[Is resting heart rate a cardiovascular risk factor?]

During recent years, resting heart rate was not considered as a cardiovascular risk factor. However, new evidences have showed that resting heart rate is an important prognostic factor for sudden cardiac death and heart failure in the general population, and especially among patients with known cardiac disease. Interestingly, resting heart rate not only predicts cardiac mortality but also all-cause mortality. The most common pathophysiological explanation is related to the fact that increased heart rate increases myocardial oxygen consumption and in parallel reduces coronary blood flow (reduction in the diastolic duration).

Limited open reduction and internal fixation of displaced intra-articular fractures of the calcaneum

The extended lateral L-shaped approach for the treatment of displaced intra-articular fractures of the calcaneum may be complicated by wound infection, haematoma, dehiscence and injury to the sural nerve. In an effort to reduce the risk of problems with wound healing a technique was developed that combined open reduction and fixation of the joint fragments and of the anterior process with percutaneous reduction and screw fixation of the tuberosity. A group of 24 patients with unilateral isolated closed Sanders type II and III fractures was treated using this technique and compared to a similar group of 26 patients managed by the extended approach and lateral plating. The operation was significantly shorter (p < 0.001) in the first group, but more minor secondary procedures and removal of heel screws were necessary. There were no wound complications in this group, whereas four minor complications occurred in the second group. The accuracy and maintenance of reduction, and ultimate function were equivalent.

Lifestyle and stroke risk: a review

PURPOSE OF REVIEW: In recent years, many epidemiological studies have given new insights into old and new lifestyle factors that influence the risk of cerebrovascular events. In this review, we refer to the most important articles to highlight recent advances, especially those important for stroke prevention. RECENT FINDINGS: This review focuses on the most recent studies that show the association of environmental factors, nutrition, alcohol, tobacco, education, lifestyle and behavior with the risk of vascular disease, including ischemic stroke and cerebral hemorrhage. The link between air pollution and stroke risk has become evident. Low education levels and depression are established as risk factors. This is also true for heavy alcohol consumption, although moderate drinking may be protective. Active and passive smoking are independent risk factors, and a smoking ban in public places has already reduced cardiovascular events in the short term. Physical activity reduces stroke risk; overweight increases it. However, clinical trials to assess the effect of weight reduction on stroke risk are still lacking. Fruits, vegetables, fish, fibers, low-fat dairy products, potassium and low sodium consumption are known and recommended to reduce cardiovascular risk. Data on omega 3 fatty acid, folic acid and B vitamins are inconsistent, and antioxidants are not recommended. SUMMARY: Stroke can be substantially reduced by an active lifestyle, cessation of smoking and a healthy diet. Both public and professional education should promote the awareness that a healthy lifestyle and nutrition have the potential to reduce the burden of stroke.

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Natural history of surgically treated high-risk prostate cancer

BACKGROUND No data exist on the patterns of biochemical recurrence (BCR) and their effect on survival in patients with high-risk prostate cancer (PCa) treated with surgery. The aim of our investigation was to evaluate the natural history of PCa in patients treated with radical prostatectomy (RP) alone. MATERIALS AND METHODS Overall, 2,065 patients with high-risk PCa treated with RP at 7 tertiary referral centers between 1991 and 2011 were identified. First, we calculated the probability of experiencing BCR after surgery. Particularly, we relied on conditional survival estimates for BCR after RP. Competing-risks regression analyses were then used to evaluate the effect of time to BCR on the risk of cancer-specific mortality (CSM). RESULTS Median follow-up was 70 months. Overall, the 5-year BCR-free survival rate was 55.2%. Given the BCR-free survivorship at 1, 2, 3, 4, and 5 years, the BCR-free survival rates improved by+7.6%,+4.1%,+4.8%,+3.2%, and+3.7%, respectively. Overall, the 10-year CSM rate was 14.8%. When patients were stratified according to time to BCR, patients experiencing BCR within 36 months from surgery had higher 10-year CSM rates compared with those experiencing late BCR (19.1% vs. 4.4%; P<0.001). At multivariate analyses, time to BCR represented an independent predictor of CSM (P<0.001). CONCLUSIONS Increasing time from surgery is associated with a reduction of the risk of subsequent BCR. Additionally, time to BCR represents a predictor of CSM in these patients. These results might help provide clinicians with better follow-up strategies and more aggressive treatments for early BCR.

Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients

BACKGROUND AND PURPOSE Treatment with statins reduces the rate of cardiovascular events in high-risk patients, but residual risk persists. At least part of that risk may be attributable to atherogenic dyslipidemia characterized by low high-density lipoprotein cholesterol (≤40 mg/dL) and high triglycerides (triglycerides≥150 mg/dL). METHODS We studied subjects with stroke or transient ischemic attack in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM; n=19,100) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL; n=4731) trials who were treated with a statin and who had high-density lipoprotein cholesterol and triglycerides measurements 3 months after randomization (n=10,498 and 2900, respectively). The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We also performed a time-varying analysis to account for all available high-density lipoprotein cholesterol and triglyceride measurements. RESULTS A total of 10% of subjects in PERFORM and 9% in SPARCL had atherogenic dyslipidemia after ≥3 months on start statin therapy. After a follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1123 and 485 patients in the 2 trials, respectively. The risk of major cardiovascular events was higher in subjects with versus those without atherogenic dyslipidemia in both PERFORM (hazard ratio, 1.36; 95% confidence interval, 1.14-1.63) and SPARCL (hazard ratio, 1.40; 95% confidence interval, 1.06-1.85). The association was attenuated after multivariable adjustment (hazard ratio, 1.23; 95% confidence interval, 1.03-1.48 in PERFORM and hazard ratio, 1.24; 95% confidence interval, 0.93-1.65 in SPARCL). Time-varying analysis confirmed these findings. CONCLUSIONS The presence of atherogenic dyslipidemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischemic attack receiving statin therapy. Specific therapeutic interventions should now be trialed to address this residual risk.

Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.

Reducing fall risk in the elderly: risk factors and fall prevention, a systematic review

Falls in the elderly are a major source of injury resulting in disability and hospitalization. They have a significant impact on individual basis (loss of quality of live, nursing home admissions) and social basis (healthcare costs). Even though falls in the elderly are common there are some well studied risk factors. Special emphasis should be put on sarcopenia/frailty, polypharmacy, multimorbidity, vitamin D status and home hazards. There are several well evaluated fall prevention approaches that either target a single fall risk factor or focus on multiple risk factors. It has to be kept in mind that not all fall prevention strategies are useful for all patients as for example dietary substitution of vitamin D is only recommended in people with increased risk for a vitamin D deficiency. Home hazard reduction strategies are more effective when combined with other fall prevention approaches such as for example exercise programs. In conclusion elderly patients should routinely be screened for relevant risk factors and if need an indiviudally targeted fall prevention program compiled.

Risk of infections during interferon-based treatment in patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Pegylated interferon-based treatment is still the backbone of current hepatitis C therapy and is associated with bone marrow suppression and an increased risk of infections. The aim of this retrospective cohort study was to assess the risk of infections during interferon-based treatment among patients with chronic HCV infection and advanced hepatic fibrosis and its relation to treatment-induced neutropenia. METHODS This cohort study included all consecutive patients with chronic HCV infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) who started treatment between 1990 and 2003 in five large hepatology units in Europe and Canada. Neutrophil counts between 500/μL-749/μL and below 500/μL were considered as moderate and severe neutropenia, respectively. RESULTS This study included 723 interferon-based treatments, administered to 490 patients. In total, 113 infections were reported during 88 (12%) treatments, of which 24 (21%) were considered severe. Only one patient was found to have moderate neutropenia and three patients were found to have severe neutropenia at the visit before the infection. Three hundred and twelve (99.7%) visits with moderate neutropenia and 44 (93.6%) visits with severe neutropenia were not followed by an infection. Multivariable analysis showed that cirrhosis (OR 2.85, 95%CI 1.38-5.90, p=0.005) and severe neutropenia at the previous visit (OR 5.42, 95%CI 1.34-22.0, p=0.018) were associated with the occurrence of infection, while moderate neutropenia was not. Among a subgroup of patients treated with PegIFN, severe neutropenia was not significantly associated (OR 1.63, 95%CI 0.19-14.2, p=0.660). CONCLUSIONS In this large cohort of patients with bridging fibrosis and cirrhosis, infections during interferon-based therapy were generally mild. Severe interferon-induced neutropenia rarely occurred, but was associated with on-treatment infection. Moderate neutropenia was not associated with infection, suggesting that current dose reduction guidelines might be too strict.

Reduction of cement leakage by sequential PMMA application in a vertebroplasty model

PURPOSE Leakage is the most common complication of percutaneous cement augmentation of the spine. The viscosity of the polymethylmethacrylate (PMMA) cement is strongly correlated with the likelihood of cement leakage. We hypothesized that cement leakage can be reduced by sequential cement injection in a vertebroplasty model. METHODS A standardized vertebral body substitute model, consisting of aluminum oxide foams coated by acrylic cement with a preformed leakage path, simulating a ventral vein, was developed. Three injection techniques of 6 ml PMMA were assessed: injection in one single step (all-in-one), injection of 1 ml at the first and 5 ml at the second step with 1 min latency in-between (two-step), and sequential injection of 0.5 ml with 1-min latency between the sequences (sequential). Standard PMMA vertebroplasty cement was used; each injection type was tested on ten vertebral body substitute models with two possible leakage paths per model. Leakage was assessed by radiographs using a zonal graduation: intraspongious = no leakage and extracortical = leakage. RESULTS The leakage rate was significantly lower in the "sequential" technique (2/20 leakages) followed by "two-step" (15/20) and "all-in-one" (20/20) techniques (p < 0.001). The RR for a cement leakage was 10.0 times higher in the "all-in-one" compared to the "sequential" group (95 % confidence intervals 2.7-37.2; p < 0.001). CONCLUSIONS The sequential cement injection is a simple approach to minimize the risk for leakage. Taking advantage of the temperature gradient between body and room temperature, it is possible to increase the cement viscosity inside the vertebra while keeping it low in the syringe. Using sequential injection of small cement volumes, further leakage paths are blocked before further injection of the low-viscosity cement.

Prospective analysis of adrenal function in patients with acute exacerbations of COPD: the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial

OBJECTIVE To analyze prospectively the hypothalamic-pituitary-adrenal (HPA) axis and clinical outcome in patients treated with prednisone for exacerbated chronic obstructive pulmonary disease (COPD). DESIGN Prospective observational study. SUBJECTS AND METHODS Patients presenting to the emergency department were randomized to receive 40 mg prednisone daily for 5 or 14 days in a placebo-controlled manner. The HPA axis was longitudinally assessed with the 1 μg corticotropin test and a clinical hypocortisolism score at baseline, on day 6 before blinded treatment, at hospital discharge, and for up to 180 days of follow-up. Prednisone was stopped abruptly, irrespective of the test results. Patients discharged with pathological test results received instructions about emergency hydrocortisone treatment. RESULTS A total of 311 patients were included in the analysis. Mean basal and stimulated serum total cortisol levels were highest on admission (496±398 and 816±413 nmol/l respectively) and lowest on day 6 (235±174 and 453±178 nmol/l respectively). Pathological stimulation tests were found in 63, 38, 9, 3, and 2% of patients on day 6, at discharge, and on days 30, 90, and 180 respectively, without significant difference between treatment groups. Clinical indicators of hypocortisolism did not correlate with stimulation test results, but cortisol levels were inversely associated with re-exacerbation risk. There were no hospitalizations or deaths as a result of adrenal crisis. CONCLUSION Dynamic changes in the HPA axis occur during and after the treatment of acute exacerbations of COPD. In hypocortisolemic patients who were provided with instructions about stress prophylaxis, the abrupt termination of prednisone appeared safe.

Radiation dose in pneumatic reduction of ileo-colic intussusceptions--results from a single-institution study

BACKGROUND Air enema under fluoroscopy is a well-accepted procedure for the treatment of childhood intussusception. However, the reported radiation doses of pneumatic reduction with conventional fluoroscopy units have been high in decades past. OBJECTIVE To compare current radiation doses at our institution to past doses reported by others for fluoroscopic-guided pneumatic reduction of ileo-colic intussusception in children. MATERIALS AND METHODS Since 2007 radiologists and residents in our department who perform reduction of intussusceptions have received a radiation risk training. We retrospectively analyzed the data of 45 children (5 months-8 years) who underwent a total of 48 pneumatic reductions of ileo-colic intussusception between 2008 and 2012. We analyzed data for screening time and dose area product (DAP) and compared these data to those reported up to and including the year 2000. RESULTS Our mean screening time measured by the DAP-meter was 53.8 s (range 1-320 s, median 33.0 s). The mean DAP was 11.4 cGy ∙ cm(2) (range 1-145 cGy ∙ cm(2), median 5.45 cGy ∙ cm(2)). There was one bowel perforation, in a 1-year-old boy requiring surgical revision. Only three studies in the literature presented radiation exposure results on children who received pneumatic or hydrostatic reduction of intussusception under fluoroscopy. Screening times and dose area products in those studies, which were published in the 1990 s and in the year 2000, were substantially higher than those in our sample. CONCLUSION Low-frequency pulsed fluoroscopy and other dose-saving keys as well as the radiation risk training might have helped to improve the quality of the procedure in terms of radiation exposure.

Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma.

BACKGROUND Newly diagnosed WHO grade II-III or any WHO grade recurrent meningioma exhibit an aggressive behavior and thus are considered as high- or intermediate risk tumors. Given the unsatisfactory rates of disease control and survival after primary or adjuvant radiation therapy, optimization of treatment strategies is needed. We investigated the potential of dose-painting intensity-modulated proton beam-therapy (IMPT) for intermediate- and high-risk meningioma. MATERIAL AND METHODS Imaging data from five patients undergoing proton beam-therapy were used. The dose-painting target was defined using [68]Ga-[1,4,7,10-tetraazacyclododecane tetraacetic acid]- d-Phe(1),Tyr(3)-octreotate ([68]Ga-DOTATATE)-positron emission tomography (PET) in target delineation. IMPT and photon intensity-modulated radiation therapy (IMRT) treatment plans were generated for each patient using an in-house developed treatment planning system (TPS) supporting spot-scanning technology and a commercial TPS, respectively. Doses of 66 Gy (2.2 Gy/fraction) and 54 Gy (1.8 Gy/fraction) were prescribed to the PET-based planning target volume (PTVPET) and the union of PET- and anatomical imaging-based PTV, respectively, in 30 fractions, using simultaneous integrated boost. RESULTS Dose coverage of the PTVsPET was equally good or slightly better in IMPT plans: dose inhomogeneity was 10 ± 3% in the IMPT plans vs. 13 ± 1% in the IMRT plans (p = 0.33). The brain Dmean and brainstem D50 were small in the IMPT plans: 26.5 ± 1.5 Gy(RBE) and 0.002 ± 0.0 Gy(RBE), respectively, vs. 29.5 ± 1.5 Gy (p = 0.001) and 7.5 ± 11.1 Gy (p = 0.02) for the IMRT plans, respectively. The doses delivered to the optic structures were also decreased with IMPT. CONCLUSIONS Dose-painting IMPT is technically feasible using currently available planning tools and resulted in dose conformity of the dose-painted target comparable to IMRT with a significant reduction of radiation dose delivered to the brain, brainstem and optic apparatus. Dose escalation with IMPT may improve tumor control and decrease radiation-induced toxicity.

Certolizumab treatment during late pregnancy in patients with rheumatic diseases: Low drug levels in cord blood but possible risk for maternal infections. A case series of 13 patients

OBJECTIVE Due to reduction of immune-suppressive drugs, patients with rheumatic diseases can experience an increase in disease activity during pregnancy. In such cases, TNF-inhibitors may be prescribed. However, monoclonal antibodies with the Fc moiety are actively transported across the placenta, resulting in therapeutic drug levels in the newborn. As certolizumab (CZP) lacks the Fc moiety, it may bear a lower risk for the child. METHOD We report a case series of thirteen patients (5 with rheumatoid arthritis and 8 with spondyloarthritis) treated with CZP during late pregnancy to control disease activity. RESULT CZP measured in cord blood of eleven infants ranged between undetectable levels and 1μg/mL whereas the median CZP level of maternal plasma was 32.97μg/mL. Three women developed an infection during the third trimester, of whom one had a severe infection and one had an infection that resulted in a pre-term delivery. During the postpartum period, 6 patients remained on CZP while breastfeeding. CZP levels in the breast milk of two breastfeeding patients were undetectable. CONCLUSION The lack of the active transplacental transfer of CZP gives the possibility to treat inflammatory arthritis during late gestation without potential harm to the newborn. However, in pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause prematurity. CZP treatment can be continued while breastfeeding.