Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Training of vertical versus horizontal reading in patients with hemianopia - a randomized and controlled study.

HYPOTHESIS: Patients with hemianopic field defects (HFD) might benefit from reading text in vertical orientation if they place the text in the seeing hemifield along the vertical midline. METHODS: We assigned 21 patients with HFD randomly to either vertical or horizontal reading training. They trained reading single lines of texts from a computer screen at home for 2 × 30 min/day, 5 days/week, for 4 weeks. The main outcome variable was reading speed (RS) during reading standardized paragraphs of printed text (IReST) aloud. RS was assessed before training (T1), directly after training (T2) and 4 weeks later (T3). Quality of life (QoL) was assessed by Impact of Visual Impairment (IVI) questionnaire. RESULTS: Vertical training improved RS in the vertical direction significantly. Only patients with right HFD benefited. Horizontal training improved RS in horizontal diection significantly, but much more in patients with left than in those with right HFD. Both effects remained stable at T3. RS during training at the computer improved highly significantly and correlated strongly with RS of printed text (Pearson r= > 0.9). QoL: Vertical training showed a statistically significant improvement in the complete IVI-score, patients with right HFD in the emotional IVI-score. CONCLUSIONS: The improvements of RS were specific for the training. The stable effect indicates that the patients can apply the newly learned strategies to everyday life. The side of the HFD plays an essential role: Left-HFD patients benefitted from horizontal training, right-HFD patients from vertical training. However, the vertical RS did not reach the level of horizontal RS. The study was registered in the German Clinical Trials register (DRKS-ID: DRKS00018843).

(2 + 1)D-CAIPIRINHA accelerated MR spectroscopic imaging of the brain at 7T.

PURPOSE: To compare a new parallel imaging (PI) method for multislice proton magnetic resonance spectroscopic imaging (1 H-MRSI), termed (2 + 1)D-CAIPIRINHA, with two standard PI methods: 2D-GRAPPA and 2D-CAIPIRINHA at 7 Tesla (T). METHODS: (2 + 1)D-CAIPIRINHA is a combination of 2D-CAIPIRINHA and slice-CAIPIRINHA. Eight healthy volunteers were measured on a 7T MR scanner using a 32-channel head coil. The best undersampling patterns were estimated for all three PI methods. The artifact powers, g-factors, Cramér-Rao lower bounds (CRLB), and root mean square errors (RMSE) were compared quantitatively among the three PI methods. Metabolic maps and spectra were compared qualitatively. RESULTS: (2 + 1)D-CAIPIRINHA allows acceleration in three spatial dimensions in contrast to 2D-GRAPPA and 2D-CAIPIRINHA. Thus, this sequence significantly decreased the RMSE of the metabolic maps by 12.1 and 6.9%, on average, for 4 < R < 11, compared with 2D-GRAPPA and 2D-CAIPIRINHA, respectively. The artifact power was 22.6 and 8.4% lower, and the CRLB were 3.4 and 0.6% lower, respectively. CONCLUSION: (2 + 1)-CAIPIRINHA can be implemented for multislice MRSI in the brain, enabling higher accelerations than possible with two-dimensional (2D) parallel imaging methods. An eight-fold acceleration was still feasible in vivo with negligible PI artifacts with lipid decontamination, thus decreasing the measurement time from 120 to 15 min for a 64 × 64 × 4 matrix. Magn Reson Med 78:429-440, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Electronic Stopping of Slow Protons in Transition and Rare Earth Metals: Breakdown of the Free Electron Gas Concept.

The electronic stopping cross sections (SCS) of Ta and Gd for slow protons have been investigated experimentally. The data are compared to the results for Pt and Au to learn how electronic stopping in transition and rare earth metals correlates with features of the electronic band structures. The extraordinarily high SCS observed for protons in Ta and Gd cannot be understood in terms of a free electron gas model, but are related to the high densities of both occupied and unoccupied electronic states in these metals.

[Biological mechanisms of radiation effects]. / Biologische Mechanismen der Strahlenwirkung.

BACKGROUND: Exposure to ionizing radiation for diagnostic purposes is inevitable in modern medicine. The therapeutic application of irradiation is highly effective against cancer; however, this implies exposure of normal tissue structures to significant doses of radiation. Diagnostic or therapeutic exposure to ionizing radiation can result in tissue changes and tumor induction in the long term. Knowledge of the biological mechanisms underlying these effects is essential for individualization of the application. OBJECTIVES: This article examines the biological mechanisms at the tissue and molecular level, the clinical manifestation of radiation effects, dose-dependence of the risk and the temporal progression as well as influencing factors. RESULTS AND CONCLUSION: The time course of the reaction of tissues to radiation exposure extends over wide ranges up to many decades. The effects of radiation on tissues are classified into early and late and their pathobiology is significantly different. Various factors (R) influencing the clinical manifestation of radiation effects have been identified related to the exposure pattern. The radiation tolerance of normal tissue structures regarding the induction of functional deficits shows great variation but always has a threshold value, which is usually not exceeded in diagnostic procedures. The risk of a radiation-induced fatal malignancy (total body exposure 5%/Gy) for a medical administration of radiation must be considered as very low in comparison to the natural risks. Informed consent of patients must reflect this in a balanced way.

[The reverse shoulder arthroplasty Delta Xtend : Mid-term results]. / Die inverse Schulterendoprothese Delta Xtend : Mittelfristige Ergebnisse.

BACKGROUND: Reverse shoulder arthroplasty (RSA) has become a frequently used and established treatment for patients with cuff tear arthropathy, increasingly also for patients with fracture sequelae (FS), failed rotator cuff reconstruction and omarthrosis with cuff insufficiency. Since 2007 new generation prostheses, for example Delta Xtend (Depuy, Warsaw, USA), have been used, but few mid-term results have been published. OBJECTIVES: The aim of this study is to report on the outcome after RSA after a mean follow-up of 68 months (range 63-75), to verify the already published, encouraging early results and to learn about the function and pain situation after RSA in the mid-term period. METHODS: 60 patients underwent RSA with the Depuy Delta Xtend prosthesis in the years 2007 and 2008, performed by the senior author of this study. 39 of these patients were available for follow up and were asked to complete a questionnaire (msCS, modified subjective Constant Score). In addition, 28 patients agreed to a clinical examination. With these patients, in addition, the constant score, age and gender-adjusted constant score and range of motion were evaluated. RESULTS: The mean msCS of preoperative 39.15 points (range 12-69) improved to 71.74 points (range 44-100) after 5 years. The mean CS at 5 years was 65.79 points (range 21-93) and the mean age and gender-adjusted constant score was 92%. The mean active anterior elevation was 139° (range 70-180°), the mean abduction was 135° (range 50-170°) and the mean active external rotation was 17° (range -20-40°). CONCLUSION: This study confirms good early results after RSA after more than 5 years. We see very good outcomes in patients with CTA and omarthrosis, whilst the rate of complication is low.

Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder.

Converging evidence suggests bioenergetic abnormalities in bipolar disorder (BD). In the brain, phosphocreatine (PCr) acts a reservoir of high-energy phosphate (HEP) bonds, and creatine kinases (CK) catalyze the transfer of HEP from adenosine triphosphate (ATP) to PCr and from PCr back to ATP, at times of increased need. This study examined the activity of this mechanism in BD by measuring the levels of HEP molecules during a stimulus paradigm that increased local energy demand. Twenty-three patients diagnosed with BD-I and 22 healthy controls (HC) were included. Levels of phosphorus metabolites were measured at baseline and during visual stimulation in the occipital lobe using (31)P magnetic resonance spectroscopy at 4T. Changes in metabolite levels showed different patterns between the groups. During stimulation, HC had significant reductions in PCr but not in ATP, as expected. In contrast, BD patients had significant reductions in ATP but not in PCr. In addition, PCr/ATP ratio was lower at baseline in patients, and there was a higher change in this measure during stimulation. This pattern suggests a disease-related failure to replenish ATP from PCr through CK enzyme catalysis during tissue activation. Further studies measuring the CK flux in BD are required to confirm and extend this finding.

Diffusion-weighted imaging of breast tumours at 3 Tesla and 7 Tesla: a comparison.

OBJECTIVES: To compare bilateral diffusion-weighted MR imaging (DWI) at 3 T and 7 T in the same breast tumour patients. METHODS: Twenty-eight patients were included in this IRB-approved study (mean age 56 ± 16 years). Before contrast-enhanced imaging, bilateral DWI with b = 0 and 850 s/mm(2) was performed in 2:56 min (3 T) and 3:48 min (7 T), using readout-segmented echo planar imaging (rs-EPI) with a 1.4 × 1.4 mm(2) (3 T)/0.9 × 0.9 mm(2) (7 T) in-plane resolution. Apparent diffusion coefficients (ADC), signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were assessed. RESULTS: Twenty-eight lesions were detected (18 malignant, 10 benign). CNR and SNR were comparable at both field strengths (p > 0.3). Mean ADC values at 7 T were 4-22% lower than at 3 T (p ≤ 0.03). An ADC threshold of 1.275 × 10(-3) mm(2)/s resulted in a diagnostic specificity of 90% at both field strengths. The sensitivity was 94% and 100% at 3 T and 7 T, respectively. CONCLUSION: 7-T DWI of the breast can be performed with 2.4-fold higher spatial resolution than 3 T, without significant differences in SNR if compared to 3 T. KEY POINTS: • 7 T provides a 2.4-fold higher resolution in breast DWI than 3 T • 7 T DWI has a high diagnostic accuracy comparable to that at 3 T • At 7 T malignant lesions had 22 % lower ADC than at 3 T (p < 0.001).

The effect of healthy dietary consumption on executive cognitive functioning in children and adolescents: a systematic review.

A systematic review was conducted to evaluate whether healthier dietary consumption among children and adolescents impacts executive functioning. PubMed, Education Resources Information Center, PsychINFO and Thomson Reuters' Web of Science databases were searched, and studies of executive functioning among children or adolescents aged 6-18 years, which examined food quality, macronutrients and/or foods, were included. Study quality was also assessed. In all, twenty-one studies met inclusion criteria. Among the twelve studies examining food quality (n 9) or macronutrient intakes (n 4), studies examining longer-term diet (n 6) showed positive associations between healthier overall diet quality and executive functioning, whereas the studies examining the acute impact of diet (n 6) were inconsistent but suggestive of improvements in executive functioning with better food quality. Among the ten studies examining foods, overall, there was a positive association between healthier foods (e.g. whole grains, fish, fruits and/or vegetables) and executive function, whereas less-healthy snack foods, sugar-sweetened beverages and red/processed meats were inversely associated with executive functioning. Taken together, evidence suggests a positive association between healthy dietary consumption and executive functioning. Additional studies examining the effects of healthier food consumption, as well as macronutrients, on executive functioning are warranted. These studies should ideally be conducted in controlled environments and use validated cognitive tests.

Safety and efficacy of pharmacological cardioversion of recent-onset atrial fibrillation: a single-center experience.

BACKGROUND AND AIM: The management of patients with recent-onset atrial fibrillation (AF) presenting at emergency departments (EDs) varies widely. Our aim was to describe the management of patients with recent-onset (<48 hours) AF, to determine safety and efficacy of pharmacological cardioversion at the ED, and to evaluate the incidence of thromboembolism or death at 30 days. METHODS: In a prospective, observational, single-center study, 236 subjects with recent-onset AF were consecutively enrolled from January 2011 until January 2013. Follow-up information was obtained by reviewing all available clinical records. RESULTS: As first-line therapy, 45.3% (n = 107) received ibutilide, 28.8% (n = 68) vernakalant, 25% (n = 59) flecainide, and 0.8% (n = 2) amiodarone, respectively. Successful cardioversion was achieved in 72.5% (n = 171) of patients after first-line therapy. There was no significant difference between treatment groups. In univariable logistic regression analysis, age (odds ratio [OR] = 1.027; 95% confidence interval [CI], 1.003-1.052; P= .03), duration of symptoms (OR = 0.968; 95% CI, 0.938-0.999; P= .045), as well as the CHA2DS2-VASc score (1 point for Congestive heart failure, Hypertension, Age between 65 and 74 years, Diabetes, Vascular disease, Sex category if female and 2 points for previous TIA/Stroke and Age ≥ 75 years) (OR = 1.237; 95% CI, 1.01-1.515; P= .04) were associated with success of pharmacological cardioversion. Within 30 days, 1 patient suffered from fatal ischemic stroke. CONCLUSION: Pharmacological cardioversion followed by discharge after a short observation period is safe. There was no significant difference between the agents used in terms of short-term safety and efficacy. Importantly, the coherence of the ED to recent guidelines regarding first-line therapy is high.

Three decades of longlining in Bimini, Bahamas, reveals long-term trends in lemon shark Negaprion brevirostris (Carcharhinidae) catch per unit effort.

In Bimini, Bahamas, the consistent employment of longlines, beginning in 1982, provided a rare opportunity to explore population trends for large resident sharks. This study assessed three shallow water longline survey periods at this location; 1982-1989, 1992-2002 and 2003-2014, with the aim of determining trends in annual catch per unit effort (CPUE) for an IUCN listed near-threatened species, the lemon shark Negaprion brevirostris. A general additive model (GAM) was used to analyse the non-linear annual CPUE values over the entire 32-year research period. The GAM displayed high variability of annual CPUE, with a peak value of 0·026 N. brevirostris per hook day (hooks day(-1) ) in 2000. The temporal pattern of CPUE indicated an abundance trend with a complete cycle, from trough to trough, occurring over a period of approximately 18 years. The 1982-1989 survey period saw the highest proportion of mature individuals (19·8%) and the smallest average pre-caudal length (LPC ; 124·8 cm). The 1992-2002 survey period had the highest average annual CPUE (0·018 hooks day(-1) ), while the 2003-2014 research period saw largest average LPC size (134·8 cm) and the lowest average CPUE values (0·009 hooks day(-1) ) of the entire research period. The long-term trend identified in this study provides a baseline for future assessment.

Using genetic inference to re-evaluate the minimum longevity of the lemon shark Negaprion brevirostris.

A combination of mark-recapture and genetic sampling was used to extend the minimum longevity of an elasmobranch species and the life span estimate of the lemon shark Negaprion brevirostris was increased conservatively from 20·2 to 37 years. This increase in longevity means higher vulnerability and a longer recovery time from exploitation.

The behaviour and recovery of juvenile lemon sharks Negaprion brevirostris in response to external accelerometer tag attachment.

Behavioural responses of lemon sharks Negaprion brevirostris to a fin-mounted tag package (CEFAS G6A tri-axial accelerometer with epoxied Sonotronics PT4 acoustic transmitter) were measured in a controlled captive environment (n = 10, total length, LT range 80-140 cm) and in free-ranging sharks upon release (n = 7, LT range 100-160 cm). No changes were detected in behaviour (i.e. swimming speed, tailbeat frequency, time spent resting and frequency of chafing) between control and tagged captive shark trials, suggesting that the tag package itself does not alter behaviour. In the free-ranging trials, an initial period of elevated swimming activity was found in all individuals (represented by overall dynamic body acceleration). Negaprion brevirostris, however, appeared to recover quickly, returning to a steady swimming state between 2 and 35 min after release. Post-release tracking found that all sharks swim immediately for the shoreline and remain within 100 m of shore for prolonged periods. Hence, although N. brevirostris are capable of quick adaptation to stressors and demonstrate rapid recovery in terms of activity, tracking data suggest that they may modify their spatial use patterns post release. This research is important in separating deviation in behaviour due to environmental stressors from artefacts caused by experimental techniques.

Occurrence and habitat use of the critically endangered smalltooth sawfish Pristis pectinata in the Bahamas.

This study documents and discusses recent (2002-2015) sightings and captures of smalltooth sawfish Pristis pectinata in the Bahamas. Movement patterns and habitat preferences of five P. pectinata are examined: two tracked with acoustic telemetry in Bimini and three tagged with pop-up archival transmitting tags in Andros. Historically, P. pectinata may have been distributed throughout the Bahamas; however, since 2002 only 61 encounters were recorded including: Andros (30), Bimini (19) and a handful across other Islands (12). In Bimini, all P. pectinata were >225 cm (stretched total length, LST) suggesting that it is not used as a nursery area. Pristis pectinata in Andros ranged from c. 80 to 450 cm (LST) indicating that this island might be an important nursery and breeding habitat. Pristis pectinata tracked in both islands remained at depths <3 m, often adjacent to mangrove habitats, displaying residency from 42 days (Bimini) to 180 days (Andros). These preliminary findings confirm the Bahamas as an important habitat for P. pectinata and emphasize the urgent need for national protection and management of this population.

Genetic structure, population demography and seasonal occurrence of blacktip shark Carcharhinus limbatus in Bimini, the Bahamas.

A longline survey was conducted from 2004 to 2014 to investigate the demographic population structure and seasonal abundance of the blacktip shark Carcharhinus limbatus in the Bimini Islands, the Bahamas. All individuals sampled (n = 242) were sub-adult or adults [70·1-145·1 cm pre-caudal length (LPC) range] with no neonates or YOY recorded in Bimini. Carcharhinus limbatus abundance peaked in September, coincident with the largest ratio of female to male sharks and a peak in fresh mating wounds on females. Mitochondrial control region (mtCR) DNA sequences were obtained from C. limbatus at Bimini to test whether Bimini C. limbatus are most closely related to geographically proximate populations sampled on the south-eastern coast of the U.S.A., the closest known nursery areas for this species. Nine mtCR haplotypes were observed in 32 individuals sampled at Bimini [haplotype diversity (h) = 0·821, nucleotide diversity (π) = 0·0015]. Four haplotypes observed from Bimini matched those previously found in the northern Yucatan (Mexico)-Belize and two matched a haplotype previously found in the U.S.A. Four haplotypes were novel but were closely related to the northern Yucatan-Belizean haplotypes. Pair-wise ΦST analysis showed that Bimini was significantly differentiated from all of the populations previously sampled (U.S.A. Atlantic, U.S.A. Gulf of Mexico, northern Yucatan, Belize and Brazil). This indicates that C. limbatus sampled from Bimini are unlikely from the described, proximate U.S.A. nurseries.

Clinical application of bilateral high temporal and spatial resolution dynamic contrast-enhanced magnetic resonance imaging of the breast at 7 T.

OBJECTIVE: The objective of our study was to evaluate the clinical application of bilateral high spatial and temporal resolution dynamic contrast-enhanced magnetic resonance imaging (HR DCE-MRI) of the breast at 7 T. METHODS: Following institutional review board approval 23 patients with a breast lesion (BIRADS 0, 4-5) were included in our prospective study. All patients underwent bilateral HR DCE-MRI of the breast at 7 T (spatial resolution of 0.7 mm(3) voxel size, temporal resolution of 14 s). Two experienced readers (r1, r2) and one less experienced reader (r3) independently assessed lesions according to BI-RADS®. Image quality, lesion conspicuity and artefacts were graded from 1 to 5. Sensitivity, specificity and diagnostic accuracy were assessed using histopathology as the standard of reference. RESULTS: HR DCE-MRI at 7 T revealed 29 lesions in 23 patients (sensitivity 100 % (19/19); specificity of 90 % (9/10)) resulting in a diagnostic accuracy of 96.6 % (28/29) with an AUC of 0.95. Overall image quality was excellent in the majority of cases (27/29) and examinations were not hampered by artefacts. There was excellent inter-reader agreement for diagnosis and image quality parameters (κ = 0.89-1). CONCLUSION: Bilateral HR DCE-MRI of the breast at 7 T is feasible with excellent image quality in clinical practice and allows accurate breast cancer diagnosis. KEY POINTS: • Dynamic contrast-enhanced 7-T MRI is being developed in several centres. • Bilateral high resolution DCE-MRI of the breast at 7 T is clinically applicable. • 7-T HR DCE-MRI of the breast provides excellent image quality. • 7-T HR DCE-MRI should detect breast cancer with high diagnostic accuracy.

[Young rehabilitants in vocational training at the transition to the labour market]. / Junge Rehabilitanden in der Ausbildung am Übergang in den Arbeitsmarkt.

This study tackles the question, whether and to what extent labour market integration is achieved by young rehabilitants participating in an apprenticeship provided by the Federal Employment Agency. In order to identify salient determinants for the entry into as well as the sustainability of fi rst employment, event history analyses are applied. After a relatively short period, first integrated rehabilitants mostly fi nd unsubsidized employment. The entry into employment is determined by factors similar to those influencing the labour market transition of young adults without disabilities: higher educational achievements, a successfully completed apprenticeship at best within an establishment, high regional mobility and good structural conditions favour labour market integration. Furthermore, physically disabled graduates and those with shorter unemployment and sickness periods stay longer in fi rst employment than graduates showing other disabilities and those with longer periods in unemployment and sickness.

Vertical and horizontal reading training in patients with hemianopia and its effect on reading eye movements.

Vertical reading training (VRTr) increases reading speed (RS) significantly in patients with hemianopic field defects (HFD). We ask, how eye movements (EM) contribute to this improvement and whether EM-behavior is affected by the side of HFD. Twenty-one patients, randomly assigned to VRTr or horizontal RTr, trained reading single lines from a screen at home, for 4 weeks. In the clinic, we recorded EM while reading short sentences aloud from a screen before training (T1), directly (T2) and 4 weeks afterwards (T3). RS-screen was correlated with RS during reading printed paragraphs (RS-print) to assess the transfer to everyday life. RS-screen and RS-print correlated positively (horizontal: r > 0.8, vertical: r > 0.9) at all times. Vertical RS did not exceed horizontal RS. We found significant negative correlations of EM-variables and RS-print: in right-HFD with the number of forward saccades (T1: r = - 0.79, T2: r = - 0.94), in left-HFD with the steps during return sweeps (T1: r = - 0.83, T2: r = - 0.56). Training effects remained stable at T3. EM-improvement was specific for the RTr and the side of the HFD: in right-HFD fewer forward saccades after VRTr, in left-HFD fewer steps during return sweeps after HRTr. RTr on a screen transfers to reading printed text in real-life situations.Trial registration: The study was retrospectively registered in the German Clinical Trials register: DRKS-ID: DRKS00018843, March 13th, 2020.