Stratification of high-risk prostate cancer into prognostic categories: a European multi-institutional study

BACKGROUND High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory. OBJECTIVE To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high-risk PCa based on combinations of unfavorable risk factors. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high-volume centers. INTERVENTION Retropubic radical prostatectomy with pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (< cT3 vs cT3-4), Gleason score (GS) (2-7 vs 8-10), and prostate-specific antigen (PSA; ≤ 20 ng/ml vs > 20 ng/ml). The first "extended" model includes all seven possible combinations; the second "simplified" model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3-4); and a poor prognosis subgroup (GS 8-10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups. RESULTS AND LIMITATIONS The simplified model yielded an R(2) of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R(2): 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period. CONCLUSIONS This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting.

Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.

OBJECTIVE To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? METHODS A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. RESULTS Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. SIGNIFICANCE This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B*15:02 and HLA-A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Use of diuretics and risk of incident gout: a population-based case-control study

OBJECTIVE Use of diuretics has been associated with an increased risk of gout. Data on different types of diuretics are scarce. We undertook this study to investigate the association between use of loop diuretics, thiazide or thiazide-like diuretics, and potassium-sparing agents and the risk of developing incident gout. METHODS We conducted a retrospective population-based case-control analysis using the General Practice Research Database established in the UK. We identified case patients who were diagnosed as having incident gout between 1990 and 2010. One control patient was matched to each case patient for age, sex, general practice, calendar time, and years of active history in the database. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs), and we adjusted for potential confounders. RESULTS We identified 91,530 incident cases of gout and the same number of matched controls. Compared to past use of diuretics from each respective drug class, adjusted ORs for current use of loop diuretics, thiazide diuretics, thiazide-like diuretics, and potassium-sparing diuretics were 2.64 (95% CI 2.47-2.83), 1.70 (95% CI 1.62-1.79), 2.30 (95% CI 1.95-2.70), and 1.06 (95% CI 0.91-1.23), respectively. Combined use of loop diuretics and thiazide diuretics was associated with the highest relative risk estimates of gout (adjusted OR 4.65 [95% CI 3.51-6.16]). Current use of calcium channel blockers or losartan slightly attenuated the risk of gout in patients who took diuretics. CONCLUSION Use of loop diuretics, thiazide diuretics, and thiazide-like diuretics was associated with an increased risk of incident gout, although use of potassium-sparing agents was not.

Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: a population-based case-control study

OBJECTIVE The aim of this study was to explore the risk of incident gout in patients with type 2 diabetes mellitus (T2DM) in association with diabetes duration, diabetes severity and antidiabetic drug treatment. METHODS We conducted a case-control study in patients with T2DM using the UK-based Clinical Practice Research Datalink (CPRD). We identified case patients aged ≥18 years with an incident diagnosis of gout between 1990 and 2012. We matched to each case patient one gout-free control patient. We used conditional logistic regression analysis to calculate adjusted ORs (adj. ORs) with 95% CIs and adjusted our analyses for important potential confounders. RESULTS The study encompassed 7536 T2DM cases with a first-time diagnosis of gout. Compared to a diabetes duration <1 year, prolonged diabetes duration (1-3, 3-6, 7-9 and ≥10 years) was associated with decreased adj. ORs of 0.91 (95% CI 0.79 to 1.04), 0.76 (95% CI 0.67 to 0.86), 0.70 (95% CI 0.61 to 0.86), and 0.58 (95% CI 0.51 to 0.66), respectively. Compared to a reference A1C level of <7%, the risk estimates of increasing A1C levels (7.0-7.9, 8.0-8.9 and ≥9%) steadily decreased with adj. ORs of 0.79 (95% CI 0.72 to 0.86), 0.63 (95% CI 0.55 to 0.72), and 0.46 (95% CI 0.40 to 0.53), respectively. Neither use of insulin, metformin, nor sulfonylureas was associated with an altered risk of incident gout. CONCLUSIONS Increased A1C levels, but not use of antidiabetic drugs, was associated with a decreased risk of incident gout among patients with T2DM.

What is the best time point to identify patients at risk of developing persistent low back pain?

BACKGROUND Early identification of patients at risk of developing persistent low back pain (LBP) is crucial. OBJECTIVE Aim of this study was to identify in patients with a new episode of LBP the time point at which those at risk of developing persistent LBP can be best identified.METHODS: Prospective cohort study of 315 patients presenting to a health practitioner with a first episode of acute LBP. Primary outcome measure was functional limitation. Patients were assessed at baseline, three, six, twelve weeks and six months looking at factors of maladaptive cognition as potential predictors. Multivariate logistic regression analysis was performed for all time points. RESULTS The best time point to predict the development of persistent LBP at six months was the twelve-week follow-up (sensitivity 78%; overall predictive value 90%). Cognitions assessed at first visit to a health practitioner were not predictive. CONCLUSIONS Maladaptive cognitions at twelve weeks appear to be suitable predictors for a transition from acute to persistent LBP. Already three weeks after patients present to a health practitioner with acute LBP cognitions might influence the development of persistent LBP. Therefore, cognitive-behavioral interventions should be considered as early adjuvant LBP treatment in patients at risk of developing persistent LBP.

Low back pain risk factors associated with persistence, recurrence and delayed presentation

BACKGROUND: There is little knowledge in the literature on the role of time-related variables for the prognosis of acute and subacute low back pain (LBP). OBJECTIVE: The aim of this study was to estimate the relationship between time-related LBP characteristics and prognostic factors for acute/subacute LBP. METHODS: We performed a prospective inception cohort study of 315 patients attending a health practitioner for acute/subacute LBP or recurrent LBP. One-tailed correlations were conducted between patient characteristics and time-related variables. RESULTS: The pattern of correlation between risk factors for and resources against persistent LBP differed between three time-related variables. 'Subacute LBP' and 'delayed presentation' were positively associated with psychological factors. Both indicators were negatively correlated with resources against development of persistent LBP. Moreover, 'delayed presentation' was related positively with occupational stressors. In contrast, 'recurrent LBP' was only related to more impaired health-related factors. CONCLUSIONS: Patients with current LBP waiting longer until seeking help in primary care have a more disadvantageous profile of occupational and psychological risk factors and lower resource levels. A similar but less pronounced pattern occurred in those with subacute LBP compared to those with acute LBP. Consideration of time characteristics of LBP may help to better understand LBP.

Risk factors for potentially avoidable readmissions due to end-of-life care issues

BACKGROUND Repeated hospitalizations are frequent toward the end of life, where each admission should be an opportunity to initiate advance-care planning to high-risk patients. OBJECTIVE To identify the risk factors for having a 30-day potentially avoidable readmission due to end-of-life care issues among all medical patients. DESIGN Nested case-control study. SETTING/PATIENTS All 10,275 consecutive discharges from any medical service of an academic tertiary medical center in Boston, Massachusetts between July 1, 2009 and June 30, 2010. MEASUREMENTS A random sample of all the potentially avoidable 30-day readmissions was independently reviewed by 9 trained physicians to identify the ones due to end-of-life issues. RESULTS Among 534, 30-day potentially avoidable readmission cases reviewed, 80 (15%) were due to an end-of-life care issue. In multivariable analysis, the following risk factors were significantly associated with a 30-day potentially avoidable readmission due to end-of-life care issues: number of admissions in the previous 12 months (odds ratio [OR]: 1.10 per admission, 95% confidence interval [CI]: 1.02-1.20), neoplasm (OR: 5.60, 95% CI: 2.85-10.98), opiate medications at discharge (OR: 2.29, 95% CI: 1.29-4.07), Elixhauser comorbidity index (OR: 1.16 per 5-point increase, 95% CI: 1.10-1.22). The discrimination of the model (C statistic) was 0.85. CONCLUSIONS In a medical population, we identified 4 main risk factors that were significantly associated with 30-day potentially avoidable readmission due to end-of-life care issues, producing a model with very good to excellent discrimination. Patients with these risk factors might benefit from palliative care consultation prior to discharge in order to improve end-of-life care and possibly reduce unnecessary rehospitalizations.

Risk factors for colic in horses hospitalized for ocular disease

OBJECTIVE: To evaluate the incidence of colic and risk factors for colic in equids hospitalized for ocular disease. DESIGN: Retrospective observational study. Animals-337 equids (317 horses, 19 ponies, and 1 donkey) hospitalized for ocular disease. PROCEDURES: Medical records of equids hospitalized for > 24 hours for treatment of ocular disease between January 1997 and December 2008 were reviewed. Information from only the first hospitalization was used for equids that were hospitalized for ocular disease on more than 1 occasion. Information gathered included the signalment, the type of ocular lesion and the treatment administered, and any colic signs recorded during hospitalization as well as the severity, presumptive diagnosis, and treatment of the colic. Statistical analysis was used to identify any risk factors for colic in equids hospitalized for ocular disease. RESULTS: 72 of 337 (21.4%) equids hospitalized for ocular disease had signs of colic during hospitalization. Most equids (59.7% [43/72]) had mild signs of colic, and most (87.5% [63/72]) were treated medically. Ten of 72 (13.9%) equids with colic had a cecal impaction. Risk factors for colic in equids hospitalized for ocular disease were age (0 to 1 year and ≥ 21 years) and an increased duration of hospitalization (≥ 8 days). CONCLUSIONS AND CLINICAL RELEVANCE: There was a high incidence of colic in equids hospitalized with ocular disease in this study. Findings from this study may help identify equids at risk for development of colic and thereby help direct implementation of prophylactic measures.

Reliable prediction of clinical outcome in patients with chronic HCV infection and compensated advanced hepatic fibrosis: a validated model using objective and readily available clinical parameters.

OBJECTIVE Reliable tools to predict long-term outcome among patients with well compensated advanced liver disease due to chronic HCV infection are lacking. DESIGN Risk scores for mortality and for cirrhosis-related complications were constructed with Cox regression analysis in a derivation cohort and evaluated in a validation cohort, both including patients with chronic HCV infection and advanced fibrosis. RESULTS In the derivation cohort, 100/405 patients died during a median 8.1 (IQR 5.7-11.1) years of follow-up. Multivariate Cox analyses showed age (HR=1.06, 95% CI 1.04 to 1.09, p<0.001), male sex (HR=1.91, 95% CI 1.10 to 3.29, p=0.021), platelet count (HR=0.91, 95% CI 0.87 to 0.95, p<0.001) and log10 aspartate aminotransferase/alanine aminotransferase ratio (HR=1.30, 95% CI 1.12 to 1.51, p=0.001) were independently associated with mortality (C statistic=0.78, 95% CI 0.72 to 0.83). In the validation cohort, 58/296 patients with cirrhosis died during a median of 6.6 (IQR 4.4-9.0) years. Among patients with estimated 5-year mortality risks <5%, 5-10% and >10%, the observed 5-year mortality rates in the derivation cohort and validation cohort were 0.9% (95% CI 0.0 to 2.7) and 2.6% (95% CI 0.0 to 6.1), 8.1% (95% CI 1.8 to 14.4) and 8.0% (95% CI 1.3 to 14.7), 21.8% (95% CI 13.2 to 30.4) and 20.9% (95% CI 13.6 to 28.1), respectively (C statistic in validation cohort = 0.76, 95% CI 0.69 to 0.83). The risk score for cirrhosis-related complications also incorporated HCV genotype (C statistic = 0.80, 95% CI 0.76 to 0.83 in the derivation cohort; and 0.74, 95% CI 0.68 to 0.79 in the validation cohort). CONCLUSIONS Prognosis of patients with chronic HCV infection and compensated advanced liver disease can be accurately assessed with risk scores including readily available objective clinical parameters.

Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥20 g/day for ≥5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

Impact of cardiovascular risk factors on severity of peripheral artery disease

OBJECTIVE The development of peripheral artery disease is affected by the presence of cardiovascular risk factors. It is unclear, whether particular risk factors are leading to different clinical stages of peripheral artery disease. The aim of this retrospective cross-sectional study was to assess the association of cardiovascular risk factors with the presence of critical limb ischaemia. METHODS The study cohort was derived from a consecutive registry of patients undergoing endovascular therapy in a tertiary referral centre between January 2000 and April 2014. Patients undergoing first-time endovascular intervention for chronic peripheral artery disease of the lower extremities were included. Univariate and multivariate logistic regression models were used to assess the association of age, sex, diabetes mellitus, hypertension, dyslipidaemia, smoking, and renal insufficiency with critical limb ischaemia vs. intermittent claudication. RESULTS A total of 3406 patients were included in the study (mean age 71.7 ± 11.8 years, 2075 [61%] male). There was a significant association of age (OR 1.67, 95%-CI 1.53-1.82, p < 0.001), male gender (OR 1.23, 95%-CI 1.04-1.47, p = 0.016), diabetes (OR 1.99, 95%-CI 1.68-2.36, p < 0.001) and renal insufficiency (OR 1.62, 95%-CI 1.35-1.96, p < 0.001) with the likelihood of critical limb ischaemia. Smoking was associated with intermittent claudication rather than critical limb ischaemia (OR 0.78, 95%-CI 0.65-0.94, p = 0.010), while hypertension and dyslipidaemia did not show an association with critical limb ischaemia. CONCLUSIONS In peripheral artery disease patients undergoing first-time endovascular treatment, age, male gender, diabetes, and renal insufficiency were the strongest predictors for the presence of critical limb ischaemia.

Effect of Health Risk Assessment and Counselling on Health Behaviour and Survival in Older People: A Pragmatic Randomised Trial.

BACKGROUND Potentially avoidable risk factors continue to cause unnecessary disability and premature death in older people. Health risk assessment (HRA), a method successfully used in working-age populations, is a promising method for cost-effective health promotion and preventive care in older individuals, but the long-term effects of this approach are unknown. The objective of this study was to evaluate the effects of an innovative approach to HRA and counselling in older individuals for health behaviours, preventive care, and long-term survival. METHODS AND FINDINGS This study was a pragmatic, single-centre randomised controlled clinical trial in community-dwelling individuals aged 65 y or older registered with one of 19 primary care physician (PCP) practices in a mixed rural and urban area in Switzerland. From November 2000 to January 2002, 874 participants were randomly allocated to the intervention and 1,410 to usual care. The intervention consisted of HRA based on self-administered questionnaires and individualised computer-generated feedback reports, combined with nurse and PCP counselling over a 2-y period. Primary outcomes were health behaviours and preventive care use at 2 y and all-cause mortality at 8 y. At baseline, participants in the intervention group had a mean ± standard deviation of 6.9 ± 3.7 risk factors (including unfavourable health behaviours, health and functional impairments, and social risk factors) and 4.3 ± 1.8 deficits in recommended preventive care. At 2 y, favourable health behaviours and use of preventive care were more frequent in the intervention than in the control group (based on z-statistics from generalised estimating equation models). For example, 70% compared to 62% were physically active (odds ratio 1.43, 95% CI 1.16-1.77, p = 0.001), and 66% compared to 59% had influenza vaccinations in the past year (odds ratio 1.35, 95% CI 1.09-1.66, p = 0.005). At 8 y, based on an intention-to-treat analysis, the estimated proportion alive was 77.9% in the intervention and 72.8% in the control group, for an absolute mortality difference of 4.9% (95% CI 1.3%-8.5%, p = 0.009; based on z-test for risk difference). The hazard ratio of death comparing intervention with control was 0.79 (95% CI 0.66-0.94, p = 0.009; based on Wald test from Cox regression model), and the number needed to receive the intervention to prevent one death was 21 (95% CI 12-79). The main limitations of the study include the single-site study design, the use of a brief self-administered questionnaire for 2-y outcome data collection, the unavailability of other long-term outcome data (e.g., functional status, nursing home admissions), and the availability of long-term follow-up data on mortality for analysis only in 2014. CONCLUSIONS This is the first trial to our knowledge demonstrating that a collaborative care model of HRA in community-dwelling older people not only results in better health behaviours and increased use of recommended preventive care interventions, but also improves survival. The intervention tested in our study may serve as a model of how to implement a relatively low-cost but effective programme of disease prevention and health promotion in older individuals. TRIAL REGISTRATION International Standard Randomized Controlled Trial Number: ISRCTN 28458424.

Twelve-month psychosis-predictive value of the ultra-high risk criteria in children and adolescents

Objective The validity of current ultra-high risk (UHR) criteria is under-examined in help-seeking minors, particularly, in children below the age of 12 years. Thus, the present study investigated predictors of one-year outcome in children and adolescents (CAD) with UHR status. Method Thirty-five children and adolescents (age 9–17 years) meeting UHR criteria according to the Structured Interview for Psychosis-Risk Syndromes were followed-up for 12 months. Regression analyses were employed to detect baseline predictors of conversion to psychosis and of outcome of non-converters (remission and persistence of UHR versus conversion). Results At one-year follow-up, 20% of patients had developed schizophrenia, 25.7% had remitted from their UHR status that, consequently, had persisted in 54.3%. No patient had fully remitted from mental disorders, even if UHR status was not maintained. Conversion was best predicted by any transient psychotic symptom and a disorganized communication score. No prediction model for outcome beyond conversion was identified. Conclusions Our findings provide the first evidence for the predictive utility of UHR criteria in CAD in terms of brief intermittent psychotic symptoms (BIPS) when accompanied by signs of cognitive impairment, i.e. disorganized communication. However, because attenuated psychotic symptoms (APS) related to thought content and perception were indicative of non-conversion at 1-year follow-up, their use in early detection of psychosis in CAD needs further study. Overall, the need for more in-depth studies into developmental peculiarities in the early detection and treatment of psychoses with an onset of illness in childhood and early adolescence was further highlighted.

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Lateral impact in closed head injury: A substantially increased risk for diffuse axonal injury—A preliminary study

OBJECTIVE: Assessment, whether location of impact causing different facial fracture patterns was associated with diffuse axonal injury in patients with severe closed head injury. METHODS: Retrospectively all patients referred to the Trauma Unit of the University Hospital of Zurich, Switzerland between 1996 and 2002 presenting with severe closed head injuries (Abbreviated Injury Scale (AIS) (face) of 2-4 and an AIS (head and neck) of 3-5) were assessed according to the Glasgow Coma Scale (GCS) and the Injury Severity Score (ISS). Facial fracture patterns were classified as resulting from frontal, oblique or lateral impact. All patients had undergone computed tomography. The association between impact location and diffuse axonal injury when correcting for the level of consciousness (using the Glasgow scale) and severity of injury (using the ISS) was calculated with a multivariate regression analysis. RESULTS: Of 200 screened patients, 61 fulfilled the inclusion criteria for severe closed head injury. The medians (interquartile ranges 25;75) for GCS, AIS(face) AIS(head and neck) and ISS were 3 (3;13), 2 (2;4), 4 (4;5) and 30 (24;41), respectively. A total of 51% patients had frontal, 26% had an oblique and 23% had lateral trauma. A total of 21% patients developed diffuse axonal injury (DAI) when compared with frontal impact, the likelihood of diffuse axonal injury increased 11.0 fold (1.7-73.0) in patients with a lateral impact. CONCLUSIONS: Clinicians should be aware of the substantial increase of diffuse axonal injury related to lateral impact in patients with severe closed head injuries.