Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies.

OBJECTIVE: Osteoarthritis causes significant pain and disability with no approved disease-modifying drugs. We systematically reviewed the evidence from both pre-clinical and human studies for the potential disease-modifying effect of metformin in osteoarthritis. METHODS: Ovid Medline, Embase and CINAHL were searched between inception and June 2021 using MeSH terms and key words to identify studies examining the association between metformin use and outcome measures related to osteoarthritis. Two reviewers performed the risk of bias assessment and 3 reviewers extracted data independently. Qualitative evidence synthesis was performed. This systematic review is registered on PROSPERO (CRD42021261052 and CRD42021261060). RESULTS: Fifteen (10 pre-clinical and 5 human) studies were included. Most studies (10 pre-clinical and 3 human) assessed the effect of metformin using knee osteoarthritis models. In pre-clinical studies, metformin was assessed for the effect on structural outcomes (n = 10); immunomodulation (n = 5); pain (n = 4); and molecular pathways of its effect in osteoarthritis (n = 7). For human studies, metformin was evaluated for the effect on structural progression (n = 3); pain (n = 1); and immunomodulation (n = 1). Overall, pre-clinical studies consistently showed metformin having a chondroprotective, immunomodulatory and analgesic effect in osteoarthritis, predominantly mediated by adenosine monophosphate-activated protein kinase activation. Evidence from human studies, although limited, was consistent with findings in pre-clinical studies. CONCLUSION: We found consistent evidence across pre-clinical and human studies to support a favourable effect of metformin on chondroprotection, immunomodulation and pain reduction in knee osteoarthritis. Further high-quality clinical trials are needed to confirm these findings as metformin could be a novel therapeutic drug for the treatment of osteoarthritis.

Systematic review and meta-analysis of the prevalence of neuropathic-like pain and/or pain sensitization in people with knee and hip osteoarthritis.

OBJECTIVE: To determine the prevalence of neuropathic-like pain (NP) and pain sensitization (PS) defined by self-report questionnaires in knee and hip osteoarthritis, and whether prevalence is potentially explained by disease-severity or affected joint. DESIGN: MEDLINE, EMBASE, CINAHL were systematically searched (1990-April 2020) for studies describing the prevalence of NP and PS in knee and hip osteoarthritis using self-report questionnaires. Random-effects meta-analysis was performed. Statistical heterogeneity between studies and sub-groups (affected joint and population source as a proxy for disease severity) was assessed (I2 statistic and the Chi-squared test). RESULTS: From 2,706 non-duplicated references, 39 studies were included (2011-2020). Thirty-six studies reported on knee pain and six on hip pain. For knee osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP(score ≥13) 40% (95%CI 32-48%); probable NP(score >18) 20% (95%CI 15-24%); using Self-Report Leeds Assessment of Neuropathic Symptoms and Signs, 32% (95%CI 26-38%); using Douleur Neuropathique (DN4) 41% (95% CI 24-59%). The prevalence of PS using Central Sensitization Inventory (CSI) was 36% (95% CI 12-59%). For hip osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP 29% (95%CI 22-37%%); probable NP 9% (95%CI 6-13%); using DN4 22% (95%CI 12-31%) in one study. The prevalence of possible NP pain was higher at the knee (40%) than the hip (29%) (difference 11% (95% CI 0-22%), P = 0.05). CONCLUSIONS: Using self-report questionnaire tools, NP was more prevalent in knee than hip osteoarthritis. The prevalence of NP in knee and hip osteoarthritis were similar for each joint regardless of study population source or tool used. Whether defining NP using self-report questionnaires enables more effective targeted therapy in osteoarthritis requires investigation.

Reciprocal effects of maternal and child internalizing symptoms before and after a natural disaster.

After natural disasters, mothers and children are vulnerable to internalizing symptoms, such as depression and anxiety, and levels of mothers' and children's symptoms are significantly associated. However, the disaster literature has rarely examined reciprocal effects within families. The present study capitalizes on the occurrence of Hurricane Sandy during the course of an ongoing longitudinal study to address this gap. Three-hundred and 47 children (54.2% male, 84.7% Caucasian) and their mothers completed measures of internalizing symptoms when the children were 9-years-old. Hurricane Sandy occurred an average of 1 year later. Eight weeks after the hurricane, mothers and children completed the same measures again. Mothers also reported on their family's stress exposure from Hurricane Sandy. After controlling for predisaster symptoms, longitudinal actor-partner interdependence models indicated that mother's and children's internalizing symptoms were linked. Mothers' prehurricane depression symptoms also predicted increases in children's depression symptoms over time independent of hurricane-related stress. Children's prehurricane anxiety symptoms predicted increases in mothers' depression symptoms only at low levels of hurricane-related stress. Rather than the emergence of reciprocal effects, mother's depression symptoms and children's internalizing symptoms changed in tandem after Hurricane Sandy. High levels of Hurricane Sandy stress did not produce symptom spillover effects, but rather may have interrupted the unfolding of normative developmental parent-child reciprocal symptom processes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Evidence-Based Treatment Strategies in Youth Mental Health Services: Results from a National Survey of Providers.

Previous surveys indicate infrequent use of evidence-based treatment (EBT) manuals in usual care youth mental health, but the extent to which providers use core and common EBT strategies and what contextual factors impact EBT strategy implementation need further study. In a national, multidisciplinary survey of 1092 youth-serving providers, providers reported regular use of many EBT strategies. Provider learning theory orientation, more recent degree, more standardized and ongoing assessment use, more positive attitudes toward innovation and evidence, fewer low-income clients, and perceptions that their agency valued quality care and provided fewer training resources predicted more frequent EBT strategy use.

Prospective predictors of first-onset depressive disorders in adolescent females with anxiety disorders.

BACKGROUND: Anxious youth are at increased risk for later depressive disorders, but not all anxious youth develop depression. Sequential comorbidity models emphasize shared risk factors and anxiety sequelae, but some anxious youth who later develop depression may have risk factors that are relatively specific to depression, in addition to a liability to anxiety. We examined several variables that appear relatively specific to risk for depression-the personality traits of low positive affectivity and high sadness, and an electrophysiological measure of blunted response to reward - in predicting first-onset depressive disorders and depressive symptoms in clinically anxious adolescent girls. METHODS: A sample of 114 adolescents with baseline anxiety disorders completed personality and psychopathology measures, psychophysiology tasks, and diagnostic interviews. Interviews and a measure of depressive symptoms were re-administered over 27 months. RESULTS: After controlling for baseline depressive symptoms, blunted reward sensitivity uniquely predicted first-onset depressive disorders and depressive symptoms 27 months later. Post-hoc analyses indicated that blunted reward sensitivity only predicted first-onset depressive disorders and depressive symptoms in girls with high social anxiety symptoms. LIMITATIONS: Analyses were unable to account for concurrent anxiety symptoms and disorders. CONCLUSIONS: The depression-specific risk factor, blunted reward sensitivity, may comprise one pathway to subsequent depressive disorders and symptoms in anxious youth and indicate which anxious youth need intervention to prevent later depression, particularly in socially anxious girls.

Assessment Practices of Child Clinicians.

Assessment is an integral component of treatment. However, prior surveys indicate clinicians may not use standardized assessment strategies. We surveyed 1,510 clinicians and used multivariate analysis of variance to explore group differences in specific measure use. Clinicians used unstandardized measures more frequently than standardized measures, although psychologists used standardized measures more frequently than nonpsychologists. We also used latent profile analysis to classify clinicians based on their overall approach to assessment and examined associations between clinician-level variables and assessment class or profile membership. A four-profile model best fit the data. The largest profile consisted of clinicians who primarily used unstandardized assessments (76.7%), followed by broad-spectrum assessors who regularly use both standardized and unstandardized assessment (11.9%), and two smaller profiles of minimal (6.0%) and selective assessors (5.5%). Compared with broad-spectrum assessors, unstandardized and minimal assessors were less likely to report having adequate standardized measures training. Implications for clinical practice and training are discussed.

HIV-1 drug resistance in antiretroviral-naive individuals with HIV-1-associated tuberculous meningitis initiating antiretroviral therapy in Vietnam.

BACKGROUND: Access to antiretroviral therapy (ART) for HIV-infected individuals in Vietnam is rapidly expanding, but there are limited data on HIV drug resistance (HIVDR) to guide ART strategies. METHODS: We retrospectively conducted HIVDR testing in 220 ART-naive individuals recruited to a randomized controlled trial of immediate versus deferred ART in individuals with HIV-associated tuberculous meningitis in Ho Chi Minh City (HCMC) from 2005-2008. HIVDR mutations were identified by population sequencing of the HIV pol gene and were defined based on 2009 WHO surveillance drug resistance mutations (SDRMs). RESULTS: We successfully sequenced 219/220 plasma samples of subjects prior to ART; 218 were subtype CRF01_AE and 1 was subtype B. SDRMs were identified in 14/219 (6.4%) subjects; 8/14 were resistant to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs; T69D, L74V, V75M, M184V/I and K219R), 5/14 to non-nucleoside reverse transcriptase inhibitors (NNRTIs; K103N, V106M, Y181C, Y188C and G190A), 1/14 to both NRTIs and NNRTIs (D67N and Y181C) and none to protease inhibitors. After 6 months of ART, eight subjects developed protocol-defined virological failure. HIVDR mutations were identified in 5/8 subjects. All five had mutations with high-level resistance to NNRTIs and three had mutations with high-level resistance to NRTIs. Due to a high early mortality rate (58%), the effect of pre-existing HIVDR mutations on treatment outcome could not be accurately assessed. CONCLUSIONS: The prevalence of WHO SDRMs in ART-naive individuals with HIV-associated tuberculous meningitis in HCMC from 2005-2008 is 6.4%. The SDRMs identified conferred resistance to NRTIs and/or NNRTIs, reflecting the standard first-line ART regimens in Vietnam.