Mental Health Screening in General Practices as a Means for Enhancing Uptake of Digital Mental Health Interventions: Observational Cohort Study.

BACKGROUND: Digital mental health interventions stand to play a critical role in managing the mental health impact of the COVID-19 pandemic. Thus, enhancing their uptake is a key priority. General practitioners (GPs) are well positioned to facilitate access to digital interventions, but tools that assist GPs in identifying suitable patients are lacking. OBJECTIVE: This study aims to evaluate the suitability of a web-based mental health screening and treatment recommendation tool (StepCare) for improving the identification of anxiety and depression in general practice and, subsequently, uptake of digital mental health interventions. METHODS: StepCare screens patients for symptoms of depression (9-item Patient Health Questionnaire) and anxiety (7-item Generalized Anxiety Disorder scale) in the GP waiting room. It provides GPs with stepped treatment recommendations that include digital mental health interventions for patients with mild to moderate symptoms. Patients (N=5138) from 85 general practices across Australia were invited to participate in screening. RESULTS: Screening identified depressive or anxious symptoms in 43.09% (1428/3314) of patients (one-quarter were previously unidentified or untreated). The majority (300/335, 89.6%) of previously unidentified or untreated patients had mild to moderate symptoms and were candidates for digital mental health interventions. Although less than half were prescribed a digital intervention by their GP, when a digital intervention was prescribed, more than two-thirds of patients reported using it. CONCLUSIONS: Implementing web-based mental health screening in general practices can provide important opportunities for GPs to improve the identification of symptoms of mental illness and increase patient access to digital mental health interventions. Although GPs prescribed digital interventions less frequently than in-person psychotherapy or medication, the promising rates of uptake by GP-referred patients suggest that GPs can play a critical role in championing digital interventions and maximizing the associated benefits.

An examination of the demographic predictors of adolescent breakfast consumption, content, and context.

BACKGROUND: Breakfast consumption is important to health; however, adolescents often skip breakfast, and an increased understanding of the breakfast consumption patterns of adolescents is needed. The purpose of this study was to identify the predictors of breakfast eating, including the content and context, in an adolescent sample from Australia and England. METHODS: Four-hundred and eighty-one students completed an online questionnaire measuring breakfast skipping, and breakfast content (what was eaten) and context (who they ate with, involvement in preparation). Logistic regression was conducted to investigate the predictors of skipping breakfast, breakfast context, and consumption of the ten most commonly consumed foods. Chi-square analyses were used to examine differences in breakfast content according to context. RESULTS: Most students (88%) had consumed breakfast on the day of the survey; breakfast skipping was more common in England (18%) than in Australia (8%). Country, gender, socioeconomic status, and body mass index (BMI) were all predictors of breakfast content and context. Whether adolescents ate with others and/or were involved in breakfast preparation predicted the content of breakfast consumed. CONCLUSIONS: This study provides a comprehensive examination of the factors underlying breakfast consumption (content and context) and has important implications for the development of evidence-based interventions to improve rates of breakfast consumption and the quality of food consumed amongst adolescents.

Detection of clinically relevant copy number variants with whole-exome sequencing.

Copy number variation (CNV) is a common source of genetic variation that has been implicated in many genomic disorders. This has resulted in the widespread application of genomic microarrays as a first-tier diagnostic tool for CNV detection. More recently, whole-exome sequencing (WES) has been proven successful for the detection of clinically relevant point mutations and small insertion-deletions exome wide. We evaluate the utility of short-read WES (SOLiD 5500xl) to detect clinically relevant CNVs in DNA from 10 patients with intellectual disability and compare these results to data from two independent high-resolution microarrays. Eleven of the 12 clinically relevant CNVs were detected via read-depth analysis of WES data; a heterozygous single-exon deletion remained undetected by all algorithms evaluated. Although the detection power of WES for small CNVs currently does not match that of high-resolution microarray platforms, we show that the majority (88%) of rare coding CNVs containing three or more exons are successfully identified by WES. These results show that the CNV detection resolution of WES is comparable to that of medium-resolution genomic microarrays commonly used as clinical assays. The combined detection of point mutations, indels, and CNVs makes WES a very attractive first-tier diagnostic test for genetically heterogeneous disorders.

Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual participant data.

BACKGROUND: Internet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom. METHODS: We did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683. FINDINGS: We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1·83 [95% credible interval (CrI) -2·90 to -0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0·32 [95% CrI 0·13 to 0·93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. INTERPRETATION: The individual patient data cNMA revealed potentially helpful, less helpful, or harmful components and delivery formats for iCBT packages. iCBT packages aiming to be effective and efficient might choose to include beneficial components and exclude ones that are potentially detrimental. Our web app can facilitate shared decision making by therapist and patient in choosing their preferred iCBT package. FUNDING: Japan Society for the Promotion of Science.

Acute mental health responses during the COVID-19 pandemic in Australia.

The acute and long-term mental health impacts of the COVID-19 pandemic are unknown. The current study examined the acute mental health responses to the COVID-19 pandemic in 5070 adult participants in Australia, using an online survey administered during the peak of the outbreak in Australia (27th March to 7th April 2020). Self-report questionnaires examined COVID-19 fears and behavioural responses to COVID-19, as well as the severity of psychological distress (depression, anxiety and stress), health anxiety, contamination fears, alcohol use, and physical activity. 78% of respondents reported that their mental health had worsened since the outbreak, one quarter (25.9%) were very or extremely worried about contracting COVID-19, and half (52.7%) were worried about family and friends contracting COVID-19. Uncertainty, loneliness and financial worries (50%) were common. Rates of elevated psychological distress were higher than expected, with 62%, 50%, and 64% of respondents reporting elevated depression, anxiety and stress levels respectively, and one in four reporting elevated health anxiety in the past week. Participants with self-reported history of a mental health diagnosis had significantly higher distress, health anxiety, and COVID-19 fears than those without a prior mental health diagnosis. Demographic (e.g., non-binary or different gender identity; Aboriginal and Torres Strait Islander status), occupational (e.g., being a carer or stay at home parent), and psychological (e.g., perceived risk of contracting COVID-19) factors were associated with distress. Results revealed that precautionary behaviours (e.g., washing hands, using hand sanitiser, avoiding social events) were common, although in contrast to previous research, higher engagement in hygiene behaviours was associated with higher stress and anxiety levels. These results highlight the serious acute impact of COVID-19 on the mental health of respondents, and the need for proactive, accessible digital mental health services to address these mental health needs, particularly for those most vulnerable, including people with prior history of mental health problems. Longitudinal research is needed to explore long-term predictors of poor mental health from the COVID-19 pandemic.

Stepped care mental health service in Australian primary care: codesign and feasibility study.

Objective In 2015, the Australian Government introduced several mental health reforms, including the requirement that Primary Health Networks (PHNs) provide stepped care services for Australians with mental health needs such as anxiety and depression. This paper reports on the development and feasibility study of StepCare, an online stepped mental healthcare service in general practice that screens patients, provides immediate feedback to patients and general practitioners (GPs), transmits stepped treatment recommendations to GPs and monitors patients' progress, including notification of deterioration. Methods The present codesign and feasibility study in one PHN examined: (1) the acceptability and feasibility of StepCare to GPs, practice staff and patients; (2) the impact of StepCare on clinical practice; and (3) the barriers to and facilitators of implementation. Results Thirty-two GPs, 22 practice staff and 418 patients participated in the study. Overall, patients, practice staff and GPs found StepCare acceptable and feasible, commending its privacy, the mental health screening, monitoring and feedback. They also made suggestions for service improvements. GPs reported that StepCare helped with their identification and management of patients with common mental health issues. Conclusions Preliminary data suggest that StepCare may be acceptable and feasible in Australian general practice, helping GPs identify and manage common mental health problems in their patients. The study provides implications for policy and practice, and points the way to future translational research into stepped mental health care. What is known about the topic? Depression and anxiety are common illnesses in primary care and GPs are ideally placed to implement stepped care approaches enabling early detection and accessible, effective care. What does this paper add? Developed in and for general practice, StepCare is the first fully integrated stepped approach to primary mental health care in Australia. As a first step in a translational research program evaluating the effectiveness of StepCare, this paper reports data regarding the feasibility and acceptability of the service. What are the implications for practitioners? Integrated into the workflow of general practice, StepCare is an online service that helps GPs detect new cases of depression and anxiety, provide evidence-based stepped care treatments and monitor patients' progress.

The iBobbly Aboriginal and Torres Strait Islander app project: Study protocol for a randomised controlled trial.

BACKGROUND: Suicide amongst Australian Aboriginal and Torres Strait Islander communities occurs at twice the rate of the general population and, with significant barriers to treatment, help-seeking prior to a suicide attempt is low. This trial aims to test the effectiveness of an app (iBobbly) designed with Aboriginal and Torres Strait Islander people for reducing suicidal ideation. METHODS/DESIGN: This is a two-arm randomised controlled trial that will compare iBobbly to a wait-list control condition. The trial aims to recruit Aboriginal and Torres Strait Islander participants aged 16 years and over to test iBobbly, which is a self-help app delivering content based on acceptance and commitment therapy. The primary outcome for the study is suicidal ideation, and secondary outcomes include depression, hopelessness, distress tolerance, perceived burdensomeness and thwarted belonging, and help-seeking intentions. Data will be collected for both groups at baseline, post-intervention (after 6 weeks of app use), and at 6 months post-baseline (with a final 12-month follow-up for the iBobbly group). Primary analysis will compare changes in suicidal ideation for the intervention condition relative to the wait-list control condition using mixed models. An examination of the cost-effectiveness of the intervention compared to the control condition will be conducted. DISCUSSION: If effective, iBobbly could overcome many barriers to help-seeking amongst a group of people who are at increased risk of suicide. It may provide a low-cost, accessible intervention that can reach more people. This trial will add to a sparse literature on indigenous suicide prevention and will increase our knowledge about the effectiveness of e-health interventions for suicide prevention. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12614000686606 . Registered on 30 June 2014.

General Practitioners' Attitudes Toward a Web-Based Mental Health Service for Adolescents: Implications for Service Design and Delivery.

BACKGROUND: Anxiety disorders and depression are prevalent among youth. General practitioners (GPs) are often the first point of professional contact for treating health problems in young people. A Web-based mental health service delivered in partnership with schools may facilitate increased access to psychological care among adolescents. However, for such a model to be implemented successfully, GPs' views need to be measured. OBJECTIVE: This study aimed to examine the needs and attitudes of GPs toward a Web-based mental health service for adolescents, and to identify the factors that may affect the provision of this type of service and likelihood of integration. Findings will inform the content and overall service design. METHODS: GPs were interviewed individually about the proposed Web-based service. Qualitative analysis of transcripts was performed using thematic coding. A short follow-up questionnaire was delivered to assess background characteristics, level of acceptability, and likelihood of integration of the Web-based mental health service. RESULTS: A total of 13 GPs participated in the interview and 11 completed a follow-up online questionnaire. Findings suggest strong support for the proposed Web-based mental health service. A wide range of factors were found to influence the likelihood of GPs integrating a Web-based service into their clinical practice. Coordinated collaboration with parents, students, school counselors, and other mental health care professionals were considered important by nearly all GPs. Confidence in Web-based care, noncompliance of adolescents and GPs, accessibility, privacy, and confidentiality were identified as potential barriers to adopting the proposed Web-based service. CONCLUSIONS: GPs were open to a proposed Web-based service for the monitoring and management of anxiety and depression in adolescents, provided that a collaborative approach to care is used, the feedback regarding the client is clear, and privacy and security provisions are assured.

Internet Cognitive-Behavioral Therapy for Depression in Older Adults With Knee Osteoarthritis: A Randomized Controlled Trial.

OBJECTIVE: To determine the efficacy of an internet-based cognitive-behavioral therapy (iCBT) program for depression in older adults with osteoarthritis (OA) of the knee and comorbid major depressive disorder (MDD). METHODS: We conducted a randomized controlled trial in 69 adults (ages ≥50 years) meeting criteria for MDD and OA of the knee with 1-week postintervention (week 11) and 3-month followup (week 24) end points. Patients were allocated to either a 10-week iCBT program for depression added to treatment as usual (TAU) or to a TAU control group. Primary outcomes were depression symptoms (9-Item Patient Health Questionnaire [PHQ-9]) and psychological distress (Kessler-10 [K-10]). Secondary outcomes included arthritis self-efficacy (Arthritis Self-Efficacy Scale [ASES]), OA pain, stiffness, physical function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), and physical and mental health (Short Form 12-Item health survey physical component and mental component summaries). Depression status was assessed by blinded diagnostic interview (the Mini-International Neuropsychiatric Interview) at intake and followup. RESULTS: Intent-to-treat analyses indicated between-group superiority of iCBT over TAU on the primary outcomes (PHQ-9: Hedges g = 1.01, 95% confidence interval [95% CI] 0.47, 1.54; K-10: Hedges g = 0.75, 95% CI 0.23, 1.28), at postintervention and 3-month followup (PHQ-9: Hedges g = 0.90, 95% CI 0.36, 1.44; K-10: Hedges g = 0.94, 95% CI 0.41, 1.48), and on secondary OA-specific measures (ASES: Hedges g = -0.81, 95% CI -0.29, -1.33; WOMAC: Hedges g = 0.56-0.65, 95% CI 0.04, 1.18) at the 3-month followup. The majority of iCBT participants (84%) no longer met diagnostic criteria at 3-month followup. CONCLUSION: Results support the efficacy of an iCBT program (requiring no face-to-face contact) for depression in individuals with comorbid depression and OA of the knee. Importantly, the benefits of the program extended beyond reduced depressive symptoms and distress to include increased self-efficacy and improved pain, stiffness, and physical function at followup.

School Counselors' Perspectives of a Web-Based Stepped Care Mental Health Service for Schools: Cross-Sectional Online Survey.

BACKGROUND: Mental health problems are common among youth in high school, and school counselors play a key role in the provision of school-based mental health care. However, school counselors occupy a multispecialist position that makes it difficult for them to provide care to all of those who are in need in a timely manner. A Web-based mental health service that offers screening, psychological therapy, and monitoring may help counselors manage time and provide additional oversight to students. However, for such a model to be implemented successfully, school counselors' attitudes toward Web-based resources and services need to be measured. OBJECTIVE: This study aimed to examine the acceptability of a proposed Web-based mental health service, the feasibility of providing this type of service in the school context, and the barriers and facilitators to implementation as perceived by school counselors in New South Wales (NSW), Australia. METHODS: This study utilized an online cross-sectional survey to measure school counselors' perspectives. RESULTS: A total of 145 school counselors completed the survey. Overall, 82.1% (119/145) thought that the proposed service would be helpful to students. One-third reported that they would recommend the proposed model, with the remaining reporting potential concerns. Years of experience was the only background factor associated with a higher level of comfort with the proposed service (P=.048). Personal beliefs, knowledge and awareness, Internet accessibility, privacy, and confidentiality were found to influence, both positively and negatively, the likelihood of school counselors implementing a Web-based school mental health service. CONCLUSIONS: The findings of this study confirmed that greater support and resources are needed to facilitate what is already a challenging and emotionally demanding role for school counselors. Although the school counselors in this study were open to the proposed service model, successful implementation will require that the issues outlined are carefully addressed.

Help from home for depression: A randomised controlled trial comparing internet-delivered cognitive behaviour therapy with bibliotherapy for depression.

Major Depressive Disorder (MDD) is a leading cause of the Global Burden of Disease. Cognitive Behavioural Therapy (CBT) is an effective treatment for MDD, but access can be impaired due to numerous barriers. Internet-delivered CBT (iCBT) can be utilised to overcome treatment barriers and is an effective treatment for depression, but has never been compared to bibliotherapy. This Randomised Controlled Trial (RCT) included participants meeting diagnostic criteria for MDD (n = 270) being randomised to either: iCBT (n = 61), a CBT self-help book (bCBT) (n = 77), a meditation self-help book (bMED) (n = 64) or wait-list control (WLC) (n = 68). The primary outcome was the Patient Health Questionnaire 9-item scale (PHQ-9) at 12-weeks (post-treatment). All three active interventions were significantly more effective than WLC in reducing depression at post-treatment, but there were no significant differences between the groups. All three interventions led to large within-group reductions in PHQ-9 scores at post-treatment (g = 0.88-1.69), which were maintained at 3-month follow-up, although there was some evidence of relapse in the bMED group (within-group g [post to follow-up] = 0.09-1.04). Self-help based interventions could be beneficial in treating depression, however vigilance needs to be applied when selecting from the range of materials available. Replication of this study with a larger sample is required.

Rapid IV versus oral rehydration: responses to subsequent exercise heat stress.

PURPOSE: This study sought to determine the effect of rapid intravenous (IV) versus oral (ORAL) rehydration immediately after dehydration, on cardiovascular, thermoregulatory, and perceptual responses during subsequent exercise in the heat. METHODS: Eight males (21.4 +/- 0.7 yr; 176.2 +/- 1.6 cm; 75.2 +/- 3.7 kg; 63.7 +/- 3.6 mL.kg.min VO2max, 9.0 +/- 1.7% fat) participated in three randomized trials. Each trial consisted of a 75-min dehydration phase (36 degrees C; 42.5% rh, 47 +/- 0.9% VO2max) where subjects lost 1.7 L (IV and no-fluid (NF) trials) to 1.8 L of fluid (ORAL trial). In the heat, fluid lost was matched with 0.45% saline in 20 min by either IV or ORAL rehydration; no fluid was given in the NF trial. Subjects then performed a heat-tolerance test (HTT; 37.0 degrees C, 45% rh, treadmill speed of 2.4 m.s, 2.3% grade) for 75 min or until exhaustion (Tre of 39.5 degrees C). During the HTT, thermal and thirst sensations, RPE, rectal temperature (Tre), heart rate (HR), and mean weighted skin temperature (Tsk) were measured. RESULTS: Plasma volume in the IV treatment was greater (P < 0.05) after rehydration compared with ORAL and NF. However, during the HTT there were no overall differences (P > 0.05) in HR, Tre, Tsk, RPE, thermal sensations, or HTT time (ORAL, 71 +/- 8 min; IV, 73 +/- 5 min; NF, 39 +/- 29 min) between the ORAL and IV treatments. Sensations of thirst were lower (P < 0.05) in ORAL compared with IV and NF, likely because of oropharyngeal stimuli. CONCLUSIONS: Despite a more rapid restoration of plasma volume, IV rehydration was not advantageous over ORAL rehydration in regards to physiological strain, heat tolerance, RPE, or thermal sensations.

Positive imagery cognitive bias modification (CBM) and internet-based cognitive behavioral therapy (iCBT): a randomized controlled trial.

BACKGROUND: Accruing evidence suggests that positive imagery-based cognitive bias modification (CBM) could have potential as a standalone targeted intervention for depressive symptoms or as an adjunct to existing treatments. We sought to establish the benefit of this form of CBM when delivered prior to Internet cognitive behavioral therapy (iCBT) for depression METHODS: A randomized controlled trial (RCT) of a 1-week Internet-delivered positive CBM vs. an active control condition for participants (N=75, 69% female, mean age=42) meeting diagnostic criteria for major depression; followed by a 10-week iCBT program for both groups. RESULTS: Modified intent-to-treat marginal and mixed effect models demonstrated no significant difference between conditions following the CBM intervention or the iCBT program. In both conditions there were significant reductions (Cohen׳s d .57-1.58, 95% CI=.12-2.07) in primary measures of depression and interpretation bias (PHQ9, BDI-II, AST-D). Large effect size reductions (Cohen׳s d .81-1.32, 95% CI=.31-1.79) were observed for secondary measures of distress, disability, anxiety and repetitive negative thinking (K10, WHODAS, STAI, RTQ). Per protocol analyses conducted in the sample of participants who completed all seven sessions of CBM indicated between-group superiority of the positive over control group on depression symptoms (PHQ9, BDI-II) and psychological distress (K10) following CBM (Hedges g .55-.88, 95% CI=-.03-1.46) and following iCBT (PHQ9, K10). The majority (>70%) no longer met diagnostic criteria for depression at 3-month follow-up. LIMITATIONS: The control condition contained many active components and therefore may have represented a smaller 'dose' of the positive condition. CONCLUSIONS: Results provide preliminary support for the successful integration of imagery-based CBM into an existing Internet-based treatment for depression.

Internet-based cognitive bias modification for obsessive compulsive disorder: study protocol for a randomized controlled trial.

BACKGROUND: Cognitive bias modification (CBM) interventions have demonstrated efficacy in augmenting core biases implicated in psychopathology. The current randomized controlled trial (RCT) will evaluate the efficacy of an internet-delivered positive imagery cognitive bias modification intervention for obsessive compulsive disorder (OCD) when compared to a control condition. METHODS/DESIGN: Patients meeting diagnostic criteria for a current or lifetime diagnosis of OCD will be recruited via the research arm of a not-for-profit clinical and research unit in Australia. The minimum sample size for each group (alpha set at 0.05, power at .80) was identified as 29, but increased to 35 to allow for 20% attrition. We will measure the impact of CBM on interpretations bias using the OC Bias Measure (The Ambiguous Scenarios Test for OCD ;AST-OCD) and OC-beliefs (The Obsessive Beliefs Questionnaire-TRIP; OBQ-TRIP). Secondary outcome measures include the Dimensional Obsessive-Compulsive Scale (DOCS), the Patient Health Questionnaire (PHQ-9), The Kessler Psychological Distress Scale (K10), and the Word Sentence Association Test for OCD (WSAO). Change in diagnostic status will be indexed using the OCD Mini International Neuropsychiatric Interview (M.I.N.I) Module at baseline and follow-up. Intent-to-treat (ITT) marginal and mixed-effect models using restricted maximum likelihood (REML) estimation will be used to evaluate the primary hypotheses. Stability of bias change will be assessed at 1-month follow-up. DISCUSSION: A limitation of the online nature of the study is the inability to include a behavioral outcome measure. TRIAL REGISTRATION: The trial was registered on 10 October 2013 with the Australian New Zealand Clinical Trials Registry (ACTRN12613001130752).

Exercise activation of muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling is redox sensitive.

The peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha)-activated signal transduction pathway has previously been shown to stimulate mitochondrial biogenesis in skeletal muscle in response to endurance exercise. In vitro data indicate that PGC-1alpha signaling may be sensitive to reactive oxygen species (ROS) but its role in vivo is not clear. The objectives of this study were (1) to investigate whether the PGC-1alpha pathway could be activated by a single bout of anaerobic exercise in rats, wherein a major portion of ROS was generated via the cytosolic xanthine oxidase (XO), and (2) to examine whether allopurinol (ALP), a specific XO inhibitor, would attenuate PGC-1alpha expression and signaling owing to decreased ROS generation. Female Sprague-Dawley rats were randomly divided into three groups: (1) subjected to sprinting on a treadmill at 35 m/min, 15% grade, for 3 min followed by 3 min slow running at 15 m/min, 0% grade, repeated until exhaustion (88 +/- 4 min; Exer; N= 9); (2) subjected to the same exercise protocol (88 +/- 4 min) but injected with two doses of ALP (0.4 mmol/kg, ip) 24 and 1 h before the experiment (Exer+ ALP; N= 9); and (3) rested control (C; N= 9). Exercise increased XO activity and ROS generation in the Exer rat vastus lateralis muscle (P< 0.05), whereas the Exer+ ALP group displayed only 7% XO activity and similar ROS level compared with the C group. PGC-1alpha protein content showed a 5.6-fold increase (P< 0.01) in Exer vs C, along with a 200% (P< 0.01) increase in both nuclear respiratory factor (NRF)-1 and mitochondrial transcription factor A (Tfam) content. ALP treatment decreased PGC-1alpha, NRF-1, and Tfam levels by 45, 19, and 20% (P< 0.05), respectively. Exercise doubled the content of the phosphorylated cAMP-responsive element-binding protein in the Exer group (P< 0.01) and tripled phosphorylated p38 mitogen-activated protein kinase (P< 0.01), whereas these effects were reduced by 60 and 30% (P< 0.01, P< 0.05), respectively, in Exer+ ALP rats. Nuclear factor-kappaB binding and phospho-IkappaB content were also increased in Exer rats (P< 0.01) and these increases were abolished by ALP treatment. The data indicate that contraction-activated PGC-1alpha signaling pathways in skeletal muscle are redox sensitive and that nonmitochondrial ROS play an important role in stimulating mitochondrial biogenesis.