Clinical and cost-effectiveness of remote-delivered, online lifestyle therapy versus psychotherapy for reducing depression: results from the CALM non-inferiority, randomised trial.

Background: We conducted the first non-inferiority, randomised controlled trial to determine whether lifestyle therapy is non-inferior to psychotherapy with respect to mental health outcomes and costs when delivered via online videoconferencing. Methods: An individually randomised, group treatment design with computer-generated block randomisation was used. Between May 2021-April 2022, 182 adults with a Distress Questionnaire-5 score = ≥8 (indicative depression) were recruited from a tertiary mental health service in regional Victoria, Australia and surrounds. Participants were assigned to six 90-min sessions over 8-weeks using group-based, online videoconferencing comprising: (1) lifestyle therapy (targeting nutrition, physical activity) with a dietitian and exercise physiologist (n = 91) or (2) psychotherapy (Cognitive Behavioural Therapy) with psychologists (n = 91). The primary outcome was Patient Health Questionnaire-9 (PHQ-9) depression at 8-weeks (non-inferiority margin ≤2) using Generalised Estimating Equations (GEE). Cost-minimisation analysis estimated the mean difference in total costs from health sector and societal perspectives. Outcomes were assessed by blinded research assistants using Computer Assisted Telephone Interviews. Results are presented per-protocol (PP) and Intention to Treat (ITT) using beta coefficients with 95% Confidence Intervals (CIs). Findings: The sample was 80% women (mean: 45-years [SD:13.4], mean PHQ-9:10.5 [SD:5.7]. An average 4.2 of 6 sessions were completed, with complete data for n = 132. Over 8-weeks, depression reduced in both arms (PP: Lifestyle (n = 70) mean difference:-3.97, 95% CIs:-5.10, -2.84; and Psychotherapy (n = 62): mean difference:-3.74, 95% CIs:-5.12, -2.37; ITT: Lifestyle (n = 91) mean difference:-4.42, 95% CIs: -4.59, -4.25; Psychotherapy (n = 91) mean difference:-3.82, 95% CIs:-4.05, -3.69) with evidence of non-inferiority (PP GEE ß:-0.59; 95% CIs:-1.87, 0.70, n = 132; ITT GEE ß:-0.49, 95% CIs:-1.73, 0.75, n = 182). Three serious adverse events were recorded. While lifestyle therapy was delivered at lower cost, there were no differences in total costs (health sector adjusted mean difference: PP AUD$156 [95% CIs -$182, $611, ITT AUD$190 [95% CIs -$155, $651] ]; societal adjusted mean difference: PP AUD$350 [95% CIs:-$222, $1152] ITT AUD$ 408 [95% CIs -$139, $1157]. Interpretation: Remote-delivered lifestyle therapy was non-inferior to psychotherapy with respect to clinical and cost outcomes. If replicated in a fully powered RCT, this approach could increase access to allied health professionals who, with adequate training and guidelines, can deliver mental healthcare at comparable cost to psychologists. Funding: This trial was funded by the Australian Medical Research Future Fund (GA133346) under its Covid-19 Mental Health Research Grant Scheme.

Corticosteroid Injections Within 2 Weeks After Knee Arthroscopy Are Associated With Increased Infection Risk.

PURPOSE: Our purpose was to quantify the risk of 90-day postoperative infection after arthroscopy, stratified by specific time intervals of corticosteroid injections (CSIs) postoperatively (0-2 weeks, 2-4 weeks, 4-6 weeks, and 6-8 weeks), using a large, all-payer database. METHODS: A national, all-payer database was queried. In the primary and secondary analyses, the main outcome was infection at 90 days. Infection was defined by documentation of a septic knee or surgical-site infection according to International Classification of Diseases, Ninth Revision and Tenth Revision codes, and Current Procedural Terminology codes. RESULTS: In the multivariable regression, the odds ratio (OR) of postoperative infection at 90 days was greater in the cohorts receiving CSIs within 0 to 2 weeks (OR, 3.31; 95% confidence interval, 1.85-5.92; P < .001) and 2 to 4 weeks (OR, 2.72; 95% confidence interval, 1.57-4.71; P = .003) than in the control group. On comparison of CSIs administered within 0 to 2 weeks and CSIs administered within 2 to 4 weeks, we observed a greater odds of postoperative infection (OR, 2.50) at 90 days after arthroscopy. CONCLUSIONS: CSIs given within 2 weeks after knee arthroscopy increase the risk of postoperative infection the most, whereas CSIs given within 4 weeks increase the risk but to a lesser degree. LEVEL OF EVIDENCE: Level III, retrospective, comparative, prognosis study.

Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.

A horizon scan of global biological conservation issues for 2024.

We present the results of our 15th horizon scan of novel issues that could influence biological conservation in the future. From an initial list of 96 issues, our international panel of scientists and practitioners identified 15 that we consider important for societies worldwide to track and potentially respond to. Issues are novel within conservation or represent a substantial positive or negative step-change with global or regional extents. For example, new sources of hydrogen fuel and changes in deep-sea currents may have profound impacts on marine and terrestrial ecosystems. Technological advances that may be positive include benchtop DNA printers and the industrialisation of approaches that can create high-protein food from air, potentially reducing the pressure on land for food production.

Anterior Cruciate Ligament Reconstruction With Double-Bundle Internal Bracing: A Technique Guide.

There has been a recent increase in interest for double-bundle (db) anterior cruciate ligament reconstructions (ACLRs). Although this surgical technique has shown to improve rotational and translational stability, the literature has been inconsistent, finding its graft failure rates to be superior to that of the single-bundle (sb) ACLR. So far, no studies have reported the sb ACLR to be superior to db ACLR. It is possible that the db ACLR provides the most benefit in greatest-risk patients such as young athletes, female athletes, patients with generalized ligamentous laxity, and those undergoing revision ACLRs. The senior author's db ACLR technique incorporates a FiberTape internal brace, which is applied to both bundles. Despite inconsistencies in the literature, we suspect that autologous db ACLR with internal bracing could reduce graft failure rates and provide earlier return to preinjury activity level in high-risk patients compared with sb ACLR.

Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.

Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA-protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.

A global biological conservation horizon scan of issues for 2023.

We present the results of our 14th horizon scan of issues we expect to influence biological conservation in the future. From an initial set of 102 topics, our global panel of 30 scientists and practitioners identified 15 issues we consider most urgent for societies worldwide to address. Issues are novel within biological conservation or represent a substantial positive or negative step change at global or regional scales. Issues such as submerged artificial light fisheries and accelerating upper ocean currents could have profound negative impacts on marine or coastal ecosystems. We also identified potentially positive technological advances, including energy production and storage, improved fertilisation methods, and expansion of biodegradable materials. If effectively managed, these technologies could realise future benefits for biological diversity.

Arthroscopic Anterior Cruciate Ligament Repair With Single-Bundle Hamstring Tendon Augmentation Providing Complete Femoral Footprint Restoration for Sherman Type One Tears: A Technique Guide.

There is renewed interest in performing arthroscopic anterior cruciate ligament (ACL) repairs in appropriate patients who have Sherman type 1 ACL tears. However, ACL repairs are associated with unacceptably high failure rates, which may be partly improved with suture augmentation. Our technique uses a hamstring autograft tendon to reconstruct a bundle through a femoral tunnel while inserting the native ACL tissue into the other bundle's femoral footprint. The tear pattern dictates whether the native ACL tissue is inserted into the anteromedial or posterolateral lateral femoral origin. The improved cellular and biomechanical milieu for healing of both the repair and reconstruction may translate to earlier return to sport and reduced failure rates. In addition, by restoring the entire femoral footprint with a single femoral tunnel, improved rotational control is achieved without the bone stock loss observed in traditional ACL double-bundle reconstruction.

Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4.

Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.

Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol.

BACKGROUND: There is increasing recognition of the substantial burden of mental health disorders at an individual and population level, including consequent demand on mental health services. Lifestyle-based mental healthcare offers an additional approach to existing services with potential to help alleviate system burden. Despite the latest Royal Australian New Zealand College of Psychiatrists guidelines recommending that lifestyle is a 'first-line', 'non-negotiable' treatment for mood disorders, few such programs exist within clinical practice. Additionally, there are limited data to determine whether lifestyle approaches are equivalent to established treatments. Using an individually randomised group treatment design, we aim to address this gap by evaluating an integrated lifestyle program (CALM) compared to an established therapy (psychotherapy), both delivered via telehealth. It is hypothesised that the CALM program will not be inferior to psychotherapy with respect to depressive symptoms at 8 weeks. METHODS: The study is being conducted in partnership with Barwon Health's Mental Health, Drugs & Alcohol Service (Geelong, Victoria), from which 184 participants from its service and surrounding regions are being recruited. Eligible participants with elevated psychological distress are being randomised to CALM or psychotherapy. Each takes a trans-diagnostic approach, and comprises four weekly (weeks 1-4) and two fortnightly (weeks 6 and 8) 90-min, group-based sessions delivered via Zoom (digital video conferencing platform). CALM focuses on enhancing knowledge, behavioural skills and support for improving dietary and physical activity behaviours, delivered by an Accredited Exercise Physiologist and Accredited Practising Dietitian. Psychotherapy uses cognitive behavioural therapy (CBT) delivered by a Psychologist or Clinical Psychologist, and Provisional Psychologist. Data collection occurs at baseline and 8 weeks. The primary outcome is depressive symptoms (assessed via the Patient Health Questionnaire-9) at 8 weeks. Societal and healthcare costs will be estimated to determine the cost-effectiveness of the CALM program. A process evaluation will determine its reach, adoption, implementation and maintenance. DISCUSSION: If the CALM program is non-inferior to psychotherapy, this study will provide the first evidence to support lifestyle-based mental healthcare as an additional care model to support individuals experiencing psychological distress. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12621000387820 , Registered 8 April 2021.

De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy.

Pathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.

SUMOylated Senataxin functions in genome stability, RNA degradation, and stress granule disassembly, and is linked with inherited ataxia and motor neuron disease.

BACKGROUND: Senataxin (SETX) is a DNA/RNA helicase critical for neuron survival. SETX mutations underlie two inherited neurodegenerative diseases: Ataxia with Oculomotor Apraxia type 2 (AOA2) and Amyotrophic Lateral Sclerosis type 4 (ALS4). METHODS: This review examines SETX key cellular processes and we hypothesize that SETX requires SUMO posttranslational modification to function properly. RESULTS: SETX is localized to distinct foci during S-phase of the cell cycle, and these foci represent sites of DNA polymerase/RNA polymerase II (RNAP) collision, as they co-localize with DNA damage markers 53BP1 and H2AX. At such sites, SETX directs incomplete RNA transcripts to the nuclear exosome for degradation via interaction with exosome component 9 (Exosc9), a key component of the nuclear exosome. These processes require SETX SUMOylation. SETX was also recently localized within stress granules (SGs), and found to regulate SG disassembly, a process that similarly requires SUMOylation. CONCLUSION: SETX undergoes SUMO modification to function at S-phase foci in cycling cells to facilitate RNA degradation. SETX may regulate similar processes in non-dividing neurons at sites of RNAP II bidirectional self-collision. Finally, SUMOylation of SETX appears to be required for SG disassembly. This SETX function may be crucial for neuron survival, as altered SG dynamics are linked to ALS disease pathogenesis. In addition, AOA2 point mutations have been shown to block SETX SUMOylation. Such mutations induce an ataxia phenotype indistinguishable from those with SETX null mutation, underscoring the importance of this modification.

Cartiform Implantation for focal cartilage defects in the knee: A 2-year clinical and magnetic resonance imaging follow-up study.

The purpose of this study was to evaluate clinical and magnetic resonance imaging (MRI) outcomes in patients who underwent cryopreserved viable osteochondral allograft (CVOCA) implantation for focal cartilage defects in the knee at a minimum of 2-years postoperatively. This is a retrospective follow-up study of twelve patients who underwent CVOCA implantation from 2013 to 2015 by a single surgeon for a International Cartilage Repair Society (ICRS) grade 3 or 4 chondral defect. Patient-reported outcome (PRO) measurements and MRI were obtained 2-years postoperatively. Collected PRO measures included: International Knee Documentation Committee (IKDC) form; Visual Analog Scale (VAS) pain score; Veterans RAND 12-Item Health Survey (VR-12); Knee Injury and Osteoarthritis Outcome Score (KOOS); and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Patients completed a standard return to work and sports/recreation survey. A blinded, fellowship-trained musculoskeletal radiologist independently evaluated each MRI to determine the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. Mean follow-up was 2.1 years (2.0-2.3). There were 6 women and 6 men with a mean age of 46.2 ± 11.9 years. Mean PRO scores were: IKDC 72.6 ± 17.4; VAS 2.9 ± 2.8; WOMAC 84.2 ± 15.1; KOOS- Pain 83.8 ± 18.5, Symptoms 77.6 ± 16.0, ADL 88.0 ± 16.9, Sports/Rec 67.7 ± 33.3, QOL 54.8 ± 24.2; and VR-12 PCS 45.0 ± 8.5 and MCS 51.1 ± 9.5. The mean MOCART score was 59.5 ± 12.9. To our knowledge, this is the largest study to report clinical and MRI outcomes of CVOCA implantation in the knee. With positive functional outcomes and lack of failures at 2-year follow-up, CVOCA is a promising treatment option for focal chondral defects in the knee. STUDY DESIGN: Retrospective case series, Level of evidence 4.

Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly.

The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations cause Amyotrophic Lateral Sclerosis type 4. SETX is a very low abundance protein, and its expression is tightly regulated, such that large increases in mRNA levels fail to significantly increase protein levels. Despite this, transient transfection in cell culture can boost SETX protein levels on an individual cell basis. Here we found that over-expression of normal SETX, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. As SETX interacts with the nuclear exosome to ensure degradation of incomplete RNA transcripts, and SETX localizes to sites of collision between the DNA replication machinery and the RNAP II complex, altered dosage or aberrant function of SETX may impede this process to promote S-phase cell-cycle arrest. Because neurons are enriched for long transcripts with additional antisense regulatory transcription, collisions of RNAP II complexes may occur in such post-mitotic cells, underscoring a role for SETX in maintaining neuron homeostasis.

Evaluation of Preoperative Pain Using PROMIS Pain Interference in Knee Surgery Patients.

Given that pain relief is often the primary goal of orthopaedic surgery, an accurate assessment of pain is paramount. The objectives of this cross-sectional analytical study were to (1) compare how the Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference (PI) computer adaptive test (CT) performs against the Numeric Pain Scale (NPS) measure in evaluating pain, and (2) to determine demographic, clinical, and psychosocial correlates of PI in an urban population undergoing a variety of knee surgeries. We hypothesized that there would be a strong correlation between PI and NPS, with minimal floor and ceiling effects; and that a worse PI score would be associated with a worse general health profile. The sample consisted of 412 patients undergoing knee surgery at an urban academic center. Patients were preoperatively administered measures of health-related quality of life (HRQOL). Bivariate and multivariable statistical analyses were performed to identify significant independent predictors. The mean PI score was 60.3 ± 7.2 and had no floor or ceiling effects, whereas NPS demonstrated a greater percentage of patients scoring at the extremes of the measure. Worse PI scores were associated with older age, higher body mass index (BMI), greater comorbidity, lower income, smoking, female gender, Hispanic ethnicity, Black race, unemployment, opioid use, lower expectations, and greater American Society of Anesthesiologists score (p < 0.05). Compared with other procedures, total knee arthroplasty was associated with worse PI scores and anterior cruciate ligament reconstruction was associated with better PI scores. Furthermore, PI demonstrated significant associations with a wide range of HRQOL measures. After controlling for confounding variables, worse PI was independently associated with older age, lower income, higher BMI, and smoking.

Evaluation of the PROMIS Physical Function Computer Adaptive Test in Patients Undergoing Knee Surgery.

A cross-sectional analysis of data derived from patients undergoing knee surgery at a single institution was conducted. The objectives of the study were to (1) compare how the Patient-Reported Outcomes Measurement Information System physical function (PROMIS PF) computer adaptive test performs against the International Knee Documentation Committee (IKDC) Subjective Knee Form in evaluating functional status, and (2) to determine demographic, clinical, and psychosocial correlates of each outcome measure in an urban population undergoing a variety of knee surgeries. We hypothesized that there would be a strong correlation between PROMIS PF and IKDC, with minimal floor and ceiling effects, and similar clinical correlates. The sample consisted of 412 patients undergoing knee surgery. Bivariate and multivariable statistical analyses were performed to identify significant independent predictors. The PROMIS PF and IKDC scores were strongly correlated (r s = 0.71, p < 0.001), and neither exhibited floor nor ceiling effects. Lower body mass index, no preoperative opioid use, lower Charlson comorbidity index score, employment, and lower income were found to be significant independent predictors for better scores on both PROMIS PF and IKDC. Patients undergoing total knee arthroplasty had significantly lower PROMIS PF and IKDC scores (p < 0.05). Potential explanations for these findings are presented, and clinical implications are discussed.