Health-related predictors of cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: The relationship between comorbid disease and health service use and risk of cancer of unknown primary site (CUP) is uncertain. METHODS: A prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Baseline questionnaire data were linked to cancer registration, health service records 4-27 months prior to diagnosis, and mortality data. We compared individuals with incident registry-notified CUP (n = 327; 90% C80) to two sets of randomly selected controls (3:1): (i) incident metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted models incorporating sociodemographic and lifestyle factors, people with cancer registry-notified CUP were more likely to have fair compared with excellent self-rated overall health (OR 1.78, 95% CI 1.01-3.14) and less likely to self-report anxiety (OR 0.48, 95% CI 0.24-0.97) than those registered with metastatic cancer of known primary. Compared to general cohort population controls, people registered with CUP were more likely to have poor rather than excellent self-rated overall health (OR 6.22, 95% CI 1.35-28.6), less likely to self-report anxiety (OR 0.28, 95% CI 0.12-0.63), and more likely to have a history of diabetes (OR 1.89, 95% CI 1.15-3.10) or cancer (OR 1.62, 95% CI 1.03-2.57). Neither tertiary nor community-based health service use independently predicted CUP risk. CONCLUSION: Low self-rated health may be a flag for undiagnosed cancer, and an investigation of its clinical utility in primary care appears warranted.

Demographic, social and lifestyle risk factors for cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: Little is known about the risk factors for cancer of unknown primary site (CUP). We examined the demographic, social and lifestyle risk factors for CUP in a prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. METHODS: Baseline questionnaire data were linked to cancer registration, hospitalisation, emergency department admission, and mortality data. We compared individuals with incident cancer registry-notified CUP (n = 327) to two sets of controls randomly selected (3:1) using incidence density sampling with replacement: (i) incident cancer registry-notified metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In a fully adjusted model incorporating self-rated overall health and comorbidity, people diagnosed with CUP were more likely to be older (OR 1.05, 95% CI 1.04-1.07 per year) and more likely to have low educational attainment (OR 1.77, 95% CI 1.24-2.53) than those diagnosed with metastatic cancer of known primary. Similarly, compared to general cohort population controls, people diagnosed with CUP were older (OR 1.10, 95% CI 1.08-1.12 per year), of low educational attainment (OR 1.69, 95% CI 1.08-2.64), and current (OR 3.42, 95% CI 1.81-6.47) or former (OR 1.95, 95% CI 1.33-2.86) smokers. CONCLUSION: The consistent association with educational attainment suggests low health literacy may play a role in CUP diagnosis. These findings highlight the need to develop strategies to achieve earlier identification of diagnostically challenging malignancies in people with low health literacy.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Odd-Frequency Superconductivity in Sr_{2}RuO_{4} Measured by Kerr Rotation.

We establish the existence of bulk odd-frequency superconductivity in Sr_{2}RuO_{4} and show that an intrinsic Kerr effect is direct evidence of this state. We use both general two- and three-orbital models, as well as a realistic tight-binding description of Sr_{2}RuO_{4} to demonstrate that odd-frequency pairing arises due to finite hybridization between different orbitals in the normal state, and is further enhanced by finite interorbital pairing.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

Impact of neutrophil-to-lymphocyte ratio on periprocedural myocardial infarction in patients undergoing non-urgent percutaneous coronary revascularisation.

BACKGROUND: Pro-thrombotic conditions importantly influence myocardial perfusion and procedural results after percutaneous coronary intervention (PCI). The neutrophil-to-lymphocyte ratio (NLR) has emerged as a predictor of cardiovascular events and of long-term prognosis, especially in ST-elevation myocardial infarction patients undergoing primary PCI. The aim of our study was to evaluate the role of NLR on periprocedural myocardial infarction (MI) in patients undergoing non-urgent PCI. METHODS: In a consecutive cohort of 1542 patients undergoing PCI, myonecrosis biomarkers were determined at 6, 12, 24 and 48 hours post-procedure. Patients were divided into quintiles according to NLR values. Periprocedural myonecrosis was defined as a troponin I increase of 3 times the upper limit of normal or as 50 % of an elevated baseline value, whereas periprocedural MI was defined as a CK-MB increase of 3 times the upper limit of normal or 50 % of baseline. RESULTS: Higher NLR was related to age, established risk factors and cardiovascular history. NLR was associated with severe coronary artery disease (p = 0.009), tighter stenosis (p < 0.001), coronary calcifications (p = 0.005), intracoronary thrombus or thrombectomy use (p < 0.001), TIMI flow pre- and post-PCI (p < 0.001), and inversely to restenosis (p = 0.04) and use of a drug-eluting stent (p = 0.001). NLR did not influence the occurrence of myonecrosis (p = 0.75; adjusted OR (95 % CI) = 0.99 (0.63-1.54), p = 0.96), but was associated with a higher occurrence of periprocedural MI, even after correction for baseline differences (p = 0.03; adjusted OR (95 % CI) = 1.33 (1.02-2.3), p = 0.02), with NLR ≥ 3 best predicting the risk of periprocedural MI at the receiver operating characteristic curve analysis. CONCLUSION: In patients undergoing non-urgent PCI, a higher NLR increases the risk of periprocedural MI, especially for values ≥ 3.

Serum uric acid levels during dual antiplatelet therapy with ticagrelor or clopidogrel: Results from a single-centre study.

BACKGROUND AND AIMS: New antithrombotic therapies have significantly improved the outcomes of patients with acute coronary syndrome (ACS), where the introduction of ticagrelor has provided the greatest mortality benefits. However, ticagrelor treatment has been associated with a potential increase in the serum uric acid (SUA) levels, which may influence endothelial dysfunction and prothrombotic status, thereby affecting the risk of acute cardiovascular events in patients requiring dual antiplatelet therapy (DAPT). The present study aimed to compare the impact of antiplatelet agents such as ticagrelor or clopidogrel on SUA levels and their effect on platelet reactivity. METHODS AND RESULTS: We included patients admitted for ACS or elective percutaneous coronary intervention (PCI) and discharged with ASA (acetylsalicylic acid; 100-160 mg) and clopidogrel (75 mg) or ticagrelor (90 mg twice a day). Chemistry was assessed at admission (baseline) and after a 30-90-day period of DAPT (together with platelet reactivity). The absolute and percentage variations of SUA after DAPT introduction were considered. Multiple-electrode aggregometry was used to assess platelet function. A total of 378 patients were enrolled, with 145 treated with aspirin and clopidogrel (AC) and 233 with aspirin and ticagrelor (AT). The AC patients were older (p = 0.003) and more often showed elective PCI as an indication to DAPT (<0.001); they received chronic therapy with ARB (angiotensin II receptor blocker; p = 0.001), nitrates (p = 0.044), CCB (calcium channel blocker; p = 0.005) and diuretics (p = 0.044). The AT patients displayed a higher percentage of ACS diagnosis (p < 0.001) and received chronic therapy with ACE (angiotensin-converting enzyme) inhibitors (p = 0.001), beta blockers (p = 0.001) and statins (p = 0.013). The AC patients displayed higher platelet reactivity at COL (collagen) test, ASPI test and ADP (adenosine diphosphate) test (p = 0.03, 0.001 and <0.001, respectively) and a higher percentage of HRPR (high residual platelet reactivity) in the ADP test (p = 0.001). No difference was found in the baseline uric acid and creatinine levels between AC and AT patients. At 30-90 days, a significant absolute and percentage increase in the SUA levels was found in AT as compared to AC patients (0.204 mg/dl vs. -0.165 mg/dl, p = 0.034; 6.26% vs. -0.005%, p = 0.018, respectively). Results were not influenced by variations in renal function. At multivariate analysis, in fact, ticagrelor therapy emerged as an independent predictor of increase in the uric acid levels (odds ratio (OR; 95% confidence interval (CI)) = 2.79 (1.66-4.67), p < 0.001). However, the variation in the SUA levels did not affect platelet reactivity or HRPR in both AC and AT patients. CONCLUSION: An increase in the SUA levels at 30-90 days was observed in patients receiving chronic DAPT with ticagrelor, but not clopidogrel treatment. However, the changes in the SUA levels do not influence platelet aggregation.

Extensive tumoral melanosis associated with ipilimumab-treated melanoma.

Tumoral melanosis describes a pigmented lesion clinically similar to melanoma but on histology reveals dense aggregates of melanin-laden, benign macrophages without malignant cells. In the few reported cases so far, tumoral melanosis has arisen in the skin or lymph node of a patient with a regressed melanoma or an epithelioid tumour. As a marker of regressed primary melanoma, its discovery may prompt investigation and surveillance for undiagnosed local or metastatic disease. Here, we present a unique case of extensive tumoral melanosis arising during ipilimumab treatment of in-transit metastases from a previously excised melanoma.

A case of pharyngeal diphtheria in Germany, June 2015.

BACKGROUND: In June 2015, a 45-year-old man suffering from acute necrotic tonsillitis and throat phlegmon was hospitalized in Nuremberg, Germany. After emergency surgery the patient was initially treated with antibiotics. RESULTS: A throat swab grew a toxigenic Corynebacterium diphtheriae biovar mitis strain. The patient's vaccination status was not documented and the patient was tested serologically for anti-diphtheria antibodies showing no protective immunity. Extensive control investigations were performed by the local health department showing no likely source of his infection. CONCLUSION: No secondary cases were found and the patient completely recovered.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

UNLABELLED: ESSENTIALS: Dual antiplatelet therapy (DAPT) in elderly patients requires balancing bleedings and thrombosis. Impact of age on high residual on-treatment platelet reactivity (HRPR) on DAPT was studied. A reduced effectiveness of adenosine diphosphate antagonists was observed over 70 years of age. The occurrence of HRPR was increased among elderly patients with both clopidogrel and ticagrelor. BACKGROUND: The aim of the present study was to evaluate the impact of age on platelet function and the occurrence of high residual on-treatment platelet reactivity (HRPR) in patients treated with dual antiplatelet therapy (DAPT) using acetylsalicilic acid (ASA) and clopidogrel or ticagrelor. METHODS: Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values > 417 AU*min (for ADP antagonists). Elderly patients were defined as those aged ≥ 70 years. RESULTS: Among 494 patients on DAPT, 224 (45.3%) were ≥ 70 years old. ADP-mediated platelet aggregation increased with decades of age (279.3 ± 148.6 vs. 319.6 ± 171.1 vs. 347.3 ± 190.1 vs. 345.7 ± 169.2), whereas no difference was observed for ASA response. A reduced effectiveness of ADP antagonists was observed among elderly patients; in fact, among the 117 patients displaying HRPR (23.7%), a higher prevalence was observed among patients over 70 years old (30.4% vs. 18.1%; adjusted odds ratio (OR) [95% confidence interval (CI)] = 2.19 [1.29-3.71]). Similar results were obtained among the 266 clopidogrel-treated patients (38.5% vs. 27.9%; adjusted OR [95% CI] = 2.91 [1.46-5.8]) and in the 228 patients receiving ticagrelor (19.1% vs. 8.1%; adjusted OR [95% CI] = 2.55 [1.02-8.59]). CONCLUSION: In patients receiving dual antiplatelet therapy, advanced age is independently associated with a reduced effectiveness of ADP antagonists and a higher rate of HRPR with both clopidogrel and ticagrelor.

Impact of gender difference on vitamin D status and its relationship with the extent of coronary artery disease.

BACKGROUND AND AIM: There has been a surge of interest in the cardiovascular effects of vitamin D (25(OH)D), preventing the processes leading to vascular wall degeneration and coronary artery disease (CAD). Gender differences have been suggested for vitamin D status, with a higher rate of deficiency occurring especially in post-menopausal women, increasing the risk of bone fractures and osteoporosis. However, to date, few studies have evaluated the differences in 25(OH)D levels according to gender and their impact on the extent of CAD, which was therefore the aim of the present study. METHODS AND RESULTS: In patients undergoing coronary angiography, fasting samples were collected for the assessment of 25(OH)D levels. Significant CAD was defined as at least one vessel stenosis >50%, while severe CAD was defined as left main and/or three-vessel disease. Of the 1811 patients included, 530 (29.3%) were females, who displayed older age (p < 0.001), higher rate of renal failure (p < 0.001), hypertension (p = 0.05), treatment with angiotensin-receptor blockers (p = 0.03) and diuretics (p < 0.001), acute presentation (p < 0.001), higher platelet count (p < 0.001), glycosylated haemoglobin (p = 0.02) and cholesterol (p = 0.001), but an inverse relationship with smoking (p < 0.001), previous cardiovascular events (p < 0.001), treatment with statins and acetylsalicylic acid (ASA) (p < 0.001), body mass index (p = 0.002), haemoglobin (p < 0.001), leucocytes (p = 0.03) and triglycerides (p < 0.001). Female gender was associated with lower vitamin D levels (14.5 ± 10.9 vs. 15.9 ± 9.5, p = 0.007) and independently associated with severe vitamin D deficiency (41.9% vs. 30.4%, p < 0.001; adjusted odds ratio (OR) (95% confidence interval (CI)) = 1.42 (1.08-1.87), p = 0.01). Lower tertiles of vitamin D were associated with an increased prevalence and severity of CAD in females (adjusted OR (95% CI = 1.26 (1.10-1.44), p = 0.001 for CAD; adjusted OR (95% CI) = 1.6 (1.39-1.87), p < 0.001 for severe CAD). In males, vitamin D status was independently related to the prevalence (adjusted OR (95% CI) = 1.28 (1.02-1.61), p = 0.03) of CAD, but not the extent of CAD (adjusted OR (95% CI) = 1.02 (0.86-1.2), p = 0.84). CONCLUSION: Gender significantly affects vitamin D status. The lower 25(OH)D levels observed in females, as compared to males, play a more relevant role in conditioning the severity of CAD.

Impact of diabetes on neutrophil-to-lymphocyte ratio and its relationship to coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of mortality among diabetic patients, and the neutrophil-to-lymphocyte ratio (NLR) has recently emerged from among inflammatory parameters as a potential indicator of vascular complications and poorer outcome in patients with diabetes. This study aimed to evaluate: 1) the impact of diabetes on NLR; and 2) the role of NLR on the extent of CAD among diabetic patients undergoing coronary angiography. METHODS: Consecutive patients undergoing coronary angiography were included. Diabetic status and main chemistry parameters were assessed at the time of admission. Significant CAD was defined as at least one vessel with stenosis>50%, while severe CAD was left main and/or three-vessel disease, as evaluated by quantitative coronary angiography (QCA). RESULTS: Diabetes was observed in 1377 of 3756 patients (36.7%); they were older, and displayed higher-risk cardiovascular profile and more complex CAD. Diabetic status was also associated with a significant increase in NLR (P=0.004). Among diabetics, higher NLR tertile values were related to ageing (P<0.001), dyslipidaemia (P<0.001), renal failure (P<0.001), body mass index (P<0.001), previous percutaneous coronary revascularization (P=0.004) and cerebrovascular events (P=0.003), acute presentation (P<0.001), treatment at admission with beta-blockers/statins/ASA (all P<0.001), diuretics (P=0.01) or clopidogrel (P=0.04), platelet count (P=0.03), white blood cell count, creatinine, glycaemia and C-reactive protein (P<0.001), and inversely related to haemoglobin, triglyceride levels (P<0.001) and smoking (P=0.03). NLR was associated with multivessel disease (P<0.001), degree of stenosis (P=0.01), type C lesions (P=0.02), coronary calcifications and intracoronary thrombus (P<0.001), but inversely with in-stent restenosis (P=0.003) and TIMI flow grade (P=0.02). Also, NLR was directly related to CAD prevalence (P<0.001; adjusted OR [95% CI]: 1.62 [1.27-2.07], P<0.001) and CAD severity (P<0.001; adjusted OR [95% CI]: 1.19 [1.00-1.43], P=0.05). CONCLUSION: NLR is increased among diabetic patients and, in such patients, is independently associated with the prevalence and severity of CAD. Further studies are now needed to confirm present results and to evaluate the underlying pathophysiological mechanisms behind our findings.

Uric acid levels and the risk of Contrast Induced Nephropathy in patients undergoing coronary angiography or PCI.

BACKGROUND AND AIM: Contrast Induced Nephropathy (CIN) is a common complication of procedures that require the use of contrast media, and seems to be mediated by oxidative stress and reactive oxygen species generation. Hyperuricemia is characterized by inhibited nitric oxide system and enhanced synthesis of reactive oxygen species. However, few studies have so far investigated the association between hyperuricemia and CIN that is therefore the aim of the current study among patients undergoing coronary angiography or percutaneous intervention. METHODS AND RESULTS: We analyzed a total of 1950 patients with Creatinine clearance <90 ml/min) undergoing elective or urgent coronary angiography and/or angioplasty. Patients were divided according to tertiles of baseline uric acid (Group 1, ≤ 5.5 mg/dL n = 653; Group 2, 5.6-7.0 mg/dL, n = 654; Group 3, ≥ 7.0 mg/dL, n = 643). CIN was defined as an absolute ≥ 0.5 mg/dl or a relative ≥ 25% increase in the serum creatinine level at 24 or 48 h after the procedure. Patients with higher uric acid levels were older, previous smokers, with higher prevalence of hypertension and diabetes, but with lower family history of CAD. They had more often history of a previous CABG and baseline renal dysfunction. Patients of the third Tertile had also higher levels of white blood cells, higher triglycerides and lower HDL-cholesterol and higher percentage of dilated cardiomyopathy/valvular disease as indication for angiography and consequently a lower prevalence of PCI. Patients with higher SUA were more often on therapy with ACE inhibitors and diuretics, but less often with statins, nitrate, ASA and Clopidogrel at admission. The occurrence of CIN was observed in 251 patients (12.9%), and was significantly associated with uric acid levels (12.3% in Group 1, 10.4% in Group 2 and 16.0% in Group 3; p = 0.04). Similar results were observed when the analysis was performed according to each tertiles values in both male and female gender. The association between elevated uric acid (≥ 7 mg/dl) and CIN was confirmed by multivariate analysis after correction for baseline confounding (Adjusted OR [95%CI] = 1.42 [1.04-1.93], p = 0.026). Similar results were observed across major subgroups of high-risk patients, such as patients with diabetes, female gender, renal failure, hypertension, and elderly. CONCLUSIONS: This is the first large study showing that among patients undergoing coronary angiography or percutaneous interventions elevated uric acid level is independently associated with an increased risk of CIN.

Mechanistic modelling of toxicokinetic processes within Myriophyllum spicatum.

Effects of chemicals are, in most cases, caused by internal concentrations within organisms which rely on uptake and elimination kinetics. These processes might be key components for assessing the effects of time-variable exposure of chemicals which regularly occur in aquatic systems. However, the knowledge of toxicokinetic patterns caused by time-variable exposure is limited, and gaining such information is complex. In this work, a previously developed mechanistic growth model of Myriophyllum spicatum is coupled with a newly developed toxicokinetic part, providing a model that is able to predict uptake and elimination of chemicals, as well as distribution processes between plant compartments (leaves, stems, roots) of M. spicatum. It is shown, that toxicokinetic patterns, at least for most of the investigated chemicals, can be calculated in agreement with experimental observations, by only calibrating two chemical- specific parameters, the cuticular permeability and a plant/water partition coefficient. Through the model-based determination of the cuticular permeabilities of Isoproturon, Iofensulfuron, Fluridone, Imazamox and Penoxsulam, their toxicokinetic pattern can be described with the model approach. For the use of the model for predicting toxicokinetics of other chemicals, where experimental data is not available, equations are presented that are based on the log (P oct/wat) of a chemical and estimate parameters that are necessary to run the model. In general, a method is presented to analyze time-variable exposure of chemicals more in detail without conducting time and labour intensive experiments.

Predictors of re-fracture amongst patients managed within a secondary fracture prevention program: a 7-year prospective study.

SUMMARY: This 7-year prospective observational study determined the predictors of re-fracture amongst 234 patients managed within a Secondary Fracture Prevention programme. Poor compliance, multiple co-morbidities, corticosteroid therapy, low hip bone mineral density (BMD) or low body weight were all significantly associated with re-fracture in patients commenced on long-term anti-resorptive therapy. INTRODUCTION: Risk factors for osteoporotic fracture amongst treatment-naïve patients are well established. In contrast, predictors of re-fracture in patients optimally managed within a Secondary Fracture Prevention (SFP) programme are ill-defined. METHODS: This prospective observational study included 234 subjects with incident osteoporotic fractures managed long-term by the Concord SFP programme. Using Cox proportional hazards models, predictors of re-fracture were analysed separately for patients commenced on specific pharmacotherapy (group 1, N=171) and subjects receiving calcium and/or vitamin D supplements only (group 2, N=63). Relevant anthropometric, clinical and technical data were documented at each visit. Compliance and persistence were analysed as time-varying covariates. RESULTS: During a mean follow-up of 5.2 (range 3.5-7.3) years, 20.9% of all subjects re-fractured (26.3% in group 1, 6.3% in group 2). Multivariate predictors of re-fracture in group 1 were significant co-morbidity (HR 2.04 if >3, 95% CI 1.10-3.79, p=0.024), corticosteroid use (HR 1.75, 95% CI 1.12-2.73, p=0.013) and total hip BMD (HR 1.36 per 0.1 g/cm2 decrease, 95% CI 1.08-1.70, p=0.008). In contrast, gender, prevalent fractures and lumbar spine BMD were not associated with re-fracture. Amongst patients with complete compliance data, a medication possession ratio of ≤50% (HR 3.36, 95% CI 1.32-8.53, p=0.011) and low body weight (HR 1.04 per 1-kg decrease, 95% CI 1.003-1.08, p=0.032) were significantly associated with re-fracture. CONCLUSIONS: Amongst patients managed within a dedicated SFP programme, poor compliance, multiple co-morbidities, corticosteroid therapy, low hip BMD or low body weight are all associated with increased risk of re-fracture. This subgroup of patients therefore require intensive management including strategies to improve compliance.

Effects of HDL-modifiers on cardiovascular outcomes: a meta-analysis of randomized trials.

BACKGROUND AND AIM: High density lipoproteins (HDL) have been addressed as a potential strategy for cardiovascular prevention, with great controversies on pharmacological approaches for HDL-elevation. Our aim was to compare HDL-rising treatment with niacin or CETP-inhibitors with optimal medical therapy in cardiovascular outcome. METHODS AND RESULTS: Randomized trials were searched. Primary endpoint was cardiovascular death, secondary were: non fatal myocardial infarction; coronary revascularization; cerebrovascular accidents and safety endpoints. As many as 18 randomized trials, for a total of 69,515 patients, were included. HDL-modifiers did not reduce cardiovascular mortality (2.3%vs3.4%; OR [95%CI] = 0.96 [0.87-1.05], p = 0.37, phet = 0.58), with no benefit from niacin/CETP inhibitors according to patients' risk profile (beta [95%CI] = -0.14 [-0.29 to 0.02], p = 0.09) or the amount of HDL increase (beta [95%CI] = 0.014 [-0.008 to 0.04], p = 0.21). Niacin but not CETP-I reduced myocardial infarction and coronary revascularization, but higher rate of SAE occurred with HDL-modifiers (OR [95%CI] = 1.24 [1.18-1.31], p < 0.00001, phet = 0.02), in particular new onset of diabetes with niacin and worsening of hypertension with CETP-inhibitors. CONCLUSIONS: Niacin and CETP inhibitors do not influence cardiovascular mortality. Significant benefits in MI and coronary revascularization were observed with niacin, despite the higher occurrence of diabetes.

Effects of light and temperature fluctuations on the growth of Myriophyllum spicatum in toxicity tests--a model-based analysis.

Laboratory toxicity tests are a key component of the aquatic risk assessments of chemicals. Toxicity tests with Myriophyllum spicatum are conducted based on working procedures that provide detailed instructions on how to set up the experiment, e.g., which experimental design is necessary to get reproducible and thus comparable results. Approved working procedures are established by analyzing numerous toxicity tests to find a compromise between practical reasons (e.g., acceptable ranges of ambient conditions as they cannot be kept completely constant) and the ability for detecting growth alterations. However, the benefit of each step of a working procedure, e.g., the random repositioning of test beakers, cannot be exactly quantified, although this information might be useful to evaluate working procedures. In this paper, a growth model of M. spicatum was developed and used to assess the impact of temperature and light fluctuations within the standardized setup. It was analyzed how important it is to randomly reassign the location of each plant during laboratory tests to keep differences between the relative growth rates of individual plants low. Moreover, two examples are presented on how modeling can give insight into toxicity testing. Results showed that randomly repositioning of individual plants during an experiment can compensate for fluctuations of light and temperature. A method is presented on how models can be used to improve experimental designs and to quantify their benefits by predicting growth responses.

MTHFR polymorphism and risk of periprocedural myocardial infarction after coronary stenting.

BACKGROUND AND AIM: Pro-thrombotic status and platelet hyperreactivity still represent an important challenge for periprocedural myocardial infarction (PMI) after coronary stenting. Hyperhomocysteinemia has been suggested to increase the risk of cardiovascular events. The genetic variant of methylenetetrahydrofolate reductase (MTHFR) 677 C > T has been associated to reduced function of the enzyme, thus inducing hyperhomocysteinemia. In our study we investigated whether MTHFR 677 C > T polymorphism is associated with increased risk of periprocedural MI in patients undergoing coronary stenting. METHODS AND RESULTS: We included 778 patients undergoing PCI. Homocysteinemia and genetic status were assessed at admission for all patients. Myonecrosis biomarkers were dosed at intervals from 6 to 48 h, PMI was defined as CKMB increase by 3 times the ULN or 50% of pre-PCI value, periprocedural myonecrosis for troponin I increase by 3 times the ULN or by 50% of the baseline. As many as 521 patients carried the MTHFR-T allele. No difference was found for main demographical and clinical features nor for biochemistry parameters, but for higher rate of statins treatment (p = 0.03) in T-carriers. Polymorphic patients displayed significantly higher levels of homocysteine (p = 0.005), with additive effect of the mutated T-alleles. Angiographic and procedural features were similar according to genetic status. MTHFR677T was not associated with periprocedural myocardial infarction (adjusted OR = 0.97[0.67-1.4], p = 0.87) or myonecrosis (adjusted OR = 1.03[0.83-1.36], p = 0.82). Same results were found at subgroup analysis in higher-risk subsets of patients. CONCLUSION: Our study showed that among patients undergoing PCI, MTHFR 677 C > T polymorphism is associated to higher homocysteine levels, but does not influence the risk of periprocedural myocardial infarction.

Compliance and persistence to oral bisphosphonate therapy following initiation within a secondary fracture prevention program: a randomised controlled trial of specialist vs. non-specialist management.

UNLABELLED: Following initiation of oral bisphosphonate therapy through a secondary fracture prevention program, 2-year treatment compliance and persistence remained high and were similar in patients randomised to follow-up by either the program or primary care physician. Thus, community-based and specialist management are equally effective in supporting compliance and persistence with anti-osteoporotic treatments. INTRODUCTION: The purpose of this study was to determine whether management by a secondary fracture prevention (SFP) program (aka "fracture liaison service") results in better compliance and persistence to oral bisphosphonate therapy than follow-up by the primary care physician, after initiation within an SFP program. METHODS: This prospective RCT included 102 patients with incident osteoporotic fractures referred to a SFP program in Sydney, Australia. Following oral bisphosphonate therapy initiation, patients were randomised to either 6-monthly follow-up with the SFP program (group A) or referral to their primary care physician with a single SFP program visit at 24 months (group B). Compliance and persistence to treatment were measured using pharmaceutical claims data. Predictors of compliance and persistence and associations between compliance and persistence, and changes in bone mineral density (BMD) or bone resorption marker, urinary deoxypyridinoline over 24 months were analysed. RESULTS: The median medication possession ratio at 24 months was 0.78 (IQR, 0.50-0.93) in group A and 0.79 (IQR, 0.48-0.96) in group B (p = 0.68). Persistence at 24 months was also similar in both groups (64 vs. 61%, respectively; p = 0.75). After adjusting for confounders, patients in group A were not more likely to be compliant (OR, 1.06; 95% CI, 0.46-2.47) or persistent (HR, 0.83; 95% CI, 0.27-1.67) than those randomised to group B. Time-based changes in BMD or bone turnover were not associated with compliance or persistence. CONCLUSION: Compliance and persistence to oral bisphosphonate therapy remain high amongst patients initiated within an SFP program, with community-based and SFP program management being equally effective in maintaining therapeutic compliance and persistence over 2 years. These results indicate that one of the main functions of an SFP program may be the initiation of therapy rather than continuous patient monitoring.