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IMPORTANCE: Arsenic, a contaminant of groundwater and irrigated crops, is a global public health hazard. Exposure to low levels of arsenic through food extends well beyond the areas with high arsenic content in water.OBJECTIVE: To identify cognitive impairments following commonly prevalent low-level arsenic exposure and characterize their underlying brain mechanisms.DESIGN, SETTING, AND PARTICIPANTS: This multicenter population-based cohort study analyzed cross-sectional data of the Indian Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA) cohort, recruited between November 4, 2016, and May 4, 2019. Participants aged 6 to 23 years were characterized using deep phenotyping measures of behavior, neuropsychology, psychopathology, brain neuroimaging, and exposure to developmental adversities and environmental neurotoxins. All analyses were performed between June 1, 2020, and December 31, 2021.EXPOSURE: Arsenic levels were measured in urine as an index of exposure.MAIN OUTCOMES AND MEASURES: Executive function measured using the cVEDA neuropsychological battery, gray matter volume (GMV) from T1-weighted magnetic resonance imaging, and functional network connectivity measures from resting state functional magnetic resonance imaging.RESULTS: A total of 1014 participants aged 6 to 23 years (589 male [58.1%]; mean [SD] age, 14.86 [4.79] years) were included from 5 geographic locations. Sparse-partial least squares analysis was used to describe a negative association of arsenic exposure with executive function (r = -0.12 [P = 5.4 × 10-4]), brain structure (r = -0.20 [P = 1.8 × 10-8]), and functional connectivity (within network, r = -0.12 [P = 7.5 × 10-4]; between network, r = -0.23 [P = 1.8 × 10-10]). Alterations in executive function were partially mediated by GMV (b = -0.004 [95% CI, -0.007 to -0.002]) and within-network functional connectivity (b = -0.004 [95% CI, -0.008 to -0.002]). Socioeconomic status and body mass index moderated the association between arsenic and GMV, such that the association was strongest in participants with lower socioeconomic status and body mass index.CONCLUSIONS AND RELEVANCE: The findings of this cross-sectional study suggest that low-level arsenic exposure was associated with alterations in executive functioning and underlying brain correlates. These results indicate potential detrimental consequences of arsenic exposure that are below the currently recommended guidelines and may extend beyond endemic risk areas. Precision medicine approaches to study global mental health vulnerabilities highlight widespread but potentially modifiable risk factors and a mechanistic understanding of the impact of low-level arsenic exposure on brain development.

Supplemental Digital Content is Available in the Text. Anxiety predicts onset of knee pain and drives greater osteoarthritis pain in humans. Our validated preclinical model identifies supraspinal astrocytosis as a potential mechanism., Anxiety and depression are associated with increased pain responses in chronic pain states. The extent to which anxiety drives chronic pain, or vice versa, remains an important question that has implications for analgesic treatment strategies. Here, the effect of existing anxiety on future osteoarthritis (OA) pain was investigated, and potential mechanisms were studied in an animal model. Pressure pain detection thresholds, anxiety, and depression were assessed in people with (n = 130) or without (n = 100) painful knee OA. Separately, knee pain and anxiety scores were also measured twice over 12 months in 4730 individuals recruited from the general population. A preclinical investigation of a model of OA pain in normo-anxiety Sprague-Dawley (SD) and high-anxiety Wistar Kyoto (WKY) rats assessed underlying neurobiological mechanisms. Higher anxiety, independently from depression, was associated with significantly lower pressure pain detection thresholds at sites local to (P < 0.01) and distant from (P < 0.05) the painful knee in patients with OA. Separately, high anxiety scores predicted increased risk of knee pain onset in 3274 originally pain-free people over the 1-year period (odds ratio = 1.71; 95% confidence interval = 1.25-2.34, P < 0.00083). Similarly, WKY rats developed significantly lower ipsilateral and contralateral hind paw withdrawal thresholds in the monosodium iodoacetate model of OA pain, compared with SD rats (P = 0.0005). Linear regressions revealed that baseline anxiety-like behaviour was predictive of lowered paw withdrawal thresholds in WKY rats, mirroring the human data. This augmented pain phenotype was significantly associated with increased glial fibrillary acidic protein immunofluorescence in pain-associated brain regions, identifying supraspinal astrocyte activation as a significant mechanism underlying anxiety-augmented pain behaviour.

Objective: To determine risk factors for three knee osteoarthritis (KOA) outcomes, knee pain (KP), radiographic KOA (RKOA) and total knee replacement (TKR), in professional footballers.Design: This was a cross-sectional study involving a postal questionnaire, followed by radiographic assessment in a sub-cohort of responders. Settings and Participants: 4775 questionnaires were sent to retired professional footballers, who had played in the English football league, and 1207 responded. Of these, 470 underwent knee radiographs. Assessment of Risk Factors: Potential factors include age, BMI, knee alignment, a history of football-related knee injury, and training hours (during career) were collected via the questionnaire.Main Outcome Measures: KOA outcomes were current KP (pain for most days of the previous month), TKR (self-reported) and RKOA (observed via radiographs). Results: Football-related injury was the strongest risk factor for KP [aOR 4.22, 95%CI 3.26-5.48], RKOA [aOR 2.88, 95%CI 1.81-4.59] and TKR [aOR 4.83, 95%CI 2.87-8.13]. Footballers had a 7% increased risk of RKOA for every 1000 hours trained. While age and gout were associated with all three KOA outcomes, BMI, nodal OA, a family history of OA, knee malalignment and 2D:4D ratio were associated with one or another of these three KOA outcomes.Conclusion: This study is the first to examine KOA risk factors in retired professional footballers. The study has identified several risk factors, both specific (for example, knee injury and training dose), and non-specific (for example, age and gout) to footballers. This may be used to develop prevention strategies to reduce the risk of KOA in professional footballers following retirement.

Additional file 1: Supplemental Figure 1. Recruitment and enrollment of study participants in Xiangya Osteoarthritis Study (XO Study). Supplemental Figure 2. Longitudinal ultrasonographic scan of suprapatellar recess (B mode). SH, synovial hypertrophy; E, joint effusion. Supplemental Figure 3. Longitudinal ultrasonographic scan of suprapatellar recess (Power Doppler mode). Power Doppler signal (PDS) at synovial membrane was scored using a semi-quantitative grading system, from 0 to 3 (0=absent, 1=mild, 2=moderate, 3=marked or severe). (A) grade 0, (B) grade 1, (C) grade 2. We did not detected grade 3 PDS in knee joints of participants of our study. Supplemental Figure 4. Bilateral weight-bearing posterior-anterior tibio-femoral radiographs, assessed according to Kellgren and Lawrence (KL) criteria: (A) grade 0, (B) grade 1, (C) grade 2, (D) grade 3 and (E) grade 4. Supplemental Figure 5. Skyline views of patellofemoral radiographs, assessed according to Kellgren and Lawrence (KL) criteria: (A) grade 0, (B) grade 1, (C) grade 2, (D) grade 3 and (E) grade 4. Supplemental Table 1. The intra- and inter-rater reliability for ultrasound-detected synovial abnormalities and Kellgren-Lawrence grade of knee radiography. Supplemental Table 2. Prevalence of knee synovial abnormalities on ultrasound among middle-aged and elderly persons, according to age group and sex. Supplemental Table 3. Association of knee synovial abnormalities on ultrasound and knee pain. Supplemental Table 4. Association of knee synovial abnormalities on ultrasound and knee pain among people with two knees discordant for knee pain. Supplemental Table 5. Association of knee synovial abnormalities on ultrasound and knee radiographic osteoarthritis. Supplemental Table 6. Association of knee pain stratified by knee synovial abnormalities on ultrasound and radiographic osteoarthritis status among people with two knees discordant for knee pain.

AIM: To explore risk factors that may influence knee pain (KP) through central or peripheral mechanisms.METHODS: A questionnaire-based prospective community cohort study with KP defined as pain in or around a knee on most days for at least a month. Baseline prevalence, and one year incidence and progression (KP worsening) were examined. Central (e.g., Pain Catastrophizing Scale (PCS)) and peripheral (e.g., significant injury) risk factors were examined. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using logistic regression. Proportional risk contribution (PRC) was estimated using receiver-operator-characteristic (ROC) analysis.RESULTS: Of 9506 baseline participants, 4288 (45%) had KP (men 1826; women, 2462). KP incidence was 12% (men 11%, women 13%), and KP progression 19% (men 16%, women 21%) at one year. While both central and peripheral factors contributed to prevalence, central factors contributed more to progression, and peripheral factors more to incidence of KP. For example, although PCS (OR 2.06, 95% CI 1.88-2.25) and injury (5.62, 4.92-6.42) associated with KP prevalence, PCS associated with progression (2.27, 1.83-2.83) but not incidence (1.14, 0.86-1.52), whereas injury more strongly associated with incidence (69.27, 24.15-198.7) than progression (2.52, 1.48-4.30). The PRC of central and peripheral factors were 19% and 23% for prevalence, 14% and 29% for incidence, and 29% and 5% for progression, respectively.CONCLUSIONS: Both central and peripheral risk factors influence KP but relative contributions may differ in terms of development (mainly peripheral) and progression (mainly central). Further study of such relative contributions may inform primary and secondary prevention strategies.

Background:\ud Knee pain results from a combination of nociceptive input from the joint, and processing by the central nervous system. Pressure pain detection thresholds (PPTs) are lower and pain is more severe in people with greater central sensitisation. \ud \ud Objective:\ud We hypothesised that lower PPTs predicted worse pain prognosis in people with knee pain.\ud \ud Methods:\ud KPIC participants were people aged >40 years recruited from Nottingham, UK. Participants were mailed questionnaires at baseline and 1 year. This study reports a sample of responders who attended baseline and 1 year clinical assessment, had self-reported knee pain (within the last 4 weeks) and underwent PPT. PPTs were measured at the knee, anterior tibia and the sternum. Radiographic knee OA was classified using an atlas. Questionnaires measured ICOAP (constant and intermittent knee pain), painDETECT (neuropathic-like) and average knee pain severity over 4 weeks (0-10).\ud The presence of pain at baseline and 1 year (persistent pain), or pain severity were predicted from baseline anterior tibia PPT. Additional analyses adjusted for baseline pain score, age, sex, BMI, or for radiographic knee OA. Pain persistence (Yes/No) was analysed using t tests, odds ratios (OR) and logistic regression. Pain severity was analysed using linear regression.\ud \ud Results:\ud The sample for this study contained n=419 people at baseline, and n=182 people reported knee pain persistent over both time points. The mean (SD) values were age 61 (9) years, BMI 30.1 (5.8) kg m-2, 59% female, and 36% fulfilled radiographic OA criteria at the index knee, for those with persistent knee pain at 1 year.\ud In univariate analysis, persistent knee pain was associated with a lower PPT at baseline (461 vs 424 kPa; OR (95% CI) 0.58 (0.34-0.97) p=0.020). Adjustments for age, sex and BMI removed the significance from the association (adjusted OR (95% CI) 0.64 (0.36-1.13) p=0.120). \ud In those with persistent pain, worse 1 year ICOAP-constant, ICOAP-intermittent, painDETECT and knee pain severity were correlated with lower baseline anterior tibia PPT ( r= -0.28 to -0.24; p