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Background: Persistent sleep disturbances are one of the most common symptoms of Major Depressive Disorder (MDD) in adolescence. These are not typically targeted in psychological treatments and it is not known if psychological treatment for depression improves sleep.Methods: Secondary analyses were conducted using data from a large, multi-centre, randomised controlled trial (Goodyer et al., 2017b). Young people aged 12-18 years (N = 465; 75% female) met diagnostic criteria for Major Depressive Disorder, based on the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS). They were randomised to one of three psychological treatments. Sleep difficulties were assessed at baseline, post-treatment (36 weeks) and one year follow up (86 weeks) with the K-SADS, and the Mood and Feelings Questionnaire (MFQ).Results: At baseline, 92% of young people exhibited clinically significant sleep difficulties. Exploratory analyses suggest that sleep difficulties significantly decreased from baseline to end of treatment on self-report and interview-based measures, and this decrease was maintained at follow up. Reduction in sleep difficulties did not differ between the psychological treatments. Approximately, half of young people reported residual sleep difficulties at the end of treatment and at follow-up.Limitations: This paper reports secondary data analyses and findings are exploratory.Conclusions: Tentative results suggest that psychological treatments for depression reduced sleep problems for some participants. However, young people with treatment-resistant sleep problems may benefit from adjunctive sleep interventions. Future work with a range of sleep measures is needed to determine those who have residual sleep problems at the end of treatment and post-treatment follow-up. [ABSTRACT FROM AUTHOR]

Background: The aim of this paper was to evaluate the outcomes of a homogenous series of emergency with a toe-to-hand transfer reconstructions with a different timing: immediate (same surgical step with the debridement), primary (in the first 24 h), early (24-72 h after the debridement) or delayed (72 h-7 days).Materials and Methods: Between 2001 and 2011, 31 patients received an immediate reconstruction with a toe-to-hand transfer. Data on indications, timing, type of surgery, complications and outcomes (sensory and motor recovery, patient satisfaction) were extrapolated and recorded.Results: Most of the procedures in our series (71%) were performed in the first 24 h. Survival rate was 100%. The only complications were 3 venous thrombosis (10%), solved with surgical re-exploration. Only 1 patient required secondary surgery for web deepening. No functional problems were recorded at the donor site. Sensibility recovery was acceptable in all patients; toe mobility was higher for the reconstructed thumb (85%) than for other digits (77%). Patient satisfaction was high with regard to functional results and lower but acceptable with regard to the aesthetic outcome. There was no difference in satisfaction rate of patients treated within 24 h or within 7 days.Conclusion: No conclusive evidence exists in favor of an immediate versus a primary, early or delayed emergency reconstruction. Emergency toe transfer for finger reconstruction is a safe procedure and its outcomes are comparable to those reported in the literature for secondary reconstruction. Immediate reconstruction has the advantage of an easier dissection, but early or delayed reconstruction gives more time to discuss with the patient and to plan surgery. [ABSTRACT FROM AUTHOR]

Compares the results of primary angioplasty with thrombolytic therapy for acute myocardial infarction. Decrease in mortality with primary angioplasty; Reduction of reocclusion with the use of thrombolytic therapy; Time as determinant of the outcome in patients.

: Comparing incidental dose distributions (i.e. images) of patients with different outcomes is a straightforward way to explore dose-response hypotheses in radiotherapy. In this paper, we introduced a permutation test that compares images, such as dose distributions from radiotherapy, while tackling the multiple comparisons problem. A test statistic Tmax was proposed that summarizes the differences between the images into a single value and a permutation procedure was employed to compute the adjusted p-value. We demonstrated the method in two retrospective studies: a prostate study that relates 3D dose distributions to failure, and an esophagus study that relates 2D surface dose distributions of the esophagus to acute esophagus toxicity. As a result, we were able to identify suspicious regions that are significantly associated with failure (prostate study) or toxicity (esophagus study). Permutation testing allows direct comparison of images from different patient categories and is a useful tool for data mining in radiotherapy. [ABSTRACT FROM AUTHOR]

Background: The current study was designed to assess the effect of supplementation with a 14-strain probiotic mixture on episodic and chronic migraine characteristics.Methods: Forty episodic and 39 chronic migraine patients who completed this randomized double-blind controlled trial received two capsules of multispecies probiotic or placebo. The migraine severity was assessed by visual analog scale (VAS). The number of abortive drugs consumed, migraine days, frequency and duration of attacks were recorded on paper-based headache diaries. Serum tumor necrosis factor alpha (TNF-α) and C- reactive protein (CRP) levels were measured at baseline and the end of the intervention.Results: After a 10-week intervention, among episodic migraineurs the mean frequency of migraine attacks significantly reduced in the probiotic group compare to the placebo group (mean change: -2.64 vs. 0.06; respectively, p < 0.001). A significant reduction was also evident in the migraine severity (mean decrease: -2.14 in the probiotic group and 0.11 in the placebo group; p < 0.001). Episodic migraineurs who received the probiotic also showed significant reduction in abortive drug usage per week (mean change: -0.72; p < 0.001) compare to baseline, while there was no significant changes within the placebo group. In chronic migraine patients, after an 8-week intervention, the mean frequency of migraine attacks significantly reduced in the probiotic compared to the placebo group (mean change: -9.67 vs. -0.22; p ≤ 0.001). In contrast to the placebo, probiotic supplementation significantly decreased the severity (mean changes: -2.69; p ≤ 0.001), duration (mean changes: -0.59; p ≤ 0.034) of attacks and the number of abortive drugs taken per day (mean changes: -1.02; p < 0.001), in chronic migraine patients. We failed to detect any significant differences in the serum levels of inflammatory markers at the end of the study either in chronic or in episodic migraineurs.Discussion: The results of this study showed that the 14-strain probiotic mixture could be an effective and beneficial supplement to improve migraine headache in both chronic and episodic migraineurs. Further research is required to confirm our observations. [ABSTRACT FROM AUTHOR]

Frequent falls in people with cerebellar ataxia (CA) is a significant problem Therefore, an intervention that could improve balance and reduce the number of falls is of paramount importance from the patients' perspective. Combining cognitive training with physical training to improve balance is a new approach for reducing the risk of falls in patient populations who are at risk for falls. To determine if adding structured cognitive demands to conventional balance and coordination training we designed the Cognitive-coupled Intensive Balance Training (CIBT) program. We found that the more intensive and focused CIBT intervention reduced dual-task cost, improved balance, and reduced the number of falls in a sample of individuals with CA. We hypothesize that (1) CIBT will improve balance and reduce falls; and (2) CIBT will be a cost-effective treatment option for improving balance and reduce falls. To test these hypotheses, we propose conducting a randomized controlled trial (RCT) with economic evaluation . This paper reports the findings of our study testing the feasibility of the CIBT program, rationale for testing our hypothesis and an overview of our future study design to test the effectiveness and cost-effectiveness of the CIBT program. [ABSTRACT FROM AUTHOR]

Background and Aims: Leukotriene D4 is produced by and functions as a chemotactic factor for eosinophils. Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilic infiltration, determining structural changes and dismotility symptoms. Montelukast, a selective leukotriene D4 receptor antagonist, has gained increasing consideration as a therapeutic agent for EoE. However, limited available information has shown that montelukast is not effective in reducing eosinophilic infiltration. Our paper aims at evaluating whether montelukast could be consider as a steroid-sparing therapy by assessing its efficacy in maintaining both clinical and histopathological remission achieved after topical corticosteroids in adult EoE patients.Methods: Eleven consecutively diagnosed adult EoE patients were prospectively studied. Esophageal biopsies were obtained before and after a 6-month treatment with fluticasone propionate 400 μg/twice a day. Immediately after that, montelukast 10 mg/day was instituted. A new endoscopy was foreseen after a new 3-month period, or as soon as the patients presented esophageal symptoms. Symptoms were assessed by using a questionnaire before and after fluticasone propionate treatment and after montelukast therapy.Results: Eosinophils density into the esophageal epithelium and lamina propria was significantly reduced after a 6-month treatment with topical steroids (P = 0.003) and increased to levels similar to baseline level into the first 3 months after treatment with montelukast. Baseline symptom scores significantly decreased after treatment with topical steroids (P = 0.003) and increased again after montelukast therapy, but baseline levels improved.Conclusions: Montelukast was not efficient in maintaining the histopathological or clinical response achieved by topical steroids in adult EoE patients. [ABSTRACT FROM AUTHOR]

Purpose: We conducted a meta-analysis to evaluate and compare the short- and long-term results of laparoscopy-assisted and open rectal surgery for the treatment of patients with rectal cancer.Methods: We searched MEDLINE, EMBASE, Science Citation Index, and the Cochrane Controlled Trial Register for relevant papers published between January 1990 and April 2011 by using the search terms "laparoscopy," "laparoscopy assisted," "surgery," "rectal cancer," and "randomized controlled trials." We analyzed outcomes over short- and long-term periods.Results: We identified 12 papers reporting results from randomized controlled trials that compared laparoscopic surgery with open surgery for rectal cancer. Our meta-analysis included 2,095 patients with rectal cancer; 1,096 had undergone laparoscopic surgery, and 999 had undergone open surgery. In the short-term period, 13 outcome variables were examined. In the long-term period, eight oncologic variables, as well as late morbidity, urinary function, and sexual function were analyzed. Laparoscopic surgery for rectal cancer was associated with a reduction in intraoperative blood loss and the number of transfused patients, earlier resumption of oral intake, and a shorter duration of hospital stay over the short-term, but with similar short-term and long-term oncologic outcomes compared to conventional open surgery.Conclusions: Laparoscopic surgery may be an acceptable alternative treatment option to conventional open surgery for rectal cancer. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment.Methods: In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3-8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day [range 14-18 was acceptable]) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121).Findings: Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h [SD 1·50]) significantly reduced off time compared with placebo (-2·47 h per day [SD 3·70] in the apomorphine group vs -0·58 h per day [2·80] in the placebo group; difference -1·89 h per day, 95% CI -3·16 to -0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events.Interpretation: Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy.Funding: Britannia Pharmaceuticals. [ABSTRACT FROM AUTHOR]

The current paper describes the natural history and management of mucopolysaccharidosis VI (MPS VI) in all patients currently diagnosed with the disease in Italy. Nine patients (5.5-14.4 years) were included in the data review in March 2008. Gestational and perinatal data were normal for all patients. Median age at diagnosis was 1.9 years. During the course of the disease, all patients developed coarsened facial features, short stature, heart valve disease, eye problems, musculoskeletal problems, hepatosplenomegaly and neurological abnormalities. All patients received rhASB enzyme replacement therapy (ERT) and showed improvement or stabilisation in clinical manifestations after onset of therapy. The most frequently reported improvements were increased joint mobility and reduced hepatosplenomegaly. No relevant safety issues of ERT were reported. In conclusion, patients in Italy with MPS VI are diagnosed early in life. All patients have access to ERT and appear to benefit from this therapy. [ABSTRACT FROM AUTHOR]

Effective management of pain remains an important indicator of the quality of care provided to neonates. Since the review of McIntosh in this journal over a decade ago, an extensive number of papers on assessment, prevention, and treatment of pain have been reported. In addition, preclinical insights into neurodevelopmental aspects of pain processing and the neuro-apoptotic effects of analgesics and sedatives were unveiled. Based on the newly collected evidence, the practice of "one-drug, one dose and one treatment fits all" became obsolete, necessitating a more individualized analgesia, based on non-pharmacological and pharmacological therapies and preventive strategies for effective management of neonatal pain. The progress made is impressive, but the current major challenge is to implement the available knowledge in clinical care. Future research should therefore focus on the evaluation of the effectiveness of non-opioid and moderately potent opioids compared to morphine and should also describe the methods to facilitate effective implementation. Finally, there is an extensive field of procedural techniques that need to be evaluated on their pain related response. [ABSTRACT FROM AUTHOR]

Traditional hair-removal techniques have included shaving, waxing, chemical depilation, and electrolysis. All of these methods result in temporary hair removal. The theory of selective photo thermolysis led to the development of a variety of different laser systems. These lasers range from the short end of spectrum, with the 694-nm ruby laser, to the middle, with the 755-nm alexandrite and 810-nm diode lasers, and to the long end with the 1,064-nm Nd:YAG laser. We made a systematic review on the clinical trials with use of various laser sources for hair removal, so all clinical trials related to hair removal lasers in 1998-2003 were considered after elimination of heterogenite sources in data store. Trial results were synthetized on the basis of kind of laser. Our study clarified that hair reduction at least 6 months after the last treatment and hair reductions were 57.5, 42.3, 54.7, and 52.8% after three sessions for diode, Nd:YAG, alexandrite and ruby, respectively. We compared the result with use of analysis of variance method (Scheffes) and double comparison with use of Student's t test. Our results clarified that diode laser is the most effective, and Nd:YAG has the least effect of hair removal.It seems that diode and alexandrite lasers are proper for hair removal, but as we need high fluence in the darker skin types and this is accompanied with higher complications, diode is advised for lighter skin, and we advised alexandrite laser for darker skin types. [ABSTRACT FROM AUTHOR]

Phototherapy is the most frequently used treatment for the neonatal jaundice. However, recent papers report that phototherapy increased apoptosis in peripheral mononuclear leukocytes in vivo and in mouse lymphoma cell line in vitro. We have investigated the cytotoxicity of phototherapy on the small intestine of neonatal rat using conventional halogen-quartz device (conventional device) and blue light-emitting device (LED device) by measuring apoptotic cells. Four-day-old male Wistar rats were divided into three groups as follows: group 1, exposure to conventional device for 72 h; group 2, exposure to LED device for 72 h; and group 3, control (without phototherapy). After light exposure, the small intestine was examined for apoptosis. Apoptotic cells were detected by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay, by immunohistochemistry for caspase-3 and by transmission electron microscopy. The proportion of positive cells by the TUNEL method in the epithelium of the small intestine was 6.2, 3.1 and 1.7% in the conventional device group, the LED device group and the control group, respectively. The apoptotic cells of the conventional device group is significantly higher than the LED device group (P < 0.01) and that of the LED device group was higher than that of the control group (P < 0.05). We suspected that phototherapy induced apoptosis in neonatal small intestine and the conventional device introduces more apoptosis than the LED device. [ABSTRACT FROM AUTHOR]

Parenteral nutrition associated liver disease (PNALD) is the major source of morbidity and mortality in children with short bowel syndrome (SBS). There is emerging evidence that omega-6 fatty acids (omega6FA) within the parenteral solution play a major role in PNALD and their effects may be reversed or ameliorated by substitution with omega-3 fatty acids (omega3FA). This paper reviews the mechanisms whereby omega3FAs may influence PNALD by improving bile flow, inhibiting steatosis, and having immunomodulatory effects. The early clinical experience with omega3FAs in SBS and PNALD is briefly reviewed and the implications of such, and future directions are considered. [ABSTRACT FROM AUTHOR]

In a retrospective study, intraoperative photos and video documentations of 884 children demonstrate that inguinal hernias and their recurrences are aspects of a full spectrum, which ranges from fully closed internal inguinal rings (IIR) and small openings to all-the way-down-into-the-scrotum open processus; 92% of the children had indirect and 2% direct hernias, 4% had no open IIR, 1% was femoral, 2% were hernias en pantalon and 1% combinations of indirect, direct and femoral hernias; 3% were recurrences. Among the 28 children with recurrences, the IIR was fully open in only 36%, partially open in 25%, had only a small opening in 21% and even a closed IIR in 18%. The present paper demonstrates that the yes/no concept of inguinal hernia needs to be redefined. Hernias and their recurrences constitute a spectrum. There are hernias and recurrences without a laparoscopically visible open IIR. [ABSTRACT FROM AUTHOR]

The results of lumbar fusion in chronic low back pain (LBP) patients vary considerably, and there is a need for proper patient selection. Lumbosacral orthoses have been widely used to predict outcome, however, with little scientific support. The aim of the present study was to determine the value of a pantaloon cast test in selecting chronic LBP patients for lumbar fusion or conservative management. First, a systematic review of the literature was carried out in which two independent reviewers identified studies in Medline, Cochrane and Current Contents databases. Three papers met the selection criteria. In the only study with a control group, a significantly better outcome after fusion compared to conservative treatment was found in patients who reported significant pain relief while in a cast (i.e. a positive cast test). The results of lumbar fusion, however, were not significantly different for patients with a positive and those with a negative cast test. In addition to the review, a clinical cohort study of 257 LBP patients, who had been allocated to either lumbar fusion or conservative management by a temporary external transpedicular fixation trial, was performed. Prior to allocation, all had undergone a pantaloon cast test. Patients with no history of prior spine surgery and with a positive pantaloon cast test had a better outcome after lumbar fusion than those treated conservatively (P = 0.002, chi (2 )test). In patients with previous spine operations the outcomes were poor and the test was of no value. From the literature and the present patient cohort, it was concluded that only in chronic LBP patients without prior spine surgery, a pantaloon cast test with substantial pain relief suggests a favorable outcome of lumbar fusion compared to conservative management. The test has no value in patients who have had previous spine surgery. [ABSTRACT FROM AUTHOR]

The aim of this paper is to assess the benefit to treat plantar fasciitis with low-dose energy extracorporeal shock wave therapy (ESWT) and the efficacy of such treatment to abate the painful symptoms allowing a rapid return to the running activity. Our study included 54 running athletes treated for plantar fasciitis associated with a heel spur who received four sessions (once weekly) of low-dose ESWT, and followed prospectively on average 45 days, 6 and 24 months after their last session. The clinical results were excellent in 59% of cases, good in 12%, satisfactory in 21% and distinctly unsatisfactory in 8%. No patient was observed a significant modification of the heel spur at the follow-up X-ray. The ultrasound examination at 24 months showed a disappearance of the inflammation signs in 61% of cases. A strong correlation between ultrasound improvement and clinical results were found. Low-energy ESWT seems to be a good mean to treat plantar fasciitis in runners with a 71% of good or excellent results and a persistent improvement lasting 24 months. A randomized multicentric study seems to be necessary to define the type of energy that should be used in the future to treat plantar fasciitis, in particular in the athletic patients, to allow a faster return to sports activities. [ABSTRACT FROM AUTHOR]

Most of the papers published on spigelian hernia are either case reports or small retrospective series. In this prospective multicenter study, we aimed to outline the specific features of spigelian hernias and patients' characteristics more clearly. Surgeons enrolled patients to be entered into the database as they diagnosed and treated the hernias at will. The baseline and surgical outcome parameters were noted in each patient. A painful mass was the main presenting complaint in half of 34 patients. Accurate preoperative diagnosis was possible in 31 patients. Open intraperitoneal mesh repair was the preferred technique. The mean hospital stay and time until return to normal daily activities were 4.1 and 15.6 days. Although a rare condition, diagnosis of a spigelian hernia is not difficult once remembered. Its surgical repair seems to cause few complications and is very well tolerated by the patient. [ABSTRACT FROM AUTHOR]

Encephalopathy associated with autoimmune thyroid disease, currently known as Hashimoto’s encephalopathy, but also defined as corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis, is a relatively rare condition observed in a small percentage of patients presenting with autoimmune thyroid disease. It consists of a subacute, relapsing-remitting, steroid-responsive encephalopathy characterised by protean neurologic and neuropsychiatric symptoms, diffuse electroencephalographic abnormalities and increased titres of antithyroid antibodies in serum and/or in cerebrospinal fluid. Most of the cases presenting this neurologic complication are affected by Hashimoto’s thyroiditis or, less frequently, by other autoimmune thyroid diseases, chiefly Graves’ disease. The pathogenesis of this encephalopathy is still unknown and largely debated, because of extremely varied clinical presentation, possibly referable to different aetiologic and pathophysiologic mechanisms, as confirmed by the two clinical cases we report in this paper. Autoimmune aetiology is, however, very likely in view of the well established favourable response to corticosteroid administration. Both vasculitis and autoimmunity directed against common brainthyroid antigens represent the most probable aetiologic pathways. Clinical manifestations include consciousness changes, neurologic diffuse or focal signs, headache, and altered cognitive function. Although unspecific, cerebral oedema has also been described. Cerebrospinal fluid examination often discloses an inflammatory process, with a mild increase in protein content and occasionally in lymphocyte count. In this review, clinical criteria for the diagnosis of defined, probable, or possible encephalopathy associated with autoimmune thyroid disease are suggested. Corticosteroid therapy currently allows us to obtain rapid remission of disease symptoms, but adverse outcomes as well as spontaneous remissions have also been reported. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to describe our experience with endovascular obliteration of duodenal varices in patients with liver cirrhosis and portal hypertension. Balloon-occluded transvenous retrograde and percutaneous transhepatic anterograde embolizations were performed for duodenal varices in five patients with liver cirrhosis, portal hypertension, and decreased liver function. All patients had undergone previous endoscopic treatments that failed to stop bleeding and were poor surgical candidates. Temporary balloon occlusion catheters were used to achieve accumulation of an ethanolamine oleate-iopamidol mixture inside the varices. Elimination of the varices was successful in all patients. Retrograde transvenous obliteration via efferent veins to the inferior vena cava was enough to achieve adequate sclerosant accumulation in three patients. A combined anterograde-retrograde embolization was used in one patient with balloon occlusion of afferent and efferent veins. Transhepatic embolization through the afferent vein was performed in one patient under balloon occlusion of both efferent and afferent veins. There was complete variceal thrombosis and no bleeding was observed at follow-up. No major complications were recorded. Endovascular obliteration of duodenal varices is a feasible and safe alternative procedure for managing patients with portal hypertension and hemorrhage from this source. [ABSTRACT FROM AUTHOR]

Objective: To estimate the cost effectiveness (from the UK NHS and personal social services perspective) of the cholinesterase inhibitors donepezil, rivastigmine and galantamine compared with usual care in the treatment of mild to moderately severe Alzheimer's disease. Patients had a mean age of 74 years, a mean disease duration of 1 year and a mean Alzheimer's disease assessment scale-cognitive subscale score of 24.Methods: A pharmacoeconomic model was used to predict long-term outcomes over a 5-year time horizon and to estimate the cost effectiveness of cholinesterase inhibitors for the management of Alzheimer's disease. The model structure is informed by a systematic review of the literature on the clinical and cost effectiveness of cholinesterase inhibitors and a review of the literature on the costs and outcomes associated with treatment for Alzheimer's disease. The main outcome measure used was the cost per quality-adjusted life-year (QALY) gained. All healthcare costs (excluding cholinesterase inhibitor costs) were indexed to pounds sterling (2003 values). Drug costs are 2005 values. Multivariate probabilistic sensitivity analysis and scenario analysis were undertaken to assess uncertainty in the results.Results: The clinical benefits on cognition from treatment with cholinesterase inhibitors resulted in an incremental cost per QALY gained ranging from 53,780 pounds sterling to 74,735 pounds sterling, over 5 years (vs usual care). Uncertainty analysis suggests that the probability of any of these treatments having an incremental cost per QALY of < 30,000 pounds sterling is < 21%. The key determinants of cost effectiveness were the effectiveness of treatment, the mean treatment cost and the cost savings associated with an expected delay in disease progression.Conclusions: Results presented in this paper suggest that the use of cholinesterase inhibitors may not be a cost-effective use of NHS resources. Guidance from the National Institute for Health and Clinical Effectiveness (NICE) in the UK on their judgements surrounding the acceptability of technologies as an effective use of resources, indicates there would need to be special reasons for accepting cholinesterase inhibitors as a cost-effective use of NHS resources. [ABSTRACT FROM AUTHOR]

The purpose of this paper is twofold: on the one hand, to confirm the positive results on n-3 PUFA from the overall results Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GlSSI)-Prevenzione trial; on the other, to summarize and describe how the results of an important trial can help generate hypotheses either on mechanisms of action or on differential results in particular subgroups of patients, as well as test the pathophysiological hypotheses that have accompanied in the years the story of the hypothesized mechanisms of action of a drug. GISSI-Prevenzione was conceived as a pragmatic population trial on patients with recent myocardial infarction and it was conducted in the framework of the Italian public health system. In GISSI-Prevenzione, 11,323 patients were enrolled in a clinical trial aimed at testing the effectiveness of n-3 polyunsaturated fatty acids (PUFA) and vitamin E. Patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA at 1 g daily, but not vitamin E at 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall (-20%), cardiovascular (-30%), and sudden death (-45%). At variance from the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis", GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction. [ABSTRACT FROM AUTHOR]

Chemoradiotherapy (CRT) is accepted as the standard initial treatment for squamous cell anal cancer. However, frail elderly patients cannot always tolerate full-dose CRT. This paper reports the results of a modified regimen for this group of patients. In all, 16 patients with biopsy-proven squamous cell carcinoma of the anal canal or margin and performance status or co-morbidity precluding the use of full-dose CRT were included in this protocol. The median age was 81 (range 77-91). Patients received a dose of 30 Gy to the gross tumour volume plus 3 cm margin in all directions. Concurrent chemotherapy comprised 5-fluorouracil 600 mg m(-2) given over 24 h on days 1-4 of radiotherapy. The treatment was well tolerated. All 16 patients completed treatment as planned. Only one patient experienced any grade 3 toxicity (skin). The local control at a median follow-up of 16 months was 73% (13 out of 16). The overall survival was 69% and disease-specific survival 86%. This is a well-tolerated regimen for elderly/poor performance patients with anal cancer, which can achieve high rates of local control and survival. Longer follow-up will determine whether these encouraging results are maintained. [ABSTRACT FROM AUTHOR]

Objective: Physicians may prescribe buprenorphine for opioid agonist maintenance treatment outside of narcotic treatment programs, but treatment guidelines for patients with co-occurring cocaine and opioid dependence are not available. This study compares effects of buprenorphine and methadone and evaluates the efficacy of combining contingency management with maintenance treatment for patients with co-occurring cocaine and opioid dependence.Method: Subjects with cocaine and opioid dependence (N=162) were provided manual-guided counseling and randomly assigned in a double-blind design to receive daily sublingual buprenorphine (12-16 mg) or methadone (65-85 mg p.o.) and to contingency management or performance feedback. Contingency management subjects received monetary vouchers for opioid- and cocaine-negative urine tests, which were conducted three times a week; voucher value escalated during the first 12 weeks for consecutive drug-free tests and was reduced to a nominal value in weeks 13-24. Performance feedback subjects received slips of paper indicating the urine test results. The primary outcome measures were the maximum number of consecutive weeks abstinent from illicit opioids and cocaine and the proportion of drug-free tests. Analytic models included two-by-two analysis of variance and mixed-model repeated-measures analysis of variance.Results: Methadone-treated subjects remained in treatment significantly longer and achieved significantly longer periods of sustained abstinence and a greater proportion drug-free tests, compared with subjects who received buprenorphine. Subjects receiving contingency management achieved significantly longer periods of abstinence and a greater proportion drug-free tests during the period of escalating voucher value, compared with those who received performance feedback, but there were no significant differences between groups in these variables during the entire 24-week study.Conclusions: Methadone may be superior to buprenorphine for maintenance treatment of patients with co-occurring cocaine and opioid dependence. Combining methadone or buprenorphine with contingency management may improve treatment outcome. [ABSTRACT FROM AUTHOR]

Task-oriented repetitive movements can improve muscle strength and movement co-ordination in patients with impairments due to neurological lesions. The application of robotics and automation technology can serve to assist, enhance, evaluate and document the rehabilitation of movements. The paper provides an overview of existing devices that can support movement therapy of the upper extremities in subjects with neurological pathologies. The devices are critically compared with respect to technical function, clinical applicability, and, if they exist, clinical outcomes. [ABSTRACT FROM AUTHOR]

Inhaled nitric oxide (iNO) was first used in neonatal practice in 1992 and has subsequently been used extensively in the management of neonates and children with cardiorespiratory failure. This paper assesses evidence for the use of iNO in this population as presented to a consensus meeting jointly organised by the European Society of Paediatric and Neonatal Intensive Care, the European Society of Paediatric Research and the European Society of Neonatology. Consensus Guidelines on the Use of iNO in Neonates and Children were produced following discussion of the evidence at the consensus meeting. [ABSTRACT FROM AUTHOR]

Purpose: This paper reports on the development and validation of two biologic response modifier (BRM) subscales for use with the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life (QOL) questionnaire.Methods: Using the FACT-G as a base, 17 additional questions related to symptoms common to interferon and retinoid therapy were developed. Data collected at baseline (n = 191) and week 2 (n = 168) in a randomized trial of interferon +/- 13-cis-retinoic acid in advanced renal cell carcinoma patients were used to validate this measure.Results: Using a combined empirical and conceptual approach, the 17 questions were reduced to 13 questions consisting of two subscales: 'BRM-physical' (7 items; baseline coefficient alpha(alpha) = 0.70; week-2 alpha = 0.75) and 'BRM-mental' (6 items; baseline alpha = 0.79; week-2 alpha = 0.78). Internal consistency of the trial outcome index (TOI) combining physical well-being, functional well-being and the BRM subscales, was 0.91 for baseline assessments and 0.92 for week 2. Discriminant validity was demonstrated for the TOI by its ability to differentiate among prognostic risk groups, and for the total FACT-G, TOI and total FACT-BRM scores by their ability to distinguish between groups differing in performance, response and toxicity status.Conclusions: The 'BRM-physical' and 'BRM-mental' subscales can be combined with the FACT-G to form the 'FACT BRM' scale, useful for measuring QOL in cancer patients who are receiving treatment with biologic response modifiers. [ABSTRACT FROM AUTHOR]

Purpose: This paper describes the impact of a care recommendation (CR) letter intervention on patients with multisomatoform disorder (MSD) and analysis of patient factors that affect the response to the intervention.Methods: One hundred eighty-eight patients from 3 family practices, identified through screening of 2,902 consecutive patients, were classified using somatization diagnoses based on the number of unexplained physical symptoms from a standardized mental health interview. In a controlled, single-crossover trial, patients were randomized to have their primary care physician receive the CR letter either immediately following enrollment or 12 months after enrollment. The CR letter notified the physician of the patient's somatization status and provided recommendations for the patient's care. Patients were followed for 24 months with assessments of functional status at baseline, 12, and 24 months.Results: Longitudinal analysis revealed a 12-month intervention effect for patients with multisomatoform disorder (MSD) of 5.5 points (P < .001) on the physical functioning (PCS) scale of the SF-36. Analysis of scores on the MCS scale of the SF-36 found no significant effect on mental functioning. The intervention was more effective for patients with 1 or more comorbid chronic physical diseases (P = .01).Conclusions: The CR letter has a favorable impact on physical impairment of primary care patients with MSD, especially for patients with comorbid chronic physical disease. Multisomatoform disorder appears to be a useful diagnostic classification for managing and studying somatization in primary care patients. [ABSTRACT FROM AUTHOR]

Introduction: Laparoscopic gastric banding (LGB) is currently the most popular purely restrictive bariatric operation in Europe and many other countries. It has a low operative morbidity, but is associated with a substantial late complication rate. Many late complications have been attributed to technical errors or to the learning curve. The aim of this paper is to present our results with gastric banding after the learning curve in order to disclose the true incidence of long-term complications.Methods: LGB was introduced in our department in December 1995. Thirty patients were operated on until June 1997 using the early banding technique (band within the lesser sac), at which time the surgical technique was slightly modified in order to place the band above the lesser sac. Then another 300 patients underwent LGB using either the Lapband or the SAGB system. This report focuses on the latter patients. All the data were collected prospectively.Results: The series includes 300 patients (257 women and 43 men) with a mean age of 38.3 years (19-64). The mean initial weight was 119.2 kg (57-179), initial body mass index (BMI) was 43.3 kg/m2 (21-64), and initial excess weight was 96.5% (0-191). The mean duration of surgery was 90 min, decreasing over time to a mean of 75 min for the last 50 cases. Early overall morbidity was 6.6%. Major complications occurred in 7 patients (2.3%). Excess weight loss (EWL) was at least 50% in 66% of the patients after 2 years, averaging 60%, with no substantial change until 4 years, and the BMI stabilized between 30 and 31 kg/m2. Forty-nine patients developed a total of 52 long-term complications, of which 23 (7.6%) were related only to the port or catheter. Band erosion occurred in 17 (5.6%), pouch dilatation with slippage in 8 (2.6%), and infection in 4 (1.3%) patients. Fifty-five reoperations were necessary. Twenty-five of these were related only to the port. The band was removed from 26 (9%) patients, of whom 17 were converted to Roux-en-Y gastric bypass.Conclusions: LGB gives satisfactory results in terms of weight loss in about two-thirds of the patients. Even beyond the learning curve, the long-term morbidity is not negligible, but is acceptable compared to other procedures such as vertical banded gastroplasty. Conversion to gastric bypass is possible when complications occur and can be performed when the band is removed in most cases. [ABSTRACT FROM AUTHOR]

Objective: Treatment approaches for pathological gambling have been modelled after preexisting substance addiction models. This paper reviews cognitive-behavioural models in a search for original insights that are specific to gambling treatment.Method: A computerized search of major health care databases (Medline and PsycINFO) was performed.Results: New cognitive-behavioural approaches to the treatment of pathological gambling provide 3 original additions to the traditional multimodal treatment of addictions: cognitive restructuring, in vivo exposure, and imaginal desensitization. Other cognitive-behavioural techniques, such as relapse prevention, problem solving, and social skill training, are shared by gambling treatment and addictions treatment.Conclusions: When treating pathological gamblers, clinicians must consider introducing techniques to address cognitive distortions related to gambling. Also, cue exposure--whether in vivo or imaginal--may help deal with urges prompted by such cues. The blending of these new techniques into a multimodal addiction treatment potentially balances the rational and external orientation of the cognitive-behavioural approach with interpersonal and introspective components of the traditional addiction treatment. [ABSTRACT FROM AUTHOR]

Since the early work of RA Fisher, exact methods have been recognized as important tools in data analysis because they provide valid statistical inference even with small sample sizes, or with sparse or skewed data. With the recent advance of computational power and the availability of commercial software packages, exact methods have gained substantial popularity over the past two decades. However, most of these exact methods have been devoted to testing classical null hypotheses of no differences, and until recently little was known about exact methods dealing with non-inferiority or equivalence hypotheses. The presence of nuisance parameters in testing non-inferiority/equivalence hypotheses presents a special challenge for exact methods because of the intense computational requirement. In this paper, we review exact methods available for proving non-inferiority or equivalence of two treatments with a dichotomous endpoint. First, we present the general methodology for conducting exact tests for non-inferiority or equivalence; we then discuss several unconditional and conditional methods available for constructing hypothesis tests and confidence intervals based on three commonly used measures, namely, the difference, relative risk, and odds ratio of two independent proportions or rates. Finally, we illustrate with several examples the application of these exact methods in analysing and planning non-inferiority or equivalence trials. [ABSTRACT FROM AUTHOR]

All models of this paper involve R x C contingency tables in which the total frequency is fixed (full multinomial model), or in which the row totals are fixed (product multinomial model). For the most part, we assume that the column categories are ordered. For the full multinomial model the null hypothesis of interest is independence, i.e., the (ij)th cell probability is the product of the marginal probabilities of the ith row and jth column. In the product multinomial model the null hypothesis is that the R multinomial distributions have the same vector of cell probabilities. Our review includes (1) a careful listing of two-sided and one-sided alternatives, and (2) methodology to reduce the loss of efficiency of tests because of the discreteness of the model (The methodologies discussed are efficient in several senses. Tests are exact. Tests have very favorable and robust power properties. Tests make use of back-up statistics, thereby providing a finer grid of p-values. In some special cases, e.g., a 2 x C table and a one-sided alternative, conditional p-values are found, within seconds, simply by entering row frequencies into a given website. Thus, computational efficiency is exceptional.), and (3) a critique of some exact linear permutation tests (that are conditional on row and column margins) for both two-sided and some one-sided alternatives. Furthermore, recommendations as to which tests to use for specific alternatives are made. [ABSTRACT FROM AUTHOR]

Only a few papers have been published concerning the incidence and outcome of patients with a pathological complete response after cytotoxic treatment in breast cancer. The purpose of this retrospective study was to assess the outcome of patients found to have a pathological complete response in both the breast and axillary lymph nodes after neoadjuvant chemotherapy for operable breast cancer. Our goal was also to determine whether the residual pathological size of the tumour in breast could be correlated with pathological node status. Between 1982 and 2000, 451 consecutive patients were registered into five prospective phase II trials. After six cycles, 396 patients underwent surgery with axillary dissection for 277 patients (69.9%). Pathological response was evaluated according to the Chevallier's classification. At a median follow-up of 8 years, survival was analysed as a function of pathological response. A pathological complete response rate was obtained in 60 patients (15.2%) after induction chemotherapy. Breast tumour persistence was significantly related to positive axillary nodes (P=5.10(-6)). At 15 years, overall survival and disease-free survival rates were significantly higher in the group who had a pathological complete response than in the group who had less than a pathological complete response (P=0.047 and P=0.024, respectively). In the absence of pathological complete response and furthermore when there is a notable remaining pathological disease, axillary dissection is still important to determine a major prognostic factor and subsequently, a second non cross resistant adjuvant regimen or high dose chemotherapy could lead to a survival benefit. [ABSTRACT FROM AUTHOR]

In this paper, the effectiveness of the treatment program developed by Proyecto Hombre ('Project Mankind') in Asturias, Spain, is evaluated. In a long-term follow-up (range from 73 days to 8 years) with a sample of 249 subjects, the results obtained by subjects completing the treatment (194) were compared with pre-treatment results and with those of the group that dropped out (55). The measurements used were relapses in illegal drugs, alcohol, changes in family situation, educational level, employment, criminal involvement and state of health. External validation of self-report measures given in the questionnaire was carried out. Findings support the effectiveness of the treatment in all measures and the validity of self-report items. Relapse rate in 'treatment-completed' group was 10.3%, whilst in the non-completers group it reached 63.6% (significant difference, p < 0.001). Relapses of non-completers were more severe, occurred sooner after leaving the program (they stayed abstinent for shorter periods) and lasted longer than those of subjects completing the treatment. [ABSTRACT FROM AUTHOR]

Objective: This paper reviews the current status of gene therapy in the neuroendocrine system and discusses the interventive potential of this methodology for neuroendocrine pathologies associated with aging.Background and Results: A brief description is first presented of the viral-vector-based gene delivery systems being currently used in the neuroendocrine system, namely the adenoviral and herpetic (HSV1) vector systems. Next, an account of the neuroendocrine pathologies for which gene therapy approaches in animal models are being implemented is provided. This includes the treatment of experimental pituitary tumors by adenoviral-vector-mediated transfer of the suicide gene for the HSV-1 thymidine kinase. At the hypothalamic level, an adenovirus harboring the cDNA for arginine vasopressin has been used in Brattleboro rats to correct their diabetes insipidus. Next, the interventive potential of gene therapy for correcting age-associated neurodegenerative processes at neuroendocrine level is outlined. Finally, the role that emerging technologies may play in the development of future genetic therapies for aging is considered.Conclusion: Although effective implementation of gene therapy strategies still faces significant technical obstacles, these are likely to be progressively overcome as gene delivery systems are refined. [ABSTRACT FROM AUTHOR]

Background: The great majority of post-infarction studies of beta-blockers were conducted in an era when these agents were widely held to be contra-indicated for the management of heart failure. We now know that beta-blockers are highly effective for the management of patients with chronic stable heart failure. However, there remains uncertainty about their role in the setting of post-infarction heart failure and ventricular dysfunction.Aim: the primary objective in this paper, was to investigate the extent to which heart failure or evidence of major cardiac dysfunction influenced outcome in previous trials of beta-blockers in heart failure after myocardial infarction.Methods: We assessed the extent to which the inclusion of patients with heart failure or major cardiac dysfunction influenced outcome in randomised trials of long-term use of beta-blockade after myocardial infarction. The primary analysis was to assess the extent to which the proportion of patients included in each trial with heart failure influenced the relative odds of all-cause mortality in the trials. All randomised trials without crossover with treatment lasting more than one month and with 50 or more patients were considered. All those that provided information on the proportion of patients with heart failure or major cardiac dysfunction in the original or subsequent articles were included in the analysis.Results: Overall treatment with a beta-blocker was associated with a 22.6% reduction in the odds of death (95% C1 11-32.3%). There were very few data on the effects of beta-blockers after myocardial infarction in patients with documented left ventricular systolic dysfunction. In the analysis that included heart failure as a factor, treatment with a beta-blocker was associated with a non-significant interaction with the presence of heart failure. However, because the group including heart failure patients were at higher risk, the absolute benefit of treatment with beta-blockers appeared greater in this group.Conclusions: This analysis suggests that the relative benefit of beta-blockers on mortality after a myocardial infarction is similar in the presence or absence of heart failure but that the absolute benefit may be greater in the former. However, as current clinical practice has changed radically from the time when the majority of these trials were conducted, further trial evidence would be desirable. [ABSTRACT FROM AUTHOR]

In the present paper, we report on the use of the heteroduplex PCR technique to detect the presence of clonally rearranged VDJ segments of the heavy chain immunoglobulin gene (VDJH) in the apheresis products of patients with multiple myeloma (MM) undergoing autologous peripheral blood stem cell (APBSC) transplantation. Twenty-three out of 31 MM patients undergoing APBSC transplantation with VDJH segments clonally rearranged detected at diagnosis were included in the study. Samples of the apheresis products were PCR amplified using JH and VH (FRIII and FRII) consensus primers and subsequently analyzed with the heteroduplex technique, and compared with those obtained at diagnosis. 52% of cases yielded positive results (presence of clonally rearranged VDJH segments in at least one apheresis). The presence of positive results in the apheresis products was not related to any pretransplant characteristics with the exception of response status at transplant. Thus, while no one patient with positive apheresis products was in complete remission (CR), negative immunofixation, before the transplant, five cases (46%) with negative apheresis were already in CR at transplant (P = 0.01). The remaining six cases with heteroduplex PCR negative apheresis were in partial remission before transplant. Patients with clonally free products were more likely to obtain CR following transplant (64% vs 17%, P= 0.02) and a longer progression-free survival, (40 months in patients transplanted with polyclonal products vs 20 with monoclonal ones, P = 0.03). These results were consistent when the overall survival was considered, since it was better in those patients with negative apheresis than it was in those with positive (83% vs 36% at 5 years from diagnosis, P= 0.01). These findings indicate that the presence of clonality rearranged VDJH segments is related to the response and outcome in MM transplanted patients. [ABSTRACT FROM AUTHOR]

This paper describes the 2-year post-treatment follow-up of preschool children identified as having high levels of disruptive behavior at kindergarten entry. They were assigned to four treatment conditions: A no-treatment group, parent-training only, treatment classroom only, and the combination of parent training with the treatment classroom. Interventions lasted the entire kindergarten academic year. Initial post-treatment results reported previously indicated no effects for the parent-training program but some efficacy for the classroom intervention program. For this report, the disruptive behavior (DB) children were subdivided into those who did (n = 74) and did not (n = 77) receive the treatment classroom. Two-year post-treatment follow-up results indicated no differences between the classroom treated and untreated DB groups. These groups also failed to differ in the percentage of children using available treatments across the follow-up period. The DB children in both groups had significantly more symptoms of ADHD and ODD than a community control group (N = 47) at follow-up. They also received higher ratings of externalizing problems on the parent Child Behavior Checklist, more severe ratings of behavior problems at home, and ratings of more pervasive behavior problems at school, and had poorer academic skills. Results suggested that early intervention classrooms for DB children may not produce enduring effects once treatment is withdrawn, and that better approaches are needed for identifying those DB children at greatest risk for later maladjustment. [ABSTRACT FROM AUTHOR]

In 1975, serial subculture of human keratinocytes was first described. Clinical application of this discovery was made possible after the preparation of these cells into epithelial sheets. In 1981, the earliest application of cultured autologous epithelia was made for the treatment of extensive third-degree burns. Although the most important advantage is the large surface area obtained from a relatively small biopsy of healthy skin from the patient, a disadvantage is the delay, which is too long, especially for the treatment of extensive deep burns. This delay leads to denutrition and infection of the burn wounds, which in turn risks the life of the patient and jeopardizes the engraftment of the cultures. More recently, allogenic cultured epidermis, obtained more quickly from donor skin, has been described in the treatment of leg ulcers, repair of skin donor site harvested for split thickness autograft, dermatological diseases and in second-degree burns, although limited to certain areas. In this last case, grafted cells act by stimulation of epithelialisation from the adnexal appendages. To be able rapidly to treat patients suffering extensive and deep second-degree burns, a bank of allogenic keratinocytes has been created, with due attention to safety and security. The paper demonstrates the advantages of using allogenic keratinocytes in the first phase of treatment of a 97% deep second-degree burn patient awaiting autologous cultured keratinocytes. The time required for complete healing achieved using such a strategy is compared with the results obtained after treatment using autologous sheets of two patients burnt on 80% and 82% of their total body area. The treatment of these two latter patients is relatively long and complicated by potentially lethal problems. In the 97% burnt patient, however, the clinical course is shorter and without complication. Moreover, autologous and allogenic cultured epithelia give good aesthetic results, without the mesh aspect obtained with a split-thickness autograft, and also without the discomfort for the patient of removing a sample of skin. Deep second-degree burns are an application of choice for the cultured epithelia, as the presence of the dermis avoids retractions responsible for functional complications usually observed in third-degree burns where dermis is absent. Because of the safety of the bank of allogenic keratinocytes, the treatment of extensive and deep second-degree burns has become safer and faster, with better functional and aesthetic results. [ABSTRACT FROM AUTHOR]

A 'poor response' in the context of in-vitro fertilization (IVF) can be defined as failure to produce an adequate number of mature follicles, and/or a peak oestradiol concentration less than a defined minimum. The cut-off points implied in this definition vary between different centres. Many opt to cancel the IVF cycle when their defined minimum concentrations are not reached despite the lack of evidence of improved outcome in subsequent cycles. Patients attending the Oxford Fertility Unit who are 'poor responders' have always been given the option of continuing with treatment. The first cycles of IVF in 124 patients, with normal day 3 follicle stimulating hormone (FSH), who produced less than five follicles within a 2 year period were studied. The patients were divided into three groups according to the number of follicles produced: A (one or two follicles; n = 33), B (three follicles; n = 33) and C (four follicles; n = 58). The three groups were similar in age, day 3 FSH, total gonadotrophin dose, duration of stimulation, peak oestradiol concentration, oocyte yield, fertilization rate and the clinical pregnancy rate. However, group A had a significantly higher oestradiol concentration per follicle (P < 0.001). The clinical pregnancy rate/cycle in the three groups was comparable to our overall rate in the study period (25.5%). This paper suggests that poor responders with a normal day 3 FSH may still achieve a pregnancy rate similar to that of normal responders. [ABSTRACT FROM AUTHOR]

The high prevalence of post traumatic stress disorder (PTSD) among people with heroin dependence and its impact on short term outcomes has been well established. The impact of PTSD on long-term recovery is, however, unknown. This paper examines the impact of current and lifetime PTSD on long-term recovery from heroin dependence among participants who took part in the 11-year follow-up of the Australian Treatment Outcome Study (ATOS), a prospective naturalistic longitudinal study of 615 people with heroin dependence recruited from Sydney, Australia, in 2001-2002. Seventy-one percent of the cohort (n = 431) were re-interviewed 11-years post study entry. Outcomes examined included heroin and other drug use, dependence, general physical and mental health, depression, PTSD, employment, and the incidence of trauma exposure, overdose, imprisonment, and attempted suicide over the 11- year follow-up. Despite having a poorer profile at baseline, individuals with current PTSD or a history of PTSD at baseline demonstrated similar levels of improvement to those without a history of PTSD in all outcome domains across the 11-year follow-up, PTSD was associated with consistently higher levels of major depression, and attempted suicide, subsequent trauma exposure, and poorer occupational functioning across the 11-year follow-up. These findings highlight the importance of interventions aimed at occupational rehabilitation, reducing the likelihood of retraumatisation, and addressing PTSD and associated comorbidities among people with heroin dependence. [ABSTRACT FROM AUTHOR]

Background: Dry eye disease is a common chronic condition that is characterized by ocular discomfort and visual disturbances that decrease quality of life. Many clinicians recommend the use of supplements of n-3 fatty acids (often called omega-3 fatty acids) to relieve symptoms.Methods: In a multicenter, double-blind clinical trial, we randomly assigned patients with moderate-to-severe dry eye disease to receive a daily oral dose of 3000 mg of fish-derived n-3 eicosapentaenoic and docosahexaenoic acids (active supplement group) or an olive oil placebo (placebo group). The primary outcome was the mean change from baseline in the score on the Ocular Surface Disease Index (OSDI; scores range from 0 to 100, with higher scores indicating greater symptom severity), which was based on the mean of scores obtained at 6 and 12 months. Secondary outcomes included mean changes per eye in the conjunctival staining score (ranging from 0 to 6) and the corneal staining score (ranging from 0 to 15), with higher scores indicating more severe damage to the ocular surface, as well as mean changes in the tear break-up time (seconds between a blink and gaps in the tear film) and the result on Schirmer's test (length of wetting of paper strips placed on the lower eyelid), with lower values indicating more severe signs.Results: A total of 349 patients were assigned to the active supplement group and 186 to the placebo group; the primary analysis included 329 and 170 patients, respectively. The mean change in the OSDI score was not significantly different between the active supplement group and the placebo group (-13.9 points and -12.5 points, respectively; mean difference in change after imputation of missing data, -1.9 points; 95% confidence interval [CI], -5.0 to 1.1; P=0.21). This result was consistent across prespecified subgroups. There were no significant differences between the active supplement group and the placebo group in mean changes from baseline in the conjunctival staining score (mean difference in change, 0.0 points; 95% CI, -0.2 to 0.1), corneal staining score (0.1 point; 95% CI, -0.2 to 0.4), tear break-up time (0.2 seconds; 95% CI, -0.1 to 0.5), and result on Schirmer's test (0.0 mm; 95% CI, -0.8 to 0.9). At 12 months, the rate of adherence to treatment in the active supplement group was 85.2%, according to the level of n-3 fatty acids in red cells. Rates of adverse events were similar in the two trial groups.Conclusions: Among patients with dry eye disease, those who were randomly assigned to receive supplements containing 3000 mg of n-3 fatty acids for 12 months did not have significantly better outcomes than those who were assigned to receive placebo. (Funded by the National Eye Institute, National Institutes of Health; DREAM ClinicalTrials.gov number, NCT02128763 .). [ABSTRACT FROM AUTHOR]

Background: Motivated by the setting of clinical trials in low back pain, this work investigated statistical methods to identify patient subgroups for which there is a large treatment effect (treatment by subgroup interaction). Statistical tests for interaction are often underpowered. Individual patient data (IPD) meta-analyses provide a framework with improved statistical power to investigate subgroups. However, conventional approaches to subgroup analyses applied in both a single trial setting and an IPD setting have a number of issues, one of them being that factors used to define subgroups are investigated one at a time. As individuals have multiple characteristics that may be related to response to treatment, alternative exploratory statistical methods are required.Methods: Tree-based methods are a promising alternative that systematically searches the covariate space to identify subgroups defined by multiple characteristics. A tree method in particular, SIDES, is described and extended for application in an IPD meta-analyses setting by incorporating fixed-effects and random-effects models to account for between-trial variation. The performance of the proposed extension was assessed using simulation studies. The proposed method was then applied to an IPD low back pain dataset.Results: The simulation studies found that the extended IPD-SIDES method performed well in detecting subgroups especially in the presence of large between-trial variation. The IPD-SIDES method identified subgroups with enhanced treatment effect when applied to the low back pain data.Conclusions: This work proposes an exploratory statistical approach for subgroup analyses applicable in any research discipline where subgroup analyses in an IPD meta-analysis setting are of interest. [ABSTRACT FROM AUTHOR]

Motivational Interviewing (MI) is an evidence-based practice shown to be effective when working with people in treatment for substance use disorders. However, MI is a complex treatment modality optimized by training with feedback. Feedback, assessment and monitoring of treatment fidelity require measurement, which is typically done using audiotaped sessions. The gold standard for such measurement of MI skill has been an audiotaped interview, scored by a rater with a detailed structured instrument such as the Motivational Interviewing Treatment Integrity 2.0 (MITI 2.0) Coding System (Moyers, et al., 2005). The Helpful Responses Questionnaire (HRQ) (Miller, Hedrick, & Orlofsky, 1991) is a pen-and-paper test of empathy (a foundational MI skill) that does not require an audiotaped session. A randomized trial of three different regimens for training counselors in MI (live supervision using Teleconferencing, Tape-based supervision and Workshop only) (Smith et al., 2012) offered the opportunity to evaluate the performance of the HRQ as a measure of MI ability, compared to the several MITI 2.0 global scores and subscales. Participants were counselors (N=97) working at community-based substance use treatment programs, whose MI proficiency was measured at four time points: baseline (before an initial 2-day MI workshop), post-workshop, 8weeks post-workshop (i.e., post-supervision), and 20weeks post-workshop with both MITI 2.0 and HRQ. HRQ total scores correlated significantly with the Reflection to Question Ratio from the MITI 2.0 at post-workshop (r=0.33), week 8 (r=0.34), and week 20 (r=0.38), and with the Spirit (r=0.32) and Empathy (r=0.32) global scores at week 20. Correlations of HRQ with other MITI 2.0 subscales and time points after workshop were small and not significant. As predicted, HRQ scores differed between training conditions (X2(2)=7.88, p=0.02), with counselors assigned to live supervision achieving better HRQ scores than those in Workshop only. In summary, HRQ is a modestly accurate measure, mainly of the Reflection to Question Ratio, considered a core marker of MI skill. It is sensitive to training effects and may help identify counselors needing more intensive supervision. Given its ease of administration and scoring, HRQ may be a useful marker of MI skill during training efforts. [ABSTRACT FROM AUTHOR]

Objective: The Opiate Dosage Adequacy Scale (ODAS) is a clinical tool to individually measure the "adequacy" of opioid doses in patients on maintenance treatment. The aim of this paper is to provide evidence for the validity and reliability of the ODAS in a sample of patients in buprenorphine/naloxone (B/N) maintenance treatment.Method: Cross-sectional study of a convenience sample of B/N-treated patients (n = 316) from four Autonomous Communities in Spain. Participants completed a battery of instruments to assess the following: buprenorphine dose adequacy; heroin dependence severity; psychological adjustment; and patient-desired adjustment of buprenorphine dose.Results: Exploratory Factor Analysis identified four factors from the ODAS that together account for 85.4% of the total variance: "Heroin craving and use"; "Overmedication"; "Objective opiate withdrawal symptoms (OWS)" and 'Subjective OWS'. Compared to patients with an "inadequate" B/N dose (ODAS), patients with "adequate" doses had less heroin use in the last week (0.01 vs. 0.40; t = -2.73; p < 0.01, 95% CI: -0.67, -0.10), less severe heroin dependence (2.20 vs. 5.26, t = -5.14, p < 0.001; 95% CI: -4.23, -1.88), less psychological distress (3.00 vs. 6.31, t = -4.37, p < 0.001; 95% CI: -4.80, -1.81), and greater satisfaction with their doses (42.1% vs. 13.6%, χ2 = 14.44, p < 0.01). Cronbach's alpha coefficient was 0.76 (0.81, 0.92, 0.94, and 0.93, respectively, for the four factor dimensions).Conclusion: These findings support the validity and reliability of the ODAS as a tool to measure and assess buprenorphine dose adequacy in the context of an opioid dependency treatment program. [ABSTRACT FROM AUTHOR]

Background: Bipolar patients experience sleep disturbances during and between mood episodes. Yet the impact of sleep on treatment with different medications has not been fully explored. The purpose of this paper is to explore the potential impact of poor sleep at baseline on outcomes in a randomized effectiveness trial of quetiapine and lithium.Methods: The Bipolar CHOICE study was a 6-month, parallel group, multisite randomized controlled trial. Participants with bipolar disorder (N = 482; 59% female and age 18-70 years) received quetiapine or lithium. Patients were allowed to also receive adjunctive personalized treatments, which were guideline-informed, empirically-based medications added to treatment as needed. Medication changes were recorded as necessary clinical adjustments (NCA). Fisher's exact tests, mixed-regression models, and Mann-Whitney U tests were used to assess demographic and clinical characteristics as well as whether sleep disturbance would predict outcomes.Results: 63% of patients had baseline sleep disturbance. Individuals with sleep disturbance had worse bipolar illness severity, greater severity of depression, mania, anxiety, irritability, and psychosis, were less likely to have sustained response (17% vs. 29%; adjusted RR: 0.55, 95% CI: 0.38-0.78, p = 0.0006) and had more NCAs (median 0.71 vs. 0.59, p = 0.03).Limitations: Our findings were limited by how we defined sleep disturbance, and by how severity of sleep disturbance was assessed with one item with a non-sleep specific measure.Conclusions: Baseline sleep disturbance was associated with more severe bipolar symptoms and worse 6-month outcomes. Further research is warranted on improving sleep in bipolar disorder, especially the role of psychosocial interventions. [ABSTRACT FROM AUTHOR]

Background: Reducing the use of antibiotics for upper respiratory tract infections is needed to limit the global threat of antibiotic resistance. We estimated the effectiveness of probiotics and xylitol for the management of pharyngitis.Methods: In this parallel-group factorial randomized controlled trial, participants in primary care (aged 3 years or older) with pharyngitis underwent randomization by nurses who provided sequential intervention packs. Pack contents for 3 kinds of material and advice were previously determined by computer-generated random numbers: no chewing gum, xylitol-based chewing gum (15% xylitol; 5 pieces daily) and sorbitol gum (5 pieces daily). Half of each group were also randomly assigned to receive either probiotic capsules (containing 24 × 109 colony-forming units of lactobacilli and bifidobacteria) or placebo. The primary outcome was mean self-reported severity of sore throat and difficulty swallowing (scale 0-6) in the first 3 days. We used multiple imputation to avoid the assumption that data were missing completely at random.Results: A total of 1009 individuals consented, 934 completed the baseline assessment, and 689 provided complete data for the primary outcome. Probiotics were not effective in reducing the severity of symptoms: mean severity scores 2.75 with no probiotic and 2.78 with probiotic (adjusted difference -0.001, 95% confidence interval [CI] -0.24 to 0.24). Chewing gum was also ineffective: mean severity scores 2.73 without gum, 2.72 with sorbitol gum (adjusted difference 0.07, 95% CI -0.23 to 0.37) and 2.73 with xylitol gum (adjusted difference 0.01, 95% CI -0.29 to 0.30). None of the secondary outcomes differed significantly between groups, and no harms were reported.Interpretation: Neither probiotics nor advice to chew xylitol-based chewing gum was effective for managing pharyngitis. Trial registration: ISRCTN, no. ISRCTN51472596. [ABSTRACT FROM AUTHOR]

Objective: Efficacy and safety of long-term use of antidepressants (AD) in bipolar disorder (BD) patients remains highly controversial. Here we performed a meta-analysis of randomized controlled trials (RCTs) exploring the efficacy and safety of long-term AD use in BD patients.Methods: English-written literature published in peer-reviewed journal was systematically searched from Pubmed, EMBASE, CENTRAL, PsycINFO and Clinicaltrials.gov. Each database was searched from its first available time to August 31, 2016. Additional papers were searched from recent guidelines, expert consensus and systematic reviews by hand. RCTs exploring the efficacy and safety of long-term (≥4m) antidepressant treatment for patients with bipolar disorder were eligible. Two authors (HF, JL) independently extracted the data. Risk ratio (RR), number needed to treat (NNT) and/or number needed to harm (NNH) for new depressive episodes and new manic/hypomanic episodes were calculated. Subgroup analyses were performed based on treatment regimen (AD monotherapy or combined with MS), types of antidepressants, funding source, bipolar subtypes and treatment duration.Results: Eleven trials with 692 bipolar disorder patients were included in the meta-analysis. The risk of bias assessment demonstrated moderate bias risk. Antidepressants were superior to placebo in reducing new depressive episodes in bipolar disorders without increasing risk of new manic/hypomanic episodes either used as monotherapy or in combination with MS. Subgroup analyses revealed that greater benefit and lower risk may be achieved in BD II than in BD I. However, compared with MS monotherapy, AD monotherapy significantly increased the risk of affective switch with no improvement in prophylaxis of new depressive episodes.Conclusions: Reduced new depressive episodes may be achieved by long-term AD treatment with no significantly increased risk of new manic/hypomanic episodes in BD, particularly in BD II. The elevated risk of affective switch of AD monotherapy compared with MS monotherapy may be contributed to the protective effect of MS in diminishing manic/hypomanic episodes. Further studies are needed to verify our findings. [ABSTRACT FROM AUTHOR]

Background: Child maltreatment is a significant public health problem. Group Family Nurse Partnership (gFNP) is a new intervention for young, expectant mothers implemented successfully in pilot studies. This study was designed to determine the effectiveness and cost-effectiveness of gFNP in reducing risk factors for maltreatment with a potentially vulnerable population.Methods: A multi-site, randomized controlled, parallel-arm trial and prospective economic evaluation was conducted, with allocation via remote randomization (minimization by site, maternal age group) to gFNP or usual care. Participants were expectant mothers aged below 20 years with at least one live birth, or aged 20-24 years with no live births and with low educational qualifications. Data from maternal interviews at baseline and when infants were 2, 6 and 12 months, and video-recording at 12 months, were collected by researchers blind to allocation. Cost information came from weekly logs completed by gFNP family nurses and other service delivery data reported by participants. Primary outcomes measured at 12 months were parenting attitudes (Adult-Adolescent Parenting Index, AAPI-2) and maternal sensitivity (CARE Index). The economic evaluation was conducted from a UK NHS and personal social services perspective with cost-effectiveness expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. The main analyses were intention-to-treat with additional complier average causal effects (CACE) analyses.Results: Between August 2013 and September 2014, 492 names of potential participants were received of whom 319 were eligible and 166 agreed to take part, 99 randomly assigned to receive gFNP and 67 to usual care. There were no between-arm differences in AAPI-2 total (7 · 5/10 in both, SE 0.1), difference adjusted for baseline, site and maternal age group 0 · 06 (95% CI - 0 · 15 to 0 · 28, p = 0 · 59) or CARE Index (intervention 4 · 0 (SE 0 · 3); control 4 · 7 (SE 0 · 4); difference adjusted for site and maternal age group - 0 · 68 (95% CI - 1 · 62 to 0 · 16, p = 0 · 25) scores. The probability that gFNP is cost-effective based on the QALY measure did not exceed 3%.Conclusions: The trial did not support gFNP as a means of reducing the risk of child maltreatment in this population but slow recruitment adversely affected group size and consequently delivery of the intervention.Trial Registration: ISRCTN78814904 . Registered on 17 May 2013. [ABSTRACT FROM AUTHOR]

Background: Cellulitis is a painful, potentially serious, infectious process of the dermal and subdermal tissues and represents a significant disease burden. The statistical analysis plan (SAP) for the Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial is described here. The PEDOCELL trial is a multicentre, randomised, parallel-arm, double-blinded, non-inferiority clinical trial comparing the efficacy of flucloxacillin (monotherapy) with combination flucloxacillin/phenoxymethylpenicillin (dual therapy) for the outpatient treatment of cellulitis in the emergency department (ED) setting. To prevent outcome reporting bias, selective reporting and data-driven results, the a priori-defined, detailed SAP is presented here.Methods/design: Patients will be randomised to either orally administered flucloxacillin 500 mg four times daily and placebo or orally administered 500 mg of flucloxacillin four times daily and phenoxymethylpenicillin 500 mg four times daily. The trial consists of a 7-day intervention period and a 2-week follow-up period. Study measurements will be taken at four specific time points: at patient enrolment, day 2-3 after enrolment and commencing treatment (early clinical response (ECR) visit), day 8-10 after enrolment (end-of-treatment (EOT) visit) and day 14-21 after enrolment (test-of-cure (TOC) visit). The primary outcome measure is investigator-determined clinical response measured at the TOC visit. The secondary outcomes are as follows: lesion size at ECR, clinical treatment failure at each follow-up visit, adherence and persistence of trial patients with orally administered antibiotic therapy at EOT, health-related quality of life (HRQoL) and pharmacoeconomic assessments. The plan for the presentation and comparison of baseline characteristics and outcomes is described in this paper.Discussion: This trial aims to establish the non-inferiority of orally administered flucloxacillin monotherapy with orally administered flucloxacillin/phenoxymethylpenicillin dual therapy for the ED-directed outpatient treatment of cellulitis. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. The SAP for the PEDOCELL trial was developed a priori in order to minimise analysis bias.Trial Registration: EU Clinical Trials Register (EudraCT number: 2016-001528-69). Registered on 5 April 2016. ClinicalTrials.gov, ID: NCT02922686 . Registered on 9 August 2016. [ABSTRACT FROM AUTHOR]