nils-herrmann/clean_scirepeval huggingface dataset:
Physical dependence increases the relative reinforcing effects of caffeine versus placebo

Using a within-subject cross-over design, this study examined the role of physical dependence in caffeine reinforcement by experimentally manipulating physical dependence. Each subject was exposed to two chronic drug phases (300 mg/70 kg/day caffeine and placebo) for 9–12 days, with order of phases counterbalanced across subjects. On 2 separate days immediately following each of the chronic drug exposures, subjects received acute doses of either caffeine (300 mg/ 70 kg) or placebo in counterbalanced order. The reinforcing effects of these drugs were then determined by using a multiple-choice procedure in which subjects made a series of discrete choices between receiving varying amounts of money or receiving the drug again, and a choice between the two drugs. To ensure that subjects completed the form carefully, following exposure to both of the acute drug administrations, one of the subject’s previous choices from the multiple-choice form was randomly selected and the consequence of that choice was implemented. When subjects were maintained on chronic caffeine, they were willing to forfeit significantly more money and showed significant increases in typical withdrawal symptoms (e.g. fatigue, mood disturbance) after receiving placebo as compared to the other three conditions. When subjects were maintained on chronic caffeine, they also chose to receive caffeine over placebo twice as often than when they were maintained on chronic placebo. These findings provide the strongest evidence to date indicating that caffeine physical dependence increases the relative reinforcing effects of caffeine versus placebo.
Improving the management of non-ST elevation acute coronary syndromes: systematic evaluation of a quality improvement programme European QUality Improvement Programme for Acute Coronary Syndrome: The EQUIP-ACS project protocol and design

Acute coronary syndromes, including myocardial infarction and unstable angina, are important causes of premature mortality, morbidity and hospital admissions. Acute coronary syndromes consume large amounts of health care resources, and have a major negative economic and social impact through days lost at work, support for disability, and coping with the psychological consequences of illness. Several registries have shown that evidence based treatments are under-utilised in this patient population, particularly in high-risk patients. There is evidence that systematic educational programmes can lead to improvement in the management of these patients. Since application of the results of important clinical trials and expert clinical guidelines into clinical practice leads to improved patient care and outcomes, we propose to test a quality improvement programme in a general group of hospitals in Europe.



This will be a multi-centre cluster-randomised study in 5 European countries: France, Spain, Poland, Italy and the UK. Thirty eight hospitals will be randomised to receive a quality improvement programme or no quality improvement programme. Centres will enter data for all eligible non-ST segment elevation acute coronary syndrome patients admitted to their hospital for a period of approximately 10 months onto the study database and the sample size is estimated at 2,000-4,000 patients. The primary outcome is a composite of eight measures to assess aggregate potential for improvement in the management and treatment of this patient population (risk stratification, early coronary angiography, anticoagulation, beta-blockers, statins, ACE-inhibitors, clopidogrel as a loading dose and at discharge). After the quality improvement programme, each of the eight measures will be compared between the two groups, correcting for cluster effect.



If we can demonstrate important improvements in the quality of patient care as a result of a quality improvement programme, this could lead to a greater acceptance that such programmes should be incorporated into routine health training for health professionals and hospital managers.
High pathologic complete response in Her2-positive, early-stage breast cancer to a novel nonanthracycline neoadjuvant chemotherapy.

Neoadjuvant chemotherapy is widely used to downstage breast cancers before surgery and is an accepted standard of care among patients with early-stage breast cancer in whom adjuvant chemotherapy would be recommended. Pathologic complete response (pCR) rate is a robust predictor of outcome for certain breast cancer subtypes, including Her2-overexpressing breast cancer. The incorporation of Her2-targeted therapies has significantly increased the pCR rate in the neoadjuvant setting. Although regimens composed of trastuzumab, nab-paclitaxel, and vinorelbine have demonstrated clinical efficacy in patients with metastatic breast cancer, few studies have examined this combination in early-stage Her2+ breast cancer. We hypothesized that the combination of neoadjuvant nab-paclitaxel followed by vinorelbine could represent a nonanthracycline-based treatment option for early-stage Her2-overexpressing breast cancer.



Patients received 4 cycles of nab-paclitaxel 260 mg/m(2) intravenously (IV) every 14 days for 4 cycles followed by vinorelbine 25 mg/m(2) IV weekly for 12 weeks with concurrent trastuzumab (4 mg/kg loading dose, and then 2 mg/kg/wk). The primary endpoint was the rate of pCR. Secondary endpoints included clinical response, toxicity, and survival rates.



A total of 27 patients were accrued to the trial. The median tumor size was 4.0 cm, and more than 50% of patients had axillary lymph node involvement. The pCR rate was 48.1%. Among the 40% of patients who had hormone receptor-positive disease, the pCR rate was 18.2%, compared with 68.8% among patients with estrogen receptor/progesterone receptor-negative tumors.



The combination of trastuzumab with nab-paclitaxel followed by vinorelbine was well tolerated and had promising activity in the neoadjuvant setting.
Reconstitution of virus-specific CD4 proliferative responses in pediatric HIV-1 infection.

Gag-specific CD4 proliferative responses correlate inversely with HIV-1 RNA levels in infected adults, and robust responses are characteristic of long-term nonprogressive infection. However, strong responses are seldom detected in adult subjects with progressive infection and are not generally reconstituted on highly active antiretroviral therapy (HAART). To date, the role of HIV-1-specific Th responses in children has not been thoroughly examined. We characterized Gag-specific CD4 responses among 35 perinatally infected subjects, including 2 children who spontaneously control viremia without antiretroviral therapy, 21 children with viral loads (VL) of <400 on HAART, and 12 viremic children. Gag-specific Th activity was assessed by lymphoproliferative assay, and responses were mapped using overlapping Gag peptides in an IFN-gamma ELISPOT. Robust proliferative responses were detected in the children exhibiting spontaneous control of viremia, and mapping of targeted Gag regions in one such subject identified multiple epitopes. Among children >or=5 years old, 14 of 17 subjects with VL of <400 on HAART demonstrated a significant p24 proliferative response (median p24 stimulation index, 20), in contrast with only 1 of 9 viremic children (median p24 stimulation index, 2.0; p = 0.0008). However, no subject younger than 5 years of age possessed a significant response, even when viremia was fully suppressed. When compared with adults with VL of <400 on HAART, Th responses among children with VL of <400 were both more frequent (p = 0.009) and of greater magnitude (p = 0.002). These data suggest that children may have a greater intrinsic capacity to reconstitute HIV-1-specific immunity than adults, and may be excellent candidates for immune-based therapies.
Adoption of a plant-based diet by patients with recurrent prostate cancer.

The Western diet has been associated with prostate cancer incidence as well as risk of disease progression after treatment. Conversely, plant-based diets have been associated with decreased risks. A pilot clinical trial of a 6-month dietary change and stress reduction intervention for asymptomatic, hormonally untreated patients experiencing a consistently rising PSA level, the first sign of recurrence of prostate cancer after surgery or radiation therapy, was conducted to investigate the level of intake of plant-based foods and the relationship between intake and the change in the rate of PSA rise. A pre-post design was employed in which each patient served as his own control. In this multifaceted intervention, patients and their spouses were encouraged to adopt and maintain a plant-based diet. The prestudy rate of PSA rise (from the time of posttreatment recurrence to the start of the study) was ascertained by review of patients' medical records. Dietary assessments were performed and prostate-specific antigen (PSA) levels ascertained at baseline, prior to the start of intervention, and at 3 and 6 months. Changes in numbers of servings of plant-based food groups were calculated and compared with rates of PSA rise over the corresponding time intervals. Median intake of whole grains increased from 1.7 servings/d at baseline to 6.9 and 5.0 servings/d at 3 and 6 months, respectively. Median intake of vegetables increased from 2.8 servings/d at baseline to 5.0 and 4.8 servings/d at 3 and 6 months, respectively. The rate of PSA rise decreased when comparing the prestudy period (0.059) to the period from 0 to 3 months (-0.002, P < .01) and increased slightly, though not significantly, when comparing the period from 0 to 3 months to the period from 3 to 6 months (0.029, P = .4316). These results provide preliminary evidence that adoption of a plant-based diet is possible to achieve as well as to maintain for several months in patients with recurrent prostate cancer. Changes in the rate of rise in PSA, an indicator of disease progression, were in the opposite direction as changes in the intake of plant-based food groups, raising the provocative possibility that PSA may have inversely tracked intake of these foods and suggesting that adoption of a plant-based diet may have therapeutic potential in the management of this condition.
Reduction of HBV replication prolongs the early immunological response to IFNα therapy.

The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms.



We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n=5, weekly dosing of 360 μg Pegasys [PegIFNα] n=11, daily dose of 300 mg Viread [tenofovir disoproxil fumarate, TDF] n=6, or a combination of both n=6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180 μg Pegasys injected subcutaneously, weekly).



PegIFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF.



We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFNα-induced innate immune activation directly benefits from the suppression of HBV replication.
Pain responder analysis: use of area under the curve to enhance interpretation of clinical trial results.

Interpretation of results on patient-reported pain outcomes from clinical trials should be meaningful to patients and healthcare providers. This study applied an area-under-the-curve (AUC) analysis to responder profiles in a clinical trial of pregabalin for the treatment of fibromyalgia (FM). Data were from a 14-week, randomized, placebo-controlled trial of pregabalin (300, 450, or 600 mg/day) for the treatment of FM in patients meeting American College of Rheumatology criteria for FM and with a baseline pain score of at least 40 mm on the 100-mm pain visual analogue scale. Pain was evaluated in a daily diary by patients using an 11-point numeric rating scale (0 = no pain, 10 = worst possible pain). Response profiles on pain improvement scores and their differences between pregabalin and placebo were assessed using the AUC (derived using the trapezoidal rule) from the responder curve (vertical axis, proportion of subjects; horizontal axis, minimum percent improvement in pain). The AUC can be interpreted as if all responders were improved by the same percentage equal to the AUC divided by 100. The AUCs (2,100 for placebo, and 2,944, 3,170, and 3,349 for pregabalin 300, 450, and 600 mg, respectively) can be considered as if every responder improved by 21, 29, 31, and 33.5% in the responder's respective treatment group. Pain improvement was significantly better with pregabalin (P < 0.05), with pregabalin responders improving by 8.4% (300 mg/day), 10.7% (450 mg/day), and 12.5% (600 mg/day) more than placebo responders. This novel approach demonstrates that responder profiles can provide an enhanced interpretation of pain outcomes for patient care and symptom management.
The incidence of unpleasant dreams after sub-anaesthetic ketamine

Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist with psychotogenic effects and for which there are diverse reports of whether pleasant or unpleasant dreams result during anaesthesia, post-operatively or after sub-anaesthetic use. To assess in healthy volunteers the incidence of unpleasant dreams over the three nights after receiving a sub-anaesthetic dose of ketamine, in comparison to placebo, and with retrospective home nightmare frequency as a covariate. Thirty healthy volunteers completed questionnaires about retrospective home dream recall and were then given either ketamine (n = 19, males = 9, mean age = 23.5 years; mean ketamine blood plasma = 175.29 ng/mL) or placebo (n = 11, males = 5, mean age = 25.4 years). Dream recall and pleasantness/unpleasantness of dream content were recorded by questionnaire at home for the three nights after infusion. Ketamine resulted in significantly more mean dream unpleasantness relative to placebo and caused a threefold increase in the odds ratio for the incidence of an unpleasant dream. The number of dreams reported over the three nights did not differ between the groups. The incidence of unpleasant dreams after ketamine use was predicted by retrospectively assessed nightmare frequency at home. Ketamine causes unpleasant dreams over the three post-administration nights. This may be evidence of a residual psychotogenic effect that is not found on standard self-report symptomatology measures or a result of disturbed sleep electrophysiology.
Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome.

Preclinical studies suggest that exogenous surfactant may be of value in the treatment of the acute respiratory distress syndrome (ARDS), and two phase 2 clinical trials have shown a trend toward benefit. We conducted two phase 3 studies of a protein-containing surfactant in adults with ARDS.



In two multicenter, randomized, double-blind trials involving 448 patients with ARDS from various causes, we compared standard therapy alone with standard therapy plus up to four intratracheal doses of a recombinant surfactant protein C-based surfactant given within a period of 24 hours.



The overall survival rate was 66 percent 28 days after treatment, and the median number of ventilator-free days was 0 (68 percent range, 0 to 26); there was no significant difference between the groups in terms of mortality or the need for mechanical ventilation. Patients receiving surfactant had a significantly greater improvement in blood oxygenation during the initial 24 hours of treatment than patients receiving standard therapy, according to both univariate and multivariate analyses.



The use of exogenous surfactant in a heterogeneous population of patients with ARDS did not improve survival. Patients who received surfactant had a greater improvement in gas exchange during the 24-hour treatment period than patients who received standard therapy alone, suggesting the potential benefit of a longer treatment course.
Postoperative pain control: videothoracoscopic versus conservative mini-thoracotomic approach.

The management of postoperative pain in thoracic surgery is an open issue. The aim of this study was to compare postoperative pain after a videothoracoscopic lobectomy versus a mini-thoracotomy approach.



Between April 2011 and January 2013 we enrolled in a prospective, non-randomized study 145 patients undergoing pulmonary lobectomy with lymphadenectomy for Stage I lung cancer. In 75 cases (Group A), surgery was performed through a videothoracoscopic approach. In 70 cases (Group B), surgery was undertaken through a conservative mini-thoracotomy. Pain was assessed by visual analogue scale and lung function by spirometry and six-minute walking test (6MWT) before surgery, at 48 h and 1 month after surgery.



Patients were stratified by age, sex, lung function, type and duration of surgery. Length of hospital stay (median, days) was 4 for Group A and 6 for Group B (P = 0.088). The differences between mean postoperative pain values were significant at 1, 12, 24 and 48 h (6.24 vs 8.74, 5.16 vs 7.66, 4.19 vs 6.89 and 2.23 vs 5.33; P = 0.000). In Group A, mean preoperative forced expiratory volume in 1 second values were 2.65 ± 0.61, and 1.83 ± 0.65 and 2.09 ± 0.65, respectively, at 48 h and 1 month (P = 0.028); in Group B, they were 2.71 ± 0.71 preoperatively and 1.33 ± 0.52 and 1.82 ± 0.63, respectively, at 48 h and 1 month. In Group A, mean preoperative 6MWT values (m) were 426.85 ± 51.18, and 371.23 ± 55.36 and 392.07 ± 56.12, respectively, at 48 h and 1 month; in Group B, they were 421.76 ± 56.65 preoperatively and 312.03 ± 48.54 and 331.83 ± 47.99, respectively, at 48 h and 1 month (P = 0.000).



The videothoracoscopic approach in the treatment of Stage I lung cancer reduces postoperative pain, which seems to allow a rapid functional recovery of patients.
Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study

The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS.



137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus.



MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7.4 [SD 4.2] years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11.2 [4.5] years; p<0.0001) or monofocal (12.0 [3.8] years; p=0.0005) presentations. Permanent physical disability (EDSS>or=4.0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0.02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0.025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings.



Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology.
Controlled-release transdermal apomorphine treatment for motor fluctuations in Parkinson's disease

This study evaluated the efficacy in Parkinson's disease (PD) of a new pharmacologic preparation of apomorphine included in microemulsions and administered by transdermal route, which provides a constant release of the drug for several hours (Apo-TD). Twenty-one PD patients with motor fluctuations were treated with L-dopa alone, with L-dopa plus oral dopamine-agonists, or with L-dopa plus Apo-TD. Apo-TD improved UPDRS-III and tapping test scores in “off” conditions, and reduced duration of “off” periods; no improvement in “on” conditions occurred. We conclude that Apo-TD shows its efficacy particularly by reducing “off” period duration and disability rather than improving motor performances in “on” conditions and therefore it seems a promising treatment for uncontrolled “off” phases in PD patients.
Genetic variant in the glucose transporter type 2 is associated with higher intakes of sugars in two distinct populations.

Glucose sensing in the brain has been proposed to be involved in regulating food intake, but the mechanism is not known. Glucose transporter type 2 (GLUT2)-null mice fail to control their food intake in response to glucose, suggesting a potential role for this transporter as a glucose sensor in the brain. Here we show that individuals with a genetic variation in GLUT2 (Thr110Ile) have a higher daily intake of sugars in two distinct populations. In the first population, compared with individuals with the Thr/Thr genotype, carriers of the Ile allele had a significantly higher intake of sugars as assessed from 3-day food records administered on two separate visits (visit 1: 112 +/- 9 vs. 86 +/- 4 g/day, P = 0.01; visit 2: 111 +/- 8 vs. 82 +/- 4 g/day, P = 0.003), demonstrating within-population reproducibility. In a second population, carriers of the Ile allele also reported consuming a significantly greater intake of sugars (131 +/- 5 vs. 115 +/- 3 g/day, P = 0.007) over a 1-mo period as measured from a food frequency questionnaire. GLUT2 genotypes were not associated with fat, protein, or alcohol intake in either population. These observations were consistent across older and younger adults as well as among subjects with early Type 2 diabetes and healthy individuals. Taken together, our findings show that a genetic variation in GLUT2 is associated with habitual consumption of sugars, suggesting an underlying glucose-sensing mechanism that regulates food intake.