Risk factors for COVID-19 hospitalisation after booster vaccination during the Omicron period: A French nationwide cohort study.

BACKGROUND: In spite of major effectiveness, a residual risk after COVID-19 primary vaccination was identified, in particular, for vulnerable individuals of advanced age or with comorbidities. Less is known about the Omicron period in people protected by a booster dose. We aimed to identify the characteristics associated with severe COVID-19 during the Omicron period in a population that had received a booster dose in France and to compare differences with the previous periods of the pandemic. METHODS: This study was carried out using the French national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS). Individuals aged 12 years or over who received at least one booster dose were identified. Associations between socio-demographic and clinical characteristics and the risk of COVID-19 hospitalisation occurring at least 14 days after receiving a third dose of vaccine during the period of Omicron predominance, i.e., from 1 January 2022 to 10 November 2022, were assessed using Cox proportional hazard models adjusted for age, sex, time since booster dose and vaccination schedule. Analyses were performed overall and by sub-period of circulation of the strains BA.1, BA.2, and BA.4/BA.5, defined as periods where the main sub-variant accounted for more than 80 % of genotyped samples. FINDINGS: In total, 35,640,387 individuals received a booster dose (mean follow-up of 291 days) and 73,989 were hospitalised for COVID-19 during the total period. Older age (aHR 20.5 95 % CI [19.6-21.5] for 90 years of age or older versus 45-54 years of age), being male (aHR 1.52 [1.50-1.55]), and social deprivation (aHR 1.33 [1.30-1.37] for the most deprived areas versus the least deprived) were associated with an increased risk of hospitalisation for COVID-19. Most of the chronic diseases considered were also positively associated with a residual risk, in particular, cystic fibrosis (aHR 9.83 [7.68-12.56]), active lung cancer (aHR 3.26 [3.06-3.47]), chronic dialysis (aHR 3.79 [3.49-4.11]), psychological and neurodegenerative diseases (more markedly than during the periods of circulation of the alpha and delta variants), and organ transplantation. The use of immunosuppressants was also associated with an increased risk (aHR 2.24 [2.14-2.35], including oral corticosteroids aHR (2.58 [2.50-2.67]). CONCLUSION: Despite an effective booster and a generally less virulent circulating variant, a residual risk of severe COVID-19 still exists in vulnerable populations, especially those with neurological disorders.

Association Between Doses of Levonorgestrel Intrauterine Systems and Subsequent Use of Psychotropic Drugs in France.

This matched-cohort study uses data from the French National Health Insurance database to assess whether a 19.5-mg levonorgestrel intrauterine system, vs a 52-mg system, is associated with increased use of antidepressant, hypnotic, and anxiolytic medications.

Association of Statins for Primary Prevention of Cardiovascular Diseases With Hospitalization for COVID-19: A Nationwide Matched Population-Based Cohort Study.

Background There is little evidence on the relationship between statin use and the risk of hospitalization attributable to COVID-19. Methods and Results The French National Healthcare Data System database was used to conduct a matched-cohort study. For each adult aged ≥40 years receiving statins for the primary prevention of cardiovascular diseases, one nonuser was randomly selected and matched for year of birth, sex, residence area, and comorbidities. The association between statin use and hospitalization for COVID-19 was examined using conditional Cox proportional hazards models, adjusted for baseline characteristics, comorbidities, and long-term medications. Its association with in-hospital death from COVID-19 was also explored. All participants were followed up from February 15, 2020, to June 15, 2020. The matching procedure generated 2 058 249 adults in the statin group and 2 058 249 in the control group, composed of 46.6% of men with a mean age of 68.7 years. Statin users had a 16% lower risk of hospitalization for COVID-19 than nonusers (adjusted hazard ratio [HR], 0.84; 95% CI, 0.81-0.88). All types of statins were significantly associated with a lower risk of hospitalization, with the adjusted HR ranging from 0.75 for fluvastatin to 0.89 for atorvastatin. Low- and moderate-intensity statins also showed a lower risk compared with nonusers (HR, 0.78 [95% CI, 0.71-0.86] and HR, 0.84 [95% CI, 0.80-0.89], respectively), whereas high-intensity statins did not (HR, 1.01; 95% CI, 0.86-1.18). We found similar results with in-hospital death from COVID-19. Conclusions Our findings support that the use of statins for primary prevention is associated with lower risks of hospitalization for COVID-19 and of in-hospital death from COVID-19.

Effectiveness of BNT162b2, mRNA-1273, and ChAdOx1-S vaccines against severe covid-19 outcomes in a nationwide mass vaccination setting: cohort study.

Objective: To estimate the effectiveness of the three covid-19 vaccines by Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), and Oxford-AstraZeneca (ChAdOx1-S) in people after receiving two doses. Design: Cohort study. Setting: Nationwide, population based data in France, from the French National Health Data System (Système National des Données de Santé), between 27 December 2020 and 30 April 2021. Participants: Adults aged ≥50 years receiving a first dose of BNT162b2, mRNA-1273, or ChAdOx1-S were randomly selected (1:1) and matched on the date of vaccination with one unvaccinated control. Individuals were matched on year of birth, sex, region of residence, and residence in a nursing home (for individuals aged ≥75 years). All individuals were followed up until 20 August 2021. Main outcome measures: Primary outcome measure was vaccine effectiveness estimated at least 14 days after the second dose against covid-19 related hospital admission using Cox proportional hazards models adjusted for baseline characteristics and comorbidities. Vaccine effectiveness against covid-19 related death in hospital was also investigated. Results: 11 256 832 vaccinated individuals were included in the study (63.6% (n=7 161 658) with the BNT162b2 vaccine, 7.6% (n=856 599) with the mRNA-1273 vaccine, and 28.8% (n=3 238 575) with the ChAdOx1-S vaccine), along with 11 256 832 matched unvaccinated controls. During follow-up (up to 20 August 2021), 43 158 covid-19 related hospital admissions and 7957 covid-19 related deaths in hospital were registered. Compared with unvaccinated controls, vaccine effectiveness of two doses against covid-19 related hospital admission was 91% (95% confidence interval 91% to 92%), 95% (93% to 96%), and 91% (89% to 94%) for the BNT162b2, mRNA-1273, and ChAdOx1-S vaccines, respectively. Similar results were observed for vaccine effectiveness of two doses against covid-19 related deaths in hospital (BNT162b2, 91% (90% to 93%); mRNA-1273, 96% (92% to 98%); and ChAdOx1 nCoV-19, 88% (68% to 95%)). At 5-6 months after receiving the second dose of vaccine, effectiveness remained high at 94% (92% to 95%) for the BNT162b2 vaccine and 98% (93% to 100%) for the mRNA-1273 vaccine. Vaccine effectiveness of ChAdOx1-S estimated at 3-4 months was 90% (63% to 97%). All three vaccines remained effective at the time of circulation of the delta variant of SARS-CoV-2 between 1 July and 20 August 2021 (effectiveness between 89% and 95%). Conclusions: These findings provide evidence indicating that two doses of ChAdOx1-S is as effective as two doses of mRNA vaccines in France against the alpha and delta variants of SARS-CoV-2. The effectiveness of ChAdOx1-S should be further examined with a longer follow-up and in the light of the circulation of new SARS-CoV-2 variants of concern.

Healthy behaviors at age 50 years and frailty at older ages in a 20-year follow-up of the UK Whitehall II cohort: A longitudinal study.

BACKGROUND: Frailty is associated with increased risk of various health conditions, disability, and death. Health behaviors are thought to be a potential target for frailty prevention, but the evidence from previous studies is based on older populations with short follow-ups, making results susceptible to reverse causation bias. We examined the associations of healthy behaviors at age 50, singly and in combination, as well as 10-year change in the number of healthy behaviors over midlife with future risk of frailty. METHODS AND FINDINGS: In this prospective cohort study of 6,357 (29.2% women; 91.7% white) participants from the British Whitehall II cohort, healthy behaviors-nonsmoking, moderate alcohol consumption, ≥2.5 hours per week of moderate to vigorous physical activity, and consumption of fruits or vegetables at least twice a day-were measured at age 50, and change in behaviors was measured between 1985 (mean age = 44.4) and 1997 (mean age = 54.8). Fried's frailty phenotype was assessed in clinical examinations in 2002, 2007, 2012, and 2015. Participants were classified as frail if they had ≥3 of the following criteria: slow walking speed, low grip strength, weight loss, exhaustion, and low physical activity. An illness-death model accounting for both competing risk of death and interval censoring was used to examine the association between healthy behaviors and risk of frailty. Over an average follow-up of 20.4 years (standard deviation, 5.9), 445 participants developed frailty. Each healthy behavior at age 50 was associated with lower risk of incident frailty: hazard ratio (HR) after adjustment for other health behaviors and baseline characteristics 0.56 (95% confidence interval [CI] 0.44-0.71; p < 0.001) in nonsmokers, 0.73 (95% CI 0.61-0.88; p < 0.001) for moderate alcohol consumption, 0.66 (95% CI 0.54-0.81; p < 0.001) for ≥2.5 hours of physical activity per week, and 0.76 (95% CI 0.59-0.98; p = 0.03) for consumption of fruits or vegetables at least twice a day. A greater number of healthy behaviors was associated with reduced risk of frailty, with the HR for each additional healthy behavior being 0.69 (95% CI 0.62-0.76; p < 0.001) and the HR for having all versus no healthy behaviors at age 50 being 0.28 (95% CI 0.15-0.52; p < 0.001). Among participants with no or 1 healthy behavior in 1985, those who increased the number of healthy behaviors by 1997 were at a lower risk of frailty (mean follow-up = 16 years) compared with those with no such increase: the HR was 0.64 (95% CI 0.44-0.94; p = 0.02) for change to 2 healthy behaviors and 0.57 (95% CI 0.38-0.87; p < 0.001) for change to 3-4 healthy behaviors in 1997. The primary limitation of this study is potential selection bias during the follow-up due to missing data on frailty components. CONCLUSIONS: Our findings suggest that healthy behaviors at age 50, as well as improvements in behaviors over midlife, are associated with a lower risk of frailty later in life. Their benefit accumulates so that risk of frailty decreases with greater number of healthy behaviors. These results suggest that healthy behaviors in midlife are a good target for frailty prevention.

Social inequalities in multimorbidity, frailty, disability, and transitions to mortality: a 24-year follow-up of the Whitehall II cohort study.

BACKGROUND: Social inequalities in mortality persist in high-income countries with universal health care, and the mechanisms by which these inequalities are generated remain unclear. We aimed to examine whether social inequalities were present before or after the onset of adverse health conditions (multimorbidity, frailty, and disability). METHODS: Our analysis was based on data from the ongoing Whitehall II cohort study, which enrolled British civil servants aged 35-55 years in 1985-88. Participants were assessed for three indicators of socioeconomic status (education, occupational position, and literacy) at age 50 years. Participants underwent clinical examinations (in 2002-04, 2007-09, 2012-13, and 2015-16) for assessment of frailty (two or more of low physical activity, slow walking speed, poor grip strength, weight loss, and exhaustion) and disability (two or more difficulties in bathing, dressing, going to the toilet, transferring, feeding, and walking). In addition, electronic health records were used to assess the incidence of multimorbidity (two or more of diabetes, coronary heart disease, stroke, chronic obstructive pulmonary disease, depression, arthritis, cancer, dementia, and Parkinson's disease) and mortality. In analyses adjusted for sociodemographic factors, we used multistate models to examine social inequalities in transitions from healthy state to adverse health conditions and subsequently to mortality. FINDINGS: Of 10 308 individuals in the Whitehall II study cohort, 6425 had relevant data available at 50 years and to the end of follow-up on Aug 31, 2017, and were included in our analysis. Participants were followed up for a median of 23·6 years (IQR 19·6-28·9). 1694 (26·4%) of 6425 participants developed multimorbidity, 1733 (27·0%) became frail, 692 (10·8%) had a disability, and 611 (9·5%) died. Multimorbidity (hazard ratio [HR] 4·12 [95% CI 3·41-4·98]), frailty (HR 2·38 [95% CI 1·93-2·93]), and disability (HR 1·73 [95% CI 1·34-2·22]) were associated with increased risk of mortality; these associations were not modified by socioeconomic status. In multistate models, occupation was the socioeconomic status indicator that was most strongly associated with inequalities in the transition from healthy state to multimorbidity (HR 1·54 [95% CI 1·37-1·73]), to frailty (HR 2·08 [95% CI 1·85-2·33]), and to disability (HR 1·44 [95% CI 1·18-1·74]). Socioeconomic status indicators did not affect transitions to mortality in those with multimorbidity, frailty, or disability. INTERPRETATION: Socioeconomic status affects the risk of multimorbidity, frailty, and disability, but does not affect the risk of mortality after the onset of these adverse health conditions. Therefore, primary prevention is key to reducing social inequalities in mortality. Of the three adverse health conditions, multimorbidity had the strongest association with mortality, making it a central target for improving population health. FUNDING: UK Medical Research Council; National Institute on Aging, National Institutes of Health; British Heart Foundation.

Association of Hysteroscopic vs Laparoscopic Sterilization With Procedural, Gynecological, and Medical Outcomes.

Importance: Safety of hysteroscopic sterilization has been recently questioned following reports of general symptoms such as allergy, tiredness, and depression in addition to associated gynecological results such as pelvic pain, perforation of fallopian tubes or uterus, and unwanted pregnancy. Objective: To compare the risk of reported adverse events between hysteroscopic and laparoscopic sterilization. Design, Setting, and Participants: French nationwide cohort study using the national hospital discharge database linked to the health insurance claims database. Women aged 30 to 54 years receiving a first hysteroscopic or laparoscopic sterilization between 2010 and 2014 were included and were followed up through December 2015. Exposures: Hysteroscopic sterilization vs laparoscopic sterilization. Main Outcomes and Measures: Risks of procedural complications (surgical and medical) and of gynecological (sterilization failure that includes salpingectomy, second sterilization procedure, or pregnancy; pregnancy; reoperation) and medical outcomes (all types of allergy; autoimmune diseases; thyroid disorder; use of analgesics, antimigraines, antidepressants, benzodiazepines; outpatient visits; sickness absence; suicide attempts; death) that occurred within 1 and 3 years after sterilization were compared using inverse probability of treatment-weighted Cox models. Results: Of the 105 357 women included (95.5% of eligible participants; mean age, 41.3 years [SD, 3.7 years]), 71 303 (67.7% ) underwent hysteroscopic sterilization, and 34 054 (32.3%) underwent laparoscopic sterilization. During the hospitalization for sterilization, risk of surgical complications for hysteroscopic sterilization was lower: 0.13% for hysteroscopic sterilization vs 0.78% for laparoscopic sterilization (adjusted risk difference [RD], -0.64; 95% CI, -0.67 to -0.60) and was lower for medical complications: 0.06% vs 0.11% (adjusted RD, -0.05; 95% CI, -0.08 to -0.01). During the first year after sterilization, 4.83% of women who underwent hysteroscopic sterilization had a higher risk of sterilization failure than the 0.69% who underwent laparoscopic sterilization (adjusted hazard ratio [HR], 7.11; 95% CI, 5.92 to 8.54; adjusted RD, 4.23 per 100 person-years; 95% CI, 3.40 to 5.22). Additionally, 5.65% of women who underwent hysteroscopic sterilization required gynecological reoperation vs 1.76% of women who underwent laparoscopic sterilization (adjusted HR, 3.26; 95% CI, 2.90 to 3.67; adjusted RD, 4.63 per 100 person-years; 95% CI, 3.38 to 4.75); these differences persisted after 3 years, although attenuated. Hysteroscopic sterilization was associated with a lower risk of pregnancy within the first year of the procedure but was not significantly associated with a difference in risk of pregnancy by the third year (adjusted HR, 1.04; 95% CI, 0.83-1.30; adjusted RD, 0.01 per 100 person-years; 95% CI, -0.04 to 0.07). Risks of medical outcomes were not significantly increased with hysteroscopic sterilization compared with laparoscopic sterilization. Conclusions and Relevance: Among women undergoing first sterilization, the use of hysteroscopic sterilization was significantly associated with higher risk of gynecological complications over 1 year and over 3 years than was laparoscopic sterilization. Risk of medical outcomes was not significantly increased over 1 year or over 3 years. These findings do not support increased medical risks associated with hysteroscopic sterilization.

Short-Term Risk of Bleeding During Heparin Bridging at Initiation of Vitamin K Antagonist Therapy in More Than 90 000 Patients With Nonvalvular Atrial Fibrillation Managed in Outpatient Care.

BACKGROUND: Several studies have recently examined the risks of bleeding and of ischemic stroke and systemic embolism associated with perioperative heparin bridging anticoagulation in patients with nonvalvular atrial fibrillation. However, few studies have investigated bridging risks during vitamin K antagonist initiation in outpatient settings. METHODS AND RESULTS: A retrospective cohort study was conducted on individuals starting oral anticoagulation between January 2010 and November 2014 for nonvalvular atrial fibrillation managed in outpatient care and identified from French healthcare insurance. Bleeding and ischemic stroke and systemic embolism events were identified from the hospitalization database. Adjusted hazard ratios with 95% CI were estimated using Cox models during the first and 2 following months of anticoagulation. Of 90 826 individuals, 30% had bridging therapy. A total of 318 (0.35%) cases of bleeding and 151 (0.17%) ischemic stroke and systemic embolism cases were identified during the first month of follow-up and 231 (0.31%) and 122 (0.16%) during the 2 following months, respectively. At 1 month of follow-up, the incidence of bleeding was higher in the bridged group compared with the nonbridged group (0.47% versus 0.30%; P<0.001), and this increased risk persisted after adjustment for covariates (hazard ratio=1.60; 95% CI, 1.28-2.01). This difference disappeared after the first month of treatment (0.93; 0.70-1.23). No significant difference in the occurrence of ischemic stroke and systemic embolism was observed either at 1 month of follow-up or later. CONCLUSIONS: At vitamin K antagonist initiation for nonvalvular atrial fibrillation managed in ambulatory settings, bridging therapy is associated with a higher risk of bleeding and a similar risk of arterial thromboembolism compared with no bridging therapy.

Risk of bleeding and arterial thromboembolism in patients with non-valvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retrospective, matched-cohort study.

BACKGROUND: Patients with non-valvular atrial fibrillation who are receiving or have been previously exposed to a vitamin K antagonist could be switched to a non-vitamin K-antagonist oral anticoagulant (NOAC) but little information is available about the risk of bleeding and arterial thromboembolism after such a switch. We aimed to compare the risk of bleeding between individuals who switched and those who remained on a vitamin K antagonist (non-switchers) in real-world conditions. METHODS: We did a matched-cohort study with information from French health-care databases. We extracted data for adults (aged ≥18 years) with non-valvular atrial fibrillation who received their first prescription for a vitamin K antagonist (fluindione, warfarin, or acenocoumarol) between Jan 1, 2011, and Nov 30, 2012, and who were either switched to a NOAC (dabigatran or rivaroxaban) or maintained on the vitamin K antagonist. Each switcher was matched with up to two non-switchers on the basis of eight variables, including sex, age, and international normalised ratio number. The primary endpoint was incidence of bleeding (intracranial haemorrhage, gastrointestinal haemorrhage, or other) in switchers versus non-switchers, and switchers stratified by type of NOAC versus non-switchers, noted from databases of hospital admissions. Each patient was followed up to 1 year; the study closed on Oct 1, 2013. FINDINGS: Of 17,410 participants, 6705 switched to a NOAC (switchers) and 10,705 remained on vitamin K-antagonist therapy (non-switchers). Median age of participants was 75 years (IQR 67-82), 8339 (48%) were women, and the median duration of vitamin K-antagonist exposure before a switch was 8.1 months (IQR 3.9-14.0). After a median follow-up of 10.0 months (IQR 9.8-10.0), we noted no difference between groups for bleeding events (99 [1%] in switchers vs 193 [2%] in non-switchers, p=0.54). In adjusted multivariate analyses, the risk of bleeding in switchers was not different from that in non-switchers (hazard ratio [HR] 0.87; 95% CI 0.67-1.13, p=0.30). Additionally, no differences were noted when the risk of bleeding was compared between switchers from a vitamin K antagonist to dabigatran (HR 0.78, 95% CI 0.54-1.09, p=0.15), switchers from a vitamin K antagonist to rivaroxaban (HR 1.04, 95% CI 0.68-1.58, p=0.86), and non-switchers. INTERPRETATION: In this matched-cohort study, our findings suggest that patients with non-valvular atrial fibrillation who switch their oral anticoagulant treatment from a vitamin K antagonist to a non-vitamin K antagonist are not at increased risk of bleeding. Future studies with longer follow-up might be needed. FUNDING: None.

Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study.

BACKGROUND: The safety and effectiveness of non-vitamin K antagonist (VKA) oral anticoagulants, dabigatran or rivaroxaban, were compared with VKA in anticoagulant-naive patients with nonvalvular atrial fibrillation during the early phase of anticoagulant therapy. METHODS AND RESULTS: With the use of the French medico-administrative databases (SNIIRAM and PMSI), this nationwide cohort study included patients with nonvalvular atrial fibrillation who initiated dabigatran or rivaroxaban between July and November 2012 or VKA between July and November 2011. Patients presenting a contraindication to oral anticoagulants were excluded. Dabigatran and rivaroxaban new users were matched to VKA new users by the use of 1:2 matching on the propensity score. Patients were followed for up to 90 days until outcome, death, loss to follow-up, or December 31 of the inclusion year. Hazard ratios of hospitalizations for bleeding and arterial thromboembolic events were estimated in an intent-to-treat analysis using Cox regression models. The population was composed of 19 713 VKA, 8443 dabigatran, and 4651 rivaroxaban new users. All dabigatran- and rivaroxaban-treated patients were matched to 16 014 and 9301 VKA-treated patients, respectively. Among dabigatran-, rivaroxaban-, and their VKA-matched-treated patients, 55 and 122 and 31 and 68 bleeding events and 33 and 58 and 12 and 28 arterial thromboembolic events were observed during follow-up, respectively. After matching, no statistically significant difference in bleeding (hazard ratio, 0.88; 95% confidence interval, 0.64-1.21) or thromboembolic (hazard ratio, 1.10; 95% confidence interval, 0.72-1.69) risk was observed between dabigatran and VKA new users. Bleeding (hazard ratio, 0.98; 95% confidence interval, 0.64-1.51) and ischemic (hazard ratio, 0.93; 95% confidence interval, 0.47-1.85) risks were comparable between rivaroxaban and VKA new users. CONCLUSIONS: In this propensity-matched cohort study, our findings suggest that physicians should exercise caution when initiating either non-VKA oral anticoagulants or VKA in patients with nonvalvular atrial fibrillation.

Association of body mass index and waist circumference with successful aging.

OBJECTIVE: The prediction of successful aging by midlife body mass index (BMI) and waist circumference (WC) was examined. METHODS: BMI/WC were assessed in 4869 persons (mean age 51.2, range 42-63 in 1991/1993) and survival and successful aging (alive, no chronic disease at age >60 years, not in the worst age- and sex-standardized quintile of cognitive, physical, respiratory,cardiovascular, and mental health) ascertained over a 16-year follow-up, analyzed using logistic regression adjusted for sociodemographic factors and health behaviors. RESULTS: 507 participants died, 1008 met the criteria for successful aging. Those with BMI ≥ 30 kg/m(2) had lower odds of successful aging (odds ratio or OR) = 0.37; 95% confidence interval or CI: 0.27, 0.50) and survival (OR = 0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5 and 25 kg/m(2) . Those with a large WC (≥102/88 cm in men/women) had lower odds of successful aging (OR = 0.41; 95% CI: 0.31, 0.54) and survival (OR = 0.57; 95% CI: 0.44, 0.73) compared with those with a small waist (<94/80 cm in men/women). Analysis with finer categories showed lower odds of successful aging starting at BMI ≥ 23.5 kg/m(2) and WC 82/68 cm in men/women. CONCLUSIONS: Optimal midlife BMI and WC for successful aging might be substantially below the current thresholds used to define obesity.

Metabolic syndrome and disability: findings from the prospective three-city study.

BACKGROUND: Metabolic syndrome (MetS) is a potentially reversible cause of disability in the elderly people. The published literature suggests that the MetS-disability association is likely to be complex, depending on co-existing risk factors and with possible variation for each of the specific MetS components. Further evidence is needed to understand the specific consequences of the MetS as a whole and as a function of its components. METHODS: Prospective analyses included data from 6,141 participants (60.9% women) aged 65 and older from the Three-City cohort. Mixed logistic models were used to determine associations between MetS (National Cholesterol Education Program Adult Treatment Panel III criteria) and 7-year incident disability measured as social restriction, mobility limitations (Rosow and Breslau scale), and limitations in instrumental and basic activities of daily living. RESULTS: MetS was associated with incident social restriction (odds ratio = 1.55, 95% CI: 1.14-2.09), limited mobility (odds ratio = 1.52, 95% CI: 1.21-1.90), and instrumental activities of daily living limitations (odds ratio = 1.62, 95% CI: 1.24-2.10) after adjustment for a range of potential sociodemographic, health behavior, and health status confounders at baseline. These associations were independent of chronic conditions, including cardiovascular disease and dementia. There was evidence of associations between MetS components: central obesity, high triglycerides, and elevated fasting glucose and incidence of limitations in mobility and instrumental activities of daily living. CONCLUSIONS: Our results suggest that the increased risk of mobility and instrumental activities of daily living limitations in the elderly people associated with MetS is over and above that associated with its components.

Diabetes risk factors, diabetes risk algorithms, and the prediction of future frailty: the Whitehall II prospective cohort study.

OBJECTIVE: To examine whether established diabetes risk factors and diabetes risk algorithms are associated with future frailty. DESIGN: Prospective cohort study. Risk algorithms at baseline (1997-1999) were the Framingham Offspring, Cambridge, and Finnish diabetes risk scores. SETTING: Civil service departments in London, United Kingdom. PARTICIPANTS: There were 2707 participants (72% men) aged 45 to 69 years at baseline assessment and free of diabetes. MEASUREMENTS: Risk factors (age, sex, family history of diabetes, body mass index, waist circumference, systolic and diastolic blood pressure, antihypertensive and corticosteroid treatments, history of high blood glucose, smoking status, physical activity, consumption of fruits and vegetables, fasting glucose, HDL-cholesterol, and triglycerides) were used to construct the risk algorithms. Frailty, assessed during a resurvey in 2007-2009, was denoted by the presence of 3 or more of the following indicators: self-reported exhaustion, low physical activity, slow walking speed, low grip strength, and weight loss; "prefrailty" was defined as having 2 or fewer of these indicators. RESULTS: After a mean follow-up of 10.5 years, 2.8% of the sample was classified as frail and 37.5% as prefrail. Increased age, being female, stopping smoking, low physical activity, and not having a daily consumption of fruits and vegetables were each associated with frailty or prefrailty. The Cambridge and Finnish diabetes risk scores were associated with frailty/prefrailty with odds ratios per 1 SD increase (disadvantage) in score of 1.18 (95% confidence interval: 1.09-1.27) and 1.27 (1.17-1.37), respectively. CONCLUSION: Selected diabetes risk factors and risk scores are associated with subsequent frailty. Risk scores may have utility for frailty prediction in clinical practice.

Measures of frailty in population-based studies: an overview.

BACKGROUND: Although research productivity in the field of frailty has risen exponentially in recent years, there remains a lack of consensus regarding the measurement of this syndrome. This overview offers three services: first, we provide a comprehensive catalogue of current frailty measures; second, we evaluate their reliability and validity; third, we report on their popularity of use. METHODS: In order to identify relevant publications, we searched MEDLINE (from its inception in 1948 to May 2011); scrutinized the reference sections of the retrieved articles; and consulted our own files. An indicator of the frequency of use of each frailty instrument was based on the number of times it had been utilized by investigators other than the originators. RESULTS: Of the initially retrieved 2,166 papers, 27 original articles described separate frailty scales. The number (range: 1 to 38) and type of items (range of domains: physical functioning, disability, disease, sensory impairment, cognition, nutrition, mood, and social support) included in the frailty instruments varied widely. Reliability and validity had been examined in only 26% (7/27) of the instruments. The predictive validity of these scales for mortality varied: for instance, hazard ratios/odds ratios (95% confidence interval) for mortality risk for frail relative to non-frail people ranged from 1.21 (0.78; 1.87) to 6.03 (3.00; 12.08) for the Phenotype of Frailty and 1.57 (1.41; 1.74) to 10.53 (7.06; 15.70) for the Frailty Index. Among the 150 papers which we found to have used at least one of the 27 frailty instruments, 69% (n = 104) reported on the Phenotype of Frailty, 12% (n = 18) on the Frailty Index, and 19% (n = 28) on one of the remaining 25 instruments. CONCLUSIONS: Although there are numerous frailty scales currently in use, reliability and validity have rarely been examined. The most evaluated and frequently used measure is the Phenotype of Frailty.

Cardiovascular disease risk scores in identifying future frailty: the Whitehall II prospective cohort study.

OBJECTIVES: To examine the capacity of existing cardiovascular disease (CVD) risk algorithms widely used in primary care, to predict frailty. DESIGN: Prospective cohort study. Risk algorithms at baseline (1997-1999) were the Framingham CVD, coronary heart disease and stroke risk scores, and the Systematic Coronary Risk Evaluation. SETTING: Civil Service departments in London, UK. PARTICIPANTS: 3895 participants (73% men) aged 45-69 years and free of CVD at baseline. MAIN OUTCOME MEASURE: Status of frailty at the end of follow-up (2007-2009), based on the following indicators: self-reported exhaustion, low physical activity, slow walking speed, low grip strength and weight loss. RESULTS: At the end of the follow-up, 2.8% (n=108) of the sample was classified as frail. All four CVD risk scores were associated with future risk of developing frailty, with ORs per one SD increment in the score ranging from 1.35 (95% CI 1.21 to 1.51) for the Framingham stroke score to 1.42 (1.23 to 1.62) for the Framingham CVD score. These associations remained after excluding incident CVD cases. For comparison, the corresponding ORs for the risk scores and incident cardiovascular events varied between 1.36 (1.15 to 1.61) and 1.64 (1.50 to 1.80) depending on the risk algorithm. CONCLUSIONS: The use of CVD risk scores in clinical practice may also have utility for frailty prediction.

Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116,000 European men and women.

OBJECTIVE: To investigate whether work related stress, measured and defined as job strain, is associated with the overall risk of cancer and the risk of colorectal, lung, breast, or prostate cancers. DESIGN: Meta-analysis of pooled prospective individual participant data from 12 European cohort studies including 116,056 men and women aged 17-70 who were free from cancer at study baseline and were followed-up for a median of 12 years. Work stress was measured and defined as job strain, which was self reported at baseline. Incident cancers (all n=5765, colorectal cancer n=522, lung cancer n=374, breast cancer n=1010, prostate cancer n=865) were ascertained from cancer, hospital admission, and death registers. Data were analysed in each study with Cox regression and the study specific estimates pooled in meta-analyses. Models were adjusted for age, sex, socioeconomic position, body mass index (BMI), smoking, and alcohol intake RESULTS: A harmonised measure of work stress, high job strain, was not associated with overall risk of cancer (hazard ratio 0.97, 95% confidence interval 0.90 to 1.04) in the multivariable adjusted analyses. Similarly, no association was observed between job strain and the risk of colorectal (1.16, 0.90 to 1.48), lung (1.17, 0.88 to 1.54), breast (0.97, 0.82 to 1.14), or prostate (0.86, 0.68 to 1.09) cancers. There was no clear evidence for an association between the categories of job strain and the risk of cancer. CONCLUSIONS: These findings suggest that work related stress, measured and defined as job strain, at baseline is unlikely to be an important risk factor for colorectal, lung, breast, or prostate cancers.

Validating a widely used measure of frailty: are all sub-components necessary? Evidence from the Whitehall II cohort study.

There is growing interest in the measurement of frailty in older age. The most widely used measure (Fried) characterizes this syndrome using five components: exhaustion, physical activity, walking speed, grip strength, and weight loss. These components overlap, raising the possibility of using fewer, and therefore making the device more time- and cost-efficient. The analytic sample was 5,169 individuals (1,419 women) from the British Whitehall II cohort study, aged 55 to 79 years in 2007-2009. Hospitalization data were accessed through English national records (mean follow-up 15.2 months). Age- and sex-adjusted Cox models showed that all components were significantly associated with hospitalization, the hazard ratios (HR) ranging from 1.18 (95 % confidence interval = 0.98, 1.41) for grip strength to 1.60 (1.35, 1.90) for usual walking speed. Some attenuation of these effects was apparent following mutual adjustment for frailty components, but the rank order of the strength of association remained unchanged. We observed a dose-response relationship between the number of frailty components and the risk for hospitalization [1 component-HR = 1.10 (0.96, 1.26); 2-HR = 1.52 (1.26, 1.83); 3-5-HR = 2.41 (1.84, 3.16), P trend <0.0001]. A concordance index used to evaluate the predictive power for hospital admissions of individual components and the full scale was modest in magnitude (range 0.57 to 0.58). Our results support the validity of the multi-component frailty measure, but the predictive performance of the measure is poor.

Decline in low-density lipoprotein cholesterol concentration: lipid-lowering drugs, diet, or physical activity? Evidence from the Whitehall II study.

OBJECTIVE: To examine the association of lipid-lowering drugs, change in diet and physical activity with a decline in low-density lipoprotein (LDL) cholesterol in middle age. DESIGN: A prospective cohort study. SETTING: The Whitehall II study. PARTICIPANTS: 4469 British civil servants (72% men) aged 39-62 years at baseline. MAIN OUTCOME MEASURE: Change in LDL-cholesterol concentrations between the baseline (1991-3) and follow-up (2003-4). RESULTS: Mean LDL-cholesterol decreased from 4.38 to 3.52 mmol/l over a mean follow-up of 11.3 years. In a mutually adjusted model, a decline in LDL-cholesterol was greater among those who were taking lipid-lowering treatment at baseline (-1.14 mmol/l, n=34), or started treatment during the follow-up (-1.77 mmol/l, n=481) compared with untreated individuals (n=3954; p<0.001); among those who improved their diet--especially the ratio of white to red meat consumption and the ratio of polyunsaturated to saturated fatty acids intake--(-0.07 mmol/l, n=717) compared with those with no change in diet (n=3071; p=0.03) and among those who increased physical activity (-0.10 mmol/l, n=601) compared with those with no change in physical activity (n=3312; p=0.005). Based on these estimates, successful implementation of lipid-lowering drug treatment for high-risk participants (n=858) and favourable changes in diet (n=3457) and physical activity (n=2190) among those with non-optimal lifestyles would reduce LDL-cholesterol by 0.90 to 1.07 mmol/l in the total cohort. CONCLUSIONS: Both lipid-lowering pharmacotherapy and favourable changes in lifestyle independently reduced LDL-cholesterol levels in a cohort of middle-aged men and women, supporting the use of multifaceted intervention strategies for prevention.

Long-term cardiovascular mortality after radiotherapy for breast cancer.

OBJECTIVES: This study sought to investigate long-term cardiovascular mortality and its relationship to the use of radiotherapy for breast cancer. BACKGROUND: Cardiovascular diseases are among the main long-term complications of radiotherapy, but knowledge is limited regarding long-term risks because published studies have, on average, <20 years of follow-up. METHODS: A total of 4,456 women who survived at least 5 years after treatment of a breast cancer at the Institut Gustave Roussy between 1954 and 1984 were followed up for mortality until the end of 2003, for over 28 years on average. RESULTS: A total of 421 deaths due to cardiovascular diseases were observed, of which 236 were due to cardiac disease. Women who had received radiotherapy had a 1.76-fold (95% confidence interval [CI]: 1.34 to 2.31) higher risk of dying of cardiac disease and a 1.33-fold (95% CI: 0.99 to 1.80) higher risk of dying of vascular disease than those who had not received radiotherapy. Among women who had received radiotherapy, those who had been treated for a left-sided breast cancer had a 1.56-fold (95% CI: 1.27 to 1.90) higher risk of dying of cardiac disease than those treated for a right-sided breast cancer. This relative risk increased with time since the breast cancer diagnosis (p = 0.05). CONCLUSIONS: This study confirmed that radiotherapy, as delivered until the mid-1980s, increased the long-term risk of dying of cardiovascular diseases. The long-term risk of dying of cardiac disease is a particular concern for women treated for a left-sided breast cancer with contemporary tangential breast or chest wall radiotherapy. This risk may increase with a longer follow-up, even after 20 years following radiotherapy.

Role of dynamic magnetic resonance imaging in the evaluation of tumor response to preoperative concurrent radiochemotherapy for large breast cancers: a prospective phase II study.

PURPOSE: To evaluate the accuracy of clinical examination and of three imaging modalities (ultrasound [US] scan, mammography, and magnetic resonance imaging [MRI]) to assess the tumor response of breast cancer to a preoperative regimen of concurrent radiochemotherapy for large breast cancers, using pathologic data as the reference. METHODS AND MATERIALS: Sixty women were accrued. Treatment consisted of 4 cycles of (5-fluorouracil-vinorelbine) chemotherapy with, starting with the second cycle of chemotherapy, locoregional radiotherapy to the breast and the internal mammary and supraclavicular and infraclavicular lymph nodes. Breast surgery and axillary lymph node dissection were subsequently performed. Breast imaging assessments were performed both before chemotherapy and preoperatively. RESULTS: The correlation coefficients between tumor dimension at imaging and pathology were statistically significant for US scan (r = 0.4; p = 0.006) and MRI (r = 0.4; p = 0.004) but not for clinical examination (r = 0.2; p = 0.16) or mammography (r = -0.15; p = 0.31). Furthermore, the area under the receiver operating characteristic curve for MRI was 0.81, compared with 0.67 for US scan. At the optimal threshold score, MRI performed with 81% sensitivity and 75% specificity. CONCLUSION: Compared with clinical examination, US scan, or mammography, MRI substantially improved the prediction of pathologic tumor response to preoperative concurrent radiochemotherapy for large breast cancers.