Advancing our understanding of skeletal muscle across the lifecourse: Protocol for the MASS_Lifecourse study and characteristics of the first 80 participants.

INTRODUCTION: Sarcopenia, the age-related loss of skeletal muscle strength and mass, carries a significant burden for affected individuals. There has been little investigation of sarcopenia using experimental medicine techniques to study human muscle tissue in detail. The aim of the Muscle Ageing Sarcopenia Studies Lifecourse (MASS_Lifecourse) study is to recruit up to 160 participants, equally divided between females and males between ages 45 and 85 years for detailed phenotyping of skeletal muscle health. Here we describe the protocol for the study and the characteristics of the first 80 participants. METHODS: We are recruiting participants from three sources in the north-east of England. Study fieldwork comprises a home visit (or videocall) for consent and assessment of health, cognition, lifestyle, and wellbeing. This is followed by a visit to a clinical research facility for assessment of sarcopenia status and collection of samples including a vastus lateralis muscle biopsy. We produced descriptive statistics for the first 80 participants, including expressing their grip strength relative to normative data in the form of Z-scores. RESULTS: The first 80 participants (53.8 % female) covered the target ages, ranging from 48 to 84 years. They were regularly physically active, reported good physical function and had a prevalence of sarcopenia (including probable sarcopenia) of 11.3 % based on the revised European consensus. Their grip strength was similar to that in the general population, with a mean Z-score of 0.09 standard deviations (95 % CI: -1.64, 1.83) above that expected. CONCLUSIONS: The MASS_Lifecourse study combines comprehensive health and lifestyle data with a range of biological samples including skeletal muscle. The findings from planned analyses should contribute to improvements in the diagnosis, treatment, and prevention of sarcopenia.

Statistical controversies in clinical research: Value of adverse events relatedness to study treatment: analyses of data from randomized double-blind placebo-controlled clinical trials.

BACKGROUND: Collection and reporting of adverse events (AEs) and their relatedness to study treatment, known commonly as attribution, in clinical trials is mandated by regulatory agencies (the National Cancer Institute and the Food and Drug Administration). Attribution is assigned by the treating physician using judgment based on various factors including patient's baseline status, disease history, and comorbidity as well as knowledge about the safety profile of the study treatments. We evaluate the patterns of AE attribution (unrelated, unlikely, possibly, probably, and definitely related to the treatment) in treatment, symptom intervention (cancer patients) and cancer prevention (participants at high risk for cancer) setting. MATERIALS AND METHODS: Nine multicenter placebo-controlled trials (two treatment, two symptom intervention, and five cancer prevention) were analysed separately (2155 patients). Frequency and severity of AEs were summarized by arm. Attribution and percentage of repeated AEs whose attribution changed overtime were summarized for the placebo arms. Percentage of physician over- or under-reporting of AE relatedness was calculated for the treatment arms using the placebo arm as the reference. RESULTS: Across all trials and settings, a very high proportion of AEs reported as related to treatment were classified as possibly related, a significant proportion of AEs in the placebo arm were incorrectly reported as related to treatment, and clinician-reported attribution over-estimated the rate of AEs related to treatment. Fatigue, nausea, vomiting, diarrhea, constipation, and neurosensory were the common AEs that were over reported by clinician as related to treatment. CONCLUSIONS: These analyses demonstrate that assigning causality to AE is a complex and difficult process that produces unreliable and subjective data. In randomized double-blind placebo-controlled trials where data are available to objectively assess relatedness of AE to treatment, attribution assignment should be eliminated.

Comparison of Solomon technique with selective laser ablation for twin-twin transfusion syndrome: a systematic review.

OBJECTIVE: To compare the Solomon and selective techniques for fetoscopic laser ablation (FLA) for the treatment of twin-twin transfusion syndrome (TTTS) in monochorionic-diamniotic twin pregnancies. METHODS: This was a systematic review conducted in accordance with the PRISMA statement. Electronic searches were performed for relevant citations published from inception to September 2014. Selected studies included pregnancies undergoing FLA for TTTS that reported on recurrence of TTTS, occurrence of twin anemia-polycythemia sequence (TAPS) or survival. RESULTS: From 270 possible citations, three studies were included, two cohort studies and one randomized controlled trial (RCT), which directly compared the Solomon and selective techniques for FLA. The odds ratios (OR) of recurrent TTTS when using the Solomon vs the selective technique in the two cohort studies (n = 249) were 0.30 (95% CI, 0.00-4.46) and 0.45 (95% CI, 0.07-2.20). The RCT (n = 274) demonstrated a statistically significant reduction in risk of recurrent TTTS with the Solomon technique (OR, 0.21 (95% CI, 0.04-0.98); P = 0.03). The ORs for the development of TAPS following the Solomon and the selective techniques were 0.20 (95% CI, 0.00-2.46) and 0.61 (95% CI, 0.05-5.53) in the cohort studies and 0.16 (95% CI, 0.05-0.49) in the RCT, with statistically significant differences for the RCT only (P < 0.001). Observational evidence suggested overall better survival with the Solomon technique, which was statistically significant for survival of at least one twin. The RCT did not demonstrate a significant difference in survival between the two techniques, most probably owing to the small sample size and lack of power. CONCLUSION: This systematic review of observational, comparative cohort and RCT data suggests a trend towards a reduction in TAPS and recurrent TTTS and an increase in twin survival, with no increase in the occurrence of complications or adverse events, when using the Solomon compared to the selective technique for the treatment of TTTS. These findings need to be confirmed by an appropriately-powered RCT with long-term neurological follow-up.

Physicochemical and toxicological profiling of ash from the 2010 and 2011 eruptions of Eyjafjallajökull and Grímsvötn volcanoes, Iceland using a rapid respiratory hazard assessment protocol.

The six week eruption of Eyjafjallajökull volcano in 2010 produced heavy ash fall in a sparsely populated area of southern and south eastern Iceland and disrupted European commercial flights for at least 6 days. We adopted a protocol for the rapid analysis of volcanic ash particles, for the purpose of informing respiratory health risk assessments. Ash collected from deposits underwent a multi-laboratory physicochemical and toxicological investigation of their mineralogical parameters associated with bio-reactivity, and selected in vitro toxicology assays related to pulmonary inflammatory responses. Ash from the eruption of Grímsvötn, Iceland, in 2011 was also studied. The results were benchmarked against ash from Soufrière Hills volcano, Montserrat, which has been extensively studied since the onset of eruptive activity in 1995. For Eyjafjallajökull, the grain size distributions were variable: 2-13 vol% of the bulk samples were <4 µm, with the most explosive phases of the eruption generating abundant respirable particulate matter. In contrast, the Grímsvötn ash was almost uniformly coarse (<3.5 vol%<4 µm material). Surface area ranged from 0.3 to 7.7 m2 g(-1) for Eyjafjallajökull but was very low for Grímsvötn (<0.6 m2 g(-1)). There were few fibre-like particles (which were unrelated to asbestos) and the crystalline silica content was negligible in both eruptions, whereas Soufrière Hills ash was cristobalite-rich with a known potential to cause silicosis. All samples displayed a low ability to deplete lung antioxidant defences, showed little haemolysis and low acute cytotoxicity in human alveolar type-1 like epithelial cells (TT1). However, cell-free tests showed substantial hydroxyl radical generation in the presence of hydrogen peroxide for Grímsvötn samples, as expected for basaltic, Fe-rich ash. Cellular mediators MCP-1, IL-6, and IL-8 showed chronic pro-inflammatory responses in Eyjafjallajökull, Grímsvötn and Soufrière Hills samples, despite substantial differences in the sample mineralogy and eruptive styles. The value of the pro-inflammatory profiles in differentiating the potential respiratory health hazard of volcanic ashes remains uncertain in a protocol designed to inform public health risk assessment, and further research on their role in volcanic crises is warranted.

Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia.

The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to 2-week-old GSD-Ia mice (n = 9). Median survival was prolonged to 7 months following vector administration, in contrast to untreated GSD-Ia mice that survived for only 2 weeks. Although GSD-Ia mice were initially growth-retarded, treated mice increased fourfold in weight to normal size. Blood glucose was partially corrected by 2 weeks following treatment, whereas blood cholesterol normalized. Glucose-6-phosphatase activity was partially corrected to 25% of the normal level at 7 months of age in treated mice, and blood glucose during fasting remained lower in treated, affected mice than in normal mice. Glycogen storage was partially corrected in the liver by 2 weeks following treatment, but reaccumulated to pre-treatment levels by 7 months old (m.o.). Vector genome DNA decreased between 3 days and 3 weeks in the liver following vector administration, mainly through the loss of single-stranded genomes; however, double-stranded vector genomes were more stable. Although CD8+ lymphocytic infiltrates were present in the liver, partial biochemical correction was sustained at 7 m.o. The development of efficacious AAV vector-mediated gene therapy could significantly reduce the impact of long-term complications in GSD-Ia, including hypoglycemia, hyperlipidemia and growth failure.

A phase II trial of edatrexate, vinblastine, adriamycin, cisplastin, and filgrastim (EVAC/G-CSF) in patients with non-small-cell carcinoma of the lungs: a North Central Cancer Treatment Group Trial.

Edatrexate is an antifolate agent with improved in vitro antineoplastic activity as compared with methotrexate. A Mayo phase I trial of edatrexate (E), vinblastine (V), doxorubicin (Adriamycin) (A), cisplatin (C), and filgrastim (GCSF), (EVAC-GCSF) showed promising antineoplastic activity in non-small-cell lung cancer (NSCLC) (Colon-Otero G, et al. Cancer J Sci Am 1997;3:297-302) leading to a phase II trial of this regimen, the results of which are reported here. A total of 34 patients with stage IIIB or IV measurable or evaluable NSCLC were entered in this North Central Cancer Treatment Group phase II study. Treatment consisted of edatrexate 100 mg/m2 intravenously on day 1 and cisplatin 30 mg/m2/d on day 1 and day 2 followed by vinblastine 3 mg/m2 intravenously and doxorubicin 30 mg/m2 intravenously on day 2. Filgrastim was given at 300 microg subcutaneously daily from day 4 to day 18 or until an absolute neutrophil count of 2,000/mm3 or more was obtained. Cycles were repeated every 21 days until either progression or the development of intolerable toxicity. Sixteen of 34 evaluable patients responded to therapy, for a response rate of 47.1% with a 95% CI of 30.3% to 63.8%. Median time to disease progression was 132 days, median survival time was 219 days, and the estimated 1-year survival was 41.2% (95% CI of 27.6-61.5%). The EVAC/G-CSF regimen has significant antineoplastic activity as seen by the response rates for patients with NSCLC. However, this study had significant myelosuppressive toxicity; 56% patients had grade III or higher leukopenia with three treatment-related deaths observed. In addition, Quality of Life assessments indicate that patients experienced an overall decline in quality of life during the course of treatment. These mitigating factors need to be considered regarding further evaluation of this regimen in this patient population.

Storytelling. A strategy for living and coping with cancer.

The purpose of this focused program evaluation was to explore attitudes and beliefs about storytelling as a strategy for coping with cancer among participants who attended a cancer-related storytelling workshop. The response rate was 70% (n = 94) and included persons with a diagnosis of cancer, their loved ones, and members of the public. The program coordinators used a theoretical model described by Heiney (1995) that explains how storytelling may produce therapeutic effects in four domains: cognitive, affective, interpersonal, and personal. A questionnaire was designed to determine the extent that conference participants perceived therapeutic benefits in these domains as a result of attending the workshop. Statistical analysis consisted of descriptive summaries of individual questions and domain scores. Findings showed that 97% of the respondents agreed that storytelling was a helpful way to cope with cancer. Most of the respondents reported agreement with the therapeutic benefits of storytelling in all domains, with 85% agreeing that hearing others' stories of living with cancer gave them hope. Although the results of the evaluation were very positive, further study is needed to demonstrate the efficacy of storytelling as a strategy for coping with cancer.

Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma.

PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response. RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (> or = grade 3) than those who received ODTI (12.3% v 5.3%; P =.05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation. CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.

Rapid diagnosis of homocystinuria and other hypermethioninemias from newborns' blood spots by tandem mass spectrometry.

We report a new method for the diagnosis of homocystinuria and other hypermethioninemias from dried blood spots on newborn screening cards, based on isotope-dilution tandem mass spectrometry. The mean concentration of methionine in 909 unaffected newborns was 19 micromol/L (CV 44%). The variability of results was reduced when the concentration of methionine was expressed relative to that of another amino acid in the same specimen. The mean ratio of methionine to leucine plus isoleucine for these same newborn blood spots was 0.16 (CV 25%). In newborn samples from a collection categorized by a Guthrie bacterial inhibition assay as true positive, unaffected, or falsely positive for hypermethioninemias, the ratio of methionine to leucine for each true-positive specimen was at least 2.5 times greater than for respective age-matched unaffected blood specimens. The ratio for falsely positive samples did not differ from that for unaffected blood samples. We predict that the ratio of methionine to leucine plus isoleucine determined by tandem mass spectrometry will successfully detect hypermethioninemias with very low rates for false positives and false negatives.

Power of the independent samples t test under a prevalent psychometric measure distribution.

Studies in psychology often have low power because of inadequate sample size. Thus, recent articles in this journal have suggested making sample size determinations through readily available tables that are based on population normality. Questions have been raised on the use of these power tables because prevalent psychometric distributions, such as the discrete mass at zero with gap that occurs with first use or onset variables, are radically nonnormal. In addition to demonstrating the robustness of the independent samples t test with respect to type I error, the major finding of this study shows that researchers may use these power tables without modification for this radically nonnormal distribution.

Maternal employment and early adolescent substance use.

Research stimulated by increases in maternal employment has focused primarily on children, even though mothers of adolescents are more likely to be employed. It is adolescents who experience developmental changes that promote participation in adult behaviors in advance of their abilities. This study investigated the effects of maternal employment on the use of alcohol, cigarettes, marijuana, and other substances by early adolescents. A sample of ninth-grade students responded to a 48-item survey about their substance use behavior. A comparison of maternal employment patterns (full-time vs. part-time/not employed outside the home) indicated no significant differences in substance use behavior. These results confirmed and extended the growing literature regarding the nonharmful effects of maternal employment on adolescent adjustment and behavior.