Serum levels of hydroxylated metabolites of arachidonic acid cross-sectionally and longitudinally predict knee pain progression: an observational cohort study.

OBJECTIVE: To examine associations between serum oxylipins, which regulate tissue repair and pain signalling, and knee pain/radiographic osteoarthritis (OA) at baseline and knee pain at 3 year follow-up. METHOD: Baseline, and 3 year follow-up, knee pain phenotypes were assessed from 154 participants in the Knee Pain in the Community (KPIC) cohort study. Serum and radiographic Kellgren and Lawrence (KL) and Nottingham line drawing atlas OA scores were collected at baseline. Oxylipin levels were quantified using liquid chromatography coupled with mass spectrometry. Associations were measured by linear regression and receiver operating characteristics (ROC). RESULTS: Serum levels of 8,9-epoxyeicosatrienoic acid (EET) (ß(95% confidence intervals (CI)) = 1.809 (-0.71 to 2.91)), 14,15-dihydroxyeicosatrienoic acid (DHET) (ß(95%CI) = 0.827 (0.34-1.31)), and 12-hydroxyeicosatetraenoic acid (HETE) (ß(95%CI) = 4.090 (1.92-6.26)) and anandamide (ß(95%CI) = 3.060 (1.35-4.77)) were cross-sectionally associated with current self-reported knee pain scores (numerical rating scale (NRS) item 3, average pain). Serum levels of 9- (ß(95%CI) = 0.467 (0.18-0.75)) and 15-HETE (ß(95%CI) = 0.759 (0.29-1.22)), 14-hydroxydocosahexaenoic acid (ß(95%CI) = 0.483(0.24-0.73)), and the ratio of 8,9-EET:DHET (ß(95%CI) = 0.510(0.19-0.82)) were cross-sectionally associated with KL scores. Baseline serum concentrations of 8,9-EET (ß(95%CI) = 2.166 (0.89-3.44)), 5,6-DHET (ß(95%CI) = 152.179 (69.39-234.97)), and 5-HETE (ß(95%CI) = 1.724 (0.677-2.77) showed positive longitudinal associations with follow-up knee pain scores (NRS item 3, average pain). Combined serum 8,9-EET and 5-HETE concentration showed the strongest longitudinal association (ß(95%CI) = 1.156 (0.54-1.77) with pain scores at 3 years, and ROC curves distinguished between participants with no pain and high pain scores at follow-up (area under curve (95%CI) = 0.71 (0.61-0.82)). CONCLUSIONS: Serum levels of a combination of hydroxylated metabolites of arachidonic acid may have prognostic utility for knee pain, providing a potential novel approach to identify people who are more likely to have debilitating pain in the future.

The impact of the cost-of-living crisis on population health in the UK: rapid evidence review.

BACKGROUND: In the UK, unique and unforeseen factors, including COVID-19, Brexit, and Ukraine-Russia war, have resulted in an unprecedented cost of living crisis, creating a second health emergency. We present, one of the first rapid reviews with the aim of examining the impact of this current crisis, at a population level. We reviewed published literature, as well as grey literature, examining a broad range of physical and mental impacts on health in the short, mid, and long term, identifying those most at risk, impacts on system partners, including emergency services and the third sector, as well as mitigation strategies. METHODS: We conducted a rapid review by searching PubMed, Embase, MEDLINE, and HMIC (2020 to 2023). We searched for grey literature on Google and hand-searched the reports of relevant public health organisations. We included interventional and observational studies that reported outcomes of interventions aimed at mitigating against the impacts of cost of living at a population level. RESULTS: We found that the strongest evidence was for the impact of cold and mouldy homes on respiratory-related infections and respiratory conditions. Those at an increased risk were young children (0-4 years), the elderly (aged 75 and over), as well as those already vulnerable, including those with long-term multimorbidity. Further short-term impacts include an increased risk of physical pain including musculoskeletal and chest pain, and increased risk of enteric infections and malnutrition. In the mid-term, we could see increases in hypertension, transient ischaemic attacks, and myocardial infarctions, and respiratory illnesses. In the long term we could see an increase in mortality and morbidity rates from respiratory and cardiovascular disease, as well as increase rates of suicide and self-harm and infectious disease outcomes. Changes in behaviour are likely particularly around changes in food buying patterns and the ability to heat a home. System partners are also impacted, with voluntary sectors seeing fewer volunteers, an increase in petty crime and theft, alternative heating appliances causing fires, and an increase in burns and burn-related admissions. To mitigate against these impacts, support should be provided, to the most vulnerable, to help increase disposable income, reduce energy bills, and encourage home improvements linked with energy efficiency. Stronger links to bridge voluntary, community, charity and faith groups are needed to help provide additional aid and support. CONCLUSION: Although the CoL crisis affects the entire population, the impacts are exacerbated in those that are most vulnerable, particularly young children, single parents, multigenerational families. More can be done at a community and societal level to support the most vulnerable, and those living with long-term multimorbidity. This review consolidates the current evidence on the impacts of the cost of living crisis and may enable decision makers to target limited resources more effectively.

Medio-dorsal thalamic dysconnectivity in chronic knee pain: A possible mechanism for negative affect and pain comorbidity.

The reciprocal interaction between pain and negative affect is acknowledged but pain-related alterations in brain circuits involved in this interaction, such as the mediodorsal thalamus (MDThal), still require a better understanding. We sought to investigate the relationship between MDThal circuitry, negative affect and pain severity in chronic musculoskeletal pain. For these analyses, participants with chronic knee pain (CKP, n = 74) and without (n = 36) completed magnetic resonance imaging scans and questionnaires. Seed-based MDThal functional connectivity (FC) was compared between groups. Within CKP group, we assessed the interdependence of MDThal FC with negative affect. Finally, post hoc moderation analysis explored whether burden of pain influences affect-related MDThal FC. The CKP group showed altered MDThal FC to hippocampus, ventromedial prefrontal cortex and subgenual anterior cingulate. Furthermore, in CKP group, MDThal connectivity correlated significantly with negative affect in several brain regions, most notably the medial prefrontal cortex, and this association was stronger with increasing pain burden and absent in pain-free controls. In conclusion, we demonstrate mediodorsal thalamo-cortical dysconnectivity in chronic pain with areas linked to mood disorders and associations of MDThal FC with negative affect. Moreover, burden of pain seems to enhance affect sensitivity of MDThal FC. These findings suggest mediodorsal thalamic network changes as possible drivers of the detrimental interplay between chronic pain and negative affect.

Risk clustering and psychopathology from a multi-center cohort of Indian children, adolescents, and young adults.

Developmental adversities early in life are associated with later psychopathology. Clustering may be a useful approach to group multiple diverse risks together and study their relation with psychopathology. To generate risk clusters of children, adolescents, and young adults, based on adverse environmental exposure and developmental characteristics, and to examine the association of risk clusters with manifest psychopathology. Participants (n = 8300) between 6 and 23 years were recruited from seven sites in India. We administered questionnaires to elicit history of previous exposure to adverse childhood environments, family history of psychiatric disorders in first-degree relatives, and a range of antenatal and postnatal adversities. We used these variables to generate risk clusters. Mini-International Neuropsychiatric Interview-5 was administered to evaluate manifest psychopathology. Two-step cluster analysis revealed two clusters designated as high-risk cluster (HRC) and low-risk cluster (LRC), comprising 4197 (50.5%) and 4103 (49.5%) participants, respectively. HRC had higher frequencies of family history of mental illness, antenatal and neonatal risk factors, developmental delays, history of migration, and exposure to adverse childhood experiences than LRC. There were significantly higher risks of any psychiatric disorder [Relative Risk (RR) = 2.0, 95% CI 1.8-2.3], externalizing (RR = 4.8, 95% CI 3.6-6.4) and internalizing disorders (RR = 2.6, 95% CI 2.2-2.9), and suicidality (2.3, 95% CI 1.8-2.8) in HRC. Social-environmental and developmental factors could classify Indian children, adolescents and young adults into homogeneous clusters at high or low risk of psychopathology. These biopsychosocial determinants of mental health may have practice, policy and research implications for people in low- and middle-income countries.

Identifying multiple knee pain trajectories and the prediction of opioid and NSAID medication used: A latent class growth approach.

BACKGROUND: Knee pain is a major source of distress and disability, with pain progression highly variable between individuals. Previous studies defining pain trajectories have all used a single measure of pain, and these differ across studies. Different measures reflect diverse pain mechanisms. To ascertain the clinical utility of pain trajectories, we explored associations between opioid and non-steroidal anti-inflammatory drug (NSAID) use. METHODS: We model pain trajectories using two measures-Intermittent and Constant Osteoarthritis Pain (ICOAP) and the painDETECT, in 2141 participants, across 3 waves (the baseline, 1- and 3-year assessments) of the Knee Pain In the Community (KPIC) cohort. RESULTS: Latent class growth analysis identified six trajectories using ICOAP subscales (High-Stable, Low-Stable, Moderate Worsening, Moderate Recovering, Worsening, and Recovering) and four trajectories using painDETECT (High-stable, Low-stable, Moderate Worsening, and Moderate Recovering). There was a high degree of correspondence between people assigned to pain trajectories between ICOAP intermittent and constant subscales, but less so using painDETECT. Opioid use was associated with ICOAP trajectories only (e.g., High-Stable and Worsening intermittent ICOAP trajectories) and in women. CONCLUSION: Different measures of pain produce different patterns of pain progression and these are differentially related to medication use. Opioid use is linked to trajectories of pain based on the impact of pain on behavior and not pain symptoms. Thus, managing pain's behavioral impact is more central to understanding opioid use than managing pain symptoms. These findings support more in-depth questioning about the type of pain and its progression in clinical practice.

Individual responses to topical ibuprofen gel or capsaicin cream for painful knee osteoarthritis: a series of n-of-1 trials.

OBJECTIVES: To determine individual responses to ibuprofen gel or capsaicin cream for painful, radiographic knee OA using a series of n-of-1 trials. METHODS: Twenty-two participants were allocated 5% ibuprofen gel (A) and 0.025% capsaicin cream (B) in random sequence (AB or BA). Patients underwent up to 3 treatment cycles, each comprising one treatment for 4 weeks, an individualized washout period (maximum 4 weeks), then the other treatment for 4 weeks. Differential (ibuprofen or capsaicin) response was defined when change-from-baseline pain intensity scores (0-10 NRS) differed by ≥1 between treatments in ≥2 cycles within a participant. RESULTS: A total of 104 treatment periods were aggregated. Mean pain reduction was 1.2 (95% CI: 0.5, 1.8) on ibuprofen and 1.6 (95% CI: 0.9, 2.4) on capsaicin (P = 0.221). Of 22 participants, 4 (18%) had a greater response to ibuprofen, 9 (41%) to capsaicin, 4 (18%) had similar responses, and 5 (23%) were undetermined. CONCLUSION: Irrespective of equal efficacy overall, 59% of people displayed a greater response to one treatment over the other. Patients who do not benefit from one type of topical treatment should be offered to try another, which may be more effective. N-of-1 trials are useful to identify individual response to treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, NCT03146689.

The Consortium on Vulnerability to Externalizing Disorders and Addictions (c-VEDA): an accelerated longitudinal cohort of children and adolescents in India.

The global burden of disease attributable to externalizing disorders such as alcohol misuse calls urgently for effective prevention and intervention. As our current knowledge is mainly derived from high-income countries such in Europe and North-America, it is difficult to address the wider socio-cultural, psychosocial context, and genetic factors in which risk and resilience are embedded in low- and medium-income countries. c-VEDA was established as the first and largest India-based multi-site cohort investigating the vulnerabilities for the development of externalizing disorders, addictions, and other mental health problems. Using a harmonised data collection plan coordinated with multiple cohorts in China, USA, and Europe, baseline data were collected from seven study sites between November 2016 and May 2019. Nine thousand and ten participants between the ages of 6 and 23 were assessed during this time, amongst which 1278 participants underwent more intensive assessments including MRI scans. Both waves of follow-ups have started according to the accelerated cohort structure with planned missingness design. Here, we present descriptive statistics on several key domains of assessments, and the full baseline dataset will be made accessible for researchers outside the consortium in September 2019. More details can be found on our website [cveda.org].

Risk Factors for Knee Osteoarthritis in Retired Professional Footballers: A Cross-Sectional Study.

OBJECTIVE: To determine risk factors for 3 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 subcohort of responders. SETTINGS AND PARTICIPANTS: Four thousand seven hundred seventy-five 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, body mass index (BMI), knee alignment, a history of football-related knee injury, and training hours (during career) were collected through the questionnaire. MAIN OUTCOME MEASURES: Knee osteoarthritis outcomes were current KP (pain for most days of the previous month), TKR (self-reported), and RKOA (observed through radiographs). RESULTS: Football-related injury was the strongest risk factor for KP [adjusted odds ratio (aOR), 4.22; 95% confidence interval (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. Although age and gout were associated with all 3 KOA outcomes, BMI, nodal osteoarthritis (OA), a family history of OA, knee malalignment, and 2D:4D ratio were associated with one or another of these 3 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 (eg, knee injury and training dose) and nonspecific (eg, age and gout) to footballers. This may be used to develop prevention strategies to reduce the risk of KOA in professional footballers after retirement.

Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA): A developmental cohort study protocol.

BACKGROUND: Low and middle-income countries like India with a large youth population experience a different environment from that of high-income countries. The Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA), based in India, aims to examine environmental influences on genomic variations, neurodevelopmental trajectories and vulnerability to psychopathology, with a focus on externalizing disorders. METHODS: cVEDA is a longitudinal cohort study, with planned missingness design for yearly follow-up. Participants have been recruited from multi-site tertiary care mental health settings, local communities, schools and colleges. 10,000 individuals between 6 and 23 years of age, of all genders, representing five geographically, ethnically, and socio-culturally distinct regions in India, and exposures to variations in early life adversity (psychosocial, nutritional, toxic exposures, slum-habitats, socio-political conflicts, urban/rural living, mental illness in the family) have been assessed using age-appropriate instruments to capture socio-demographic information, temperament, environmental exposures, parenting, psychiatric morbidity, and neuropsychological functioning. Blood/saliva and urine samples have been collected for genetic, epigenetic and toxicological (heavy metals, volatile organic compounds) studies. Structural (T1, T2, DTI) and functional (resting state fMRI) MRI brain scans have been performed on approximately 15% of the individuals. All data and biological samples are maintained in a databank and biobank, respectively. DISCUSSION: The cVEDA has established the largest neurodevelopmental database in India, comparable to global datasets, with detailed environmental characterization. This should permit identification of environmental and genetic vulnerabilities to psychopathology within a developmental framework. Neuroimaging and neuropsychological data from this study are already yielding insights on brain growth and maturation patterns.

Prevalence of knee pain, radiographic osteoarthritis and arthroplasty in retired professional footballers compared with men in the general population: a cross-sectional study.

OBJECTIVES: To determine the prevalence of knee pain, radiographic knee osteoarthritis (RKOA), total knee replacement (TKR) and associated risk factors in male ex-professional footballers compared with men in the general population (comparison group). METHODS: 1207 male ex-footballers and 4085 men in the general population in the UK were assessed by postal questionnaire. Current knee pain was defined as pain in or around the knees on most days of the previous month. Presence and severity of RKOA were assessed on standardised radiographs using the Nottingham Line Drawing Atlas (NLDA) in a subsample of 470 ex-footballers and 491 men in the comparison group. The adjusted risk ratio (aRR) and adjusted risk difference (aRD) with 95% CI in ex-footballers compared with the general population were calculated using the marginal model in Stata. RESULTS: Ex-footballers were more likely than the comparison group to have current knee pain (aRR 1.91, 95% CI 1.77 to 2.06), RKOA (aRR 2.21, 95% CI 1.92 to 2.54) and TKR (aRR 3.61, 95% CI 2.90 to 4.50). Ex-footballers were also more likely to present with chondrocalcinosis (aRR 3.41, 95% CI 2.44 to 4.77). Prevalence of knee pain and RKOA were higher in ex-footballers at all ages. However, even after adjustment for significant knee injury and other risk factors, there was more than a doubling of risk of these outcomes in footballers. CONCLUSIONS: The prevalence of all knee osteoarthritis outcomes (knee pain, RKOA and TKR) were two to three times higher in male ex-footballers compared with men in the general population group. Knee injury is the main attributable risk factor. Even after adjustment for recognised risk factors, knee osteoarthritis appear to be an occupational hazard of professional football.

Long-term persistence and adherence on urate-lowering treatment can be maintained in primary care-5-year follow-up of a proof-of-concept study.

Objectives: To evaluate the persistence and adherence on urate-lowering treatment (ULT) in primary care 5 years after an initial nurse-led treatment of gout. Methods: One hundred gout patients initiated on up-titrated ULT between March and July 2010 were sent a questionnaire that elicited information on current ULT, reasons for discontinuation of ULT if applicable, medication adherence and generic and disease-specific quality-of-life measures in 2015. They were invited for one visit at which height and weight were measured and blood was collected for serum uric acid measurement. Results: Seventy-five patients, mean age 68.13 years ( s . d . 10.07) and disease duration 19.44 years ( s . d . 13), returned completed questionnaires. The 5-year persistence on ULT was 90.7% (95% CI 81.4, 91.6) and 85.3% of responders self-reported taking ULT ⩾6 days/week. Of the 65 patients who attended the study visit, the mean serum uric acid was 292.8 µmol/l ( s . d . 97.2). Conclusion: An initial treatment that includes individualized patient education and involvement in treatment decisions results in excellent adherence and persistence on ULT >4 years after the responsibility of treatment is taken over by the patient's general practitioner, suggesting that this model of gout management should be widely adopted.

Cardiovascular disease and osteoarthritis: common pathways and patient outcomes.

BACKGROUND: Osteoarthritis (OA) and cardiovascular disease (CVD) are the two most prevalent conditions in the population aged over 70 in developed countries. Both conditions share common risk factors, in particular age and body mass index. However, the very high level of co-occurrence of both diseases cannot be accounted by common risk factors alone. MATERIALS AND METHODS: We reviewed the recent literature published in English in PubMed for articles relating to osteoarthritis and cardiovascular disease. RESULTS: On the one hand, the disability caused by OA increases the risk of CVD and in particular of ischemic events and mortality beyond what can be explained by known common risk factors, such as ageing and obesity. Moreover, the presence of OA has a synergistic effect on CVD symptoms considerably worsening them. On the other hand, at least in women, there appears to be a common pathogenic mechanism underlying atherosclerosis (but not hypertension) and actual joint damage. CONCLUSION: There are some possible molecular mechanisms underlying both diseases, in particular relating to low grade inflammation and female hormones. However, the data available to date also indicate that OA may be considered as an indirect cause of CVD by increasing walking disability and the use of analgesic medication such as NSAIDs. We discuss future directions that need to be taken to address these highly prevalent, costly and disabling morbidities.

IOC Olympian Health Cohort: a study protocol for a 15-year, prospective, Olympian health study across Summer and Winter Olympic sports.

Prevention of sports injury and illness and protection of athlete health are key mandates of the IOC. Methodological limitations in Olympic Games surveillance and retired Olympian studies mean there are gaps in the available evidence on Olympian health and the varied challenges occurring at different stages throughout an athlete's career. This (protocol) paper describes the methods for implementation of the IOC Olympian Health Cohort. The study aims to establish a longitudinal cohort of current Olympians and follow them prospectively (around 15 years) throughout their Olympic careers and retirement. The study will use participants who have completed self-report questionnaires. Olympians will be recruited after each Summer and Winter Olympic Games, and all National Olympic Committee (NOC) athletes aged 16 years or older are eligible. The first phase included the Tokyo 2020/2021 and Beijing 2022 Olympians, with the study promoted via IOC platforms, Athlete365 and NOCs. Questionnaires include baseline demographics, sports exposure and history of injuries and illnesses impacting the athlete's ability to continue to train and/or compete for at least 2 weeks. Questions also address retirement from sports, musculoskeletal, mental and general health, and quality of life measures. This protocol describes the methods for the 15-year global IOC Olympian Health Cohort Study, from participant recruitment to the development and distribution of the study questionnaire. This protocol will be updated to report future changes in the study's conduct or questionnaire content. These data will help identify risk factors and inform risk-reduction strategies. The ultimate goal is to protect the health of all athletes during their careers and retirement.

The association of alcohol dependence and consumption during adolescence with depression in young adulthood, in England: a prospective cohort study.

BACKGROUND: The role of alcohol use in the development of depression is unclear. We aimed to investigate whether alcohol dependence, but not high frequency or quantity of consumption, during adolescence increased the risk of depression in young adulthood. METHODS: In this prospective cohort study, we included adolescents who were born to women recruited to the Avon Longitudinal Study of Parents and Children in Avon, UK, with delivery dates between April 1, 1991, and Dec 31, 1992. Alcohol dependence and consumption were measured at about age 16 years, 18 years, 19 years, 21 years, and 23 years using the self-reported Alcohol Use Disorders Identification Test, and at about age 18 years, 21 years, and 23 years using items corresponding to DSM-IV symptoms. The primary outcome was depression at age 24 years, assessed using the Clinical Interview Schedule Revised. Analyses were probit regressions between growth factors for alcohol dependence and consumption and depression, before and after adjustments for confounders: sex, housing tenure, maternal education, maternal depressive symptoms, parents' alcohol use, conduct problems at age 4 years, being bullied from age 12-16 years, and frequency of smoking cigarettes or cannabis. Adolescents were included in analyses if they had data from at least one timepoint for alcohol use and confounders. FINDINGS: We included 3902 adolescents (2264 [58·0%] female; 1638 [42·0%] male) in our analysis, and 3727 (96·7%) of 3853 participants with data on ethnicity were White. After adjustments, we found a positive association between alcohol dependence at 18 years of age (latent intercept) and depression at 24 years of age (probit coefficient 0·13 [95% CI 0·02 to 0·25]; p=0·019), but no association between rate of change (linear slope) and depression (0·10 [-0·82 to 1·01]; p=0·84). There was no evidence of an association between alcohol consumption and depression (latent intercept probit coefficient -0·01 [-0·06 to 0·03]; p=0·60; linear slope 0·01 [-0·40 to 0·42]; p=0·96) after adjustments. INTERPRETATION: Psychosocial or behavioural interventions that reduce the risk of alcohol dependence during adolescence could contribute to preventing depression in young adulthood. FUNDING: UK Medical Research Council and Alcohol Research UK (grant number MR/L022206/1).

How people with knee pain understand why their pain changes or remains the same over time: A qualitative study.

Objectives: Guidelines recommend knee osteoarthritis pain management based on biopsychosocial mechanisms. Treatment adherence and effectiveness may be affected if there is a mismatch between patient perspectives and treatment focus. We therefore examined patient perspectives on mechanisms of their knee pain, why it persisted or changed over the past year, whether their understanding had changed, and whether their understanding aligned with that of others with whom they interact. Methods: Individuals with chronic knee pain (n â€‹= â€‹50) were purposively recruited from the Knee Pain and related health In the Community (KPIC) cohort to represent worsened, improved, or unchanged pain or anxiety between baseline and one year later. Framework analysis, a comparative form of thematic analysis, was used across transcripts of semi-structured telephone interviews. Results: Data were collapsed into themes of diagnosis, joint structure, ageing, physical activity, weight management, and treatment. Participants focused on biomechanical rather than psychological pain mechanisms. Some participants attributed pain improvement to increased and others to decreased physical activity. Participants reported no change in their understanding of their pain during the preceding year, but that their attitudes to pain, for example acceptance, had changed. Participants reported that they and others around them lacked understanding of their pain and why it did or did not change. Conclusion: People report a predominantly biomechanical understanding of why their knee pain remains constant or changes over time. Clinicians should support patients to develop a biopsychosocial understanding of knee pain aligned to treatment across the range of biological, psychological, and social modalities.

Heading Frequency and Risk of Cognitive Impairment in Retired Male Professional Soccer Players.

Importance: Although professional soccer players appear to be at higher risk of neurodegenerative disease, the reason remains unknown. Objective: To examine whether heading frequency is associated with risk of cognitive impairment in retired professional soccer players. Design, Setting, and Participants: A UK nationwide cross-sectional study was conducted between August 15, 2020, and December 31, 2021, in 459 retired male professional soccer players older than 45 years and registered with the Professional Footballers' Association or a League Club Players' Association. Exposure: Data on heading frequency in 3 bands-0 to 5, 6 to 15, and more than 15 times per match or training session and other soccer-specific risk factors, such as player position and concussion-were collected through a self-reported questionnaire. Main Outcomes and Measures: Cognitive impairment was defined using the Telephone Interview for Cognitive Status-modified as scores of less than or equal to 21. Hopkins Verbal Learning Test, verbal fluency, and independent activities of daily living were also assessed. Test Your Memory and physician-diagnosed dementia/Alzheimer disease were self-reported via the questionnaire. Adjusted odds ratios (AORs) with 95% CIs were calculated. Results: Of 468 retired male professional soccer players who completed questionnaires (mean [SD] age, 63.68 [10.48]; body mass index, 27.22 [2.89]), 459 reported heading frequency: 114 headed 0 to 5 times, 185 headed 6 to 15 times, 160 headed more than 15 times per match, and 125 headed 0 to 5 times, 174 headed 6 to 15 times, and 160 headed more than 15 times per training session during their careers. The prevalence of cognitive impairment was 9.78% (0-5 times), 14.78% (6-15 times), and 15.20% (>15 times) per match (P = .51). Compared with players reporting 0 to 5 headers per match, the AORs were 2.71 (95% CI, 0.89-8.25) for players reporting 6 to 15 headers per match and 3.53 (95% CI, 1.13-11.04) for players reporting more than 15 headers per match (P = .03 for trend). Corresponding AORs for heading frequency per training session were 2.38 (95% CI, 0.82-6.95) for those reporting 6 to 15, and 3.40 (95% CI, 1.13-10.23) for those reporting more than 15 in comparison with those who reported 0 to 5 (P = .03 for trend). Concussion involving memory loss was also associated with a greater risk of cognitive impairment (AOR, 3.16; 95% CI, 1.08-9.22). Similar results were observed with other cognitive tests and self-reported physician-diagnosed dementia/Alzheimer disease. Conclusions and Relevance: The findings of this study suggest that repetitive heading during a professional soccer career is associated with an increased risk of cognitive impairment in later life. Further study is needed to establish the upper threshold for heading frequency to mitigate this risk.

Cognitive Impairment and Self-Reported Dementia in UK Retired Professional Soccer Players: A Cross Sectional Comparative Study.

BACKGROUND: Previous studies based on death certificates have found professional soccer players were more likely to die with neurodegenerative diseases, including dementia. Therefore, this study aimed to investigate whether retired professional male soccer players would perform worse on cognitive tests and be more likely to self-report dementia diagnosis than general population control men. METHODS: A cross-sectional comparative study was conducted between August 2020 and October 2021 in the United Kingdom (UK). Professional soccer players were recruited through different soccer clubs in England, and general population control men were recruited from the East Midlands in the UK. We obtained self-reported postal questionnaire data on dementia and other neurodegenerative diseases, comorbidities and risk factors from 468 soccer players and 619 general population controls. Of these, 326 soccer players and 395 general population controls underwent telephone assessment for cognitive function. RESULTS: Retired soccer players were approximately twice as likely to score below established dementia screening cut-off scores on the Hopkins Verbal Learning Test (OR 2.06, 95%CI 1.11-3.83) and Verbal Fluency (OR 1.78, 95% CI 1.18-2.68), but not the Test Your Memory, modified Telephone Interview for Cognitive Status, and Instrumental Activities of Daily Living. Analyses were adjusted for age, education, hearing loss, body mass index, stroke, circulatory problems in the legs and concussion. While retired soccer players were younger, had fewer cardiovascular diseases and other morbidities and reported healthier lifestyles, 2.8% of retired soccer players reported medically diagnosed dementia and other neurodegenerative disease compared to 0.9% of controls (OR = 3.46, 95% CI 1.25-9.63) after adjustment for age and possible confounders. CONCLUSIONS: UK male retired soccer players had a higher risk of performing below established cut-off scores of dementia screening tests and were more likely to self-report medically diagnosed dementia and neurodegenerative diseases, despite having better overall physical health and fewer dementia risk factors. Further study is needed to determine specific soccer-related risk factors.

Associations of Muscle Strength with Central Aspects of Pain: Data from the Knee Pain and Related Health in the Community (KPIC) Cohort.

Knee pain is associated with lower muscle strength, and both contribute to disability. Peripheral and central neurological mechanisms contribute to OA pain. Understanding the relative contributions of pain mechanisms to muscle strength might help future treatments. The Knee Pain and related health In the Community (KPIC) cohort provided baseline and year 1 data from people with early knee pain (n = 219) for longitudinal analyses. A cross-sectional analysis was performed with baseline data from people with established knee pain (n = 103) and comparative data from people without knee pain (n = 98). Quadriceps and handgrip strength indicated local and general muscle weakness, respectively. The indices of peripheral nociceptive drive were knee radiographic and ultrasound scores. The indices associated with central pain mechanisms were Pressure Pain detection Threshold (PPT) distal to the knee, and a validated self-report Central Aspects of Pain Factor (CAPF). The associations were explored using correlation and multivariable regression. Weaker quadriceps strength was associated with both high CAPF and low PPT at baseline. Year 1 quadriceps weakness was predicted by higher baseline CAPF (ß = -0.28 (95% CI: -0.55, -0.01), p = 0.040). Weaker baseline and year 1 handgrip strength was also associated with higher baseline CAPF. Weaker baseline quadriceps strength was associated with radiographic scores in bivariate but not adjusted analyses. Quadriceps strength was not significantly associated with total ultrasound scores. Central pain mechanisms might contribute to muscle weakness, both locally and remote from the knee.

Neurocognitive Analysis of Low-level Arsenic Exposure and Executive Function Mediated by Brain Anomalies Among Children, Adolescents, and Young Adults in India.

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.