nils-herrmann/clean_scirepeval huggingface dataset:
Exercise pressor reflex in humans with end-stage renal disease.

Previous work has suggested that end-stage renal disease (ESRD) patients may have an exaggerated sympathetic nervous system (SNS) response during exercise. We hypothesized that ESRD patients have an exaggerated blood pressure (BP) response during moderate static handgrip exercise (SHG 30%) and that the exaggerated BP response is mediated by SNS overactivation, characterized by augmented mechanoreceptor activation and blunted metaboreceptor control, as has been described in other chronic diseases. We measured hemodynamics and muscle sympathetic nerve activity (MSNA) in 13 ESRD and 16 controls during: 1) passive hand movement (PHM; mechanoreceptor isolation); 2) low-level rhythmic handgrip exercise (RHG 20%; central command and mechanoreceptor activation); 3) SHG 30%, followed by posthandgrip circulatory arrest (PHGCA; metaboreceptor activation); and 4) cold pressor test (CPT; nonexercise stimulus). ESRD patients had exaggerated increases in systolic BP during SHG 30%; however, the absolute and relative increase in MSNA was not augmented, excluding SNS overactivation as the cause of the exaggerated BP response. Increase in MSNA was not exaggerated during RHG 20% and PHM, demonstrating that mechanoreceptor activation is not heightened in ESRD. During PHGCA, MSNA remained elevated in controls but decreased rapidly to baseline levels in ESRD, indicative of markedly blunted metaboreceptor control of MSNA. MSNA response to CPT was virtually identical in ESRD and controls, excluding a generalized sympathetic hyporeactivity in ESRD. In conclusion, ESRD patients have an exaggerated increase in SBP during SHG 30% that is not mediated by overactivation of the SNS directed to muscle. SBP responses were also exaggerated during mechanoreceptor activation and metaboreceptor activation, but without concomitant augmentation in MSNA responses. Metaboreceptor control of MSNA was blunted in ESRD, but the overall ability to mount a SNS response was not impaired. Other mechanisms besides SNS overactivation, such as impaired vasodilatation, should be explored to explain the exaggerated exercise pressor reflex in ESRD.
DO IT Trial: vitamin D Outcomes and Interventions in Toddlers – a TARGet Kids! randomized controlled trial

Vitamin D levels are alarmingly low (<75 nmol/L) in 65-70% of North American children older than 1 year. An increased risk of viral upper respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of 'high dose' (2000 IU/day) vs. 'standard dose' (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of 'high dose' vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI.



This study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1-5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the 'standard dose' or 'high dose' oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups.



Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers.
The at-risk registers in severe asthma (ARRISA) study: a cluster-randomised controlled trial examining effectiveness and costs in primary care.

Patients at risk of severe exacerbations contribute disproportionally to asthma mortality, morbidity and costs. We evaluated the effectiveness and costs of using 'asthma risk registers' for these patients in primary care.



In a cluster-randomised trial, 29 primary care practices identified 911 at-risk asthma patients using British asthma guideline criteria (severe asthma plus adverse psychosocial characteristics). Intervention practices added electronic alerts to identified patients' records to flag their at-risk status and received practice-based training about using the alerts to improve patient access and opportunistic management. Control practices continued routine care. Numbers of patients experiencing the primary outcome of a moderate-severe exacerbation (resulting in death, hospitalisation, accident and emergency attendance, out-of-hours contact, or a course/boost in oral prednisolone for asthma), other healthcare and medication usage, and costs over 1 year were derived from practice-based records.



There was no significant effect on exacerbations (control: 46.5%; intervention: 53.6%, OR, 95% CI 1.30, 0.93 to 1.80). However, this composite outcome masked relative reductions in intervention patients experiencing hospitalisations (OR 0.50, 95% CI 0.26 to 0.94), accident and emergency (OR 0.74, 95% CI 0.42 to 1.31) and out-of-hours contacts (OR 0.79, 95% CI 0.45 to 1.37); and a relative increase in prednisolone prescription for exacerbations (OR 1.31, 95% CI 0.92 to 1.85). Furthermore, prescription of nebulised short-acting β-agonists reduced and long-acting β-agonists increased for intervention relative to control patients. The adjusted mean per patient healthcare cost was £138.21 lower (p=0.837) among intervention practices.



Using asthma risk registers in primary care did not reduce treated exacerbations, but reduced hospitalisations and increased prescriptions of recommended preventative therapies without increasing costs.
Recent patterns of sex-specific midlife stroke hospitalization rates in the United States.

Little is known about sex-specific stroke hospitalization rates among middle-aged individuals. This study assessed recent temporal trends in stroke hospitalizations among persons aged 35 to 64 years in the United States.



The Nationwide Inpatient Sample was used to identify individuals with a primary or secondary discharge diagnosis of stroke between 1997 and 2006 (n=3,161,752). Age-adjusted sex-specific rates of ischemic and hemorrhagic stroke hospitalizations were assessed among individuals aged 35 to 64 years.



Over the study period, stroke hospitalization rates per 100 000 decreased by 10% from 66.7 to 60.3 (trend P<0.01) in men and 8% from 52.7 to 48.3 (trend P<0.001) in women. The 55- to 64-year age group drove reductions in hospitalization rates: slope (rate of change per year)=-12.3 for men and -8.9 for women (both P<0.001). Rates increased slightly in men and women aged 35 to 44 years and remained stable for persons aged 45 to 54 years. Stroke subtype analysis revealed that rates of ischemic stroke hospitalization increased and hemorrhagic stroke hospitalization remained stable among individuals aged 35 to 44 years. Rates of ischemic and hemorrhagic stroke hospitalizations remained stable among those aged 45 to 54 years and decreased among persons aged 55 to 64 years.



From 1997 to 2006, ischemic and hemorrhagic stroke hospitalization rates declined among individuals aged 55 to 64 years and remained stable among persons aged 45 to 54 years; ischemic stroke hospitalization rates increased among individuals aged 35 to 44 years. Further studies are needed to assess and address increases in ischemic stroke hospitalizations among younger individuals.
Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker.

Thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all cause reactive rises in plasma renin activity. We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering. In 3 open-label studies in which blood pressure was assessed with ambulatory measurement, aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (n=23), ramipril (n=21), or irbesartan (n=23). In the diuretic combination study, the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure, compared with aliskiren monotherapy (systolic/diastolic mean change from baseline [SEM]: daytime: -18.4 [2.1]/ -10.6 [1.7] versus -10.4 [1.8]/-5.8 [1.4]; nighttime: -15.6 [2.7]/-8.1 [1.8] versus -8.8 [2.9]/-5.0 [2.2]). In the angiotensin-converting enzyme inhibitor combination study, the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy (daytime: -10.5 [2.9]/-8.1 [2.1] and -14 [3.7]/-8.7 [2.3] versus -6.1 [2.4]/-5.9 [1.5]; nighttime: -8.1 [2.6]/-5.3 [2.4] and -9.6 [3.4]/-5.3 [2.4] versus -2 [2.3]/-0.7 [2.2]). In the angiotensin receptor blocker combination study, the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone, for 3 weeks, resulted in significantly lower nighttime pressures compared with irbesartan monotherapy (daytime: -14.8 . Aliskiren (150 mg) alone significantly inhibited plasma renin activity by 65% (P<0.0001). Ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was coadministered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased (combination therapy versus untreated; median [interquartile range]; aliskiren and hydrochlorothiazide: 0.4 [0.2 to 1.1] versus 0.7 [0.5 to 1.3]; ramipril and aliskiren: 0.5 [0.3 to 0.9] versus 0.6 [0.5 to 0.8]; irbesartan and aliskiren: 0.4 [0.2 to 0.9] versus 0.6 [0.4 to 0.9]). These results suggest that renin inhibition with aliskiren in these combinations increases renin-angiotensin system suppression, improves 24-hour blood pressure control, and may ultimately provide better end-organ protection in patients with hypertension.
Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma.

The objective of this multicentre, randomised, double blind, parallel group study was to compare the efficacy and safety of the addition of salmeterol with that of doubling the dose of fluticasone propionate in asthmatic patients not controlled by a low or intermediate dose of inhaled corticosteroids.



After a four week run in period of treatment with fluticasone propionate (100 micrograms twice daily if pre-trial dose was 400-600 micrograms inhaled corticosteroids or 250 micrograms twice daily if pre-trial dose was 800-1200 micrograms inhaled corticosteroids), 274 patients were randomised to treatment for 12 weeks with either salmeterol 50 micrograms twice daily plus the run in dose of fluticasone propionate or twice the run in dose of fluticasone propionate (200 or 500 micrograms twice daily). Outcome measures were daily records of peak expiratory flow (PEF), symptom scores, and clinic lung function.



The improvements in both the morning and evening PEF were better in the salmeterol than in the fluticasone propionate group, the mean increase in morning PEF being 19 l/min higher (95% CI 11.0 to 26.1) and in evening PEF being 16 l/min (95% CI 18.4 to 24.0) higher in the salmeterol group. The increase in forced expiratory volume in one second (FEV1) was 0.09 1 greater in the salmeterol group than in the fluticasone propionate group after four weeks of treatment (95% CI 0.01 to 0.18), but not after 12 weeks. Both regimens showed an increase in symptom free days and a reduction in the need for rescue salbutamol both during the day and the night, but these improvements were greater in the salmeterol group. There were no significant differences between the groups in adverse effects or in the number of rescue course of oral corticosteroids.



In this group of patients still symptomatic despite 100 or 250 micrograms fluticasone propionate twice daily, the addition of salmetterol caused a greater improvement in lung function and symptom control than doubling the dose of fluticasone propionate.
Cognitive mechanisms of social anxiety reduction: an examination of specificity and temporality.

Cognitive theories posit that exposure-based treatments exert their effect on social anxiety by modifying judgmental biases. The present study provides a conservative test of the relative roles of changes in judgmental biases in governing social anxiety reduction and addresses several limitations of previous research. Longitudinal, within-subjects analysis of data from 53 adults with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) social phobia diagnosis revealed that reductions in probability and cost biases accounted for significant variance in fear reduction achieved during treatment. However, whereas the reduction in probability bias resulted in fear reduction, the reduction in cost bias was merely a consequence of fear reduction. A potential implication is that exposure-based treatments for social anxiety might focus more attention on correcting faulty appraisals of social threat occurrence.
Implementation of Cognitive Therapy for PTSD in routine clinical care: Effectiveness and moderators of outcome in a consecutive sample☆

Trauma-focused psychological treatments are recommended as first-line treatments for Posttraumatic Stress Disorder (PTSD), but clinicians may be concerned that the good outcomes observed in randomized controlled trials (RCTs) may not generalize to the wide range of traumas and presentations seen in clinical practice. This study investigated whether Cognitive Therapy for PTSD (CT-PTSD) can be effectively implemented into a UK National Health Service Outpatient Clinic serving a defined ethnically mixed urban catchment area.



A consecutive sample of 330 patients with PTSD (age 17-83) following a wide range of traumas were treated by 34 therapists, who received training and supervision in CT-PTSD. Pre and post treatment data (PTSD symptoms, anxiety, depression) were collected for all patients, including dropouts. Hierarchical linear modeling investigated candidate moderators of outcome and therapist effects.



CT-PTSD was well tolerated and led to very large improvement in PTSD symptoms, depression and anxiety. The majority of patients showed reliable improvement/clinically significant change: intent-to-treat: 78.8%/57.3%; completer: 84.5%/65.1%. Dropouts and unreliable attenders had worse outcome. Statistically reliable symptom exacerbation with treatment was observed in only 1.2% of patients. Treatment gains were maintained during follow-up (M=280 days, n=220). Few of the selection criteria used in some RCTs, demographic, diagnostic and trauma characteristics moderated treatment outcome, and only social problems and needing treatment for multiple traumas showed unique moderation effects. There were no random effects of therapist on symptom improvement, but therapists who were inexperienced in CT-PTSD had more dropouts than those with greater experience.



The results support the effectiveness of CT-PTSD and suggest that trauma-focused cognitive behavior therapy can be successfully implemented in routine clinical services treating patients with a wide range of traumas.
Cocoa Consumption Alters the Global DNA Methylation of Peripheral Leukocytes in Humans with Cardiovascular Disease Risk Factors: A Randomized Controlled Trial

DNA methylation regulates gene expression and can be modified by different bioactive compounds in foods, such as polyphenols. Cocoa is a rich source of polyphenols, but its role in DNA methylation is still unknown. The objective was to assess the effect of cocoa consumption on DNA methylation and to determine whether the enzymes involved in the DNA methylation process participate in the mechanisms by which cocoa exerts these effects in humans. The global DNA methylation levels in the peripheral blood were evaluated in 214 volunteers who were pre-hypertensive, stage-1 hypertensive or hypercholesterolemic. The volunteers were divided into two groups: 110 subjects who consumed cocoa (6 g/d) for two weeks and 104 control subjects. In addition, the peripheral blood mononuclear cells (PBMCs) from six subjects were treated with a cocoa extract to analyze the mRNA levels of the DNA methyltransferases (DNMTs), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase reductase (MTRR) genes. Cocoa consumption significantly reduced the DNA methylation levels (2.991±0.366 vs. 3.909±0.380, p<0.001). Additionally, we found an association between the cocoa effects on DNA methylation and three polymorphisms located in the MTHFR, MTRR, and DNMT3B genes. Furthermore, in PBMCs, the cocoa extract significantly lowered the mRNA levels of the DNMTs, MTHFR, and MTRR. Our study demonstrates for the first time that the consumption of cocoa decreases the global DNA methylation of peripheral leukocytes in humans with cardiovascular risk factors. In vitro experiments with PBMCs suggest that cocoa may exert this effect partially via the down-regulation of DNMTs, MTHFR and MTRR, which are key genes involved in this epigenetic process.
An isolated perfused pig heart model for the development, validation and translation of novel cardiovascular magnetic resonance techniques

Novel cardiovascular magnetic resonance (CMR) techniques and imaging biomarkers are often validated in small animal models or empirically in patients. Direct translation of small animal CMR protocols to humans is rarely possible, while validation in humans is often difficult, slow and occasionally not possible due to ethical considerations. The aim of this study is to overcome these limitations by introducing an MR-compatible, free beating, blood-perfused, isolated pig heart model for the development of novel CMR methodology.



6 hearts were perfused outside of the MR environment to establish preparation stability. Coronary perfusion pressure (CPP), coronary blood flow (CBF), left ventricular pressure (LVP), arterial blood gas and electrolyte composition were monitored over 4 hours. Further hearts were perfused within 3T (n = 3) and 1.5T (n = 3) clinical MR scanners, and characterised using functional (CINE), perfusion and late gadolinium enhancement (LGE) imaging. Perfusion imaging was performed globally and selectively for the right (RCA) and left coronary artery (LCA). In one heart the RCA perfusion territory was determined and compared to infarct size after coronary occlusion.



All physiological parameters measured remained stable and within normal ranges. The model proved amenable to CMR at both field strengths using typical clinical acquisitions. There was good agreement between the RCA perfusion territory measured by selective first pass perfusion and LGE after coronary occlusion (37% versus 36% of the LV respectively).



This flexible model allows imaging of cardiac function in a controllable, beating, human-sized heart using clinical MR systems. It should aid further development, validation and clinical translation of novel CMR methodologies, and imaging sequences.
Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study

To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.



ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued.



Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%).



Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement.