study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development.
We conducted the sub-study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir-based ART (DTG) and non-dolutegravir-based standard-of-care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24-weekly in all ODYSSEY participants. Samples analysed in the sub-study were collected between September 2016 and October 2020.
A total of 229 children aged ≥6 years were included in the sub-study with median age at trial enrolment of 12.3 (interquartile range IQR 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference DTG-SOC 1.6 ng/ml, 95% CI 0.8, 2.3; p<0.001), and this difference persisted to week ≥96 (2.7 ng/ml, 95% CI 1.7, 3.7; p<0.001). Mean RBC folate at ≥96 weeks was also higher in the DTG arm (difference 73 ng/ml, 95% CI 3, 143; p = 0.041). There was no difference in the treatment arms for vitamin B12 levels at ≥96 weeks or change in MCV through trial follow-up.
Plasma and RBC folate levels were higher in children and adolescents receiving dolutegravir-based ART than on other ART regimens. Further studies are needed to clarify the mechanisms of these interactions and the clinical implications of increased blood folate levels.
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