Paper, prices and politics : an evaluation of the Swedish support to the Bai Bang project in Vietnam : a Sida evaluation report

Sweden’s protest against the Vietnam War was given tangible form in 1969 through the decision to give economic aid to the Government of North Vietnam. The main outcome was an integrated pulp and paper mill in the Vinh Phu Province north-west of Hanoi. Known as Bai Bang after its location, the mill became the most costly, one of the longest lasting and the most controversial project in the history of Swedish development cooperation. In 1996 Bai Bang produced at its full capacity. Today the mill is exclusively managed and staffed by the Vietnamese and there are plans for future expansion. At the same time a substantial amount of money has been spent to reach these achievements. Looking back at the cumbersome history of the project the results are against many’s expectations. To learn more about the conditions for sustainable development Sida commissioned two studies of the Bai Bang project. Together they touch upon several important issues in development cooperation over a period of almost 30 years: the change of aid paradigms over time, the role of foreign policy in development cooperation, cultural obstacles, recipient responsibility versus donor led development etc. The two studies were commissioned by Sida’s Department for Evaluation and Internal Audit which is an independent department reporting directly to Sida’s Board of Directors. One study assesses the financial and economic viability of the pulp and paper mill and the broader development impact of the project in Vietnam. It has been carried out by the Centre for International Economics, an Australian private economic research agency. The other study analyses the decision-making processes that created and shaped the project over a period of two decades, and reflects on lessons from the project for development cooperation in general. This study has been carried out by the Chr. Michelsen Institute, a Norweigan independent research institution.

Moving MobileMums forward: protocol for a larger randomized controlled trial of an improved physical activity program for women with young children

Background: Women with young children (under 5 years) are a key population group for physical activity intervention. Previous evidence highlights the need for individually tailored programs with flexible delivery mechanisms for this group. Our previous pilot study suggested that an intervention primarily delivered via mobile phone text messaging (MobileMums) increased self-reported physical activity in women with young children. An improved version of the MobileMums program is being compared with a minimal contact control group in a large randomised controlled trial (RCT). Methods/design: This RCT will evaluate the efficacy, feasibility and acceptability, cost-effectiveness, mediators and moderators of the MobileMums program. Primary (moderate-vigorous physical activity) and secondary (intervention implementation data, health service use costs, intervention costs, health benefits, theoretical constructs) outcomes are assessed at baseline, 3-months (end of intervention) and 9-months (following 6-month no contact: maintenance period). The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12611000481976; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336109).The intervention commences with a face-to-face session with a behavioural counsellor to initiate rapport and gather information for tailoring the 12-week text message program. During the program participants also have access to a: MobileMums Participant Handbook, MobileMums refrigerator magnet, MobileMums Facebook(C) group, and a MobileMums website with a searchable, on-line exercise directory. A nominated support person also receives text messages for 12-weeks encouraging them to offer their MobileMum social support for physical activity. Discussion: Results of this trial will determine the efficacy and cost-effectiveness of the MobileMums program, and the feasibility of delivering it in a community setting. It will inform the broader literature of physical activity interventions for women with young children and determine whether further investment in the translation of the program is warranted.

The life course of Australian researchers : experiences of applying for research funding

The life course of Australian researchers includes regular funding applications, which incur large personal and time costs. We previously estimated that Australian researchers spent 550 years preparing 3,727 proposals for the 2012 NHMRC Project Grant funding round, at an estimated annual salary cost of AU$66 million. Despite the worldwide importance of funding rounds, there is little evidence on what researchers think of the application process. We conducted a web-based survey of Australian researchers (May–July 2013) asking about their experience with NHMRC Project Grants. Almost all researchers (n=224 at 31 May) supported changes to the application (96%) and peer-review (88%) processes; 73% supported the introduction of shorter initial Expressions of Interest; and half (50%) provided extensive comments on the NHMRC processes. Researchers agreed preparing their proposals always took top priority over other work (97%) and personal (87%) commitments. More than half (57%) provided extensive comments on the ongoing personal impact of concurrent grant-writing and holiday seasons on family, children and other relationships. Researchers with experience on Grant Review Panels (34%) or as External Reviewers (78%) reported many sections of the proposals were rarely or never read, which suggests these sections could be cut with no impact on the quality of peer review. Our findings provide evidence on the experience of Australian researchers as applicants. The process of preparing, submitting and reviewing proposals could be streamlined to minimise the burden on applicants and peer reviewers, giving Australian researchers more time to work on actual research and be with their families.

A high-throughput panel for identifying clinically relevant mutation profiles in melanoma

Success with molecular-based targeted drugs in the treatment of cancer has ignited extensive research efforts within the field of personalized therapeutics. However, successful application of such therapies is dependent on the presence or absence of mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Building on these findings, we developed a high-throughput mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. An extensive literature search and interrogation of the Catalogue of Somatic Mutations in Cancer database identified more than 1,000 melanoma mutations. Applying a filtering strategy to focus on mutations amenable to the development of targeted drugs, we initially screened 120 known mutations in 271 samples using the Sequenom MassARRAY system. A total of 252 mutations were detected in 17 genes, the highest frequency occurred in BRAF (n = 154, 57%), NRAS (n = 55, 20%), CDK4 (n = 8, 3%), PTK2B (n = 7, 2.5%), and ERBB4 (n = 5, 2%). Based on this initial discovery screen, a total of 46 assays interrogating 39 mutations in 20 genes were designed to develop a melanoma-specific panel. These assays were distributed in multiplexes over 8 wells using strict assay design parameters optimized for sensitive mutation detection. The final melanoma-specific mutation panel is a cost effective, sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular-based therapeutics for the treatment of melanoma. When used in a clinical research setting, the panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecularly targeted drugs

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene

High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation ‘‘hotspot’’ at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.

Whole genome and exome sequencing of melanoma

Melanoma has historically been refractive to traditional therapeutic approaches. As such, the development of novel drug strategies has been needed to improve rates of overall survival in patients with melanoma, particularly those with late stage or disseminated disease. Recent success with molecularly based targeted drugs, such as Vemurafenib in BRAF-mutant melanomas, has now made “personalized medicine” a reality within some oncology clinics. In this sense, tailored drugs can be administered to patients according to their tumor “mutation profiles.” The success of these drug strategies, in part, can be attributed to the identification of the genetic mechanisms responsible for the development and progression of metastatic melanoma. Recently, the advances in sequencing technology have allowed for comprehensive mutation analysis of tumors and have led to the identification of a number of genes involved in the etiology of metastatic melanoma. As the methodology and costs associated with next-generation sequencing continue to improve, this technology will be rapidly adopted into routine clinical oncology practices and will significantly impact on personalized therapy. This review summarizes current and emerging molecular targets in metastatic melanoma, discusses the potential application of next-generation sequencing within the paradigm of personalized medicine, and describes the current limitations for the adoption of this technology within the clinic.

The increased risks of death and extra lengths of hospital and ICU stay from hospital-acquired bloodstream infections : a case-control study

Objectives Hospital-acquired bloodstream infections are known to increase the risk of death and prolong hospital stay, but precise estimates of these two important outcomes from well-designed studies are rare, particularly for non-intensive care unit (ICU) patients. We aimed to calculate accurate estimates, which are vital for estimating the economic costs of hospital-acquired bloodstream infections.

Low muscle glycogen concentration does not suppress the anabolic response to resistance exercise

We determined the effect of muscle glycogen concentration and postexercise nutrition on anabolic signaling and rates of myofibrillar protein synthesis after resistance exercise (REX). Sixteen young, healthy men matched for age, body mass, peak oxygen uptake (VO2peak) and strength (one repetition maximum; 1RM) were randomly assigned to either a nutrient or placebo group. After 48 h diet and exercise control, subjects undertook a glycogen-depletion protocol consisting of one-leg cycling to fatigue (LOW), whereas the other leg rested (NORM). The next morning following an overnight fast, a primed, constant infusion of L-[ring-13C6] phenylalanine was commenced and subjects completed 8 sets of 5 unilateral leg press repetitions at 80% 1RM. Immediately after REX and 2 h later, subjects consumed a 500 ml bolus of a protein/CHO (20 g whey + 40 g maltodextrin) or placebo beverage. Muscle biopsies from the vastus lateralis of both legs were taken at rest and 1 and 4 h after REX. Muscle glycogen concentration was higher in the NORM than LOW at all time points in both nutrient and placebo groups (P < 0.05). Postexercise Akt-p70S6K-rpS6 phosphorylation increased in both groups with no differences between legs (P < 0.05). mTORSer2448 phosphorylation in placebo increased 1 h after exercise in NORM (P < 0.05), whereas mTOR increased ?4-fold in LOW (P < 0.01) and ?11 fold in NORM with nutrient (P < 0.01; different between legs P < 0.05). Post-exercise rates of MPS were not different between NORM and LOW in nutrient (0.070 ± 0.022 vs. 0.068 ± 0.018 %/h) or placebo (0.045 ± 0.021 vs. 0.049 ± 0.017 %/h). We conclude that commencing high-intensity REX with low muscle glycogen availability does not compromise the anabolic signal and subsequent rates of MPS, at least during the early (4 h) postexercise recovery period.

Sex-based comparisons of myofibrillar protein synthesis after resistance exercise in the fed state

Sex-based comparisons of myofibrillar protein synthesis after resistance exercise in the fed state. J Appl Physiol 112: 1805-1813, 2012. First published March 1, 2012; doi:10.1152/japplphysiol.00170.2012.- We made sex-based comparisons of rates of myofibrillar protein synthesis (MPS) and anabolic signaling after a single bout of high-intensity resistance exercise. Eight men (20 ± 10 yr, BMI = 24.3 ± 2.4) and eight women (22 ± 1.8 yr, BMI = 23.0 ± 1.9) underwent primed constant infusions of L-[ring-13C6]phenylalanine on consecutive days with serial muscle biopsies. Biopsies were taken from the vastus lateralis at rest and 1, 3, 5, 24, 26, and 28 h after exercise. Twenty-five grams of whey protein was ingested immediately and 26 h after exercise. We also measured exercise-induced serum testosterone because it is purported to contribute to increases in myofibrillar protein synthesis (MPS) postexercise and its absence has been hypothesized to attenuate adaptative responses to resistance exercise in women. The exercise-induced area under the testosterone curve was 45-fold greater in men than women in the early (1 h) recovery period following exercise (P < 0.001). MPS was elevated similarly in men and women (2.3- and 2.7-fold, respectively) 1-5 h postexercise and after protein ingestion following 24 h recovery. Phosphorylation of mTORSer2448 was elevated to a greater extent in men than women acutely after exercise (P = 0.003), whereas increased phosphorylation of p70S6K1Thr389 was not different between sexes. Androgen receptor content was greater in men (main effect for sex, P = 0.049). Atrogin-1 mRNA abundance was decreased after 5 h recovery in both men and women (P < 0.001), and MuRF-1 expression was elevated in men after protein ingestion following 24 h recovery (P = 0.003). These results demonstrate minor sex-based differences in signaling responses and no difference in the MPS response to resistance exercise in the fed state. Interestingly, our data demonstrate that exerciseinduced increases in MPS are dissociated from postexercise testosteronemia and that stimulation of MPS occurs effectively with low systemic testosterone concentrations in women.

Rapid aminoacidemia enhances myofibrillar protein synthesis and anabolic intramuscular signaling responses after resistance exercise

Background: Ingestion of whey or casein yields divergent patterns of aminoacidemia that influence whole-body and skeletal muscle myofibrillar protein synthesis (MPS) after exercise. Direct comparisons of the effects of contrasting absorption rates exhibited by these proteins are confounded by their differing amino acid contents. Objective: Our objective was to determine the effect of divergent aminoacidemia by manipulating ingestion patterns of whey protein alone on MPS and anabolic signaling after resistance exercise. Design: In separate trials, 8 healthy men consumed whey protein either as a single bolus (BOLUS; 25-g dose) or as repeated, small, "pulsed" drinks (PULSE; ten 2.5-g drinks every 20 min) to mimic a more slowly digested protein. MPS and phosphorylation of signaling proteins involved in protein synthesis were measured at rest and after resistance exercise. Results: BOLUS increased blood essential amino acid (EAA) concentrations above those of PULSE (162% compared with 53%, P < 0.001) 60 min after exercise, whereas PULSE resulted in a smaller but sustained increase in aminoacidemia that remained elevated above BOLUS amounts later (180-220 min after exercise, P < 0.05). Despite an identical net area under the EAA curve, MPS was elevated to a greater extent after BOLUS than after PULSE early (1-3 h: 95% compared with 42%) and later (3-5 h: 193% compared with 121%) (both P < 0.05). There were greater changes in the phosphorylation of the Akt-mammalian target of rapamycin pathway after BOLUS than after PULSE. Conclusions: Rapid aminoacidemia in the postexercise period enhances MPS and anabolic signaling to a greater extent than an identical amount of protein fed in small pulses that mimic a more slowly digested protein. A pronounced peak aminoacidemia after exercise enhances protein synthesis.

Nutrient provision increases signalling and protein synthesis in human skeletal muscle after repeated sprints

The effect of nutrient availability on the acute molecular responses following repeated sprint exercise is unknown. The aim of this study was to determine skeletal muscle cellular and protein synthetic responses following repeated sprint exercise with nutrient provision. Eight healthy young male subjects undertook two sprint cycling sessions (10 × 6 s, 0.75 N m torque kg -1, 54 s recovery) with either pre-exercise nutrient (24 g whey, 4.8 g leucine, 50 g maltodextrin) or non-caloric placebo ingestion. Muscle biopsies were taken from vastus lateralis at rest, and after 15 and 240 min post-exercise recovery to determine muscle cell signalling responses and protein synthesis by primed constant infusion of L-[ring- 13C 6] phenylalanine. Peak and mean power outputs were similar between nutrient and placebo trials. Post-exercise myofibrillar protein synthetic rate was greater with nutrient ingestion compared with placebo ( ? 48%, P<0.05) but the rate of mitochondrial protein synthesis was similar between treatments. The increased myofibrillar protein synthesis following sprints with nutrient ingestion was associated with coordinated increases in Akt-mTOR-S6KrpS6 phosphorylation 15 min post-exercise (?200-600%, P<0.05), while there was no effect on these signalling molecules when exercise was undertaken in the fasted state. For the first time we report a beneficial effect of nutrient provision on anabolic signalling and muscle myofibrillar protein synthesis following repeated sprint exercise. Ingestion of protein/carbohydrate in close proximity to high-intensity sprint exercise provides an environment that increases cell signalling and protein synthesis.

Effect of recovery modality on 4-hour repeated treadmill running performance and changes in physiological variables

The purpose of this study was to compare the effectiveness of three different recovery modalities - active (ACT), passive (PAS) and contrast temperature water immersion (CTW) - on the performance of repeated treadmill running, lactate concentration and pH. Fourteen males performed two pairs of treadmill runs to exhaustion at 120% and 90% of peak running speed (PRS) over a 4-hour period. ACT, PAS or CTW was performed for 15-min after the first pair of treadmill runs. ACT consisted of running at 40% PRS, PAS consisted of standing stationary and CTW consisted of alternating between 60-s cold (10°C) and 120-s hot (42°C) water immersion. Run times were converted to time to cover set distance using critical power. Type of recovery modality did not have a significant effect on change in time to cover 400 m (Mean±SD; ACT 2.7±3.6 s, PAS 2.9±4.2 s, CTW 4.2±6.9 s), 1000 m (ACT 2.2±4.0 s, PAS 4.8±8.6 s, CTW 2.1±7.2 s) or 5000 m (ACT 1.4±29.0 s, PAS 16.7±58.5 s, CTW 11.7±33.0 s). Post exercise blood lactate concentration was lower in ACT and CTW compared with PAS. Participants reported an increased perception of recovery in the CTW compared with ACT and PAS. Blood pH was not significantly influenced by recovery modality. Data suggest both ACT and CTW reduce lactate accumulation after high intensity running, but high intensity treadmill running performance is returned to baseline 4-hours after the initial exercise bout regardless of the recovery strategy employed.

Long-term survival after intensive care unit discharge in Thailand : a retrospective study

Introduction Economic evaluations of interventions in the hospital setting often rely on the estimated long-term impact on patient survival. Estimates of mortality rates and long-term outcomes among patients discharged alive from the intensive care unit (ICU) are lacking from lower- and middle-income countries. This study aimed to assess the long-term survival and life expectancy (LE) amongst post-ICU patients in Thailand, a middle-income country. Methods In this retrospective cohort study, data from a regional tertiary hospital in northeast Thailand and the regional death registry were linked and used to assess patient survival time after ICU discharge. Adult ICU patients aged at least 15 years who had been discharged alive from an ICU between 1 January 2004 and 31 December 2005 were included in the study, and the death registry was used to determine deaths occurring in this cohort up to 31st December 2010. These data were used in conjunction with standard mortality life tables to estimate annual mortality and life expectancy. Results This analysis included 10,321 ICU patients. During ICU admission, 3,251 patients (31.5%) died. Of 7,070 patients discharged alive, 2,527 (35.7%) were known to have died within the five-year follow-up period, a mortality rate 2.5 times higher than that in the Thai general population (age and sex matched). The mean LE was estimated as 18.3 years compared with 25.2 years in the general population. Conclusions Post-ICU patients experienced much higher rates of mortality than members of the general population over the five-year follow-up period, particularly in the first year after discharge. Further work assessing Health Related Quality of Life (HRQOL) in both post-ICU patients and in the general population in developing countries is needed.

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis : protocol for a randomised controlled trial

Background Recurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children. Methods A multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW(135)) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and >= 6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged >= 6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine-related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged >= 6 years; and vaccine safety. Discussion As H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.