Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome – Prospective Clinical Trial

BackgroundFibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the quality of life of 2–4% of the population, with 9:1 female-to-male incidence ratio. FMS is an important representative example of central nervous system sensitization and is associated with abnormal brain activity. Key symptoms include chronic widespread pain, allodynia and diffuse tenderness, along with fatigue and sleep disturbance. The syndrome is still elusive and refractory. The goal of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on symptoms and brain activity in FMS.ConclusionsThe study provides evidence that HBOT can improve the symptoms and life quality of FMS patients. Moreover, it shows that HBOT can induce neuroplasticity and significantly rectify abnormal brain activity in pain related areas of FMS patients.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01827683","term_id":"NCT01827683"}}NCT01827683     

Outcome of Central Nervous System Relapses In Childhood Acute Lymphoblastic Leukaemia – Prospective Open Cohort Analyses of the ALLR3 Trial

The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25·1, 55·6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2·64, 95% CI 1·32, 5·31, p = 0·006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses.

Trial Registration

Controlled-Trials.com ISRCTN45724312     

Prospective Validation of Immunological Infiltrate for Prediction of Response to Neoadjuvant Chemotherapy in HER2-Negative Breast Cancer – A Substudy of the Neoadjuvant GeparQuinto Trial

Introduction

We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). The aim of this study was to prospectively validate the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT.

Patients and Methods

The immunological infiltrate was prospectively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study, a substudy of the neoadjuvant GeparQuinto study. Intratumoral lymphocytes (iTuLy), stromal lymphocytes (strLy) as well as lymphocyte-predominant breast cancer (LPBC) were evaluated by histopathological assessment. Pathological complete response (pCR) rates were analyzed and compared between the defined subgroups using the exact test of Fisher.

Results

Patients with lymphocyte-predominant breast cancer (LPBC) had a significantly increased pCR rate of 36.6%, compared to non-LPBC patients (14.3%, p<0.001). LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis (LPBC: OR 2.7, p = 0.003, strLy: OR 1.2, p = 0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p = 0.01) but not in multivariate logistic regression analysis (OR 1.2, p = 0.11).

Conclusion

Confirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies.     

Tinnitus Suppression by Intracochlear Electrical Stimulation in Single Sided Deafness – A Prospective Clinical Trial: Follow-Up

IntroductionEarlier studies show that a Cochlear Implant (CI), capable of providing intracochlear electrical stimulation independent of environmental sounds, appears to suppress tinnitus at least for minutes. The current main objective is to compare the long-term suppressive effects of looped (i.e. repeated) electrical stimulation (without environmental sound perception) with the standard stimulation pattern of a CI (with environmental sound perception). This could open new possibilities for the development of a “Tinnitus Implant” (TI), an intracochlear pulse generator for the suppression of tinnitus.ResultsResults show that tinnitus can be suppressed with intracochlear electrical stimulation independent of environmental sounds, even long term. No significant difference in tinnitus suppression was found between the standard clinical CI and the TI.ConclusionIt can be concluded that coding of environmental sounds is no requirement for tinnitus suppression with intracochlear electrical stimulation. It is therefore plausible that tinnitus suppression by CI is not solely caused by an attention shift from the tinnitus to environmental sounds. Both the standard clinical CI and the experimental TI are potential treatment options for tinnitus. These findings offer perspectives for a successful clinical application of the TI, possibly even in patients with significant residual hearing.

Trial Registration

TrialRegister.nl NTR3374     

TRICHOMONIASIS—Clinical Trial of Metronidazole (Flagyl?)

Metronidazole was given in various dosage regimens to 97 patients having microscopically diagnosed trichomoniasis.At the first examination after treatment all 97, including 76 to whom metronidazole had been given orally only, were found by culture and wet smear to be free of trichomonads.Reexamination of the 65 patients followed up for periods ranging from two weeks to 14 months revealed reappearance of trichomonads in eight cases.Nineteen husbands were treated. No patient had a recurrence after treatment of the husband.No effect of metronidazole on pregnancy or on fetal development was seen. Side effects, noted in 19 cases (20 per cent), generally were mild and transient and in no case were severe enough to terminate therapy before cure was effected.     

Ten Years after the International Committee of Medical Journal Editors’ Clinical Trial Registration Initiative,One Quarter of Phase 3 Pediatric Epilepsy Clinical Trials Still Remain Unpublished: A Cross Sectional Analysis

Introduction

Although selective reporting of clinical trial results introduces bias into evidence based clinical decision making, publication bias in pediatric epilepsy is unknown today. Since there is a considerable ambiguity in the treatment of an important and common clinical problem, pediatric seizures, we assessed the public availability of results of phase 3 clinical trials that evaluated treatments of seizures in children and adolescents as a surrogate for the extent of publication bias in pediatric epilepsy.

Methods

We determined the proportion of published and unpublished study results of phase 3 clinical trials that were registered as completed on ClinicalTrials.gov. We searched ClinicalTrials.gov, PubMed, and Google Scholar for publications and contacted principal investigators or sponsors. The analysis was performed according to STROBE criteria.

Results

Considering studies that were completed before 2014 (N = 99), 75 (76%) pediatric phase 3 clinical trials were published but 24 (24%) remained unpublished. The unpublished studies concealed evidence from 4,437 patients. Mean time-to-publication was 25 SD ± 15.6 months, more than twice as long as mandated.

Conclusion

Ten years after the ICMJE’s clinical trials registration initiative there is still a considerable amount of selective reporting and delay of publication that potentially distorts the body of evidence in the treatment of pediatric seizures.     

Does Visceral Osteopathic Treatment Accelerate Meconium Passage in Very Low Birth Weight Infants?- A Prospective Randomized Controlled Trial

Background

To determine whether the complementary approach of visceral manipulative osteopathic treatment accelerates complete meconium excretion and improves feeding tolerance in very low birth weight infants.

Methods

This study was a prospective, randomized, controlled trial in premature infants with a birth weight <1500 g and a gestational age <32 weeks who received a visceral osteopathic treatment 3 times during their first week of life or no treatment.

Results

Passage of the last meconium occurred after a median of 7.5 days (95% confidence interval: 6–9 days, n = 21) in the intervention group and after 6 days (95% confidence interval: 5-9 days, n = 20,) in the control group (p = 0.11). However, osteopathic treatment was associated with a 8 day longer time to full enteral feedings (p = 0.02), and a 34 day longer hospital stay (Median = 66 vs. 100 days i.e.; p=0.14). Osteopathic treatment was tolerated well and no adverse events were observed.

Conclusions

Visceral osteopathic treatment of the abdomen did not accelerate meconium excretion in VLBW (very low birth weight)-infants. However infants in the osteopathic group had a longer time to full enteral feedings and a longer hospital stay, which could represent adverse effects. Based on our trial results, we cannot recommend visceral osteopathic techniques in VLBW-infants.

Trial registration

Clinical trials.gov: NCT02140710     

A Prospective Study of Seasonal Variation in Shift‐Work Tolerance

Seasonal effects on shift‐work tolerance were assessed using the Standardized Shiftwork Index and the 21‐item Hamilton Depression Scale. Participants (N=88) mainly worked a two‐day, two‐night, four‐off rotation with 12 h shifts changing at 06∶00 and 18∶00 h in Vancouver, Canada. At this latitude (～49° N), daylength varies seasonally from ～16 to ～8 h, and both daily commutes occur in the dark in mid‐winter and in sunlight in mid‐summer. Questionnaires were completed twice, near the summer and winter solstices (order counterbalanced). Outcome variables were mood, general psychological health, sleep quality, chronic fatigue, physical health, job satisfaction, and social and domestic disruption. Of these, general psychological health and mood were significantly worse in winter, while sleep was more disturbed in summer. In winter, 31% exceeded the cutoff for psychological distress, and >70% scored in the higher than normal range for depressive symptoms. In summer, the proportions dropped to 19% and 53%, respectively. Measures of physical health and psychosocial well‐being showed no seasonal effects. Relationships among explanatory and outcome variables, assessed by linear regression and canonical correlations, were also stable across season. Neuroticism was the strongest predictor of tolerance to shift work. Age was predictive only of sleep disturbance in both summer and winter. These results indicate that time of year can affect important outcome measures in shift‐work assessment and intervention studies. The high average scores on measures of psychological distress and depression in winter suggest that at northern latitudes, some shift schedules may increase the risk of seasonal‐type depression.     

Parkinson’s Disease and Risk of Fracture: A Meta-Analysis of Prospective Cohort Studies

Backgrounds/Objective

Parkinson’s disease (PD) is the second most common neurodegenerative disease among the elderly population. However, epidemiological evidence on the relationship of PD with risk of fracture has not been systematically assessed. Therefore, we performed this meta-analysis of prospective studies to explore the association between PD and risk of fracture.

Methods

PubMed, Embase, Web of Science and Cochrane Library up to February 26, 2014 were searched to identify eligible studies. Random-effects model was used to pool the results.

Results

Six studies that totally involved 69,387 participants were included for analysis. Overall, PD patients had an increased risk of fracture compared with control subjects (pooled hazard ratio = 2.66, 95% confidence interval: 2.10–3.36). No publication bias was observed across studies and the subgroup as well as sensitivity analysis suggested that the general results were robust.

Conclusion

The present study suggested that PD is associated with an increased risk of fracture. However, given the limited number and moderate quality of included studies, well-designed prospective cohort studies are required to confirm the findings from this meta-analysis.     

Measurement of waist circumference for retrospective studies – Prospective validation of use of CT images to assess abdominal circumference

IntroductionTo validate the use of supine position and CT images for assessing abdominal circumference (AC).MethodA prospective study in consecutive patients undergoing scheduled abdominal CT at our center between 17 and 25 September 2012.AC was measured four times:

• 1.Standing.
• 2.While lying on the CT table.
• 3.On CT images with a skin contour line, using OsiriX software.
• 4.On CT images with an ellipse perimeter formula, using RAIM Alma 2010 software.

Measurements 1 and 2 were sequentially done by the same trained nurse before abdominal CT just above the iliac crest, while measurements 3 and 4 were done on the last abdominal CT slice not showing the iliac bone. Student's t tests and Q-Q and Bland–Altman plots were used for statistical analysis.ResultsA total of 102 patients were recruited. Mean age, 60 (35–78) years. Mean BMI, 25 (18–39) kg/m². Mean AC, 93.2 (73–135) cm.No significant differences were found between the four ACs measured (Student's t test, P = 0.83).Q-Q and Bland–Altman plots showed good overlapping for the low and central values (73–110 cm) with a greater scatter for extremely high values.For the ellipse estimation, R² was 0.987 with a mean error of 0.4 cm and a stretch dispersion between 1.1 and −0.3 cm.ConclusionSupine (either measured or estimated on CT images by free hand elliptical ROI or ellipse formula) and standing measurements appear to be equivalent for abdominal circumferences <110 cm.     

Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study

BackgroundHigher serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with a lower risk of multiple cancer types across a range of 25(OH)D concentrations.ObjectivesTo investigate whether the previously reported inverse association between 25(OH)D and cancer risk could be replicated, and if a 25(OH)D response region could be identified among women aged 55 years and older across a broad range of 25(OH)D concentrations.MethodsData from two cohorts representing different median 25(OH)D concentrations were pooled to afford a broader range of 25(OH)D concentrations than either cohort alone: the Lappe cohort (N = 1,169), a randomized clinical trial cohort (median 25(OH)D = 30 ng/ml) and the GrassrootsHealth cohort (N = 1,135), a prospective cohort (median 25(OH)D = 48 ng/ml). Cancer incidence over a multi-year period (median: 3.9 years) was compared according to 25(OH)D concentration. Kaplan-Meier plots were developed and the association between 25(OH)D and cancer risk was examined with multivariate Cox regression using multiple 25(OH)D measurements and spline functions. The study included all invasive cancers excluding skin cancer.ResultsAge-adjusted cancer incidence across the combined cohort (N = 2,304) was 840 cases per 100,000 person-years (1,020 per 100,000 person-years in the Lappe cohort and 722 per 100,000 person-years in the GrassrootsHealth cohort). Incidence was lower at higher concentrations of 25(OH)D. Women with 25(OH)D concentrations ≥40 ng/ml had a 67% lower risk of cancer than women with concentrations <20 ng/ml (HR = 0.33, 95% CI = 0.12–0.90).Conclusions25(OH)D concentrations ≥40 ng/ml were associated with substantial reduction in risk of all invasive cancers combined.     

Body Mass Index and Risk of Parkinson’s Disease: A Dose-Response Meta-Analysis of Prospective Studies

Background

A number of epidemiologic studies examining the relationship between body mass index (BMI) and the future occurrence of Parkinson’s disease (PD) reported largely inconsistent findings. We conducted a dose-response meta-analysis of prospective studies to clarify this association.

Methods

Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute study-specific relative risks (RR) and 95% confidence intervals (CI) for an increase in BMI of 5 kg/m², and the random-effects model was used to compute summary RR and 95% CI.

Results

A total of 10 prospective studies were included in the final analysis. An increase in BMI of 5 kg/m² was not associated with PD risk, with a summary RR of 1.00 (95% CI = 0.89-1.12). Results of subgroup analysis found similar results except for a week positive association in studies that adjusted for alcohol consumption (RR = 1.13, 95% CI = 0.99-1.29), and a week inverse association in studies that did not (RR = 0.90, 95% CI = 0.78-1.04). In a separate meta-analysis, no significant association between overweight (25 kg/m² ≤ BMI ≤29.9 kg/m²), obesity (BMI≥30 kg/m²) or excess weight (BMI≥25 kg/m²) and PD risk was observed.

Conclusion

This meta-analysis does not support the notion that higher BMI materially increases PD risk. However, a week positive BMI-PD association that may be masked by confounders still cannot be excluded, and future prospective studies with a good control for potential confounding factors are needed.     

Is Postoperative Imaging Mandatory after Meningioma Removal? Results of a Prospective Study

Background

Routine postoperative imaging (PI) following surgery for intracranial meningiomas is common practice in most neurosurgical departments. The purpose of this study was to determine the role of routine PI and its impact on clinical decision making after resection of meningioma.

Methods

Patient and tumor characteristics, details of radiographic scans, symptoms and alteration of treatment courses were prospectively collected for patients undergoing removal of a supratentorial meningioma of the convexity, falx, tentorium, or lateral sphenoid wing at the authors’ institution between January 1st, 2010 and March 31st, 2012. Patients with infratentorial manifestations or meningiomas of the skull base known to be surgically difficult (e.g. olfactory groove, petroclival, medial sphenoid wing) were not included. Maximum tumor diameter was divided into groups of < 3cm (small), 3 to 6 cm (medium), and > 6 cm (large).

Results

206 patients with meningiomas were operated between January 2010 and March 2012. Of these, 113 patients met the inclusion criteria and were analyzed in this study. 83 patients (73.5%) did not present new neurological deficits, whereas 30 patients (26.5%) became clinically symptomatic. Symptomatic patients had a change in treatment after PI in 21 cases (70%), while PI was without consequence in 9 patients (30%). PI did not result in a change of treatment in all asymptomatic patients (p<0.001) irrespective of tumor size (p<0.001) or localization (p<0.001).

Conclusions

PI is mandatory for clinically symptomatic patients but it is safe to waive it in clinically asymptomatic patients, even if the meningioma was large in size.     

Position of the Physician’s Nametag - A Randomized,Blinded Trial

Background

The patient-physician relation begins when the physician introduces himself with name and function. Most institutions request a nametag with name and function to be worn. Although nametags are consequently worn, the optimal position for the nametag is unknown. It was the purpose of this study to identify whether positioning the nametag on the right or the left chest side provides better visibility to the patient.

Method and Material

One hundred volunteers, blinded to the experimental setup, presented for an orthopedic consultation in a standardized manner. The nametag of the physician was randomly positioned on the left chest side and presented to 50 individuals (age 35 years (range 17 to 83)) or the right chest side and then presented to 50 other individuals (35 years (range 16 to 59)). The time of the participant noticing the nametag was documented. Subsequently, the participant was questioned concerning the relevance of a nametag and verbal self-introduction of the physician.

Results

38% of the participants noticed the nametag on the right as opposed to 20% who noticed it if placed on the left upper chest (p = 0.0473). The mean time to detection was 9 (range 1–40) seconds for nametags on the right and 25.2 seconds (range 3 to 49, p = 0.006) on the left. For 87% of the participants, a nametag is expected and important and nearly all participants (96%) expected the physician to introduce himself verbally.

Conclusion

It is expected that a physician wears a nametag and introduce himself verbally at the first encounter. Positioning the nametag on the right chest side results in better and faster visibility.     

Impact of Withholding Breastfeeding at the Time of Vaccination on the Immunogenicity of Oral Rotavirus Vaccine—A Randomized Trial

BackgroundBreast milk contains anti-rotavirus IgA antibodies and other innate immune factors that inhibit rotavirus replication in vitro. These factors could diminish the immunogenicity of oral rotavirus vaccines, particularly if breastfeeding occurs close to the time of vaccine administration.MethodsBetween April 2011 and November 2012, we conducted an open label, randomized trial to compare the immunogenicity of Rotarix (RV1) in infants whose breastfeeding was withheld one hour before through one hour after vaccination with that in infants breastfed at the time of vaccination. The trial was conducted in the peri-urban area of Ibrahim Hyderi in Karachi, Pakistan. Both groups received three doses of RV1 at 6, 10 and 14 weeks of age. Seroconversion (anti-rotavirus IgA antibodies ≥20 U/mL in subjects seronegative at 6 weeks of age) following three vaccine doses (6, 10 and 14 weeks) was determined at 18 weeks of age (primary objective) and seroconversion following two doses (6 and 10 weeks) was determined at 14 weeks of age (secondary objective).ResultsFour hundred eligible infants were randomly assigned in a 1:1 ratio between the withholding breastfeeding and immediate breastfeeding arms. Overall, 353 (88.3%) infants completed the study according to protocol; 181 in the withholding breastfeeding group and 172 in the immediate breastfeeding group. After three RV1 doses, anti-rotavirus IgA antibody seroconversion was 28.2% (95% CI: 22.1; 35.1) in the withholding arm and 37.8% (95% CI: 30.9; 45.2) in the immediate breastfeeding arm (difference: -9.6% [95% CI: -19.2; 0.2] p=0.07). After two doses of RV1, seroconversion was 16.6% (95% CI: 11.9; 22.7) in the withholding arm and 29.1% (95% CI: 22.8, 36.3) in the immediate breastfeeding arm (difference: -12.5% [95% CI: -21.2,-3.8] p=0.005).ConclusionsWithholding breastfeeding around the time of RV1 vaccine administration did not lead to increased anti-rotavirus IgA seroconversion compared with that seen with a breastfeed at the time of vaccination. On the contrary, IgA seroconversion in infants immediately breastfed tended to be higher than in those withheld from a feeding. Our findings suggest that breastfeeding should be continued adlib around the time of rotavirus vaccination and withholding breastfeeding at that time is unlikely to improve the vaccine immunogenicity.

Trial Registration

ClinicalTrials.gov NCT01199874     

A Questionnaire Elicitation of Surgeons’ Belief about Learning within a Surgical Trial

Introduction

Surgeons gain expertise as they repeatedly conduct a procedure. Such learning is widely acknowledged to pose a challenge to evaluating new surgical procedures. Most surgical trials report little if any information on learning. We elicited surgeons’ belief regarding learning within the context of a randomised trial which assessed two surgical procedures.

Materials and Methods

Surgeons participating in the UKUFF trial were sent a postal questionnaire requesting details on current practice, prior experience and their belief regarding acquiring proficiency and the learning curve of operation time for two surgical procedures (open and arthroscopic rotator cuff repair).

Results

In total 52 (58%) participating surgeons returned a completed questionnaire. The median (IQR) number of procedures required to acquire proficiency were 17 (10,23) and 35 (23,50) for the open and arthroscopic repairs respectively. The distribution of surgeons’ belief regarding the initial point had median (IQR) of 109 (69,128) and 145 (97,171) minutes for open and arthroscopic repair respectively. Corresponding values for the plateau point were 60 (46, 82) and 79 (58, 110).

Conclusions

We have shown that information on the current practice, prior experience and beliefs on the learning process of a surgical procedure can be elicited using a short questionnaire. The approach could aid the interpretation of trial results in terms of generalisability and be used a priori in the design of a trial.     

Translating “Mind-in-Body”: Two Models of Patient Experience Underlying a Randomized Controlled Trial of Qigong

This study explores two conflictingmodels of how patients experience mind-bodytherapies; these models frame the design of aclinical trial examining the effects of qigong (a traditional Chinese movementtherapy) on the immune systems of former cancerpatients. Data consist of ethnographic researchand in-depth interviews conducted at the Bostonteaching hospital where the trial is to takeplace. These interviews, with biomedicalresearchers who designed the trial and with theqigong master responsible for the qigong arm of the trial, reveal twofundamentally different understandings of howqigong is experienced and how thatexperience may be beneficial. The biomedicalteam sees qigong as a non-specifictherapy which combines relaxation and exercise. The qigong master, on the other hand,sees qigong as using specific movementsand visualizations to direct mental attentionto specific areas of the body. Thus while thebiomedical team frames qigong as amind-body practice, the qigong masterframes it as a mind-in-body practice.This research suggests that the biomedicalnotion that mind-body therapies work byeliciting mental relaxation is only one way ofthinking about how patients experiencemodalities like qigong: indeed,characterizations of mind-body therapies whichemphasize a mental sense of relaxation may bespecific to biomedicine and the cultures whichsurround it. More broadly, the paper arguesthat gaps in understanding between researchersand practitioners may be hindering scientificefforts to assess therapies like qigong.It concludes by proposing that clinical trialsof traditional and alternative therapies buildethnographic inquiry about practitionerexperience into the design process.