Aims
To determine the effect of exercise training on clinical events and health‐related quality of life (HRQoL) of patients with systolic heart failure.
Methods and results
We searched electronic ...databases including Medline, EMBASE, and Cochrane Library up to January 2008 to identify randomized controlled trials (RCTs) comparing exercise training and usual care with a minimum follow‐up of 6 months. Nineteen RCTs were included with a total of 3647 patients, the majority of whom were male, low‐to‐medium risk, and New York Heart Association class II–III with a left ventricular ejection fraction of <40%. There was no significant difference between exercise and control in short‐term (≤12 months) or longer‐term all‐cause mortality or overall hospital admissions. Heart failure‐related hospitalizations were lower relative risk: 0.72, 95% confidence interval (CI): 0.52–0.99 and HRQoL improved (standardized mean difference: −0.63, 95% CI: −0.80 to −0.37) with exercise therapy. Any effect of cardiac exercise training on total mortality and HRQoL was independent of degree of left ventricular dysfunction, type of cardiac rehabilitation, dose of exercise intervention, length of follow‐up, trial quality, and trial publication date.
Conclusion
Compared with usual care, in selected heart failure patients, exercise training reduces heart failure‐related hospitalizations and results in clinically important improvements in HRQoL. High‐quality RCT and cost‐effectiveness evidence is needed for the effect of exercise training in community‐based settings and in more severe heart failure patients, elderly people, and women.
Abstract
Aims
Pluripotent stem cell-derived endothelial cell products possess therapeutic potential in ischaemic vascular disease. However, the factors that drive endothelial differentiation from ...pluripotency and cellular specification are largely unknown. The aims of this study were to use single-cell RNA sequencing (scRNA-seq) to map the transcriptional landscape and cellular dynamics of directed differentiation of human embryonic stem cell-derived endothelial cells (hESC-EC) and to compare these cells to mature endothelial cells from diverse vascular beds.
Methods and results
A highly efficient directed 8-day differentiation protocol was used to generate a hESC-derived endothelial cell product (hESC-ECP), in which 66% of cells co-expressed CD31 and CD144. We observed largely homogeneous hESC and mesodermal populations at Days 0 and 4, respectively, followed by a rapid emergence of distinct endothelial and mesenchymal populations. Pseudotime trajectory identified transcriptional signatures of endothelial commitment and maturation during the differentiation process. Concordance in transcriptional signatures was verified by scRNA-seq analysis using both a second hESC line RC11, and an alternative hESC-EC differentiation protocol. In total, 105 727 cells were subjected to scRNA-seq analysis. Global transcriptional comparison revealed a transcriptional architecture of hESC-EC that differs from freshly isolated and cultured human endothelial cells and from organ-specific endothelial cells.
Conclusion
A transcriptional bifurcation into endothelial and mesenchymal lineages was identified, as well as novel transcriptional signatures underpinning commitment and maturation. The transcriptional architecture of hESC-ECP was distinct from mature and foetal human EC.
To determine whether vitrectomy surgery rates have changed over the past decade and factors affecting the odds of undergoing this procedure.
Retrospective, longitudinal cohort study.
All enrollees 21 ...years of age or older between 2001 and 2012 in a United States managed care network.
Claims data from a managed care network were analyzed to identify all enrollees who underwent 1 vitrectomy or more each year from 2001 through 2012. Rates of vitrectomy per 1000 enrollees were computed each year from 2001 through 2012 for the entire group and separately for patients with and without diabetes mellitus. Multivariate logistic regression assessed factors affecting the odds of undergoing vitrectomy surgery.
Annual rates of vitrectomy surgery from 2001 through 2012 and odds ratios (ORs) of undergoing a vitrectomy with 95% confidence intervals (CIs).
Among the 11 161 907 eligible enrollees, 40 892 (0.4%) underwent vitrectomy over the 12-year period. The average age of those undergoing vitrectomy was 57±13 years. Overall vitrectomy rates increased 31% from 2001 to 2012 (from 1.47 to 1.92 per 1000 patients). During this same period, the vitrectomy rate among persons with diabetes mellitus decreased by 43% (from 5.84 to 3.31 per 1000 patients with diabetes). Women had 24% decreased odds of undergoing vitrectomy (adjusted odds ratio OR, 0.76; 95% confidence interval CI, 0.72-0.79). The odds of undergoing a vitrectomy were 17% greater for black persons (adjusted OR, 1.17; 95% CI, 1.07-1.27) and 7% higher for persons with diabetes (adjusted OR, 1.07; 95% CI, 1.01-1.14).
Overall, we observed an increase in the vitrectomy rates per 1000 enrollees in this large managed care network over the course of the past decade. However, among persons with diabetes mellitus, vitrectomy rates declined substantially over this period. These changes may be explained, in part, by advances in surgical instrumentation and imaging methods to detect retinal diseases changing indications for surgery, improvements in diabetes care, and alternative treatment options for managing retinal conditions. These results may be useful for future planning of manpower needs and highlight the need for aggressive prevention of complications in black persons with diabetes.
ABSTRACT
Purpose
To classify the crystallization behavior of amorphous active pharmaceutical ingredients (API) exposed to aqueous environments.
Methods
A set of approximately 50 chemically and ...physically diverse active pharmaceutical ingredients (APIs) was selected for this study. Two experimental setups were employed to characterize the crystallization behavior of the amorphous API in an aqueous environment. For the first approach, precipitation, as evidenced by the development of turbidity, was induced using the solvent shift method, by mixing concentrated API solutions in DMSO with an aqueous buffer in a capillary. Subsequently, crystallization was monitored
in situ
over time using synchrotron radiation (simultaneous SAXS/WAXS beamline 12-ID-B at the Advanced Photon Source, Argonne National Laboratories, Argonne, IL). In the second approach, amorphous films were prepared by melt quenching; after adding buffer, crystallization was monitored with time using polarized light microscopy.
Results
In general, the crystallization behavior of a given compound was similar irrespective of the experimental method employed. However, the crystallization behavior among different compounds varied significantly, ranging from immediate and complete crystallization to no observable crystallization over biorelevant time scales. Comparison of the observed behavior with previous studies of crystallization tendency in non-aqueous environments revealed that the crystallization tendency of individual APIs was somewhat similar regardless of the crystallization environment.
Conclusions
API properties, rather than the method by which amorphous materials are generated, tend to dictate crystallization behavior in aqueous media.
To assess potential future impacts on shallow aquifers by leakage of natural gas from unconventional energy resource development it is essential to establish a reliable baseline. Occurrence of ...methane in shallow groundwater in Alberta between 2006 and 2014 was assessed and was ubiquitous in 186 sampled monitoring wells. Free and dissolved gas sampling and measurement approaches yielded comparable results with low methane concentrations in shallow groundwater, but in 28 samples from 21 wells methane exceeded 10mg/L in dissolved gas and 300,000ppmv in free gas. Methane concentrations in free and dissolved gas samples were found to increase with well depth and were especially elevated in groundwater obtained from aquifers containing coal seams and shale units. Carbon isotope ratios of methane averaged −69.7±11.1‰ (n=63) in free gas and −65.6±8.9‰ (n=26) in dissolved gas. δ13C values were not found to vary with well depth or lithology indicating that methane in Alberta groundwater was derived from a similar source. The low δ13C values in concert with average δ2HCH4 values of −289±44‰ (n=45) suggest that most methane was of biogenic origin predominantly generated via CO2 reduction. This interpretation is confirmed by dryness parameters typically >500 due to only small amounts of ethane and a lack of propane in most samples. Comparison with mud gas profile carbon isotope data revealed that methane in the investigated shallow groundwater in Alberta is isotopically similar to hydrocarbon gases found in 100–250meter depths in the WCSB and is currently not sourced from thermogenic hydrocarbon occurrences in deeper portions of the basin. The chemical and isotopic data for methane gas samples obtained from Alberta groundwater provide an excellent baseline against which potential future impact of deeper stray gases on shallow aquifers can be assessed.
Display omitted
•Analysis of gas geochemical data from 186 monitoring wells in Alberta revealed that methane is ubiquitous;•Methane concentrations increased with depth and were elevated in aquifers containing coals and shales;•A multi-isotope approach revealed that methane is of biogenic origin formed predominantly via CO2 reduction;•Comparison of free and dissolved gas sampling approaches for baseline groundwater monitoring yielded similar results;
The opioid crisis has adversely affected West Virginia's pregnant and infant populations. With high rates of opioid use disorder and neonatal abstinence syndrome, West Virginia has the highest rates ...of Hepatitis C (HCV) acute infection among pregnant women. To better understand how HCV impacts an already high‐risk population, the study purpose was to (1) describe its prevalence among women receiving prenatal care at a single tertiary care clinic in Appalachia and compare with state and national rates, and (2) determine whether it is associated with preterm birth (gestation <37 weeks). Data were collected on a retrospective cohort of pregnant patients universally screened for HCV between 2017 and 2021. The study cohort had an HCV infection rate of 119/988 = 11.94% or 119.4 per 1000. This is five times the rate of 22.6 per 1000 live births in West Virginia in 2014 and 35 times the national rate of 3.4 per 1000 live births (MMWR Morb Mortal Wkly Rep 66, 2017 and 470). Viral loads were detected in 63 (6.38%) of patients. The study cohort with birth outcome data had high rates of tobacco use (326/720; 45.3%) and substance abuse (209/720; 29.0%). The preterm birth rate was 17.8% (128/720), almost double the national average (10.09%) (Natl Vital Stat Rep 70, 2021 and 1). There was no statistically significant difference in preterm birth between HCV‐positive (15/92; 16.3%) and HCV‐negative (113/628; 18.0%) patients. HCV infection in our population presents a significant public health issue and missed opportunity for treatment in a population with continuity of care challenges. These findings could be used to justify a pilot program for early postpartum referral for treatment.
Rare cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported after AZD1222. Anti-platelet factor-4 (PF4) antibodies were observed in patients following presentation of TTS, ...however it is unclear if AZD1222 was responsible for inducing production of anti-PF4. Paired samples (baseline and day-15) from a phase 3 trial of AZD1222 vs placebo were analyzed for anti-PF4 levels; 19/1727 (1.1%, AZD1222) vs 7/857 (0.8%, placebo) participants were anti-PF4-IgG-negative at baseline but had moderate Day-15 levels (P = 0.676) and 0/35 and 1/20 (5.0%) had moderate levels at baseline but high Day-15 levels. These data indicate that AZD1222 does not induce a clinically relevant general increase in anti-PF4 IgG.
Introduction
The impact of neoadjuvant therapy on postpancreatectomy complications is inadequately described.
Methods
Data from the NSQIP Pancreatectomy Demonstration Project (11/2011 to 12/2012) was ...used to identify patients with pancreatic adenocarcinoma who did and did not receive neoadjuvant therapy. Neoadjuvant therapy was classified as chemotherapy alone or radiation ± chemotherapy. Outcomes in the neoadjuvant vs. surgery first groups were compared.
Results
Of 1,562 patients identified at 43 hospitals, 199 (12.7 %) received neoadjuvant therapy (99 chemotherapy alone and 100 radiation ± chemotherapy). Preoperative biliary stenting (57.9 vs. 44.7 %,
p
= 0.0005), vascular resection (41.5 vs. 17.3 %,
p
< 0.0001), and open resections (94.0 vs. 91.4 %,
p
= 0.008) were more common in the neoadjuvant group. Thirty-day mortality (2.0 vs. 1.5 %,
p
= 0.56) and postoperative morbidity rates (56.3 vs. 52.8 %,
p
= 0.35) were similar between groups. Neoadjuvant therapy patients had fewer organ space infections (3.0 vs. 10.3 %,
p
= 0.001), and neoadjuvant radiation patients had fewer pancreatic fistulas (7.3 vs. 15.4 %,
p
= 0.03).
Conclusions
Despite evidence for more extensive disease, patients receiving neoadjuvant therapy did not experience more complications. Neoadjuvant radiation was associated with lower pancreatic fistula rates. These data provide evidence against higher postoperative complication rates in patients with pancreatic cancer who are treated with neoadjuvant therapy.
Cystic fibrosis (CF) is a life-shortening, multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction and exaggerated inflammatory ...responses that contribute to tissue injury. To define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum.
To define the transcriptional profile of sputum cells and its implication in the pathogenesis of immune function and the development of CF lung disease.
We performed single-cell RNA sequencing of sputum cells from nine subjects with CF and five healthy control subjects. We applied novel computational approaches to define expression-based cell function and maturity profiles, herein called transcriptional archetypes.
The airway immune cell repertoire shifted from alveolar macrophages in healthy control subjects to a predominance of recruited monocytes and neutrophils in CF. Recruited lung mononuclear phagocytes were abundant in CF and were separated into the following three archetypes: activated monocytes, monocyte-derived macrophages, and heat shock-activated monocytes. Neutrophils were the most prevalent in CF, with a dominant immature proinflammatory archetype. Although CF monocytes exhibited proinflammatory features, both monocytes and neutrophils showed transcriptional evidence of abnormal phagocytic and cell-survival programs.
Our findings offer an opportunity to understand subject-specific immune dysfunction and its contribution to divergent clinical courses in CF. As we progress toward personalized applications of therapeutic and genomic developments, we hope this inflammation-profiling approach will enable further discoveries that change the natural history of CF lung disease.
Objective To determine whether a difference in systolic blood pressure readings between arms can predict a reduced event free survival after 10 years.Design Cohort study.Setting Rural general ...practice in Devon, United Kingdom.Participants 230 people receiving treatment for hypertension in primary care.Intervention Bilateral blood pressure measurements recorded at three successive surgery attendances.Main outcome measures Cardiovascular events and deaths from all causes during a median follow-up of 9.8 years.Results At recruitment 24% (55/230) of participants had a mean interarm difference in systolic blood pressure of 10 mm Hg or more and 9% (21/230) of 15 mm Hg or more; these differences were associated with an increased risk of all cause mortality (adjusted hazard ratio 3.6, 95% confidence interval 2.0 to 6.5 and 3.1, 1.6 to 6.0, respectively). The risk of death was also increased in 183 participants without pre-existing cardiovascular disease with an interarm difference in systolic blood pressure of 10 mm Hg or more or 15 mm Hg or more (2.6, 1.4 to 4.8 and 2.7, 1.3 to 5.4). An interarm difference in diastolic blood pressure of 10 mm Hg or more was weakly associated with an increased risk of cardiovascular events or death.Conclusions Differences in systolic blood pressure between arms can predict an increased risk of cardiovascular events and all cause mortality over 10 years in people with hypertension. This difference could be a valuable indicator of increased cardiovascular risk. Bilateral blood pressure measurements should become a routine part of cardiovascular assessment in primary care.
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