N-acetyl cysteine for depressive symptoms in bipolar disorder - a double blind, randomized, placebo-controlled trial

Background: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorderare complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.

Methods: A randomized, double-blind, multicenter, placebo-controlled study of individuals (n 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning.

Results: NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: 8.05 [13.16, 2.95], p .002) a n d most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p .968) and no significant between-group differences inadverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts.

Conclusions: NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar  disorder.

N-Acetyl cysteine as a glutathione precursor for schizophrenia : a double blind, randomized, placebo-controlled trial

Background: Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period.

Methods: A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment.

Results: Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [5.97 (10.44, 1.51), p .009], PANSS negative [mean difference 1.83 (95% confidence interval: 3.33, .32), p .018], and PANSS general [2.79 (5.38, .20), p .035], CGI-Severity (CGI-S) [.26 (.44,.08), p .004], and CGI-Improvement (CGI-I) [.22 (.41, .03), p .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p .022). Effect sizes at end point were consistent with moderate benefits.

Conclusions: These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.

The use of complementary and alternative medicine among people living with diabetes in Sydney

Background: Complementary and alternative medicine (CAM) is common in patients with chronic disease such as diabetes mellitus. The primary objective of the study was to determine the overall prevalence and type of CAM use in individuals with diabetes mellitus (DM) in Western Sydney and to compare the prevalence and factors associated with CAM use with the literature.

Methods: A multicenter cross-sectional study was undertaken using a self-completed questionnaire distributed to patients with DM attending a public hospital and specialist endocrinology clinics in the region. The type of DM and pattern of CAM utilisation were analyzed.

Results: Sixty nine people responded to the questionnaire: age range of 18-75 years during a twelve week collection period. Overall, 32 respondents with diabetes were using some form of CAM, resulting in a utilisation rate of 46.3%. Twenty of the 32 CAM users used CAM specifically to treat their diabetes accounting for 28.9% of the respondent sample population. Multivitamins (40%), cinnamon, Co-enzyme q10 and prayer were the most frequently used CAM modalities. There was no significant difference between males and females, age range, income or diabetes complications between CAM and non-CAM users. (p values each > 0.05) The factor most significantly associated with CAM usage was being born overseas (p = 0.044).

Conclusions: Almost half the respondents (46.3%) used CAM: 28% used CAM specifically to treat their diabetes. Individuals born overseas were significantly more likely to use CAM than those born in Australia. Other factors such as age, gender, wealth and duration of living with diabetes were not associated with higher rate of CAM usage.

Resolving controversies in hip fracture care : the need for large collaborative trials in hip fractures

Summary: Hip fractures are a significant cause of morbidity and mortality worldwide and the burden of disability associated with hip fractures globally vindicates the need for high-quality research to advance the care of patients with hip fractures. Historically, large, multi-centre randomized controlled trials have been rare in the orthopaedic trauma literature. Similar to other medical specialties, orthopaedic research is currently undergoing a paradigm shift from single centre initiatives to larger collaborative groups. This is evident with the establishment of several collaborative groups in Canada, in the United States, and in Europe, which has proven that multi-centre trials can be extremely successful in orthopaedic trauma research.

Despite ever increasing literature on the topic of his fractures, the optimal treatment of hip ftractures remains unknown and controversial. To resolve this controversy large multi-national collaborative randomized controlled trials are required. In 2005, the International Hip Fracture Research Collaborative was officially established following funding from the Canadian Institute of Health Research International Oppurtunity Program with the mandate of resolving controversies in hip fracture management. This manuscript will describe the need, the information, the organization, and the accomplishments to date of the International Hip Fracture Research Collaborative.

Additional Saturday rehabilitation improves functional independence and quality of life and reduces length of stay: a randomised controlled trial

Background

Many inpatients receive little or no rehabilitation on weekends. Our aim was to determine what effect providing additional Saturday rehabilitation during inpatient rehabilitation had on functional independence, quality of life and length of stay compared to 5 days per week of rehabilitation.

This was a multicenter, single-blind (assessors) randomized controlled trial with concealed allocation and 12-month follow-up conducted in two publically funded metropolitan inpatient rehabilitation facilities in Melbourne, Australia. Patients were eligible if they were adults (aged ≥18 years) admitted for rehabilitation for any orthopedic, neurological or other disabling conditions excluding those admitted for slow stream rehabilitation/geriatric evaluation and management. Participants were randomly allocated to usual care Monday to Friday rehabilitation (control) or to Monday to Saturday rehabilitation (intervention). The additional Saturday rehabilitation comprised physiotherapy and occupational therapy. The primary outcomes were functional independence (functional independence measure (FIM); measured on an 18 to 126 point scale), health-related quality of life (EQ-5D utility index; measured on a 0 to 1 scale, and EQ-5D visual analog scale; measured on a 0 to 100 scale), and patient length of stay. Outcome measures were assessed on admission, discharge (primary endpoint), and at 6 and 12 months post discharge.

We randomly assigned 996 adults (mean (SD) age 74 (13) years) to Monday to Saturday rehabilitation (n = 496) or usual care Monday to Friday rehabilitation (n = 500). Relative to admission scores, intervention group participants had higher functional independence (mean difference (MD) 2.3, 95% confidence interval (CI) 0.5 to 4.1, P = 0.01) and health-related quality of life (MD 0.04, 95% CI 0.01 to 0.07, P = 0.009) on discharge and may have had a shorter length of stay by 2 days (95% CI 0 to 4, P = 0.1) when compared to control group participants. Intervention group participants were 17% more likely to have achieved a clinically significant change in functional independence of 22 FIM points or more (risk ratio (RR) 1.17, 95% CI 1.03 to 1.34) and 18% more likely to have achieved a clinically significant change in health-related quality of life (RR 1.18, 95% CI 1.04 to 1.34) on discharge compared to the control group. There was some maintenance of effect for functional independence and health-related quality of life at 6-month follow-up but not at 12-month follow-up. There was no difference in the number of adverse events between the groups (incidence rate ratio = 0.81, 95% CI 0.61 to 1.08).

Providing an additional day of rehabilitation improved functional independence and health-related quality of life at discharge and may have reduced length of stay for patients receiving inpatient rehabilitation. 

Development and implementation of a novel measure for quantifying training loads in rowing : the T2minute method

Development and implementation of a novel measure for quantifying training loads in rowing: The T2minute method. J Strength Cond Res 28(4): 1172–1180, 2014—The systematic management of training requires accurate training load measurement. However, quantifying the training of elite Australian rowers is challenging because of (a) the multicenter, multistate structure of the national program; (b) the variety of training undertaken; and (c) the limitations of existing methods for quantifying the loads accumulated from varied training formats. Therefore, the purpose of this project was to develop a new measure for quantifying training loads in rowing (the T2minute method). Sport scientists and senior coaches at the National Rowing Center of Excellence collaborated to develop the measure, which incorporates training duration, intensity, and mode to quantify a single index of training load. To account for training at different intensities, the method uses standardized intensity zones (T zones) established at the Australian Institute of Sport. Each zone was assigned a weighting factor according to the curvilinear relationship between power output and blood lactate response. Each training mode was assigned a weighting factor based on whether coaches perceived it to be “harder” or “easier” than on-water rowing. A common measurement unit, the T2minute, was defined to normalize sessions in different modes to a single index of load; one T2minute is equivalent to 1 minute of on-water single scull rowing at T2 intensity (approximately 60–72% V[Combining Dot Above]O2max). The T2minute method was successfully implemented to support national training strategies in Australian high performance rowing. By incorporating duration, intensity, and mode, the T2minute method extends the concepts that underpin current load measures, providing 1 consistent system to quantify loads from varied training formats.

Association between surgical indications, operative risk, and clinical outcome in infective endocarditis: a prospective study from the International Collaboration on Endocarditis.

Use of surgery for the treatment of infective endocarditis (IE) as related to surgical indications and operative risk for mortality has not been well defined.

Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients

Venous thromboembolism (VTE) is a common complication of acute illness, and its prevention is a ubiquitous aspect of inpatient care. A multicenter blinded, randomized trial compared the effectiveness of the most common pharmocoprevention strategies, unfractionated heparin (UFH) and the low-molecular-weight heparin (LMWH) dalteparin, finding no difference in the primary end point of leg deep-vein thrombosis but a reduced rate of pulmonary embolus and heparin-induced thrombocytopenia among critically ill medical-surgical patients who received dalteparin.

Prospective observational study of emergent endotracheal intubation practice in the intensive care unit and emergency department of an Australian regional tertiary hospital

Objective: The present study aimed to describe the characteristics and outcomes of intubation occurring in the ICU and ED of an Australian tertiary teaching hospital. Methods: This was a prospective observational study of intubation practice across the Geelong Hospital over a 6 month period from 1 August 2012 to 31 January 2013. Data were entered by the intubating team through an online data collection form. Results: There were 119 patients intubated and 134 attempts at intubation in the ED and ICU over a 6 month period. The first-pass success rate was 104/119 (87.4%), and all but a single patient was intubated by the second attempt. Propofol, fentanyl, midazolam and suxamethonium were the most common drugs used in rapid sequence induction. AEs were reported in 44/134 (32.8%) of intubation attempts, with transient hypoxia and hypotension being the most common. A significant adverse outcome, namely aspiration pneumonitis, occurred in one patient. There were no peri-intubation deaths. Conclusion: The majority of airways are managed by ICU and ED consultants and trainees, with success rates and AE rates comparable with other published studies. © 2014 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

The ProCaSP study: quality of life outcomes of prostate cancer patients after radiotherapy or radical prostatectomy in a cohort study urological oncology

Background: This study describes and compares health-related quality of life (HRQOL) of prostate cancer patients who received either radical prostatectomy (nerve-sparing, nsRP, or non-nerve-sparing, nnsRP) or radiotherapy (external RT, brachytherapy, or both combined) for treatment of localised prostate cancer. Methods: The prospective, multicenter cohort study included 529 patients. Questionnaires included the IIEF, QLQ-C30, and PORPUS-P. Data were collected before (baseline), three, six, twelve, and twenty-four months after treatment. Differences between groups' baseline characteristics were assessed; changes over time were analysed with generalised estimating equations (GEE). Missing values were treated with multiple imputation. Further, scores at baseline and end of follow-up were compared to German reference data. Results: The typical time trend was a decrease of average HRQOL three months after treatment followed by (partial) recovery. RP patients experienced considerable impairment in sexual functioning. The covariate-adjusted GEE identified a significant - but not clinically relevant - treatment effect for diarrhoea (b∈=∈7.0 for RT, p∈=∈0.006) and PORPUS-P (b∈=∈2.3 for nsRP, b∈=∈2.2 for RT, p∈=∈0.045) compared to the reference nnsRP. Most of the HRQOL scores were comparable to German norm values. Conclusions: Findings from previous research were reproduced in a specific setting of a patient cohort in the German health care system. According to the principle of evidence-based medicine, this strengthens the messages regarding treatment in prostate cancer and its impacts on patients' health-related quality of life. After adjustment for baseline HRQOL and other covariates, RT patients reported increased symptoms of diarrhoea, and nnsRP patients decreased prostate-specific HRQOL. RP patients experienced considerable impairment in sexual functioning. These differences should be taken into account by physicians when choosing the best therapy for a patient.

Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes: hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial. RESEARCH DESIGN AND METHODS: Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies. RESULTS: After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420-780] vs. 710 [460-1,260], P = 0.02; metanephrine, 2,412 [-3,026 to 7,279] vs. 5,180 [-771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation. CONCLUSIONS: Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.

Prevalence of Myopia in adults: implications for refractive surgeons

BACKGROUND: We reviewed the research on the prevalence of myopia in the adult population to compare the refractive distribution of patients being treated with excimer laser photorefractive keratectomy to correct myopia, and assess the potential market for excimer laser surgery. METHODS: All published reports of myopia prevalence in adults were reviewed, as well as the prevalence in the Melbourne Visual Impairment Project and the distribution of refractive errors treated by the Melbourne Excimer Laser Group in 1994. RESULTS: A large population-based study of people aged 4 to 74 years in the U.S. showed that 43% had low myopia (less than -5.00 diopters (D)), 3.2% had high myopia (-5.01 to -10.00 D), and 0.2% had extreme myopia (more than -10.00 D). In Asian populations these proportions may be much higher and in African and Pacific island groups, much lower. In the Melbourne Visual Impairment Project, we found the prevalence of low myopia was 21%, high myopia 2%, and extreme myopia 0.3%. A single excimer laser has operated for 3 years in Melbourne. Of those treated, 45% had low myopia, 42% high myopia, and 13% extreme myopia. Compared to low myopes, high myopes were ten times (OR: 9.8; Confidence interval: 6.69 to 12.91) more likely to have excimer laser treatment and extreme myopes were 16 times (OR: 16.40; Confidence interval: 12.53 to 20.27) more likely. CONCLUSIONS: Although there are many more people with lower amounts of myopia in the population and the clinical results have been more predictable after one procedure in this group, the perceived benefits of excimer laser treatment may be greater for those with higher amounts of myopia, thus influencing their decision to undergo excimer laser surgery to correct their myopia. There is clearly a large market potential for excimer laser surgery in people with low myopia.

The efficacy of a clinician referral and 12 week physical activity program among men living with prostate cancer: a multicentre cluster randomised controlled trial

BACKGROUND : The purpose of this study was to determine the efficacy of a clinician referral and exercise program in improving exercise levels and quality of life for men with prostate cancer.

METHODS : This was a multicenter cluster randomized controlled trial in Melbourne, Australia comprising 15 clinicians: 8 clinicians were randomized to refer eligible participants (n = 54) to a 12-week exercise program comprising 2 supervised gym sessions and 1 home-based session per week, and 7 clinicians were randomized to follow usual care (n = 93). The primary outcome was self-reported physical activity; the secondary outcomes were quality of life, anxiety, and symptoms of depression.

RESULTS : A significant intervention effect was observed for vigorous-intensity exercise (effect size: Cohen's d, 0.46; 95% confidence interval [CI], 0.09-0.82; P = .010) but not for combined moderate and vigorous exercise levels (effect size: d, 0.08; 95% CI, −0.28 to 0.45; P = .48). Significant intervention effects were also observed for meeting exercise guidelines (≥150 min/wk; odds ratio, 3.9; 95% CI, 1.9-7.8; P = .002); positive intervention effects were observed in the intervention group for cognitive functioning (effect size: d, 0.34; 95% CI, −0.02 to 0.70; P = .06) and depression symptoms (effect size: d, −0.35; 95% CI, −0.71 to 0.02; P = .06). Eighty percent of participants reported that the clinician's referral influenced their decision to participate in the exercise program.

CONCLUSIONS : The clinician referral and 12-week exercise program significantly improved vigorous exercise levels and had a positive impact on mental health outcomes for men living with prostate cancer. Further research is needed to determine the sustainability of the exercise program and its generalizability to other cancer populations.

Cognitive remission: a novel objective for the treatment of major depression?

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD.

DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD.