The CODATwins Project: The Current Status and Recent Findings of COllaborative Project of Development of Anthropometrical Measures in Twins.

The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

Long-term effects of functional impairment on fracture risk and mortality in postmenopausal women.

Our findings imply that simple functional tests can predict both hip fracture risk and excess mortality in postmenopausal women. Since the tests characterize general functional capacity (one-legged stance, squatting down, and grip strength), these simple measures should have clinical utility in the assessment of women at risk of falls and fragility fracture. INTRODUCTION: Functional impairment is associated with the risk of fall, which is the leading cause of hip fracture. We aimed to determine how clinical assessments of functional impairment predict long-term hip fracture and mortality. METHODS: A population-based prospective cohort involved 2815 Caucasian women with the average baseline age of 59.1 years. The mean follow-up time in 1994-2014 was 18.3 years. Three functional tests and their combinations assessed at baseline were treated as dichotomous risk factors: (1) inability to squat down and touch the floor (SQ), (2) inability to stand on one leg for 10 s (SOL), and (3) having grip strength (GS) within the lowest quartile (≤ 58 kPa, mean 45.6 kPa). Bone mineral density (BMD) at the proximal femur was measured by DXA. Fractures and deaths were verified from registries. Hazard ratios were determined by using Cox proportional models. Age, body mass index (BMI), and BMD were included as covariates for fracture risk estimates. Age, BMI, and smoking were used for mortality. RESULTS: Altogether, 650 (23.1%) women had 718 follow-up fractures, including 86 hip fractures. The mortality during the follow-up was 16.8% (n = 473). Half of the women (56.8%, n = 1600) had none of the impairments and were regarded as the referent group. Overall, women with any of the three impairments (43.2%, n = 1215) had higher risks of any fracture, hip fracture, and death, with hazard ratios (HR) of 1.3 ((95% CI) 1.0-1.5, p < 0.01), 2.4 (1.5-3.4, p < 0.001), and 1.5 (1.3-1.8, p < 0.001), respectively. The strongest single predictor for hip fracture was failing to achieve a one-leg stand for 10 s (prevalence 7.1%, n = 200), followed by inability to squat down (27.0%, n = 759) and weak grip strength (24.4%, n = 688), with their respective HRs of 4.3 (2.3-8.0, p < 0.001), 3.1 (2.0-5.0, p < 0.001), and 2.0 (1.2-3.4, p < 0.001). In addition, age, lower BMD, BMI, and smoking were significant covariates. CONCLUSIONS: These findings suggest that functional tests provide long-term prediction of fracture and death in postmenopausal women. Whether reversal of these impairments is associated with a reduction in adverse outcomes is an area for future trials.

The role of metformin and statins in the incidence of epithelial ovarian cancer in type 2 diabetes: a cohort and nested case-control study.

OBJECTIVE: To obtain evidence of the effects of metformin and statins on the incidence of ovarian cancer in women with type 2 diabetes (T2D). DESIGN: A retrospective cohort study and nested case-control study. SETTING: The data were obtained from a diabetes database (FinDM) combining information from several nationwide registers. POPULATION: A cohort of 137 643 women over 40 years old and diagnosed with T2D during 1996-2011 in Finland. METHODS: In full cohort analysis Poisson regression was used to estimate the hazard ratios (HR) in relation to ever use of metformin, insulin other oral anti-diabetic medication or statins. In the nested case-control analysis 20 controls were matched to each case of ovarian cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different medications. The estimates were adjusted for age and duration of T2D. MAIN OUTCOME MEASURE: Incidence of ovarian cancer. RESULTS: In all, 303 women were diagnosed with ovarian cancer during the follow up. Compared with other forms of oral anti-diabetic medication, metformin (HR 1.02, 95% CI: 0.72-1.45) was not found to be associated with the incidence of ovarian cancer. Neither was there evidence for statins to affect the incidence (HR 0.99, 95% CI: 0.78-1.25). In nested case-control analysis the results were essentially similar. CONCLUSIONS: No evidence of an association between the use of metformin or statins and the incidence of ovarian cancer in women with T2D was found. TWEETABLE ABSTRACT: No evidence found for metformin or statins reducing the incidence of ovarian cancer.

Shoulder Capsular Surgery in Finland Between 1999 and 2008: A Nationwide Register Analysis.

BACKGROUND AND AIMS: Shoulder capsular surgery is nowadays usually performed arthroscopically, and the proportion of arthroscopic method has rapidly increased during the last two decades. We assessed the incidence of shoulder capsular surgery procedures in Finland between 1999 and 2008. MATERIAL AND METHODS: We gathered the shoulder capsular surgery procedures for all kinds of shoulder instability in Finland between 1999 and 2008 from National Hospital Discharge Register and limited the patient material to include only certain diagnosis (International Classification of Diseases, 10th Edition) and Nordic Medico-Statistical Committee procedure code combinations. We analyzed the data in the whole country, between different age groups, and in university hospital districts. RESULTS: The total incidence of shoulder capsular surgery procedures in Finland increased from 17 to 33 per 100,000 person-years. The incidence of arthroscopic procedures increased from 11 to 30 per 100,000 person-years and the proportion of arthroscopic procedures increased from 63% to 92% between years 1999 and 2007. The incidence of shoulder capsular surgery procedures increased on average around 90% in almost all age groups and particularly in the older age groups. We observed no significant geographical variation between university hospital districts. CONCLUSION: The incidence of shoulder capsular surgery procedures increased on average round 90% in almost all age groups. It seems to be difficult to support the rapidly increased rates of shoulder capsular surgery procedures or the arthroscopic method based on scientific evidence. While also older patients are treated with shoulder capsular surgery, well-defined indications for surgical intervention are needed so that the operations are conducted for the symptomatic patients benefitting most regardless of patients' age.

Cause-specific mortality in endometrioid endometrial cancer patients with type 2 diabetes using metformin or other types of antidiabetic medication.

AIM: To obtain further evidence of the association between metformin or other types of antidiabetic medication (ADM) and mortality from endometrial cancer (EC) and other causes of death in patients with endometrioid EC and type 2 diabetes (T2D). MATERIALS AND METHODS: A retrospective cohort of women with existing T2D and diagnosed with endometrioid EC from 1998 to 2011, obtained from a nationwide diabetes database (FinDM), were included in the study. Cumulative mortality from EC and that from other causes was described by using the Aalen-Johansen estimator. Cause-specific mortality rates were analyzed by using Cox models, and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of ADM during the three-year period preceding EC diagnosis. RESULTS: From the FinDM cohort we identified 1215 women diagnosed with endometrioid EC, of whom 19% were metformin users, 12% were users of other types of oral antidiabetic medication, 25% used other types of oral antidiabetic medication plus metformin, 26% used insulin and 14% had no antidiabetic medication. Mortality from EC was not found to be different in women using metformin (HR 0.89, 95% Cl 0.52-1.54) but mortality from other causes was lower (HR 0.52, 95% Cl 0.31-0.88) compared with women using other types of oral ADM. CONCLUSIONS: Our findings are inconclusive as to the possible effect of metformin on the prognosis of endometrioid EC in women with T2D. However, use of metformin may reduce mortality from other causes.

Toe Pressure and Toe Brachial Index are Predictive of Cardiovascular Mortality, Overall Mortality, and Amputation Free Survival in Patients with Peripheral Artery Disease.

OBJECTIVE/BACKGROUND: Peripheral haemodynamic parameters are used to assess the presence and severity of peripheral artery disease (PAD). The prognostic value of ankle brachial index (ABI) has been thoroughly delineated. Nonetheless, the relative usefulness of ankle pressure (AP), ABI, toe pressure (TP), and toe brachial index (TBI) in assessing patient outcome has not been investigated in a concurrent study setting. This study aimed to resolve the association of all four non-invasive haemodynamic parameters in clinically symptomatic patients with PAD with cardiovascular mortality, overall mortality, and amputation free survival (AFS). METHODS: In total, 732 symptomatic patients with PAD admitted to the Department of Vascular Surgery for conventional angiography at Turku University Hospital, Turku, Finland, between January 2009 and August 2011 were reviewed retrospectively. Demographic factors, cardiovascular mortality, all-cause mortality, and above foot level amputations were obtained and assessed in relation to AP, ABI, TP, and TBI by means of Kaplan-Meier life tables and a multivariate Cox regression model. RESULTS: The haemodynamic parameter that was associated with poor 36 month general outcome was TP < 30 mmHg. Univariate Cox regression analysis of stratified values showed that TP and TBI associated significantly with mortality. In multivariate analysis both TP and TBI were associated with a significant risk of death. For TP < 30 mmHg and TBI < 0.25 the risk of cardiovascular mortality was hazard ratio [HR] 2.84, 95% confidence interval [CI] 1.75-4.61 [p<.001]; HR 3.68, 95% CI 1.48-9.19 [p=.050], respectively; all-cause mortality (HR 2.05, 95% CI 1.44-2.92 [p<.001]; HR 2.53, 95% CI 1.35-4.74 [p=.040], respectively); and amputation or death (HR 2.13, 95% CI 1.52-2.98 [p<.001]; HR 2.46, 95% CI 1.38-4.40 [p=.050], respectively)... CONCLUSION: Among non-invasive haemodynamic measurements and pressure indices both TP and TBI appear to be associated with cardiovascular and overall mortality and AFS for patients with PAD presenting symptoms of the disease.

Incidence of osteoporotic fractures in elderly women and men in Finland during 2005-2006: a population-based study.

BACKGROUND AND AIMS: Osteoporosis is a major health concern in elderly population. Low-trauma fractures offer one way of identifying these patients for treatment. Population-specific incidences of osteoporotic fractures are essential to validate tools for clinical decision making. MATERIAL AND METHODS: To evaluate population-based osteoporotic fracture incidences in Central Finland, we performed a manual search of low-trauma fractures 2005-2006 from the records of all the local health-care organizations treating trauma patients. We identified low-trauma fracture patients from radiology reports from five health centers serving the inhabitants of nine municipalities and from the patient records of two hospitals in Central Finland. The manually collected data were then compared against data from the Finnish Health Care Register. RESULTS: The crude incidence of all osteoporotic fractures in 2005-2006 in the population aged 50 years was 1254/100,000 person years: 694/100,000 person years in men and 1718/100,000 person years in women. Fracture numbers derived from register data were similar to those manually collected for hip and humerus fractures, but clearly smaller than those for wrist and ankle fractures. CONCLUSIONS: Population-based low-trauma fracture incidences, reported here for Finland, constitute a basis for calibration of fracture risk evaluation tools (e.g. the World Health Organization fracture risk evaluation tool, FRAX). This study showed that register data underestimate the incidences of, in particular, distal radius and ankle fractures.

Indicators for comparing the incidence of diabetic amputations: a nationwide population-based register study.

OBJECTIVE: To test various indicators for comparing the outcomes of diabetic foot care. DESIGN: All 396,317 patients treated with hypoglycaemic medication in Finland were followed up based on nationwide registers on hospital discharges and causes of death during 1997-2007. MATERIALS AND METHODS: The crude and standardized incidences of lower extremity amputations (LEAs), the minor-major ratio of the first LEA and 2-year survival with a preserved leg after the first minor LEA were used as indicators for regional and temporal variation in diabetic foot care. RESULTS: A total of 13,469 LEAs were recorded in 1997-2007. The standardized population-corrected rate of first major LEA per 100,000 person-years declined from 10.0 (95% CI 9.6-10.5) to 7.3 (6.9-7.6) (p < .001), while the minor-major LEA ratio progressed from 0.86 (0.80-0.92) to 1.35 (1.26-1.46) (p < .001). By using these indicators, variation was observed between the university hospital catchment areas. Nationwide, the 2-year survival with a preserved leg after the first minor LEA increased statistically insignificantly from 50.8% (47.3-54.6%) to 55.4% (51.9-59.0%) (p = .08). CONCLUSIONS: The standardized, population-corrected incidence of major LEA, the minor-major LEA ratio, and major-amputation-free survival proved useful as indicators in comparing the outcomes of diabetic foot care.

The role of cardiorenal biomarkers for risk stratification in the early follow-up after hospitalisation for acute heart failure.

CONTEXT: Cardiorenal biomarkers (CBs) predict outcome in acute heart failure (AHF). OBJECTIVE: To evaluate CBs in early follow-up prognostication. METHODS: In 124 AHF patients, levels of CystatinC, NT-proBNP and TroponinI measured five weeks from admission (W5) and relative change from day 2 (D2) were assessed for 6-month prognosis (mortality/HF hospitalization). RESULTS: The combined end-point occurred in 33 patients (27%). D2-, W5-cystatin≥ median, and lack of ≥30%decrease in NT-proBNP were independent predictors of outcome. Additionally, a risk score established from W5 CBs identified patients with very high event rate. CONCLUSIONS: CBs at early follow-up of AHF may guide risk stratification.

Cystatin C, NT-proBNP, and inflammatory markers in acute heart failure: insights into the cardiorenal syndrome.

BACKGROUND: Inflammation is thought to be a mediator in the pathophysiology of the cardiorenal syndrome. We evaluated the interactions between kidney function, cardiac stress, and various inflammatory cytokines in patients with acute heart failure (AHF). The effect on 1-year mortality was also assessed. METHODS AND RESULTS: Plasma levels of cystatin C, NT-proBNP, and inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-α [TNF-α], IL-10) were measured in consecutive patients (n = 465) hospitalized for AHF. After adjustment for demographic characteristics and comorbidities, TNF-α had the strongest relation with renal function (ß = 0.39, P < 0.0001). Elevated TNF-α levels were seen in patients with high cystatin C, irrespective of NT-proBNP. Levels of IL-6 (ß = 0.26, P < 0.0001) and IL-10 (ß = 0.15, P < 0.01), but not TNF-α, were associated with NT-proBNP. Moreover, the most elevated levels of IL-6 were seen in patients with combined high NT-proBNP and high cystatin C. Cox regression analysis found IL-6 above median to be independently predictive of mortality (hazard ratio 1.9; 95% CI 1.2-2.9, P = 0.003). TNF-α was not significantly associated with prognosis in the overall population after adjustment for multiple covariates, but improved risk stratification in the subgroup with low cystatin C and NT-proBNP. CONCLUSION: Levels of TNF-α in AHF are related to kidney function, but not to NT-proBNP. IL-6 seems to be more associated with cardiac stress. Patients with severe dual organ dysfunction have the highest levels of IL-6 and TNF-α. Different relations of inflammatory cytokines to renal function and cardiac stress need to be considered when evaluating heart--kidney interactions.

Modeling the length of the care episode after hip fracture: does the type of fracture matter?

BACKGROUND AND AIMS: Hip fractures are common events that require intensive operative hospital care and a lengthy rehabilitation. The effect of hip fracture type on successful rehabilitation is not well known. The aim of this study is to model and compare the length of the care episodes between intra- and extracapsular hip fractures in Finland. MATERIAL AND METHODS: 15544 hip fracture patients living at home in Finland 1998-2001 were followed using register-based data. Patient characteristics, outcomes, and length of stay (LOS) distributions were analyzed using a Bayesian nonparametric multilayer perceptron (MLP) network model. RESULTS: Mortality was similar in intra- and extracapsular hip fractures. Patients were more likely to need long-term care after extracapsular hip fracture. The average LOS at the surgical ward was similar for intra- and extracapsular fractures (1.7 weeks), but there was a considerable difference for the total inpatient LOS between the groups (5.2 weeks vs. 6.9 weeks). Intracapsular fractures had a simple unimodal LOS distribution, whereas the LOS distribution for the extracapsular fractures was multimodal with two clear peaks. Patients with more comorbidities required a longer LOS. CONCLUSIONS: The causes for differences in LOS between fracture types were most likely due to the different surgical methods and rehabilitation practices for the fracture types. As national guidelines suggest similar rehabilitation for all hip fracture patients, there is a need for early and aggressive rehabilitation of patients with extracapsular fractures, including full-weight bearing for all but selected patients.

Cancer incidence among persons with fragile X syndrome in Finland: a population-based study.

BACKGROUND: Fragile X syndrome is a common inheritable cause of intellectual disability (ID) and is characterised by a large number of CGG repeats at the gene FMR1 located on the X-chromosome. It has been reported that this genetic mechanism may protect against malignant transformations. METHODS: We extracted from the Finnish registry on persons with ID a cohort of 302 persons with a fragile X diagnosis during 1982-1986. Follow-up for cancer incidence was performed in the Finnish Cancer Registry until the end of the year 2005. RESULTS: There were 11 reported cancers during the mean follow-up of 21.4 years per person. The expected number of cancers based on the average Finnish population was 13.8 and no statistically significant protective effect was detected [standardised incidence ratios (SIR) 0.80, confidence interval (CI) 95% 0.40-1.4]. An increased risk for lip cancer was found (SIR 23, CI 95% 2.8-85). CONCLUSIONS: Confirmation of hypotheses about the mechanisms linking FXS and cancer needs further research.

Quality effects of operative delay on mortality in hip fracture treatment.

BACKGROUND: Most hip fracture patients undergo surgery, but there is conflicting evidence on the relation between the timing of surgery and the outcome of treatment. There is considerable variation in the length of surgical delays between hospitals, possibly reflecting the quality of care. AIM: To examine the associations between in-hospital surgical delay and the mortality of hip fracture patients from a practical quality assessment perspective. METHODS: The effects of operative delay on mortality were estimated using various statistical methods applied to observational data from 16 881 first time hip fracture patients aged 65 or older from 47 hospitals (providers) in Finland in 1998-2001. RESULTS: A prolonged in-hospital operative delay was associated with a higher mortality of hip fracture patients in individual level analyses, but the instrumental variable approach indicated that the individual level effect was not caused by the operative delay but by inappropriate methodological assumptions. There was extensive variation between providers in the proportion of late surgery patients. Provider level analyses showed that the effects of the provider of operative delay on mortality are quite small, but there is a clear association between the proportion of late surgery patients and non-optimal treatment. CONCLUSIONS: If provider level heterogeneity is not explicitly taken into account, studies of the effects of surgical delay on outcomes are prone to serious bias. The proportion of patients with prolonged waiting time for surgery at the provider level seems to work as an effective evidence-based quality indicator. Providers should reduce unnecessary delays to surgery and identify more carefully patients not suitable for early surgery.

Enzyme changes in remodelling epithelial cells: a histochemical study of the rat jejunum in vivo during and following exposure to deoxycholic acid.

Loops of rat jejunum were exposed in vivo to different concentrations of deoxycholic acid (DOC; 0, 2.5, 5, 10 and 20 mM). Following a 30 min exposure period, DOC was washed out of the loops and the intestines were allowed to recover for 15 or 150 min. Frozen tissue for enzyme histochemistry was collected during exposure and following the recovery periods. As shown previously, exposure to DOC caused a dose-dependent loss of epithelial cells at the villous tips and denudation of the lamina propria. Flattened epithelial cells bordering the denuded areas were, however, responsible for a rapid restoration of epithelial continuity, which was completed within 15 min. In the present study, these flattened cells showed normal reactivity for non-specific esterase and succinate dehydrogenase. In contrast, following a prolonged recovery period (150 min), a subpopulation of enterocytes at the villous tips that otherwise appeared normal showed decreased reactivity for brush border enzymes and non-specific esterase, and a positive reaction for mucin. A shutdown in the synthesis of cytoplasmic enzymes and redistribution of cell surface enzymes could be responsible for these late occurring enzyme changes, that were consistently observed after 150 min of recovery from DOC at 20 mM. Alternatively, retention of goblet cells and/or a modification in enzyme synthesis may explain the presence of mucin that was demonstrated in the epithelial cells which had low enzyme reactivity.

Biliary excretion of bisacodyl and picosulphate in man: studies in gallstone patients after biliary tract surgery.

Bisacodyl (=BIS) and picosulphate (=PICO) have been given perorally to postoperative gallstone patients, who have undergone biliary tract surgery with the insertion of an indwelling T-tube. The doses corresponded to 7.7 mg of their common free diphenol desacetylbisacodyl (=DES). The bile was sampled in hourly fraction from the external limb of the T-tube; these fractions were analysed by a modification of the HPLC method previously used to study biliary excretion in the rat. In the BIS-patients (n=8), DES in conjugated form occurred in significant concentration already in the first fractions; peak excretion values equivalent to 4-8 microgram DES/ml bile were reached in 2-5 hours. Unchanged BIS could not be detected, and the concentration levels of unconjugated DES were insignificant. The PICO-patients (n=8) on the other hand showed low DES concentrations (conjugated + free less than or equal to 0.5 microgram DES/ml) in all fractions, or low initial concentrations followed by a more or less pronounced rise in the later fractions. These results are, qualitatively, as in the rat. However, the dose fractions excreted in bile (assuming a total hepatic output of 50ml/hours) seem smaller than those to be expected from rat experiments, at least as far as BIS is concerned.

Studies on hydragogue drugs: effect of surfactants on cAMP levels in the rat jejunal mucosa in short time experiments in vivo.

Theophylline and the surface active agents specified below were instilled into the jejunum of anaesthetized rats, and the cAMP levels in the mucosal tissue determined after 71/2 and 15 min. incubation in vivo. Most experiments were done in rats prepared with two tied intestinal loops; one of these served as the control loop and the other as the stimulated loop. The surfactants (mmol/l) included dodecylsulphate (17), dioctylsulphosuccinate (5.6), cetrimonium bromide (4.1), deoxycholic acid (2.4 and 3.6) and Lubrol WX (0.5% w/v). Theophylline (10 mmol/l) caused a substantial increase in cAMP (110% +/- 17, n = 7 and 60% +/- 8.9, n = 10, respectively) and dodecylsulphate a minor and transitory increase (28.1% +/- 3.8, n = 10 and 11.7% +/- 4.9, n = 8). The other agents were without stimulatory effect on cAMP, although like dodecylsulphate they may significantly affect normal intestinal cation and glucose transport under these conditions. The results, therefore, do not suggest that stimulation of cAMP and intestinal secretion induced thereby is any significant phenomenon in the overall hydragogue effect of these agents, at least not in short term jejunal experiments.

Net sodium and glucose transport in the jejunum, ileum and colon of anaesthetized rats in response to intraluminal theophylline and anionic surfactants.

Osmotically balanced solutions of sodium chloride and glucose (5-150 mmol/l) were instilled into rats prepared with two tied intestinal loops (jej-col or il-col). Luminal accumulation or disappearance of Na and glucose after 15 min. was determined, and the parameters of the linear regression lines of net Na flux (y) with initial Na concentration (x) calculated. Control cation and glucose transport were changed by dioctylsulphosuccinate and dodecylsulphate in the way described by Sund & Matheson (1978). Theophylline (10-25 mmol/l) on the other hand did not alter glucose disappearance, and had a distinctly dissimilar effect on net Na transport compared to the surfactants. This could be described as a parallel displacement of the control regression lines to the right, without improvement in correlation. This effect of theophylline was greatest in the ileum, where mean luminal Na concentration corresponding to zero net transport was raised from about 70 mmol/l under control condition to values above 200 mmol/l. The results are consistent with the view that theophylline mainly affects transcellular and the surfactants mainly paracellular sodium transport, and do not support the theory that the effect of dioctylsulphosuccinate on intestinal transport is related to an activation of the mucosal adenylate cyclase/cAMP system, at least not in short term experiments.