nils-herrmann/clean_scirepeval huggingface dataset:
Pattern of Functional TTX-Resistant Sodium Channels Reveals a Developmental Stage of Human iPSC- and ESC-Derived Nociceptors

Human pluripotent stem cells (hPSCs) offer the opportunity to generate neuronal cells, including nociceptors. Using a chemical-based approach, we generated nociceptive sensory neurons from HUES6 embryonic stem cells and retrovirally reprogrammed induced hPSCs derived from fibroblasts. The nociceptive neurons expressed respective markers and showed tetrodotoxin-sensitive (TTXs) and -resistant (TTXr) voltage-gated sodium currents in patch-clamp experiments. In contrast to their counterparts from rodent dorsal root ganglia, TTXr currents of hPSC-derived nociceptors unexpectedly displayed a significantly more hyperpolarized voltage dependence of activation and fast inactivation. This apparent discrepancy is most likely due to a substantial expression of the developmentally important sodium channel NAV1.5. In view of the obstacles to recapitulate neuropathic pain in animal models, our data advance hPSC-derived nociceptors as a better model to study developmental and pathogenetic processes in human nociceptive neurons and to develop more specific small molecules to attenuate pain.
Whooping cough in school age children with persistent cough: prospective cohort study in primary care.

To estimate the proportion of school age children with a persistent cough who have evidence of a recent Bordetella pertussis infection.



Prospective cohort study (October 2001 to March 2005).



General practices in Oxfordshire, England.



172 children aged 5-16 years who presented to their general practitioner with a cough lasting 14 days or more who consented to have a blood test.



Serological evidence of a recent Bordetella pertussis infection; symptoms at presentation; duration and severity of cough; sleep disturbance (parents and child).



64 (37.2%, 95% confidence interval 30.0% to 44.4%) children had serological evidence of a recent Bordetella pertussis infection; 55 (85.9%) of these children had been fully immunised. At presentation, children with whooping cough were more likely than others to have whooping (odds ratio 2.85, 95% confidence interval 1.39 to 5.82), vomiting (4.35, 2.04 to 9.25), and sputum production (2.39, 1.14 to 5.02). Children with whooping cough were also more likely to still be coughing two months after the start of their illness (85% v 48%; P = 0.001), continue to have more than five coughing episodes a day (P = 0.049), and cause sleep disturbance for their parents (P = 0.003).



For school age children presenting to primary care with a cough lasting two weeks or more, a diagnosis of whooping cough should be considered even if the child has been immunised. Making a secure diagnosis of whooping cough may prevent inappropriate investigations and treatment.
Polymer-free sirolimus- and probucol-eluting versus new generation zotarolimus-eluting stents in coronary artery disease: the Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol-Eluting versus Zotarolimus-eluting Stents (ISAR-TEST 5) trial.

Durable polymer coatings have been implicated in mid- and long-term adverse events after drug-eluting stent implantation. A polymer-free dual-drug sirolimus- and probucol-eluting stent and a new generation permanent polymer zotarolimus-eluting stent are recently developed technologies demonstrating encouraging results.



In a clinical trial with minimal exclusion criteria, we randomly assigned 3002 patients to treatment with sirolimus- and probucol-eluting stents versus zotarolimus-eluting stents. The trial was designed to demonstrate noninferiority of the sirolimus- and probucol-eluting stents. The primary end point was the combined incidence of cardiac death, target-vessel-related myocardial infarction, or target-lesion revascularization at 1-year follow-up. Follow-up angiography was scheduled at 6 to 8 months. The sirolimus- and probucol-eluting stent was noninferior to the zotarolimus-eluting stent in terms of occurrence of the primary end point (13.1% versus 13.5%, respectively, P(noninferiority)=0.006; hazard ratio=0.97, 95% confidence interval, 0.78 to 1.19; P(superiority)=0.74). The incidence of definite/probable stent thrombosis was low in both groups (1.1% versus 1.2%, respectively; hazard ratio=0.91 [95% confidence interval, 0.45 to 1.84], P=0.80). With regard to angiographic efficacy, there were no differences between the sirolimus- and probucol-eluting stent and the zotarolimus-eluting stent in terms of either in-segment binary angiographic restenosis (13.3% versus 13.4% respectively; P=0.95) or in-stent late luminal loss (0.31±0.58 mm versus 0.29±0.56 mm, respectively; P=0.46).



In this large-scale study powered for clinical end points, a polymer-free sirolimus- and probucol-eluting stent was noninferior to a new generation durable polymer-based zotarolimus-eluting stent out to 12 months.
Efficacy of feverfew as prophylactic treatment of migraine.

Seventeen patients who ate fresh leaves of feverfew daily as prophylaxis against migraine participated in a double blind placebo controlled trial of the herb: eight patients received capsules containing freeze dried feverfew powder and nine placebo. Those who received placebo had a significant increase in the frequency and severity of headache, nausea, and vomiting with the emergence of untoward effects during the early months of treatment. The group given capsules of feverfew showed no change in the frequency or severity of symptoms of migraine. This provides evidence that feverfew taken prophylactically prevents attacks of migraine, and confirmatory studies are now indicated, preferably with a formulation controlled for sesquiterpene lactone content, in migraine sufferers who have never treated themselves with this herb.
MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study.

To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX).



In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >or=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group.



MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P=0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>or=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay).



MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.
Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease.

Extracorporeal photochemotherapy (ECP) has been associated with clinical improvement in several patients with acute and chronic graft-versus-host disease (cGVHD) after allogeneic bone marrow transplantation, but the mechanism of action is unknown. This study tested the hypothesis that in patients with cGVHD, ECP modulates alloreactivity by affecting activated lymphocyte populations or by altering the interaction between effector lymphocytes and antigen-presenting cells (APCs). Ten patients who had refractory cGVHD were treated with ECP, and the clinical response to and immunologic effects of this therapy were assessed. Seven patients had a response and 3 had no change in clinical manifestations of cGVHD. One patient died from catheter-related sepsis. Immunologic effects observed after ECP included normalization of inverted ratios of CD4 to CD8 cells, an increase in the number of CD3-CD56+ natural killer (NK) cells, and a decrease in CD80+ and CD123+ circulating dendritic cells. The results suggest that ECP modulates both NK cells and APC populations in patients with cGVHD.
How to switch to agomelatine after an unsuccessful try with paroxetine or venlafaxine.

The present trial informs clinicians about switching conditions with the antidepressant agomelatine after the failure of a treatment with either paroxetine or venlafaxine.



The total number of discontinuation-emergent symptoms, according to the Discontinuation-Emergent Signs and Symptoms checklist, was compared in double-blind conditions after 3 switching options: immediate substitution or initiation of agomelatine (25 mg/day p.o.) with either a short- or long-tapering of the previous drug. Secondary objectives included tolerability and safety assessments and the early clinical benefit after the switch.



For all switching options, a withdrawal syndrome was observed 1 week after cessation of the selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) treatment. Psychic symptoms were the most frequently reported, and somatic symptoms were comparatively few. Early discontinuation symptoms after cessation of SSRI/SNRI treatment did not prejudice the antidepressant benefits of agomelatine over 8 weeks.



Both abrupt and start-taper switching with agomelatine are options in everyday practice for those patients who have not responded to either paroxetine or venlafaxine. However, regardless of the switching strategy, the present double-blind study shows that early discontinuation symptoms that arise upon cessation of SSRI/SNRI can alter the patients' perception of the clinical benefit of the new antidepressant. Both practitioners and patients must be warned about these early discontinuation symptoms to prevent the symptoms from being confounded with a lack of therapeutic benefit of the new treatment.
Comparison of gray matter and metabolic reduction in mild Alzheimer’s disease using FDG-PET and voxel-based morphometric MR studies

The aim of this study was to investigate regional differences between morphologic and functional changes in the same patients with mild Alzheimer’s disease (AD) using statistical parametric mapping (SPM) and voxel-based morphometry (VBM). Thirty patients with very mild AD (mean age 66.8 years, mean MMSE score 24.0) and 30 age- and sex-matched normal volunteers underwent both 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and three-dimensional spoiled gradient echo (SPGR) magnetic resonance imaging (MRI). Statistical parametric mapping was used to conduct VBM analysis of the morphological data, which were compared voxel by voxel with the results of a similar analysis of the glucose metabolic data. In AD patients, VBM data indicated a significant gray matter volume density decrease in bilateral amygdala/hippocampus complex (p<0.05, corrected), while FDG-PET analysis showed significant glucose metabolic reductions in the posterior cingulate gyri and the right parietal lobule, compared with those in the normal control group. In very mild AD, morphological change occurs in the medial temporal lobes, while in contrast, metabolic changes occur in the posterior cingulate gyri and parietal lobule.
Significance of Circulating Tumor Cells in Metastatic Triple-Negative Breast Cancer Patients within a Randomized, Phase II Trial: TBCRC 019.

Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM-based capture system (CellSearch) is effective in patients with triple-negative (TN) MBC, and whether CTC apoptosis and clustering enhances the prognostic role of CTC.



CTC enumeration and apoptosis were determined using the CXC CellSearch kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without tigatuzumab. Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan-Meier curves, and Cox proportional hazards modeling.



Nineteen of 52 (36.5%), 14 of 52 (26.9%), and 13 of 49 (26.5%) patients who were evaluable had elevated CTC (≥5 CTC/7.5 mL whole blood) at baseline and at days 15 and 29, respectively. Patients with elevated versus not elevated CTC at each time point had worse progression-free survival (PFS; P = 0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated versus low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08-0.84; P = 0.024), 0.19 (95% CI: 0.05-0.17; P = 0.014), and 0.06 (95% CI: 0.01-0.33; P = 0.001), respectively. There was no apparent prognostic effect comparing CTC apoptosis versus non-apoptosis. Presence of CTC cluster at day 15 and day 29 was associated with shorter PFS.



CTC were detected using CellSearch assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response.
Using an internet intervention to support self-management of low back pain in primary care: protocol for a randomised controlled feasibility trial (SupportBack).

Low back pain (LBP) is a prevalent and costly condition. The majority of patients experiencing LBP are managed in primary care, where first-line care recommendations consist of advice to self-manage and remain active. Internet interventions present a potential means of providing patients with tailored self-management advice and evidence-based support for increasing physical activity.



This protocol describes a single-blind, randomised controlled feasibility trial of an internet intervention developed to support the self-management of LBP in primary care. Patients are being randomised to 1 of 3 groups receiving either usual primary care, usual primary care with the addition of an internet intervention or an internet intervention with physiotherapist telephone support. Patients are followed up at 3 months. Primary outcomes are the feasibility of (1) the trial design/methods, (2) the delivery of the internet intervention and (3) the provision of telephone support by physiotherapists. Secondary outcomes will include exploratory analysis of estimates and variation in clinical outcomes of pain and disability, in order to inform a future main trial.


ETHICS/DISSEMINATION
This feasibility trial has undergone ethical scrutiny and been approved by the National Health Service (NHS) Research Ethics Committee, REC Reference 13/SC/0202. The feasibility findings will be disseminated to the research community through presentations at conferences and publication in peer review journals. Broader dissemination will come following a definitive trial.
Low skeletal muscle is associated with toxicity in patients included in phase I trials

Low muscle mass has been associated with chemotherapy toxicity. We conducted this prospective study to evaluate the effects of body composition on the occurrence of toxicity in phase I trials.  Patients were consecutively enrolled irrespective of the type of tumor or the type of drug. The Skeletal Muscle Index (SMIndex) and visceral and subcutaneous adipose tissue were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues (cm2/m2). Dose-limiting toxicity (DLT) corresponded to toxicities occurring during the 1st cycle that necessitated dose reduction, postponement or interruption of drug administration and severe toxicity events (STE) corresponded to DLT or permanent treatment withdrawal due to toxicity.  93 patients were evaluated. Ten percent of patients experienced DLT and had a lower SMIndex: 40.8 ± 4.6 vs. 48.1 ± 9.6 cm2/m2 (p = 0.01). STE occurred in 14 % of the patients. The only factor associated with STE was a low SMIndex: 42.4 ± 5.8 vs. 48.4 ± 9.7 cm2/m2 (p = 0.02). STE were observed in 25.5 % of the patients when the SMIndex was below the median value compared to 6.5 % of patients with a high SMIndex (p = 0.02).  Muscle mass is a critical predictor of severe toxicity events in phase I patients, suggesting that sarcopenia may be considered in assessing patients for eligibility of phase-1 studies.
Evaluation of rural stroke services: does implementation of coordinators and pathways improve care in rural hospitals?

The quality of hospital care for stroke varies, particularly in rural areas. In 2007, funding to improve stroke care became available as part of the Rural Stroke Project (RSP) in New South Wales (Australia). The RSP included the employment of clinical coordinators to establish stroke units or pathways and protocols, and more clinical staff. We aimed to describe the effectiveness of RSP in improving stroke care and patient outcomes.



A historical control cohort design was used. Clinical practice and outcomes at 8 hospitals were compared using 2 medical record reviews of 100 consecutive ischemic or intracerebral hemorrhage patients ≥12 months before RSP and 3 to 6 months after RSP was implemented. Descriptive statistics and multivariable analyses of patient outcomes are presented.



pre-RSP n=750; mean age 74 (SD, 13) years; women 50% and post-RSP n=730; mean age 74 (SD, 13) years; women 46%. Many improvements in stroke care were found after RSP: access to stroke units (pre 0%; post 58%, P<0.001); use of aspirin within 24 hours of ischemic stroke (pre 59%; post 71%, P<0.001); use of care plans (pre 15%; post 63%, P<0.001); and allied health assessments within 48 hours (pre 65%; post 82% P<0.001). After implementation of the RSP, patients directly admitted to an RSP hospital were 89% more likely to be discharged home (adjusted odds ratio, 1.89; 95% confidence interval, 1.34-2.66).



Investment in clinical coordinators who implemented organizational change, together with increased clinician resources, effectively improved stroke care in rural hospitals, resulting in more patients being discharged home.
Hypokalemia during the early phase of refeeding in patients with cancer

Refeeding syndrome occurs in patients with severe malnutrition when refeeding begins after a long period of starvation. This syndrome increases the risk of clinical complications and mortality. Hypophosphatemia is considered the primary characteristic of the syndrome. The aim of our study was to investigate the presence of other electrolyte alterations in patients with cancer during the early stage of refeeding.



In this observational study, we enrolled 34 patients with cancer of the upper aerodigestive tract receiving upfront radiotherapy who were also enrolled in a nutrition program. A caloric intake assessment, anthropometric measurements and biochemical laboratory tests were performed.



Significant weight loss (∼20%) was found in these patients. In the patients receiving artificial nutrition, we found lower levels of potassium and total protein compared with those who were fed orally (p = 0.03 for potassium and 0.02 for protein, respectively). Patients on enteral tube feeding had a higher caloric intake compared with those who were fed orally (25±5 kcal/kg/day vs. 10±2 kcal/kg/day).



Hypokalemia, like hypophosphatemia, could be a complication associated with refeeding in patients with cancer. Hypokalemia was present in the early stages of high-calorie refeeding.
Tendencies and outcomes in endoscopic biliary sphincterotomies among people with or without type 2 diabetes mellitus in Spain, 2003-2013.

We aimed to compare incidence and outcomes for endoscopic biliary sphincterotomies in people with or without type 2 diabetes mellitus (T2DM) in Spain (2003-2013). We collected all cases of endoscopic biliary sphincterotomies using national hospital discharge data and evaluated annual incident rates stratified by T2DM status. We analyzed trends over time for in-hospital mortality (IHM) as the primary outcome and a composite of IHM or procedure-related complications (key secondary outcome). In multivariate analyses, we tested T2DM as an independent factor of IHM and IHM or complications. We identified 126,885 endoscopic biliary sphincterotomies (23,002 [18.1%] in T2DM people). Crude incidence rates of endoscopic biliary sphincterotomies were > 3-fold higher in people with vs without T2DM (85.5/105 vs 26.9/105 population, respectively). Annual incidence rates of endoscopic biliary sphincterotomies showed 11-year relative increments of 77.5% (from 60.0 to 106.5/105) in T2DM, and 53.7% (from 21.6 to 33.2/105) in non-T2DM people (p < 0.001). We found no significant changes in mortality trends over time for the populations with or without T2DM (p = 0.15 and p = 0.21, respectively). Rates of procedural pancreatitis decreased in people without T2DM (p < 0.001). In the multivariate analysis, older age, higher comorbidity and endoscopic biliary sphincterotomy during urgent admission were associated with a higher IHM. T2DM was associated with a lower IHM after an endoscopic biliary sphincterotomy (OR = 0.82 [0.74-0.92]). Time trend multivariate analyses 2003-2013 showed significant reductions in IHM over time only in people with T2DM (OR = 0.97 [0.94-1.00]). Further studies are needed to confirm a lower IHM for endoscopic biliary sphincterotomies in people with T2DM.