Methylation status of various gene loci in localized prostate cancer: Novel biomarkers for diagnostics and biochemical recurrence.

BACKGROUND: Oncologic outcomes for patients with localized prostate cancer (PCa) undergoing radical prostatectomy (RP) can vary widely. Hypermethylation of tumor-associated genes has potential as a novel diagnostic tool and predictive biomarker in PCa. We investigated the methylation status of tumor-associated genes in patients who underwent RP. METHODS: Patients who underwent RP during 2004 to 2008 were matched retrospectively based on post-operative D'Amico risk stratification. Quantitative pyrosequencing was used to analyze methylation status of 10 gene loci in cancerous and adjacent benign tissue from histological specimen. Follow-up was performed according to EAU guideline recommendations. Statistical analyses were performed to correlate methylation levels in cancerous and benign tissue with risk profiles and biochemical recurrence (BCR). RESULTS: The cohort included 71 patients: 22 low-risk, 22 intermediate-risk, and 27 high-risk. Mean follow-up time was 74 months. Methylation status differed significantly between cancerous and adjacent benign tissue for the 5 gene loci GSTP1, APC, RASSF1, TNFRFS10c, and RUNX3 (each P < 0.001). Also, the methylation level was significantly higher in high-risk than in low-risk patients for Endoglin2 and APC (P = 0.026; P = 0.032). Using ROC analysis, hypermethylation of APC in PCa tissue was associated with higher risk of BCR (P = 0.005). CONCLUSION: Methylation status of various gene loci holds diagnostic and predictive potential in PCa. Hypermethylation of APC, RASSF1, TNFRFS10c and RUNX3 were identified as novel PCa-specific biomarkers. Furthermore, increased methylation levels of APC and Endoglin2 were associated with high-risk PCa. Additionally, hypermethylation of APC was associated with increased risk of BCR after RP.

Peripheral and Portal Venous KRAS ctDNA Detection as Independent Prognostic Markers of Early Tumor Recurrence in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: KRAS circulating tumor DNA (ctDNA) has shown biomarker potential for pancreatic ductal adenocarcinoma (PDAC) but has not been applied in clinical routine yet. We aim to improve clinical applicability of ctDNA detection in PDAC and to study the impact of blood-draw site and time point on the detectability and prognostic role of KRAS mutations. METHODS: 221 blood samples from 108 PDAC patients (65 curative, 43 palliative) were analyzed. Baseline peripheral and tumor-draining portal venous (PV), postoperative, and follow-up blood were analyzed and correlated with prognosis. RESULTS: Significantly higher KRAS mutant detection rates and copy numbers were observed in palliative compared to curative patients baseline blood (58.1% vs 24.6%; P = 0.002; and P < 0.001). Significantly higher KRAS mutant copies were found in PV blood compared to baseline (P < 0.05) samples. KRAS detection in pre- and postoperative and PV blood were significantly associated with shorter recurrence-free survival (all P < 0.015) and identified as independent prognostic markers. KRAS ctDNA status was also an independent unfavorable prognostic factor for shorter overall survival in both palliative and curative cohorts (hazard ratio [HR] 4.9, P = 0.011; HR 6.9, P = 0.008). CONCLUSIONS: KRAS ctDNA detection is an independent adverse prognostic marker in curative and palliative PDAC patients-at all sites of blood draw and a strong follow-up marker. The most substantial prognostic impact was seen for PV blood, which could be an effective novel tool for identifying prognostic borderline patients-guiding future decision-making on neoadjuvant treatment despite anatomical resectability. In addition, higher PV mutant copy numbers contribute to an improved technical feasibility.

Vitamin D oral intermittent treatment (DO IT) study, a randomized clinical trial with individual loading regimen.

Comparison of several regimens of oral vitamin D including an individually calculated loading regimen with the aim of achieving serum values > 75 nmol/l. Interventional, randomized, 3-arm study in vitamin D-deficient outpatients. Participants were allocated to supplementation of 24,000 IU vitamin D monthly over three months, using either a monthly drinking solution (Vi-De 3) or capsule (D3 VitaCaps), or an individualized loading regimen with the capsules taken weekly. For the loading regimen, the cumulative dose was calculated according to baseline 25-hydroxy-vitamin D (25(OH)D) serum value and body weight. Main inclusion criteria were age ≥ 18 years and 25(OH)D serum concentration < 50 nmol/l. The primary outcome was 25(OH)D serum concentration one week after treatment termination. Secondary endpoints were patient's preferences and adverse events. Full datasets were obtained from 52 patients. Mean 25(OH)D values were statistically significant higher after a loading regimen compared to a monthly administration of 24,000 IU vitamin D (76.4 ± 15.8 vs 61.4 ± 10.8 nmol/l; p < 0.01). All patients treated with the loading regimen reached sufficient 25(OH)D values > 50 nmol/l. Serum 25(OH)D values > 75 nmol/l were observed more frequently in patients taking the loading regimen (47% vs 11% drinking solution vs 12% capsules). Vitamin D-related adverse effects did not occur in any treatment groups. Capsules were preferred by 88.5% of the patients. Compared to treatments with monthly intake of 24,000 IU vitamin D, the intake of an individually calculated weekly loading regimen was able to raise serum concentrations > 50 nmol/l in all cases within a safe range.

Identification of Patients with Cobalamin Deficiency Crucially Depends on the Diagnostic Strategy.

BACKGROUND: Our goal was to determine vitamin B12 (cobalamin) deficiency with different diagnostic strategies, to propose the best possible laboratory strategy, and to synthesize the relevance of biomarkers in the diagnosis of a cobalamin deficiency. METHODS: We performed a secondary data analysis. The testing strategies were (i) vitamin B12 solely, (ii) holotranscobolamin solely, (iii) vitamin B12 and holotranscobolamin, and (iv) reflex testing of holotranscobalamin in samples with vitamin B12 < 300 pmol. A set of 3,044 laboratory samples with vitamin B12 and holotranscobalamin serum values from unselected in- and outpatients from a secondary care hospital. A sample was classified as cobalamin deficient when low values of vitamin B12 < 137 pmol/L or holotranscobalamin ≤ 37 pmol/L were measured. RESULTS: Low cobalamin values were identified in 591 (19.4%) samples either according to low vitamin B12 values (305; 10.0%) or low holotranscobalamin values (436; 14.3%). For 2,404 values with vitamin B12 < 300 pmol/L, the additional measurement of holotranscobalamin (reflex-testing) enabled the detection of an additional 278 (9.1%) deficiencies. When the grey zone was decreased to 138 - 219 pmol/L, the reflex testing of an additional 1,240 samples identified a total of 511 (16.8%) samples as cobalamin deficient. CONCLUSIONS: The identification of cobalamin deficiency or sufficiency highly depends on the diagnostic strategy. A reflex testing with a grey zone for vitamin B12 < 220 pmol/L identifies cobalamin deficiency cost efficiently in 86.5% cases (511 out of 591). Physicians should apply a uniform strategy on how to address the diagnosis of cobalamin deficiency and indication for treatment. In-hospital guidelines, which describe methodology and sensitivity of the locally used assays for vitamin B12 and holotranscobalamin could guide them.

Dyskalemias in patients with acute kidney injury presenting to the emergency department are common and independent predictors of adverse outcome.

BACKGROUND: No data concerning the prevalence and risk factors of dyskalemia in acute kidney injury (AKI) exist. We investigated (a) prevalence rates, (b) risk factors and (c) outcome of hypo- and hyperkalemia in emergency patients. METHODS: In this cross-sectional analysis, all patients admitted to the emergency department of a large public hospital in Switzerland between January 1st 2017 and December 31st 2018 with measurements of creatinine and potassium were included. Baseline characteristics, medication and laboratory data were extracted. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract their baseline creatinine. For all other patients, the ADQI backformula was used in order to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of hyperkalemia and outcome. RESULTS: AKI was found in 8% of patients. Hyperkalemia was present in 13% and hypokalemia in 11% of patients with AKI. AKI stage, potassium-sparing diuretics, ACE inhibitors and underlying CKD were the strongest risk factors for hyperkalemia. Hyperkalemia as well as profound hypokalemia were independently associated with prolonged length of stay and in-hospital mortality. The study is limited by its dependency on chart review data in order to identify patients with chronic kidney disease and by limitations of the ADQI backformula to calculate baseline creatinine. CONCLUSIONS: Dyskalemias are common in emergency patients with AKI and are independent risk factors for adverse outcomes. Potassium-sparing diuretics, ACE-inhibitors, AKIN stage and CKD are predictors of hyperkalemia in AKI.

Oral intermittent vitamin D substitution: influence of pharmaceutical form and dosage frequency on medication adherence: a randomized clinical trial.

BACKGROUND: To assess adherence to and preference for vitamin D substitution with different pharmaceutical forms and frequencies of administration. METHODS: A focus group of stakeholders aimed at preparing the design of an interventional, randomized, cross-over study with 2 × 2 groups obtaining monthly or weekly vitamin D products in liquid or solid form for 3 months each. Dosage corresponds to cumulated amount of recommended 800 IU daily (5.600 IU weekly / 24.000 IU monthly). Main inclusion criteria were a vitamin D serum value < 50 nmol/l and age ≥ 18 years. Primary endpoint was adherence, secondary endpoints were preferences and vitamin D serum levels. RESULTS: The focus group reached consensus for preference of a monthly administration of solid forms to adults. Full datasets were obtained from 97 participants. Adherence was significantly higher with monthly (79.5-100.0%) than weekly (66.4-98.1%) administration. Vitamin D levels increased significantly (p < 0.001) in all participants. An optimal value of > 75 nmol/l was achieved by 32% after 3 months and by 50% after 6 months. Preferred formulation was solid form (tablets, capsules) for 71% of participants, and preferred dosage frequency was monthly for 39% of participants. CONCLUSIONS: Monthly oral vitamin D in solid form lead to the highest adherence, and is preferred by the participants. However, only one third of study participants achieved values in the optimal range of > 75 nmol/l cholecalciferol using weekly or monthly administration providing an average daily cholecalciferol dose of 800 IU. TRIAL REGISTRATION: NCT03121593 | SNCTP000002251 . Registered 30. May 2017,. Prospectively registered.

Dysnatremias in emergency patients with acute kidney injury: A cross-sectional analysis.

PURPOSE: We aimed to investigate the prevalence, risk factors and outcome of hypo- and hypernatremia in emergency patients with acute kidney injury (AKI). METHODS: In this cross-sectional analysis all emergency patients between January 1st 2017 and December 31st 2018 with measurements of creatinine and sodium were included. Baseline characteristics, medication and laboratory data were gathered. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract baseline creatinine. For all other patients the ADQI backformula was used to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of dysnatremias and outcome. RESULTS: AKI was found in 8% of patients. 392 patients (23.16%) had hyponatremia, 24 (1.4%) had hypernatremia. Use of potassium sparing diuretics, a medical cause for emergency referral, use of thiazide diuretics and AKI stage were the strongest risk factors for hyponatremia. Loop diuretics, a medical cause for emergency referral and AKI stage were risk factors for hypernatremia. In patients with all classes of hyponatremia, length of hospital stay was significantly longer compared to patients with a normal serum sodium. In the binary logistic regression analysis with death as outcome, hyponatremia as well as severe hypernatremia were independent risk factors for mortality. CONCLUSIONS: Dysnatremias are common in emergency patients with AKI. Diuretic medication is a major risk factor for hypo- and hypernatremia. Both hyponatremia and severe hypernatremia were independent risk factors for adverse outcome.

Oral Anticoagulation in Patients in the Emergency Department: High Rates of Off-Label Doses, No Difference in Bleeding Rates.

BACKGROUND: Empirically, a significant proportion of patients using direct oral anticoagulation (DOAC) take off-label reduced doses. We aimed to investigate the prevalence, indications, dosages, and bleeding complications of oral anticoagulants on admission to the emergency department. METHODS: In this retrospective analysis, patients presenting to our emergency department between January 1 and December 31, 2018, with therapeutic oral anticoagulation were included (ie, vitamin-K antagonists, rivaroxaban, apixaban, edoxaban, and dabigatran). A detailed chart review was performed for each case concerning characteristics, indication, and bleeding complications. RESULTS: A total of 19,662 consecutive cases in the emergency department were reported: 1721 (9%) had therapeutic oral anticoagulation. Vitamin-K antagonists (41%), rivaroxaban (36%), and apixaban (19%) were the most common. Stroke prophylaxis in patients with atrial fibrillation (63.2%) and venous thromboembolism (24.1%) were the most common indications. In 27 cases (1.6%), no indication could be identified; further, 32% of patients were classified to have either off-label doses of DOACs or an international normalized ratio (INR) out of range (in vitamin-K antagonists), whereas 20% were classified as off-label underdosed and 12% as overdosed. No difference in the likelihood of bleeding on admission could be found between the respective drugs. Only concomitant use of aspirin was significantly associated with presence and higher severity of bleeding. CONCLUSIONS: Vitamin-K antagonists are still the most widely used drug followed by rivaroxaban. A significant proportion of patients are being prescribed off label-doses. While no difference was found for the respective anticoagulants with respect to bleeding, concomitant aspirin use was a significant predictor for bleeding in our collective.

The impact of species, respiration type, growth phase and genetic inventory on absolute metal content of intact bacterial cells.

Metal ions are abundant in microbial proteins and have structural, catalytic or electron-transferring roles. Metalloproteins are especially prevalent in respiratory chains where they couple electron flow with proton translocation across the membrane. Here, we explore the hypothesis that anaerobic respiratory chains can be investigated by quantitative whole-cell metallomics of the key metals Fe, Co, Ni and Mo. Sensitive and strictly quantitative data were obtained by inductively-coupled plasma mass spectrometry when using a triple quadrupole instrument (ICP-QqQ-MS). Our experiments provide data on the absolute cellular metal content of E. coli, an enrichment culture of "Ca. Kuenenia stuttgartiensis", Dehalococcoides mccartyi, Desulfovibrio vulgaris, Geobacter sulfurreducens and Geobacter metallireducens. A major obstacle in whole-cell metallomics is the interference caused by metal precipitates, observed for G. metallireducens and D. vulgaris. In the other investigated organisms, whole-cell metallomics gave biologically meaningful information, e.g. high Fe and Co content in "Ca. K. stuttgartiensis" and higher Mo content in E. coli when grown under nitrate-reducing conditions. The content of all four metals was almost constant in E. coli from the late exponential phase allowing precise measurements independent of the exact duration of cultivation. Deletion or overexpression of genes involved in metal homeostasis (Ni transport or Mo-cofactor metabolism) was mirrored by dramatic changes in whole-cell metal content. Deletion of genes encoding abundant metalloproteins or heterologous overexpression of metalloproteins was also reflected in the whole-cell metal content. Our study provides a reference point for absolute microbial metallomics and paves the way for the development of fast and easy mutation screens.

Impact of type 2 Diabetes and Metformin use on Vitamin B12 Associated Biomarkers - an Observational Study.

AIMS: Assessment of the impact of type 2 diabetes (T2DM) and metformin use on vitamin B12 (VB12) associated biomarkers and their suitability to represent VB12 supply. METHODS: Differences of VB12, holotranscobalamine (HoloTc), the biologically active fraction (%AB12)=HoloTc/VB12*100 and homocystein (Hcy) were analysed i) among diabetic outpatients with (DMMet+ ) and without metformin use (DMMet-) and ii) in comparison to an external non-diabetic reference group with low VB12 (<200 pmol/L). RESULTS: VB12 associated biomarkers were distributed equally between DMMet+ (n=29, 58%) and DMMet- (n=21, 42%). Significant differences in %AB12 in diabetic patients with low VB12 (n=19) compared to the non-diabetic reference group (n=31) were found. Higher %AB12 was associated with diabetes. Hcy levels were significantly associated with age, folic acid level, renal function and HoloTc but not with VB12. CONCLUSIONS: In T2DM patients with low VB12, %AB12 was confirmed as being higher in comparison to nondiabetic patients. The effect was not clearly attributable to metformin use. HoloTc was unaffected by the lowering of VB12 and significantly associated with the functional marker Hcy. Both findings support the use of HoloTc for the assessment of VB12 supply in diabetic patients.

Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial.

BACKGROUND: Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (i.m.) injection of VB12. Whenever alternative routes of administration exist, patient preferences should be considered when choosing the treatment. We aimed to assess outpatient preferences towards oral or IM VB12 substitution and confirm noninferiority of early biomarker response with oral treatment, in a typical primary care population. METHODS: Prospective randomised nonblinded parallel-group trial. Patients were recruited by their general practitioner and randomly assigned to oral or IM treatment. Group O-oral was given 28 tablets of 1000 µg cyanocobalamin in a monthly punch card fitted with an electronic monitoring system. Group I-IM received four, weekly injections of 1000 µg hydroxocobalamin. Blood samples were drawn before the first administration and after 1, 2 and 4 weeks of treatment, and analysed for VB12, holotranscobalamin (HoloTc), homocysteine (Hcy) and methylmalonic acid (MMA). For group O-oral, treatment adher-ence and percentage of days with 2 dosing events were calcu-lated. Before and after 28 days of treatment, patients were asked to fill in a questionnaire about their preference for the therapy options and associated factors. RESULTS: Between November 2013 and December 2015, 37 patients (age: 49.5 ± 18.5 years; women: 60.5%) were recruited for oral (19) or IM (18) treatment. Baseline values with 95% confidence intervals for serum VB12, HoloTc, Hcy and MMA were 158 pmol/l [145-172], 49.0 pmol/l [40.4-57.5], 14.8 µmol/l [12.0-17.7] and 304 nmol/l [219-390], respective-ly, in group O-oral and 164 pmol/l [154-174], 50.1 pmol/l [38.7-61.6], 13.0 µmol/l [11.0-15.1] and 321 nmol/l [215-427], respectively, in group I-IM (not significant). After 1 month of treatment, levels of VB12 and HoloTc showed a significant increase compared with baseline (group O-oral: VB12 354 pmol/l [298-410] and HoloTc 156 pmol/l [116-196]; group I-IM: VB12 2796 pmol/l [1277-4314] and HoloTc 1269 pmol/l [103-2435]). Hcy and MMA levels showed a significant decrease compared with baseline (group O-oral: Hcy 13.8 µmol/l [10.7-16.8] and MMA 168 nmol/l [134-202]; group I-IM: Hcy 8.5 µmol/l [7.1-9.8] and MMA 156 nmol/l [121-190]). HoloTc and MMA levels were normalised in all patients after 4 weeks of treatment, whereas normalisation of VB12 and Hcy was reached by all patients in group I-IM only. Response of VB12, HoloTc and Hcy was more pronounced in group I-IM (p <0.01) and the primary hypothesis that oral VB12 treatment would be noninfe-rior to IM treatment was rejected. Average adherence to thera-py was 99.6 ± 1.1% and days with 2 dosing events reached 5.6%. Before randomisation, preference was in favour of oral treatment (45.9%, n = 17) over IM administration (21.6%, n = 8). Twelve patients (32.4%) had no preference. Nine (24.3%) patients changed their preference after treatment. Patients who obtained their preferred route of administration main-tained their preference in the case of oral treatment and changed their preference after IM treatment. CONCLUSIONS: Differences in VB12 levels between groups were higher than expected. Therefore, noninferiority of oral treat-ment had to be rejected. However, normalisation of HoloTc and MMA was reached by all patients after a 1-month treatment period. The clinical benefit of the exaggerated biomarker re-sponse after IM treatment within a typical primary care popula-tion is questionable. Midterm biomarker effects and patient preferences should be considered when a therapeutic scheme is chosen. Initial rating in favour of either IM or oral therapy can change over time and justifies repeated re-evaluation of patient preferences. (ClinicalTrials.gov ID NCT01832129).

The 8-item Morisky Medication Adherence Scale translated in German and validated against objective and subjective polypharmacy adherence measures in cardiovascular patients.

RATIONALE, AIMS AND OBJECTIVES: To translate in German the 8-item Morisky Medication Adherence Scale (MMAS-8D). To validate it against objective and subjective measures of adherence in cardiovascular patients with polypharmacy. METHODS: A standard forward-backward procedure was used to translate the MMAS-8 into German. Validation took place on a convenience sample of ambulatory patients on chronic antiplatelet therapy between June 2010 and June 2011. Objective adherence was obtained from electronically monitored multi-drug punch cards. Internal consistency was assessed using Cronbach's alpha coefficient, construct validity using exploratory factor analyses and correlations between MMAS-8D and related measures. Convergent validity was assessed with a subjective questionnaire about beliefs about medicines (BMQ Specific, two sub-scales). RESULTS: A total of 70 patients were included (mean age 65.7 ± 9.9 years; 31.4% women). The mean score of the MMAS-8D was 7.5 (SD 0.8; range 4.5-8). Moderate internal consistency (alpha = 0.31) was observed due to multidimensionality of the scale. Factor analysis yielded four components that accounted for 71.7% of the total variance. Convergent validity was supported by significant correlations with BMQ Necessity (r = 0.31, P < 0.01), BMQ Concerns (r = -0.16, P < 0.05) and with electronic adherence reports (U-values 44 and 471, P < 0.05). Platelet aggregation values were within therapeutic range for 80% of the patients. Blood values of the antiplatelet agent within therapeutic range were associated with a higher MMAS-8D score (U-value 125, P < 0.05). CONCLUSIONS: The German MMAS-8 appears to be a reliable instrument to catch medication adherence in cardiovascular patients. It may be useful in patients with chronic therapy for detecting non-adherence.

Prevalence of femoro-acetabular impingement in international competitive track and field athletes.

PURPOSE: The aim of our study was to analyse the prevalence of femoro-acetabular impingement (FAI) in national elite track and field athletes compared to peers using magnetic resonance imaging (MRI) and clinical examination including impingement tests. METHODS: A total of 44 participants (22 national elite track and field athletes and 22 non-athletes) underwent an MRI for radiological findings associated with FAI, including alpha angle, lateral centre edge angle (CEA), findings of labral and cartilage lesions. The study group was furthermore investigated by the hip outcome score (HOS) and a clinical hip examination including range of motion (ROM) and impingement tests. RESULTS: Concerning the cam impingement, there was a significant difference measured by mean alpha angle between the athlete group (52.2 ± 7.29°) and the control group (48.1 ± 5.45°, P = 0.004). Eleven athletes showed a cam impingement, while two probands of the control group had a pincer impingement and one a mixed form (P = 0.0217). There was no statistically significant difference concerning the CEA upon evaluating pincer impingement. Seven track and field athletes had a positive impingement test, whereof three had an increased alpha angle >55°. No participant of the control group showed pathological results in the impingement test (P = 0.0121). CONCLUSIONS: MRI evidence and clinical examination suggest that cam impingement is more common in elite athletes in comparison to non-athletes. At a professional level, the intense practice of track and field athletics is susceptible for FAI.

Comparative study of the femoroacetabular impingement (FAI) prevalence in male semiprofessional and amateur soccer players.

INTRODUCTION: Femoroacetabular impingement (FAI) represents a novel approach to the mechanical etiology of hip osteoarthritis. The cam-type femoroacetabular impingement deformity occurs frequently in young male athletes. The aim of our study was to evaluate the prevalence of FAI in male semiprofessional soccer players using clinical examination and magnetic resonance imaging (MRI), compared to amateur soccer players. In MRI, the α angle of Nötzli is determined for quantifying FAI. MATERIALS AND METHODS: According to power analysis, a total of 22 asymptomatic semiprofessional soccer players with a median of 23.3 years of age (range 18-30 years) and 22 male amateur soccer players with a median of 22.5 years of age (control group, range 18-29 years) underwent an MRI to measure the hip α angle of Nötzli. The α angle of the kicking legs of the semiprofessional group and the amateur group were analyzed. The study group was moreover evaluated by the Hip Outcome Score (HOS) and a clinical hip examination including range of motion (ROM) and impingement tests. RESULTS: In the semiprofessional group, 19 soccer players had a right kicking leg and 1 soccer player had a left kicking leg. 2 soccer players kicked with two feet. In the semi-professional group, the mean value of the α angle of the kicking leg (57.3 ± 8.2°) was significantly higher than in the amateur group (51.7 ± 4.8°, P = 0.008). In the semi-professional group, 15 (62.5 %) of 24 kicking legs had an increased α angle >55°, while 5 (27.3 %) kicking legs of the amateur group had an α angle >55°. Five semi professional soccer players had findings in clinical examination, whereof 4 had an increased α angle >55°. No participant of the amateur group showed pathological results in the clinical examination (P = 0.0484). Overall, semiprofessional soccer players had a higher proportion of an increased α angle than the amateur group. CONCLUSIONS: Semiprofessional players have a higher prevalence of an increased α angle in the kicking leg than the amateur group at the same age. The kicking leg is predisposed for FAI.

Biomechanical and functional indicators in male semiprofessional soccer players with increased hip alpha angles vs. amateur soccer players.

BACKGROUND: Femoroacetabular impingement (FAI) is predominant in young male athletes, but not much is known about gait differences in cases of increased hip alpha angles. In our study, the hip alpha angle of Nötzli of soccer players was quantified on the basis of magnetic resonance imaging (MRI) with axial oblique sequences. The aim of the current study was to compare the rearfoot motion and plantar pressure in male semiprofessional soccer players with increased alpha angles to age-matched amateur soccer players. METHODS: In a prospective analysis, male semiprofessional and amateur soccer players had an MRI of the right hip to measure the alpha angle of Nötzli. In a biomechanical laboratory setting, 14 of these participants in each group ran in two shoe conditions. Simultaneously in-shoe pressure distribution, tibial acceleration, and rearfoot motion measurements of the right foot were performed. RESULTS: In the semiprofessional soccer group, the mean value of the alpha angle of group was 55.1 ± 6.58° (range 43.2-76.6°) and 51.6 ± 4.43° (range 41.9-58.8°) in the amateur group. In both shoe conditions, we found a significant difference between the two groups concerning the ground reaction forces, tibial acceleration, rearfoot motion and plantar pressure parameters (P < 0.01, P < 0.05, P = 0.04). Maximum rearfoot motion is about 22% lower in the semiprofessional group compared to the amateur group in both shoe conditions. CONCLUSIONS: This study confirmed that semiprofessional soccer players with increased alpha angles showed differences in gait kinematics compared to the amateur group. These findings support the need for a screening program for competitive soccer players. In cases of a conspicuous gait analysis and symptomatic hip pain, FAI must be ruled out by further diagnostic tests.

Antiplatelet resistance in outpatients with monitored adherence.

Antiplatelet resistance with aspirin and clopidogrel has been associated with clinical, cellular and pharmacogenetic factors; and non-adherence has been considered as a major contributor to resistance in outpatients. We aimed at assessing factors to resistance when adherence to the antiplatelet drugs and all other oral solid drugs was controlled for. In a pilot study, we tested arachidonic acid and/or ADP-induced in vitro platelet aggregation of 82 outpatients with chronic aspirin and/or clopidogrel treatment before and after a one-week period of measuring the patient's adherence with the polymedication electronic monitoring system (POEMS). Resistance was found in 20% (aspirin; n = 69) and 25% (clopidogrel; n = 32) of the patients after monitored adherence. Mean platelet aggregation was not (aspirin) or non-significantly (clopidogrel) lowered when compared to baseline. Diabetes mellitus and inflammation were consistently associated with resistance to both drugs, but CYP2C19 polymorphisms could not be confirmed as predictors of clopidogrel response. Electronically compiled multidrug dosing histories allowed the concomitant intake of high-dose lipophilic statins to be identified as a risk factor of impaired response to clopidogrel and revealed that exposure to further potential drug-drug interactions (DDIs) was too low for analysis. Multidrug adherence monitoring allowed thus dismissing non-adherence as a major contributor to resistance and inter-individual response variability in an outpatient setting. Additionally, it allowed analysing the impact of DDIs according to the actual exposure to the potentially interfering drugs. Further studies based on this methodology are essential to prevent misleading results due to incomplete adherence and gain additional insight into the impact of timing adherence on antiplatelet drug response.

Polymedication Electronic Monitoring System (POEMS) - a new technology for measuring adherence.

INTRODUCTION: Reliable and precise measurement of patient adherence to medications is feasible by incorporating a microcircuitry into pharmaceutical packages of various designs, such that the maneuvers needed to remove a dose of drug are detected, time-stamped, and stored. The principle is called "electronic medication event monitoring" but is currently limited to the monitoring of a single drug therapy. AIM: Our aims were introducing a new technology; a clear, self-adhesive polymer film, with printed loops of conductive wires that can be affixed to multidrug punch cards for the electronic adherence monitoring of multiple medication regimens (Polymedication Electronic Monitoring System, POEMS), and illustrating potential benefits for patient care. We present a preliminary report with one patient experience. MATERIALS AND METHODS: Our illustrative case was supplied with a pre-filled 7-day multiple medication punch card with unit-of-use doses for specific times of the day (six pills in the morning cavity, two pills in the evening cavity, and one pill in case of insomnia in the bedtime cavity), with the new electronic film affixed on it. RESULTS: The intake times over 1 week were extremely skewed (median intake hours at 2:00 pm for the morning doses and at 6:40 pm for the evening doses). After an intervention aimed at optimizing the timing adherence, the morning and evening intake hours became more balanced, with 42.3% of correct dosing intervals (±3 h) for drugs with twice daily intake (vs. 0% before the intervention). DISCUSSION: The electronic monitoring of the entire therapy revealed an intake pattern that would have remained undiscovered with any other device and allowed a personalized intervention to correct an inadequate medication intake behavior. POEMS may guide health professionals when they need to optimize a pharmacotherapy because of suspected insufficient adherence. Further, knowing the intake pattern of the entire pharmacotherapy can elucidate unreached clinical outcome, drug-drug interactions, and drug resistance. In the near future, one could imagine that medication adherence data over the entire therapy plan would be available as soon as the electronic wires are activated, so that a failure to take medication could be detected immediately and intervention could be taken if appropriate.

The Rabe amination after a century: direct addition of N-heterocycles to carbonyl compounds.

A catalytic version of the Rabe electrophilic amination is presented. This kind of reaction was originally employed in 1918 in a key step for the conversion of quinotoxine to quinine. Ketones and α-substituted aldehydes give the corresponding α-aminated carbonyl compounds in moderate yield. α,α-Unsubstituted aldehydes give rise to amino ketones via a novel rearrangement.

Pattern of timing adherence could guide recommendations for personalized intake schedules.

Deviations in execution from the prescribed drug intake schedules (timing non adherence) are frequent and may pose a substantial risk for therapeutic failure. Simple methods to monitor timing adherence with multiple drugs are missing. A new technology, i.e., the polymedication electronic monitoring system (POEMS) attached to a multidrug punch card, was used in a clinical trial on outpatients with prescribed medicines for vascular risk reduction. The complete delineation of timing adherence allows for the calculation of objective adherence parameters and the linking of exposure with drug-drug interactions. A sub-analysis was performed on 68 patients, who were prescribed lipid lowering therapy. A smaller intake time variability of the lipid lowering drug was significantly associated with better levels of LDL-cholesterol, independently of the time of day. This finding may challenge current general recommendations for the timing of lipid lowering drugs' intake and substantiate that inter-individual differences in timing adherence may contribute to response variability. Thus, objective parameters based on multidrug adherence monitoring should be considered as independent variables in personalized medicine. In clinical practice, personalized intake recommendations according to patients' pattern of timing adherence may help to optimize the effectiveness of lipid lowering agents.