Capital District Health Authority

BACKGROUND: The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS: We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS: A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00). CONCLUSIONS: Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 .).

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS: Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION: The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

BACKGROUND: Frailty can be measured in relation to the accumulation of deficits using a frailty index. A frailty index can be developed from most ageing databases. Our objective is to systematically describe a standard procedure for constructing a frailty index. METHODS: This is a secondary analysis of the Yale Precipitating Events Project cohort study, based in New Haven CT. Non-disabled people aged 70 years or older (n = 754) were enrolled and re-contacted every 18 months. The database includes variables on function, cognition, co-morbidity, health attitudes and practices and physical performance measures. Data came from the baseline cohort and those available at the first 18-month follow-up assessment. RESULTS: Procedures for selecting health variables as candidate deficits were applied to yield 40 deficits. Recoding procedures were applied for categorical, ordinal and interval variables such that they could be mapped to the interval 0-1, where 0 = absence of a deficit, and 1= full expression of the deficit. These individual deficit scores were combined in an index, where 0= no deficit present, and 1= all 40 deficits present. The values of the index were well fit by a gamma distribution. Between the baseline and follow-up cohorts, the age-related slope of deficit accumulation increased from 0.020 (95% confidence interval, 0.014-0.026) to 0.026 (0.020-0.032). The 99% limit to deficit accumulation was 0.6 in the baseline cohort and 0.7 in the follow-up cohort. Multivariate Cox analysis showed the frailty index, age and sex to be significant predictors of mortality. CONCLUSION: A systematic process for creating a frailty index, which relates deficit accumulation to the individual risk of death, showed reproducible properties in the Yale Precipitating Events Project cohort study. This method of quantifying frailty can aid our understanding of frailty-related health characteristics in older adults.

Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.

BACKGROUND: Many definitions of frailty exist, but few have been directly compared. We compared the relationship between a definition of frailty based on a specific phenotype with one based on an index of deficit accumulation. METHODS: The data come from all 2305 people 70 years old and older who composed the clinical examination cohort of the second wave of the Canadian Study of Health and Aging. We tested convergent validity by correlating the measures with each other and with other health status measures, and analyzed cumulative index distributions in relation to phenotype. To test criterion validity, we evaluated survival (institutionalization and all-cause mortality) by frailty index (FI) score, stratified by the phenotypic definitions as "robust," "pre-frail," and "frail." RESULTS: The measures correlated moderately well with each other (R=0.65) and with measures of function (phenotypic definition R=0.66; FI R=0.73) but less well with cognition (phenotypic definition R=-0.35; FI R=-0.58). The median FI scores increased from 0.12 for the robust to 0.30 for the pre-frail and 0.44 for the frail. Survival was also lower with increasing frailty, and institutionalization was more common, but within each phenotypic class, there were marked differences in outcomes based on the FI values-e.g., among robust people, the median 5-year survival for those with lower FI values was 85%, compared with 55% for those with higher FI values. CONCLUSION: The phenotypic definition of frailty, which offers ready clinical operationalization, discriminates broad levels of risk. The FI requires additional clinical translation, but allows the risk of adverse outcomes to be defined more precisely.

OBJECTIVES: To evaluate the prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation. DESIGN: Prospective cohort study. SETTING: The National Population Health Survey of Canada, with frailty estimated at baseline (1994/95) and mortality follow-up to 2004/05. PARTICIPANTS: Community-dwelling older adults (N=2,740, 60.8% women) aged 65 to 102 from 10 Canadian provinces. During the 10-year follow-up, 1,208 died. MEASUREMENTS: Self-reported health information was used to construct a frailty index (Frailty Index) as a proportion of deficits accumulated in individuals. The main outcome measure was mortality. RESULTS: The prevalence of frailty increased with age in men and women (correlation coefficient=0.955-0.994, P<.001). The Frailty Index estimated that 622 (22.7%, 95% confidence interval (CI)=21.0-24.4%) of the sample was frail. Frailty was more common in women (25.3%, 95% CI=23.2-27.5%) than in men (18.6%, 95% CI=15.9-21.3%). For those aged 85 and older, the Frailty Index identified 39.1% (95% CI=31.3-46.9%) of men as frail, compared with 45.1% (95% CI=39.7-50.5%) of women. Frailty significantly increased the risk of death, with an age- and sex-adjusted hazard ratio for the Frailty Index of 1.57 (95% CI=1.41-1.74). CONCLUSION: The prevalence of frailty increases with age and at any age lessens survival. The Frailty Index approach readily identifies frail people at risk of death, presumably because of its use of multiple health deficits in multidimensional domains.

Islet transplantation offers the prospect of good glycemic control without major surgical risks. After our initial report of successful islet transplantation, we now provide further data on 12 type 1 diabetic patients with brittle diabetes or problems with hypoglycemia previous to 1 November 2000. Details of metabolic control, acute complications associated with islet transplantation, and long-term complications related to immunosuppression therapy and diabetes were noted. Insulin secretion, both acute and over 30 min, was determined after intravenous glucose tolerance tests (IVGTTs). The median follow-up was 10.2 months (CI 6.5-17.4), and the longest was 20 months. Glucose control was stable, with pretransplant fasting and meal tolerance-stimulated glucose levels of 12.5+/-1.9 and 20.0+/-2.7 mmol/l, respectively, but decreased significantly, with posttransplant levels of 6.3+/-0.3 and 7.5+/-0.6 mmol/l, respectively (P < 0.006). All patients have sustained insulin production, as evidenced by the most current baseline C-peptide levels 0.66+/-0.06 nmol/l, increasing to 1.29+/-0.25 nmol/l 90 min after the meal-tolerance test. The mean HbA1c level decreased from 8.3+/-0.5% to the current level of 5.8+/-0.1% (P < 0.001). Presently, four patients have normal glucose tolerance, five have impaired glucose tolerance, and three have post-islet transplant diabetes (two of whom need oral hypoglycemic agents and low-dose insulin (<10 U/day). Three patients had a temporary increase in their liver-function tests. One patient had a thrombosis of a peripheral branch of the right portal vein, and two of the early patients had bleeding from the hepatic needle puncture site; but these technical problems were resolved. Two patients had transient vitreous hemorrhages. The two patients with elevated creatinine levels pretransplant had a significant increase in serum creatinine in the long term, although the mean serum creatinine of the group was unchanged. The cholesterol increased in five patients, and lipid-lowering therapy was required for three patients. No patient has developed cytomegalovirus infection or disease, posttransplant lymphoproliferative disorder, malignancies, or serious infection to date. None of the patients have been sensitized to donor antigen. In 11 of the 12 patients, insulin independence was achieved after 9,000 islet equivalents (IEs) per kilogram were transplanted. The acute insulin response and the insulin area under the curve (AUC) after IVGTT were consistently maintained over time. The insulin AUC from the IVGTT correlated to the number of islets transplanted, but more closely correlated when the cold ischemia time was taken into consideration (r = 0.83, P < 0.001). Islet transplantation has successfully corrected labile type 1 diabetes and problems with hypoglycemia, and our results show persistent insulin secretion. After a minimum of 9,000 IEs per kilogram are provided, insulin independence is usually attained. An elevation of creatinine appears to be a contraindication to this immunosuppressive regimen. For the subjects who had labile type 1 diabetes that was difficult to control, the risk-to-benefit ratio is in favor of islet transplantation.

Clinical islet transplantation is gaining acceptance as a potential therapy, particularly for subjects who have labile diabetes or problems with hypoglycemic awareness. The risks of the procedure and long-term outcomes are still not fully known. We have performed 54 islet transplantation procedures on 30 subjects and have detailed follow-up in 17 consecutive Edmonton protocol-treated subjects who attained insulin independence after transplantation of adequate numbers of islets. Subjects were assessed pretransplant and followed prospectively posttransplant for immediate and long-term complications related to the procedure or immunosuppressive therapy. The 17 patients all became insulin independent after a minimum of 9,000 islets/kg were transplanted. Of 15 consecutive patients with at least 1 year of follow-up after the initial transplant, 12 (80%) were insulin independent at 1 year. In 14 subjects who have maintained demonstrable C-peptide secretion, glucose control has been stable and glycemic lability and problems with hypoglycemic reactions have been corrected. After 2 of the 54 procedures, some thrombosis was detected in the portal vein circulation. Five subjects had bleeding related to the percutaneous portal vein access procedures: three required transfusion alone, and in one subject, who had a partial thrombosis of the portal vein, an expanding intrahepatic and subscapular hemorrhage occurred while on anticoagulation, requiring transfusion and surgery. Elevated liver function test results were found in 46% of subjects but resolved in all. Complications related to the therapy have been hypercholesterolemia requiring statin therapy in 65%; a rise in creatinine in two patients, both of whom had preexisting renal disease; a rise in protein in four, all of whom had preexisting proteinuria; and antihypertensive therapy increased or started in 53%. Three of the 17 patients have required retinal laser photocoagulation. There have been no cases of posttransplant lymphoproliferative disorder or cytomegalovirus infection, and no deaths. The acute insulin response to arginine correlated better with transplanted islet mass than acute insulin response to glucose (AIR(g)) and area under the curve for insulin (AUC(i)), but the AIR(g) and AUC(i) were more closely related to glycemic control. The AUC(i) directly posttransplant was lower in those who eventually became C-peptide deficient. Our results, with a maximum follow-up of 34 months, indicate that prolonged insulin independence can be achieved after islet transplantation. There are some risks associated acutely with the procedure, and hypercholesterolemia and hypertension are treatable concerns on longer-term follow-up. All patients with persisting C-peptide secretion have had a resolution of both glycemic lability and problems with hypoglycemic reactions. Apart from the rise in serum creatinine in two subjects, no serious consequences of immunosuppressive therapy have been encountered. Islet transplantation is a reasonable option in those with severe problems with glycemic lability or hypoglycemia.

OBJECTIVES: To operationalize frailty using eight scales and to compare their content validity, feasibility, prevalence estimates of frailty, and ability to predict all-cause mortality. DESIGN: Secondary analysis of the Survey of Health, Ageing and Retirement in Europe (SHARE). SETTING: Eleven European countries. PARTICIPANTS: Individuals aged 50 to 104 (mean age 65.3 ± 10.5, 54.8% female, N = 27,527). MEASUREMENTS: Frailty was operationalized using SHARE data based on the Groningen Frailty Indicator, the Tilburg Frailty Indicator, a 70-item Frailty Index (FI), a 44-item FI based on a Comprehensive Geriatric Assessment (FI-CGA), the Clinical Frailty Scale, frailty phenotype (weighted and unweighted versions), the Edmonton Frail Scale, and the FRAIL scale. RESULTS: All scales had fewer than 6% of cases with at least one missing item, except the SHARE-frailty phenotype (11.1%) and the SHARE-Tilburg (12.2%). In the SHARE-Groningen, SHARE-Tilburg, SHARE-frailty phenotype, and SHARE-FRAIL scales, death rates were 3 to 5 times as high in excluded cases as in included ones. Frailty prevalence estimates ranged from 6% (SHARE-FRAIL) to 44% (SHARE-Groningen). All scales categorized 2.4% of participants as frail. Of unweighted scales, the SHARE-FI and SHARE-Edmonton scales most accurately predicted mortality at 2 (SHARE-FI area under the receiver operating characteristic curve (AUC) = 0.77, 95% confidence interval (CI) = 0.75-0.79); SHARE-Edmonton AUC = 0.76, 95% CI = 0.74-0.79) and 5 (both AUC = 0.75, 95% CI = 0.74-0.77) years. The continuous score of the weighted SHARE-frailty phenotype (AUC = 0.77, 95% CI = 0.75-0.78) predicted 5-year mortality better than the unweighted SHARE-frailty phenotype (AUC = 0.70, 95% CI = 0.68-0.71), but the categorical score of the weighted SHARE-frailty phenotype did not (AUC = 0.70, 95% CI = 0.68-0.72). CONCLUSION: Substantive differences exist between scales in their content validity, feasibility, and ability to predict all-cause mortality. These frailty scales capture related but distinct groups. Weighting items in frailty scales can improve their predictive ability, but the trade-off between specificity, predictive power, and generalizability requires additional evaluation.

The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.

BACKGROUND: Prognosis research aims to identify factors associated with the course of health conditions. It is often challenging to judge the overall quality of research evidence in systematic reviews about prognosis due to the nature of the primary studies. Standards aimed at improving the quality of primary studies on the prognosis of health conditions have been created, but these standards are often not adequately followed causing confusion about how to judge the evidence. METHODS: This article presents a proposed adaptation of Grading of Recommendations Assessment, Development and Evaluation (GRADE), which was developed to rate the quality of evidence in intervention research, to judge the quality of prognostic evidence. RESULTS: We propose modifications to the GRADE framework for use in prognosis research along with illustrative examples from an ongoing systematic review in the pediatric pain literature. We propose six factors that can decrease the quality of evidence (phase of investigation, study limitations, inconsistency, indirectness, imprecision, publication bias) and two factors that can increase it (moderate or large effect size, exposure-response gradient). CONCLUSIONS: We describe criteria for evaluating the potential impact of each of these factors on the quality of evidence when conducting a review including a narrative synthesis or a meta-analysis. These recommendations require further investigation and testing.

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV-related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV-related morbidity and mortality.

BACKGROUND: Surgical repair is a common method of treatment of acute Achilles rupture in North America because, despite a higher risk of overall complications, it has been believed to offer a reduced risk of rerupture. However, more recent trials, particularly those using functional bracing with early range of motion, have challenged this belief. The aim of this meta-analysis was to compare surgical treatment and conservative treatment with regard to the rerupture rate, the overall rate of other complications, return to work, calf circumference, and functional outcomes, as well as to examine the effects of early range of motion on the rerupture rate. METHODS: A literature search, data extraction, and quality assessment were conducted by two independent reviewers. Publication bias was assessed with use of the Egger and Begg tests. Heterogeneity was assessed with use of the I2 test, and fixed or random-effect models were used accordingly. Pooled results were expressed as risk ratios, risk differences, and weighted or standardized mean differences, as appropriate. Meta-regression was employed to identify causes of heterogeneity. Subgroup analysis was performed to assess the effect of early range of motion. RESULTS: Ten studies met the inclusion criteria. If functional rehabilitation with early range of motion was employed, rerupture rates were equal for surgical and nonsurgical patients (risk difference = 1.7%, p = 0.45). If such early range of motion was not employed, the absolute risk reduction achieved by surgery was 8.8% (p = 0.001 in favor of surgery). Surgery was associated with an absolute risk increase of 15.8% (p = 0.016 in favor of nonoperative management) for complications other than rerupture. Surgical patients returned to work 19.16 days sooner (p = 0.0014). There was no significant difference between the two treatments with regard to calf circumference (p = 0.357), strength (p = 0.806), or functional outcomes (p = 0.226). CONCLUSIONS: The results of the meta-analysis demonstrate that conservative treatment should be considered at centers using functional rehabilitation. This resulted in rerupture rates similar to those for surgical treatment while offering the advantage of a decrease in other complications. Surgical repair should be preferred at centers that do not employ early-range-of-motion protocols as it decreased the rerupture risk in such patients.

OBJECTIVE: To conduct a systematic review of the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. DATA SOURCES: 13 electronic databases and reference lists of relevant reviews and included studies; Associated Professional Sleep Society abstracts (1999 to 2003). STUDY SELECTION: The efficacy review included randomised controlled trials; the safety review included randomised and non-randomised controlled trials. QUALITY ASSESSMENT: Randomised controlled trials were assessed by using the Jadad Scale and criteria by Schulz et al, and non-randomised controlled trials by the Downs and Black checklist. DATA EXTRACTION AND SYNTHESIS: One reviewer extracted data and another reviewer verified the data extracted. The inverse variance method was used to weight studies and the random effects model was used to analyse data. MAIN RESULTS: Six randomised controlled trials with 97 participants showed no evidence that melatonin had an effect on sleep onset latency in people with secondary sleep disorders (weighted mean difference -13.2 (95% confidence interval -27.3 to 0.9) min). Nine randomised controlled trials with 427 participants showed no evidence that melatonin had an effect on sleep onset latency in people who had sleep disorders accompanying sleep restriction (-1.0 (-2.3 to 0.3) min). 17 randomised controlled trials with 651 participants showed no evidence of adverse effects of melatonin with short term use (three months or less). CONCLUSIONS: There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use.

BACKGROUND: Skin-to-skin care (SSC), often referred to as 'kangaroo care' (KC) due to its similarity with marsupial behaviour of ventral maternal-infant contact, is one non-pharmacological intervention for pain control in infants. OBJECTIVES: The primary objectives were to determine the effect of SSC alone on pain from medical or nursing procedures in neonates compared to no intervention, sucrose or other analgesics, or additions to simple SSC such as rocking; and to determine the effects of the amount of SSC (duration in minutes), method of administration (e.g. who provided the SSC) of SSC in reducing pain from medical or nursing procedures in neonatesThe secondary objectives were to determine the safety of SSC care for relieving procedural pain in infants; and to compare the SSC effect in different postmenstrual age subgroups of infants. SEARCH METHODS: For this update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1); MEDLINE via PubMed (1966 to 25 February 2016); Embase (1980 to 25 February 2016); and CINAHL (1982 to 25 February 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: Studies with randomisation or quasi-randomisation, double- or single-blinded, involving term infants (≥ 37 completed weeks' postmenstrual age (PMA) to a maximum of 44 weeks' PMA and preterm infants (< 37 completed weeks PMA) receiving SSC for painful procedures conducted by healthcare professionals. DATA COLLECTION AND ANALYSIS: The main outcome measures were physiological or behavioural pain indicators and composite pain scores. A mean difference (MD) with 95% confidence interval (CI) using a fixed-effect model was reported for continuous outcome measures. We included variations on type of tissue-damaging procedure, provider of care, and duration of SSC. MAIN RESULTS: Twenty-five studies (n = 2001 infants) were included. Nineteen studies (n = 1065) used heel lance as the painful procedure, one study combined venepuncture and heel stick (n = 50), three used intramuscular injection (n = 776), one used 'vaccination' (n = 60), and one used tape removal (n = 50). The studies were generally strong and had low or uncertain risk of bias. Blinding of the intervention was not possible, making them subject to high risk, depending on the method of scoring outcomes.Seventeen studies (n = 810) compared SSC to a no-treatment control. Although 15 studies measured heart rate during painful procedures, data from only five studies (n = 161) could be combined for a mean difference (MD) of -10.78 beats per minute (95% CI -13.63 to -7.93) favouring SSC. Meta-analysis of four studies (n = 120) showed no difference in heart rate following the painful procedure (MD 0.08, 95% CI -4.39 to 4.55). Two studies (n = 38) reported heart rate variability with no significant differences. Two studies (n = 101) in a meta-analysis on oxygen saturation at 30 and 60 seconds following the painful procedure did not show a difference. Duration of crying meta-analysis was performed on four studies (n = 133): two (n = 33) investigated response to heel lance (MD = -34.16, 95% CI -42.86 to -25.45), and two (n = 100) following IM injection (MD = -8.83, 95% CI -14.63 to -3.02), favouring SSC. Five studies, one consisting of two substudies (n = 267), used the Premature Infant Pain Profile (PIPP) as a primary outcome, which favoured SCC at 30 seconds (MD -3.21, 95% CI -3.94 to -2.47), at 60 seconds (3 studies; n = 156) (MD -1.64, 95% CI -2.86 to -0.43), and at 90 seconds (n = 156) (MD -1.28, 95% CI -2.53 to -0.04); but at 120 seconds there was no difference (n = 156) (MD 0.07, 95% CI -1.11 to 1.25). No studies on return of heart rate to baseline level, cortisol levels, and facial actions could be combined for meta-analysis findings.Eight studies compared SSC to another intervention with or without a no-treatment control. Two cross-over studies (n = 80) compared mother versus other provider (father, another female) on PIPP scores at 30, 60, 90, and 120 seconds with no significant difference. When SSC was compared to other interventions, there were not enough similar studies to pool results in an analysis. One study compared SSC (n = 640) with and without dextrose and found that the combination was most effective and that SSC alone was more effective than dextrose alone. Similarly, in another study SSC was more effective than oral glucose for heart rate (n = 95). SSC either in combination with breastfeeding or alone was favoured over a no-treatment control, but not different to breastfeeding. One study compared SSC alone and in combination with both sucrose and breastfeeding on heart rate (HR), NIPS scores, and crying time (n = 127). The combinations were more effective than SSC alone for NIPS and crying. Expressed breast milk was compared to SSC in one study (n = 50) and found both equally effective on PIPP scores. There were not enough participants with similar outcomes and painful procedures to compare age groups or duration of SSC. No adverse events were reported in any of the studies. AUTHORS' CONCLUSIONS: SSC appears to be effective as measured by composite pain indicators with both physiological and behavioural indicators and, independently, using heart rate and crying time; and safe for a single painful procedure. Purely behavioural indicators tended to favour SSC but with facial actions there is greater possibility of observers not being blinded. Physiological indicators were mixed although the common measure of heart rate favoured SSC. Two studies compared mother-providers to others, with non-significant results. There was more heterogeneity in the studies with behavioural or composite outcomes. There is a need for replication studies that use similar, clearly defined outcomes. Studies examining optimal duration of SSC, gestational age groups, repeated use, and long-term effects of SSC are needed. Of interest would be to study synergistic effects of SSC with other interventions.

ABSTRACT This article argues that divergent images of community result not from inadequate knowledge or confusion of purpose, but from the location of discourse and action in the context of specific struggles and dilemmas. It supports the view that ‘struggles over resources’ are also ‘struggles over meaning’. It demonstrates the ways in which contests over the distribution of property are articulated in terms of competing representations of community at a range of levels and sites. It suggests that, through the exercise of ‘practical political economy’, particular representations of community can be used strategically to strengthen the property claims of potentially disadvantaged groups. In the policy arena, advocates for ‘community based resource management’ have represented communities as sites of consensus and sustain‐ability. Though idealized, such representations have provided a vocabulary with which to defend the rights of communities vis‐à‐vis states. Poor farmers, development planners, consultants and academics can also use representations of community strategically to achieve positive effects, or at least to mitigate negative ones. Most, but not all, of the illustrations in this article are drawn from Indonesia, with special reference to Central Sulawesi.

Clinical trials in Wilms tumor (WT) have resulted in overall survival rates of greater than 90%. This achievement is especially remarkable because improvements in disease-specific survival have occurred concurrently with a reduction of therapy for large patient subgroups. However, the outcomes for certain patient subgroups, including those with unfavorable histologic and molecular features, bilateral disease, and recurrent disease, remain well below the benchmark survival rate of 90%. Therapy for WT has been advanced in part by an increasingly complex risk-stratification system based on patient age; tumor stage, histology, and volume; response to chemotherapy; and loss of heterozygosity at chromosomes 1p and 16q. A consequence of this system has been the apportionment of patients into such small subgroups that only collaboration between large international WT study groups will support clinical trials that are sufficiently powered to answer challenging questions that move the field forward. This article gives an overview of the Children's Oncology Group and International Society of Pediatric Oncology approaches to WT and focuses on four subgroups (stage IV, initially inoperable, bilateral, and relapsed WT) for which international collaboration is pressing. In addition, biologic insights resulting from collaborative laboratory research are discussed. A coordinated expansion of international collaboration in both clinical trials and laboratory science will provide real opportunity to improve the treatment and outcomes for children with renal tumors on a global level.

Currently, the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control. Quantifying these problems remains subjective. We have developed a scoring system for both hypoglycemia and glycemic lability, established normative data, and used them in patients who have undergone islet transplantation. A composite hypoglycemic score (HYPO score) was devised based on the frequency, severity, and degree of unawareness of the hypoglycemia. In addition, using 4 weeks of glucose records, a lability index (LI) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability. A mean amplitude of glycemic excursions (MAGE) was also calculated based on 2 consecutive days of seven readings each day. These scores were determined in 100 randomly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation. The mean age of the control diabetic subjects was 38.4 +/- 1.3 years (+/-SE), with a duration of diabetes of 21.5 +/- 1.1 years. The median HYPO score in the control subjects was 143 (25th to 75th interquartile range: 46-423). The LI in the diabetic control subjects was 223 (25th to 75th interquartile range: 130-329 mmol/l(2)/h.week(-1)). The LI correlated much more closely than the MAGE with the clinical assessment of lability. A HYPO score of > or = 1,047 (90th percentile) or an LI > or = 433 mmol/l(2)/h.week(-1) (90th percentile) indicated serious problems with hypoglycemia or glycemic lability, respectively. The islet transplant patients (n = 51) were 42.1 +/- 1.4 years old, with a duration of diabetes of 25.7 +/- 1.4 years. Islet transplant patients had a mean HYPO score of 1,234 +/- 184 pretransplant, which was significantly higher than that of the control subjects (P < 0.001), which became negligible posttransplantation with the elimination of hypoglycemia. The median LI pretransplant was 497 mmol/l(2)/h.week(-1) (25th to 75th interquartile range: 330-692), significantly higher than that of control subjects (P < 0.001), and fell to 40 (25th to 75th interquartile range: 14-83) within a month after the final transplant. In those who had lost graft function, the LI rose again. The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability, respectively, complement the clinical assessment of the problems with glucose control before islet transplantation, and will allow comparison of selection of subjects for transplants between centers.

BACKGROUND: It is controversial whether compulsory community treatment (CCT) for people with severe mental illness (SMI) reduces health service use, or improves clinical outcome and social functioning. OBJECTIVES: To examine the effectiveness of compulsory community treatment (CCT) for people with severe mental illness (SMI). SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (2003, 2008, 2012, 8 November 2013, 3 June 2016). We obtained all references of identified studies and contacted authors where necessary. SELECTION CRITERIA: All relevant randomised controlled clinical trials (RCTs) of CCT compared with standard care for people with SMI (mainly schizophrenia and schizophrenia-like disorders, bipolar disorder, or depression with psychotic features). Standard care could be voluntary treatment in the community or another pre-existing form of CCT such as supervised discharge. DATA COLLECTION AND ANALYSIS: Authors independently selected studies, assessed their quality and extracted data. We used Cochrane's tool for assessing risk of bias. For binary outcomes, we calculated a fixed-effect risk ratio (RR), its 95% confidence interval (95% CI) and, where possible, the number needed to treat for an additional beneficial outcome (NNTB). For continuous outcomes, we calculated a fixed-effect mean difference (MD) and its 95% CI. We used the GRADE approach to create 'Summary of findings' tables for key outcomes and assessed the risk of bias of these findings. MAIN RESULTS: The review included three studies (n = 749). Two were based in the USA and one in England. The English study had the least bias, meeting three out of the seven criteria of Cochrane's tool for assessing risk of bias. The two other studies met only one criterion, the majority being rated unclear.Two trials from the USA (n = 416) compared court-ordered 'outpatient commitment' (OPC) with entirely voluntary community treatment. There were no significant differences between OPC and voluntary treatment by 11 to 12 months in any of the main health service or participant level outcome indices: service use - readmission to hospital (2 RCTs, n= 416, RR 0.98, 95% CI 0.79 to 1.21, low-quality evidence); service use - compliance with medication (2 RCTs, n = 416, RR 0.99, 95% CI 0.83 to 1.19, low-quality evidence); social functioning - arrested at least once (2 RCTs, n = 416, RR 0.97, 95% CI 0.62 to 1.52, low-quality evidence); social functioning - homelessness (2 RCTs, n = 416, RR 0.67, 95% CI 0.39 to 1.15, low-quality evidence); or satisfaction with care - perceived coercion (2 RCTs, n = 416, RR 1.36, 95% CI 0.97 to 1.89, low-quality evidence). However, one trial found the risk of victimisation decreased with OPC (1 RCT, n = 264, RR 0.50, 95% CI 0.31 to 0.80, low-quality evidence).The other RCT compared community treatment orders (CTOs) with less intensive and briefer supervised discharge (Section 17) in England. The study found no difference between the two groups for either the main health service outcomes including readmission to hospital by 12 months (1 RCT, n = 333, RR 0.99, 95% CI 0.74 to 1.32, moderate-quality evidence), or any of the participant level outcomes. The lack of any difference between the two groups persisted at 36 months' follow-up.Combining the results of all three trials did not alter these results. For instance, participants on any form of CCT were no less likely to be readmitted than participants in the control groups whether on entirely voluntary treatment or subject to intermittent supervised discharge (3 RCTs, n = 749, RR for readmission to hospital by 12 months 0.98, 95% CI 0.82 to 1.16 moderate-quality evidence). In terms of NNTB, it would take 142 orders to prevent one readmission. There was no clear difference between groups for perceived coercion by 12 months (3 RCTs, n = 645, RR 1.30, 95% CI 0.98 to 1.71, moderate-quality evidence).There were no data for adverse effects. AUTHORS' CONCLUSIONS: These review data show CCT results in no clear difference in service use, social functioning or quality of life compared with voluntary care or brief supervised discharge. People receiving CCT were, however, less likely to be victims of violent or non-violent crime. It is unclear whether this benefit is due to the intensity of treatment or its compulsory nature. Short periods of conditional leave may be as effective (or non-effective) as formal compulsory treatment in the community. Evaluation of a wide range of outcomes should be considered when this legislation is introduced. However, conclusions are based on three relatively small trials, with high or unclear risk of blinding bias, and low- to moderate-quality evidence. In addition, clinical trials may not fully reflect the potential benefits of this complex intervention.

BACKGROUND: Medication-related visits to the emergency department are an important but poorly understood phenomenon. We sought to evaluate the frequency, severity and preventability of drug-related visits to the emergency department. METHODS: We performed a prospective observational study of randomly selected adults presenting to the emergency department over a 12-week period. Emergency department visits were identified as drug-related on the basis of assessment by a pharmacist research assistant and an emergency physician; discrepancies were adjudicated by 2 independent reviewers. RESULTS: Among the 1017 patients included in the study, the emergency department visit was identified as drug-related for 122 patients (12.0%, 95% confidence interval [CI] 10.1%-14.2%); of these, 83 visits (68.0%, 95% CI 59.0%-76.2%) were deemed preventable. Severity was classified as mild in 15.6% of the 122 cases, moderate in 74.6% and severe in 9.8%. The most common reasons for drug-related visits were adverse drug reactions (39.3%), nonadherence (27.9%) and use of the wrong or suboptimal drug (11.5%). The probability of admission was significantly higher among patients who had a drug-related visit than among those whose visit was not drug-related (OR 2.18, 95% CI 1.46-3.27, p < 0.001), and among those admitted, the median length of stay was longer (8.0 [interquartile range 23.5] v. 5.5 [interquartile range 10.0] days, p = 0.06). INTERPRETATION: More than 1 in 9 emergency department visits are due to drug-related adverse events, a potentially preventable problem in our health care system.