Clinical and biomechanical factors associated with falls and rheumatoid arthritis: baseline cohort with longitudinal nested case-control study.

OBJECTIVE: To identify the clinical and biomechanical characteristics associated with falls in people with RA. METHODS: A total of 436 people ≥60 years of age with RA completed a 1 year prospective survey of falls in the UK. At baseline, questionnaires recorded data including personal and medical history, pain and fatigue scores, health-related quality of life (HRQoL), physical activity and medication history. The occurrence of falls wasmonitored prospectively over 12 months by monthly self-reporting. A nested sample of 30 fallers (defined as the report of one or more falls in 12 months) and 30 non-fallers was evaluated to assess joint range of motion (ROM), muscle strength and gait parameters. Multivariate regression analyses were undertaken to determine variables associated with falling. RESULTS: Compared with non-fallers (n = 236), fallers (n = 200) were older (P = 0.05), less likely to be married (P = 0.03), had higher pain scores (P < 0.01), experienced more frequent dizziness (P < 0.01), were frequently taking psychotropic medications (P = 0.02) and reported lower HRQoL (P = 0.02). Among those who underwent gait laboratory assessments, compared with non-fallers, fallers showed a greater anteroposterior (AP; P = 0.03) and medial-lateral (ML) sway range (P = 0.02) and reduced isokinetic peak torque and isometric strength at 60° knee flexion (P = 0.03). Fallers also showed shorter stride length (P = 0.04), shorter double support time (P = 0.04) and reduced percentage time in swing phase (P = 0.02) and in knee range of motion through the gait cycle (P < 0.01). CONCLUSION: People with RA have distinct clinical and biomechanical characteristics that place them at increased risk of falling. Assessment for these factors may be important to offer more targeted rehabilitation interventions.

Cross-sectional associations between 24-hour activity behaviours and mental health indicators in children and adolescents: A compositional data analysis.

We examined associations between youth 24-hour activity behaviour compositions and mental health. Data were collected from 359 participants (aged 9-13 years). Activity behaviours (sleep, sedentary time (ST), light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA)) were assessed using wrist-worn accelerometers. Questionnaires and a computerized cognitive test battery assessed mental health outcomes. Linear mixed models examined associations between activity behaviour compositions and mental health. Post-hoc analyses modelled the influence of reallocating fixed durations of time between activity behaviours on mental health. ST was associated with worse internalizing problems (all participants; p< 0.05) and poorer prosocial behaviour (primary school participants only; p< 0.05), relative to the other activity behaviours. LPA was associated with worse cognitive test scores among primary school participants; p< 0.05). For all participants, reallocating time to ST from sleep and MVPA was associated with higher internalizing problems. Among primary school participants, reallocating time to ST from any other behaviour was associated with poorer prosocial behaviour, and reallocating time to LPA from any other behaviour was associated with lower executive function. Children's mental health may be promoted by schools integrating opportunities for MVPA throughout the day. Our results provide further evidence for the influence of daily activity behaviours on youth mental health.

Prescription of analgesia in emergency medicine (POEM) secondary analysis: an observational multicentre comparison of pain relief provided to adults and children with an isolated limb fracture and/or dislocation.

BACKGROUND: Acute pain is a common reason for emergency department (ED) attendance. Royal College of Emergency Medicine (RCEM) pain management audits have shown national variation and room for improvement. Previous evidence suggests that children receive less satisfactory pain management than adults. METHODS: Prescription of analgesia in emergency medicine is a cross-sectional observational study of consecutive patients presenting to 12 National Health Service EDs with an isolated long bone fracture and/or dislocation, and was carried out between 2015 and 2017. Using the recommendations in the RCEM Best Practice Guidelines, pain management in ED was assessed for differences of age (adults vs children) and hospital type (children's vs all patients). RESULTS: From the total 8346 patients, 38% were children (median age 8 years). There was better adherence to the RCEM guidance for children than adults (24% (766/3196) vs 11% (579/5123)) for the combined outcome of timely assessment, pain score and appropriate analgesia. In addition, children were significantly more likely than adults to receive analgesia appropriate to the pain score (of those with a recorded pain score 67% (1168/1744) vs 52% (1238/2361)). Children's hospitals performed much better across all reported outcomes compared with general hospitals. CONCLUSIONS: In contrast to previous studies, children with a limb fracture/dislocation are more likely than adults to have a pain score documented and to receive appropriate analgesia. Unexpectedly, children's EDs performed better than general EDs in relation to timely and appropriate analgesia but the reasons for this are not apparent from the present study.

IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis.

Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells. Immunolabeling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking Ab to the IL-6 receptor or a neutralizing Ab to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP-positive stem cells per crypt compared with IgG-treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6-induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cells and the Wnt signaling pathway.

Trajectory of social isolation following hip fracture: an analysis of the English Longitudinal Study of Ageing (ELSA) cohort.

Background: social isolation is defined as a lack of meaningful and sustained communication or interactions with social networks. There is limited understanding on the prevalence of social isolation and loneliness in people following hip fracture and no previous understanding of how this changes over time. Objective: to determine the prevalence and trajectory of social isolation and loneliness before a hip fracture, during the recovery phase and a minimum of 2 years post-hip fracture in an English population. Methods: data were from the English Longitudinal Study of Ageing (ELSA) cohort (2004/5-2014/15). The sample comprised of 215 participants who had sustained a hip fracture. Measures of social isolation and loneliness were analysed through multilevel modelling to determine their trajectories during three-time intervals (pre-fracture; interval at hip fracture and recovery; minimum 2 years post-fracture). The prevalence of social isolation and loneliness were determined pre- and post-fracture. Results: prevalence of social isolation was 19% post-hip fracture and loneliness 13% post-hip fracture. There was no statistically significant change in social isolation pre-fracture compared to a minimum of 2 years post-fracture (P = 0.78). Similarly, there was no statistically significant change in loneliness pre-fracture compared to a minimum of 2 years post-fracture (P = 0.12). Conclusion: this analysis has determined that whilst social isolation and loneliness do not change over time following hip fracture, these remain a significant problem for this population. Interventions are required to address these physical and psychological health needs. This is important as they may have short and longer term health benefits for people post-hip fracture.

Consumption of both low and high (-)-epicatechin apple puree attenuates platelet reactivity and increases plasma concentrations of nitric oxide metabolites: a randomized controlled trial.

We hypothesised that consumption of flavanol-containing apple puree would modulate platelet activity and increase nitric oxide metabolite status, and that high flavanol apple puree would exert a greater effect than low flavanol apple puree. 25 subjects consumed 230 g of apple puree containing 25 and 100mg epicatechin (low and high flavanol apple puree, respectively) and aspirin (75 mg) in random order. Measurements were made at baseline, acutely after treatment (2, 6 and 24 h), and after 14 d of treatment. Low flavanol apple puree significantly attenuated ADP and epinephrine-induced integrin-ß3 expression 2 h and 6 h after consumption and ADP and epinephrine-induced P-selectin expression within 2h of consumption. High flavanol apple puree attenuated epinephrine and ADP-induced integrin-ß3 expression after 2 and 6h. ADP and epinephrine-induced integrin-ß3 expression was significantly attenuated 2, 6 and 24 h after consumption of aspirin, whilst 14 d aspirin consumption attenuated collagen-induced P-selectin expression only. The plasma total nitric oxide metabolite conc. was significantly increased 6h after consumption of both low and high flavanol apple purees. In conclusion, consumption of apple purees containing ⩾25 or 100 mg flavanols transiently attenuated ex vivo integrin-ß3 and P-selectin expression and increased plasma nitric oxide metabolite conc. in healthy subjects, but the effect was not enhanced for the high flavanol apple puree.

Estimation of the 5-methyltetrahydrofolate apparent volume of distribution in humans.

The fractional absorption of a stable isotope-labeled folate dose can be estimated from the subsequent short-term temporal changes in the concentration of labeled L-5-methyltetrahydrofolate (L-5-methyl-THF) in plasma using mathematical modeling. However, the model is dependent on the use of an accurate value for the apparent volume of distribution of L-5-methyl-THF. Previous studies that estimated the apparent volume of distribution of L-5-methyl-THF used large (nonphysiological) doses of unlabeled folates that are not found to any great extent in the circulatory system. The current study estimates the apparent volume of distribution at steady state in 16 healthy humans aged 18-65 y after an i.v. dose (440 nmol) of a stable isotope-labeled version of the naturally circulating plasma folate, L-5-methyl-THF. Blood was collected from 2 min to 2 h postinjection and plasma assayed by specific and sensitive liquid chromatography-tandem MS. The apparent volume of distribution for L-5-methyl-THF was 32.0 ± 11.6 L (mean ± SD; 392 ± 110 mL/kg bodyweight). There was a positive association with volunteer body weight (r = 0.64; P = 0.010), which allowed a simple linear equation to be developed relating apparent volume of distribution to body weight. This has important implications for predicting apparent absorption of labeled folates in future bioavailability studies.

Low-pH cola beverages do not affect women's iron absorption from a vegetarian meal.

Preliminary data in the literature indicate that iron absorption from a meal may be increased when consumed with low-pH beverages such as cola, and it is also possible that sugar iron complexes may alter iron availability. A randomized, crossover trial was conducted to compare the bioavailability of nonheme iron from a vegetarian pizza meal when consumed with 3 different beverages (cola, diet cola, and mineral water). Sixteen women with serum ferritin concentrations of 11-54 µg/L were recruited and completed the study. The pizza meal contained native iron and added ferric chloride solution as a stable isotope extrinsic label; the total iron content of the meal was ~5.3 mg. Incorporation of iron from the meal into RBC was not affected by the type of drink (9.9% with cola, 9.4% with diet cola, and 9.6% with water). Serum ferritin and plasma hepcidin were correlated (r = 0.66; P<0.001) and both were significant predictors of iron bioavailability, but their combined effect explained only 30% of the inter-individual variation (P<0.001) and illustrates the current lack of understanding of mechanisms responsible for the fine-tuning of iron absorption. Although there was no effect of low-pH drinks on iron bioavailability in healthy women, their effect on absorption of fortification iron that requires solubilization in dilute acid, such as reduced iron, and in individuals with low gastric acid production, such as older people and individuals with Helicobacter pylori infection, warrants further investigation.

Trajectories of pain and function in the first five years after total hip and knee arthroplasty : an analysis of patient reported outcome data from the National Joint Registry.

AIMS: To determine the trajectories of patient reported pain and functional disability over five years following total hip arthroplasty (THA) or total knee arthroplasty (TKA). METHODS: A prospective, longitudinal cohort sub-study within the National Joint Registry (NJR) was undertaken. In all, 20,089 patients who underwent primary THA and 22,489 who underwent primary TKA between 2009 and 2010 were sent Oxford Hip Score (OHS) and Oxford Knee Score (OKS) questionnaires at six months, and one, three, and five years postoperatively. OHS and OKS were disaggregated into pain and function subscales. A k-means clustering procedure assigned each patient to a longitudinal trajectory group for pain and function. Ordinal regression was used to predict trajectory group membership using baseline OHS and OKS score, age, BMI, index of multiple deprivation, sex, ethnicity, geographical location, and American Society of Anesthesiologists grade. RESULTS: Data described two discrete trajectories for pain and function: 'level 1' responders (around 70% of cases) in whom a high level of improvement is sustained over five years, and 'level 2' responders who had sustained improvement, but at a lower level. Baseline patient variables were only weak predictors of pain trajectory and modest predictors of function trajectory. Those with worse baseline pain and function tended to show a greater likelihood of following a 'level 2' trajectory. Six-month patient-reported outcome measures data reliably predicted the class of five-year outcome trajectory for both pain and function. CONCLUSION: The available preoperative patient variables were not reliable predictors of postoperative pain and function after THA and TKA. Reviewing patient outcomes at six months postoperatively is a reliable indicator of outcome at five years. Cite this article: Bone Joint J 2021;103-B(6):1111-1118.

Adolescent time use and mental health: a cross-sectional, compositional analysis in the Millennium Cohort Study.

OBJECTIVE: To examine the association of 24-hour time-use compositions with mental health in a large, geographically diverse sample of UK adolescents. DESIGN: Cross-sectional, secondary data analysis. SETTING: Millennium Cohort Study (sixth survey), a UK-based prospective birth cohort. PARTICIPANTS: Data were available from 4642 adolescents aged 14 years. Analytical samples for weekday and weekend analyses were n=3485 and n=3468, respectively (45% boys, 85% white ethnicity). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures were the Strengths and Difficulties Questionnaire (SDQ, socioemotional behaviour), Mood and Feelings Questionnaire (MFQ, depressive symptoms) and Rosenberg Self-Esteem Scale (RSE, self-esteem). Behavioural exposure data were derived from 24-hour time-use diaries. RESULTS: On weekdays, participants spent approximately 54% of their time in sleep, 3% in physical activity, 9% in school-related activities, 6% in hobbies, 11% using electronic media and 16% in domestic activities. Predicted differences in SDQ, MFQ and RSE were statistically significant for all models (weekday and weekend) that simulated the addition or removal of 15 min physical activity, with an increase in activity being associated with improved mental health and vice versa. Predicted differences in RSE were also significant for simulated changes in electronic media use; an increase in electronic media use was associated with reduced self-esteem. CONCLUSION: Small but consistent associations were observed between physical activity, electronic media use and selected markers of mental health. Findings support the delivery of physical activity interventions to promote mental health during adolescence, without the need to specifically target or protect time spent in other activities.

Reduced cognitive ability in people with rheumatoid arthritis compared with age-matched healthy controls.

OBJECTIVE: The aim was to compare the cognitive ability of people with RA with healthy controls (HCs). METHODS: People with RA were recruited from the Norfolk Arthritis Register (NOAR), a population-based cohort study of people with inflammatory arthritis. Data on aged-matched HCs (people with no cognitive impairment) came from the comparison arm of The Dementia Research and Care Clinic Study (TRACC). People with RA and HCs performed a range of cognitive ability tasks to assess attention, memory, verbal fluency, language, visuospatial skills, emotional recognition, executive function and theory of mind. A score of <88 on the Addenbrooke's Cognitive Examination III was considered cognitive impairment. Scores were compared using linear regression adjusting for age, sex, smoking status, education, BMI, anxiety and depression. RESULTS: Thirty-eight people with RA [mean (S.D.) age: 69.1 (8.0) years; 25 (65.8%) women] were matched with 28 HCs [mean (S.D.) age: 68.2 (6.4) years; 15 (53.6%) women]. Twenty-three (60.5%) people with RA were considered to have mild cognitive impairment [mean (S.D.) Addenbrooke's Cognitive Examination III: RA = 85.2 (7.4), HC = 96.0 (2.5)]. People with RA had impairments in memory, verbal fluency, visuospatial functioning, executive function and emotional recognition in faces compared with HCs, after adjustment for confounders. CONCLUSION: People with RA had cognitive impairments in a range of domains. People with RA might benefit from cognitive impairment screening to allow for early administration of appropriate interventions.

Impact of COVID-19 pandemic social restriction measures on people with rheumatic and musculoskeletal diseases in the UK: a mixed-methods study.

OBJECTIVES: To determine the impact of COVID-19 pandemic social restriction measures on people with rheumatic and musculoskeletal diseases (RMDs) and to explore how people adapted to these measures over time. DESIGN: Mixed-methods investigation comprising a national online longitudinal survey and embedded qualitative study. SETTING: UK online survey and interviews with community-dwelling individuals in the East of England. PARTICIPANTS: People in the UK with RMDs were invited to participate in an online survey. A subsection of respondents were invited to participate in the embedded qualitative study. PRIMARY AND SECONDARY OUTCOME MEASURES: The online survey, completed fortnightly over 10 weeks from April 2020 to August 2020, investigated changes in symptoms, social isolation and loneliness, resilience and optimism. Qualitative interviews were undertaken assessing participant's perspectives on changes in symptoms, exercising, managing instrumental tasks such a shopping, medication and treatment regimens and how they experienced changes in their social networks. RESULTS: 703 people with RMDs completed the online survey. These people frequently reported a deterioration in symptoms as a result of COVID-19 pandemic social restrictions (52% reported increase vs 6% reported a decrease). This was significantly worse for those aged 18-60 years compared with older participants (p=0.017). The qualitative findings from 26 individuals with RMDs suggest that the greatest change in daily life was experienced by those in employment. Although some retired people reported reduced opportunity for exercise outside their homes, they did not face the many competing demands experienced by employed people and people with children at home. CONCLUSIONS: People with RMDs reported a deterioration in symptoms when COVID-19 pandemic social restriction measures were enforced. This was worse for working-aged people. Consideration of this at-risk group, specifically for the promotion of physical activity, changing home-working practices and awareness of healthcare provision is important, as social restrictions continue in the UK.

Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa.

Methylation of CpG islands (CGIs) in the promoter regions of tumour suppressor genes is common in colorectal cancer and occurs also in an age-dependent manner in the morphologically normal colorectal mucosa. In this study, we quantified the level of methylation of six genes associated with the Wnt signalling pathway (adenomatous polyposis coli, DKK1, WIF1, SFRP1, SFRP2 and SFRP5) together with long-interspersed nuclear element-1 as a surrogate for global methylation. DNA methylation was analysed in 260 individual colorectal crypts obtained from eight female patients with no evidence of colorectal disease and five with colorectal cancer. Significant variation in methylation levels for each of the six genes existed between crypts from the same biopsy. The variation in both global and gene-specific CGI methylation between crypts from the same individual was significantly less than that between individuals. Bisulphite sequencing provided insight into the mechanism of aberrant methylation showing that CGI methylation occurs in an 'all-or-none' manner by the directional spreading of methylation from further upstream. Univariate statistical analyses revealed that there were significant differences in crypt-specific methylation associated with both aging and disease status. A multivariate statistical modelling approach was able to distinguish both subject age and health status based on crypt-specific methylation profiles. Our results indicate that the differential methylation of genes associated with the Wnt signalling pathway affecting individual morphologically normal crypts may contribute to the age-dependent generation of the colonic field defect and, in combination with mutations, to the stepwise development of colorectal neoplasia.

Public engagement in research funding: a study of public capabilities and engagement methodology.

One trend in public engagement concerns involving the public in research priority setting. In this study members of the public were asked to select which of four potential projects (about food-related topics, presented by scientists) ought to be funded. The aim of the study was twofold: to trial and evaluate a method of engaging with the public about science, and to study the factors used by the public in making funding allocation decisions. Results suggest that, while participants enjoyed the process and appeared to learn from it, they were not particularly "representative"--a common problem with engagement approaches of this type. Results also suggest that participants' funding decisions were largely based on factors such as "benefit to society" and "personal relevance," though aspects such as the "likeability" and "trustworthiness" of the speaker may have played a role. Implications for involving the public in funding policy decisions are discussed.

Dietary Iron Bioavailability: A Simple Model That Can Be Used to Derive Country-Specific Values for Adult Men and Women.

BACKGROUND: Reference intakes for iron are derived from physiological requirements, with an assumed value for dietary iron absorption. A new approach to estimate iron bioavailability, calculated from iron intake, status, and requirements was used to set European dietary reference values, but the values obtained cannot be used for low- and middle-income countries where diets are very different. OBJECTIVE: We aimed to test the feasibility of using the model developed from United Kingdom and Irish data to derive a value for dietary iron bioavailability in an African country, using data collected from women of child-bearing age in Benin. We also compared the effect of using estimates of iron losses made in the 1960s with more recent data for whole body iron losses. METHODS: Dietary iron intake and serum ferritin (SF), together with physiological requirements of iron, were entered into the predictive model to estimate percentage iron absorption from the diet at different levels of iron status. RESULTS: The results obtained from the 2 different methods for calculating physiological iron requirements were similar, except at low SF concentrations. At a SF value of 30 µg/L predicted iron absorption from the African maize-based diet was 6%, compared with 18% from a Western diet, and it remained low until the SF fell below 25 µg/L. CONCLUSIONS: We used the model to estimate percentage dietary iron absorption in 30 Beninese women. The predicted values agreed with results from earlier single meal isotope studies; therefore, we conclude that the model has potential for estimating dietary iron bioavailability in men and nonpregnant women consuming different diets in other countries.

Prescription Of analgesia in Emergency Medicine (POEM): a multicentre observational survey of pain relief in patients presenting with an isolated limb fracture and/or dislocation.

BACKGROUND: Acute pain is one of the most commonly cited reasons for attendance to the emergency department (ED), and the Royal College of Emergency Medicine (RCEM) Best Practice Guideline (2014) acknowledged that the current management of acute pain in UK EDs is inadequate and has a poor evidence base. METHODS: The Prescription Of analgesia in Emergency Medicine (POEM) survey is a cross-sectional observational survey of consecutive patients presenting to 12 National Health Service (NHS) EDs with limb fracture and/or dislocation in England and Scotland and was carried out between 2015 and 2017. The primary outcome was to assess the adequacy of pain management in the ED against the recommendations in the RCEM Best Practice Guidelines. RESULTS: In all, 8346 patients were identified as attending the ED with a limb fracture and/or dislocation but adherence to RCEM guidelines could only be evaluated for the 4160 (49.8%) patients with a recorded pain score. Of these, 2409/4160 (57.9%) patients received appropriate pain relief, but only 1347 patients were also assessed within 20 minutes of their arrival in the ED. Therefore, according to the RCEM guidelines, only 16.1% (1347/8346) of all patients were assessed and had satisfactory pain management in the ED. CONCLUSIONS: The POEM survey has identified that pain relief for patients with an isolated limb fracture remains inadequate when strictly compared to the RCEM Best Practice Guidelines. However, we have found that some patients receive analgesia despite having no pain score recorded, while other analgesic modalities are provided that are not currently encompassed by the Best Practice Guidelines. Future iterations of these guidelines may wish to encompass the breadth of available modalities of pain relief and the whole patient journey. In addition, more work is needed to improve timely and repeated assessment of pain and its recording, which has been better achieved in some EDs than others.

Demographic and geographical variability in physiotherapy provision following hip and knee replacement. An analysis from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

BACKGROUND: Total hip (THR) and knee replacement (TKR) are two of the most common elective orthopaedic procedures worldwide. Physiotherapy is core to the recovery of people following joint replacement. However, there remains uncertainty as to physiotherapy provision at a national level. OBJECTIVES: To examine the relationship between patient impairment and geographical variation on the provision of physiotherapy among patients who undergo primary total hip or knee replacement (THR/TKR). DESIGN: Population-based observational cohort study. METHODS: Patients undergoing THR (n=17,338) or TKR (n=20,260) recorded in the National Joint Registry for England (NJR) between 2009 and 2010 and completed Patient Reported Outcome Measures (PROMs) questionnaires at Baseline and 12 months postoperatively. Data were analysed on the frequency of physiotherapy over the first postoperative year across England's Strategic Health Authorities (SHAs). Logistic regression analyses examined the relationship between a range of patient and geographical characteristics and physiotherapy provision. RESULTS: Following THR, patients were less likely to receive physiotherapy than following TKR patients ('some' treatment by a physiotherapist within 1st post operative year: 53% vs 79%). People with worse functional outcomes 12 months postoperatively, received more physiotherapy after THR and TKR. There was substantial variation in provision of physiotherapy according to age (younger people received more physiotherapy), gender (females received more physiotherapy) ethnicity (non-whites received more physiotherapy) and geographical location (40% of patients from South West received some physiotherapy compared to 40 73% in London after THR). CONCLUSIONS: There is substantial variation in the provision of physiotherapy nationally. This variation is not explained by differences in the patient's clinical presentation.

Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion.

Oranges are rich sources of flavonoids that are bioactive and may protect against age-related diseases. The absorption of orange flavanones may be affected by factors such as processing and subject anthropometric variables, and the bioactivity of the absorbed phytochemicals depends on how they are metabolised during absorption. In a randomised cross-over study, twenty subjects consumed a single portion of orange fruit (150 g) or juice (300 g) that contained the flavanones narirutin and hesperidin, and an additional 109 subjects across a broad age range (18-80 years) consumed the juice. Flavanone metabolites were measured in regularly collected samples of plasma and urine. After consumption of fruit or juice, flavanone conjugates, but not the aglycones, were detected in plasma and urine. The flavanone conjugates were shown to include the 7- and 4'-O-monoglucuronides of naringenin, the 7- and 3'-O-monoglucuronides of hesperetin, two hesperetin diglucuronides and a hesperetin sulfo-glucuronide, but no aglycones or rutinosides. Analysis of the plasma pharmacokinetic and urinary excretion data on a dose-adjusted basis indicated no difference in absorption or excretion of either flavanone between the fruit and juice matrices. In the extended urinary excretion dataset the individual variation was very large (range 0-59 % urinary yield). There was a small but significant (P < 0.05) decrease in the excretion of hesperetin (but not naringenin) with increasing age (P < 0.05), but the effects of sex, BMI and contraceptive pill use were shown not to be associated with the variation in flavanone excretion.

Study Protocol: randomised controlled trial to investigate the functional significance of marginal riboflavin status in young women in the UK (RIBOFEM).

BACKGROUND: The functional significance of moderate riboflavin deficiency as it is currently assessed is not well understood. Animal and human studies have suggested a role for riboflavin in the absorption and mobilisation of iron and as such may be important in maintaining haematological status. Recent National Diet and Nutrition Surveys in the United Kingdom have shown that young women in particular are at risk of moderate riboflavin deficiency and low iron status. METHODS/DESIGN: A randomised placebo controlled intervention trial was conducted to investigate the effect of riboflavin supplementation on various measures of haematological status in a group of moderately riboflavin deficient young women aged 19 to 25 years. Women who were low milk consumers were initially screened for riboflavin status as assessed by the erythrocyte glutathione reductase activation coefficient assay (EGRAC). One hundred and twenty three women with EGRAC values >1.40 were randomised to receive 2 mg, 4 mg riboflavin or placebo for 8 weeks. In addition 36 of these women were randomly allocated to an iron bioavailability study to investigate the effect of the intervention on the absorption or utilisation of iron using an established red cell incorporation technique. DISCUSSION: One hundred and nineteen women completed the intervention study, of whom 36 completed the bioavailability arm. Compliance was 96 +/- 6% (mean +/- SD). The most effective recruitment strategy for this gender and age group was e-communication (e-mail and website). The results of this study will clarify the functional significance of the current biochemical deficiency threshold for riboflavin status and will inform a re-evaluation of this biochemical threshold. TRIAL REGISTRATION: Current Controlled Trials Registration No. ISRCTN35811298.

Association between musculoskeletal pain with social isolation and loneliness: analysis of the English Longitudinal Study of Ageing.

INTRODUCTION: Musculoskeletal pain is a prevalent health challenge for all age groups worldwide, but most notably in older adults. Social isolation is the consequence of a decrease in social network size with a reduction in the number of social contacts. Loneliness is the psychological embodiment of social isolation and represents an individual's perception of dissatisfaction in the quality or quantity of their social contacts. This study aims to determine whether a relationship exists between musculoskeletal pain and social isolation and loneliness. METHODS: A cross-sectional analysis of the English Longitudinal Study of Ageing (ELSA) cohort was undertaken. ELSA is a nationally representative sample of the non-institutionalised population of individuals aged 50 years and over based in England. Data were gathered on social isolation through the ELSA Social Isolation Index, loneliness through the University of California, Los Angeles (UCLA) Loneliness Scale and musculoskeletal pain. Data for covariates included physical activity, depression score, socioeconomic status, access to transport and demographic characteristics. Logistic regression analyses were undertaken to determine the relationship between social isolation and loneliness with pain and the additional covariates. RESULTS: A total of 9299 participants were included in the analysis. This included 4125 (44.4%) males, with a mean age of 65.8 years. There was a significant association where social isolation was lower for those in pain (odd ratio (OR): 0.87; 95% confidence intervals (CI): 0.75 to 0.99), whereas the converse occurred for loneliness where this was higher for those in pain (OR: 1.15; 95% CI: 1.01 to 1.31). Age, occupation, physical activity and depression were all associated with increased social isolation and loneliness. CONCLUSION: People who experience chronic musculoskeletal pain are at greater risk of being lonely, but at less risk of being socially isolated. Health professionals should consider the wider implications of musculoskeletal pain on individuals, to reduce the risk of negative health implications associated with loneliness from impacting on individual's health and well-being.