Isomer depletion as experimental evidence of nuclear excitation by electron capture.

The atomic nucleus and its electrons are often thought of as independent systems that are held together in the atom by their mutual attraction. Their interaction, however, leads to other important effects, such as providing an additional decay mode for excited nuclear states, whereby the nucleus releases energy by ejecting an atomic electron instead of by emitting a γ-ray. This 'internal conversion' has been known for about a hundred years and can be used to study nuclei and their interaction with their electrons. In the inverse process-nuclear excitation by electron capture (NEEC)-a free electron is captured into an atomic vacancy and can excite the nucleus to a higher-energy state, provided that the kinetic energy of the free electron plus the magnitude of its binding energy once captured matches the nuclear energy difference between the two states. NEEC was predicted in 1976 and has not hitherto been observed. Here we report evidence of NEEC in molybdenum-93 and determine the probability and cross-section for the process in a beam-based experimental scenario. Our results provide a standard for the assessment of theoretical models relevant to NEEC, which predict cross-sections that span many orders of magnitude. The greatest practical effect of the NEEC process may be on the survival of nuclei in stellar environments, in which it could excite isomers (that is, long-lived nuclear states) to shorter-lived states. Such excitations may reduce the abundance of the isotope after its production. This is an example of 'isomer depletion', which has been investigated previously through other reactions, but is used here to obtain evidence for NEEC.

Training and Evaluation of Residents to Ensure Competent Physician Metrics to Recognize Struggling Residents.

Assessing competency across domains of knowledge, skills, and behavior is critical to ensure that graduating orthopaedic residents possess the requisite skills and attributes to enter independent orthopaedic practice. Of the domains, knowledge is most easily assessed. In addition to the AAOS Orthopaedic In-Training Examination®, which provides a yearly gauge of residents' orthopaedic knowledge relative to their peers, there are several online platforms such as Orthobullets, the American Academy of Orthopaedic Surgeons ResStudy program, and the Journal of Bone and Joint Surgery Clinical Classroom that offer online learning resources and question banks. Clinical skills are best assessed through a combination of observation tools, including live or video assessments, 360° evaluations, and objective structured clinical examinations. Surgical skills can be evaluated in two domains: live surgical cases or simulations. The American Board of Orthopaedic Surgery is attempting to standardize live surgical evaluations through the use of the O-P tool. Although most available models feature only arthroscopic procedures, surgical simulators provide for opportunity to objectively evaluate resident performance. Behavior and professionalism has traditionally been the most challenging domain to assess. The American Board of Orthopaedic Surgery's Behavior Assessment Tool has demonstrated success in pilot testing and is being introduced as the standard for measuring behavior and professionalism in orthopaedic training. Although no single assessment tool can accurately gauge a resident's overall performance, a combination of readily available tools should be used to assess competence across domains.

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT.

Huntington's disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ.

Lacking Advanced Degrees are not a Barrier to Entry into Academic Surgery Leadership.

BACKGROUND: Undergraduate and graduate medical education offerings continue to create opportunities for medical students to pursue MD+ degree education. These educational endeavors provide formal education in fields related to surgery, which gives trainees and surgeons diverse perspectives on surgical care. This study sought to assess current prevalence of additional advanced degrees among leaders in academic surgery to assess the relationship between dual degree attainment and holding various leadership positions within surgical departments. METHODS: The Association for Program Directors in Surgery database was used to identify academic surgical programs, which comprised our study population. Each department of surgery website in the APDS database was interrogated for departmental leaders and their reported academic degrees. RESULTS: Among 3223 identified surgeon leaders, 14.6% (470/3223) were found to possess MD+ degrees. Most common degrees possessed included MBA, MPH, and PhD. In comparing different types of surgeon leaders such as chairs, program directors, and division chiefs, no group was found to have a significantly higher prevalence of MD+ degrees than others. CONCLUSION: Prevalence of MD+ degrees among current academic surgery leaders is low, and the lack of an advanced degree should not be considered a barrier to entry into leadership positions. We hypothesize that these findings are likely to evolve as larger proportions of trainees obtain MD+ degrees during medical school and academic development time throughout residency.

Formal robotic training diminishes the learning curve for robotic pancreatoduodenectomy: Implications for new programs in complex robotic surgery.

INTRODUCTION: The learning curve associated with robotic pancreatoduodenectomy (RPD) is a hurdle for new programs to achieve optimal results. Since early analysis, robotic training has recently expanded, and the RPD approach has been refined. The purpose of this study is to examine RPD outcomes for surgeons who implemented a new program after receiving formal RPD training to determine if such training reduces the learning curve. METHODS: Outcomes for consecutive patients undergoing RPD at a single tertiary institution were compared to optimal RPD benchmarks from a previously reported learning curve analysis. Two surgical oncologists with formal RPD training performed all operations with one surgeon as bedside assistant and the other at the console. RESULTS: Forty consecutive RPD operations were evaluated. Mean operative time was 354 ± 54 min, and blood loss was 300 ml. Length of stay was 7 days. Three patients (7.5%) underwent conversion to open. Pancreatic fistula affected five patients (12.5%). Operative time was stable over the study and lower than the reported benchmark. These RPD operative outcomes were similar to reported surgeon outcomes after the learning curve. CONCLUSION: This study suggests formal robotic training facilitates safe and efficient adoption of RPD for new programs, reducing or eliminating the learning curve.

Surgical Skill Can be Objectively Measured From Fluoroscopic Images Using a Novel Image-based Decision Error Analysis (IDEA) Score.

BACKGROUND: To advance orthopaedic surgical skills training and assessment, more rigorous and objective performance measures are needed. In hip fracture repair, the tip-apex distance is a commonly used summative performance metric with clear clinical relevance, but it does not capture the skill exercised during the process of achieving the final implant position. This study introduces and evaluates a novel Image-based Decision Error Analysis (IDEA) score that better captures performance during fluoroscopically-assisted wire navigation. QUESTIONS/PURPOSES: (1) Can wire navigation skill be objectively measured from a sequence of fluoroscopic images? (2) Are skill behaviors observed in a simulated environment also exhibited in the operating room? Additionally, we sought to define an objective skill metric that demonstrates improvement associated with accumulated surgical experience. METHODS: Performance was evaluated both on a hip fracture wire navigation simulator and in the operating room during actual fracture surgery. After examining fluoroscopic image sequences from 176 consecutive simulator trials (performed by 58 first-year orthopaedic residents) and 21 consecutive surgical procedures (performed by 19 different orthopaedic residents and one attending orthopaedic surgeon), three main categories of erroneous skill behavior were identified: off-target wire adjustments, out-of-plane wire adjustments, and off-target drilling. Skill behaviors were measured by comparing wire adjustments made between consecutive images against the goal of targeting the apex of the femoral head as part of our new IDEA scoring methodology. Decision error metrics (frequency, magnitude) were correlated with other measures (image count and tip-apex distance) to characterize factors related to surgical performance on both the simulator and in the operating room. An IDEA composite score integrating decision errors (off-target wire adjustments, out-of-plane wire adjustments, and off-target drilling) and the final tip-apex distance to produce a single metric of overall performance was created and compared with the number of hip wire navigation cases previously completed (such as surgeon experience levels). RESULTS: The IDEA methodology objectively analyzed 37,000 images from the simulator and 688 images from the operating room. The number of decision errors (7 ± 5 in the operating room and 4 ± 3 on the simulator) correlated with fluoroscopic image count (33 ± 14 in the operating room and 20 ± 11 on the simulator) in both the simulator and operating room environments (R2 = 0.76; p < 0.001 and R2 = 0.71; p < 0.001, respectively). Decision error counts did not correlate with the tip-apex distance (16 ± 4 mm in the operating room and 12 ± 5 mm on the simulator) for either the simulator or the operating room (R2 = 0.08; p = 0.15 and R2 = 0.03; p = 0.47, respectively), indicating that the tip-apex distance is independent of decision errors. The IDEA composite score correlated with surgical experience (R2 = 0.66; p < 0.001). CONCLUSION: The fluoroscopic images obtained in the course of placing a guide wire contain a rich amount of information related to surgical skill. This points the way to an objective measure of skill that also has potential as an educational tool for residents. Future studies should expand this analysis to the wide variety of procedures that rely on fluoroscopic images. CLINICAL RELEVANCE: This study has shown how resident skill development can be objectively assessed from fluoroscopic image sequences. The IDEA scoring provides a basis for evaluating the competence of a resident. The score can be used to assess skill at key timepoints throughout residency, such as when rotating onto/off of a new surgical service and before performing certain procedures in the operating room, or as a tool for debriefing/providing feedback after a procedure is completed.

Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures.

OBJECTIVE: Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN: We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS: The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with ERBB2-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response. CONCLUSIONS: The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.

Miles to go (mtgo) encodes FNDC3 proteins that interact with the chaperonin subunit CCT3 and are required for NMJ branching and growth in Drosophila.

Analysis of mutants that affect formation and function of the Drosophila larval neuromuscular junction (NMJ) has provided valuable insight into genes required for neuronal branching and synaptic growth. We report that NMJ development in Drosophila requires both the Drosophila ortholog of FNDC3 genes; CG42389 (herein referred to as miles to go; mtgo), and CCT3, which encodes a chaperonin complex subunit. Loss of mtgo function causes late pupal lethality with most animals unable to escape the pupal case, while rare escapers exhibit an ataxic gait and reduced lifespan. NMJs in mtgo mutant larvae have dramatically reduced branching and growth and fewer synaptic boutons compared with control animals. Mutant larvae show normal locomotion but display an abnormal self-righting response and chemosensory deficits that suggest additional functions of mtgo within the nervous system. The pharate lethality in mtgo mutants can be rescued by both low-level pan- and neuronal-, but not muscle-specific expression of a mtgo transgene, supporting a neuronal-intrinsic requirement for mtgo in NMJ development. Mtgo encodes three similar proteins whose domain structure is most closely related to the vertebrate intracellular cytosolic membrane-anchored fibronectin type-III domain-containing protein 3 (FNDC3) protein family. Mtgo physically and genetically interacts with Drosophila CCT3, which encodes a subunit of the TRiC/CCT chaperonin complex required for maturation of actin, tubulin and other substrates. Drosophila larvae heterozygous for a mutation in CCT3 that reduces binding between CCT3 and MTGO also show abnormal NMJ development similar to that observed in mtgo null mutants. Hence, the intracellular FNDC3-ortholog MTGO and CCT3 can form a macromolecular complex, and are both required for NMJ development in Drosophila.

Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT-induced pathology while reducing Polycomb Repressive Complex2 core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation.

Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington's disease models and in Huntington's disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington's disease.

Resident Involvement Is Not Associated With Increased Risk of Postoperative Complications After Arthroscopic Knee Surgery: A Propensity-Matched Study.

PURPOSE: To investigate whether resident involvement in knee arthroscopy procedures affects postoperative complications or operative times. METHODS: The American College of Surgeons National Surgical Quality Improvement Program registry was queried to identify patients who underwent common knee arthroscopy procedures between 2006 through 2012. Patients with a history of knee arthroplasty, septic arthritis or osteomyelitis of the knee, concomitant open or mini-open procedures, or without information on resident involvement were excluded. A 1:1 propensity score match was performed based on age, sex, obesity, smoking history, and American Society of Anesthesiologist classification to match cases with resident involved to nonresident cases. Fisher exact tests, Pearson's χ2 tests, and Wilcoxon rank sum tests were used to compare patient demographics, comorbidities, and 30-day complications. Wilcoxon rank sum tests were used to compare operative time and length of hospital stay between the 2 groups, with statistical significance defined as P < .05. RESULTS: After matching, 2954 cases (50% resident involvement) were included in the study with no significant differences in demographics or comorbidities between the 2 cohorts. The overall rate of 30-day complications was 1.1% in the nonresident and resident involved group (P = 1.000). There was no significant difference in postoperative surgical (nonresident vs resident involved: 0.48% vs 0.83%, P = .2498) or medical (nonresident vs resident involved: 0.62% vs 0.83%, P = .5111) complications. However, knee arthroscopy cases that residents were involved with had significantly longer operative times (69.8 vs 66.8 minutes, P = .0002), and length of hospital stay (0.85 vs 0.21 days, P = .0332) when compared with cases performed without a resident. CONCLUSIONS: Resident involvement in knee arthroscopy procedures is not a significant risk for medical or surgical 30-day postoperative complications. Resident participation in knee arthroscopy was associated with statistically significant but likely clinically insignificant increased operative time as well as length of hospital stay. LEVEL OF EVIDENCE: Level III: Retrospective Cohort Study.

UV damage to hair and the effect of antioxidants and metal chelators.

OBJECTIVE: To study the effects of addition of a redox metal, copper, antioxidants and metal chelators on the formation of free radicals in natural white Caucasian hair subsequently exposed to UV light. Three different methods, electron paramagnetic resonance (EPR), a fluorescent probe for hydroxyl radical formation (terephthalate) and free radical photoyellowing, were used. These methods utilized different UV sources and reaction conditions, and so can give insights into the different mechanisms of action occurring during UV oxidation of hair. In addition, this study demonstrates how antioxidants and chelators can be screened to determine whether they can protect hair from UV damage. RESULTS: The three methods gave somewhat different results, illustrating the importance of reaction conditions and wavelength on the photochemical mechanisms, and the efficacy of additives to influence these reactions. EPR results showed that N-acetylcysteine (NAC) pre-treatment eliminated the intensity of the signal because of sulphur and carbon free radicals in white hair both before and after exposure to UVB radiation. Doping the hair with copper ions had no effect on the intensity of the EPR signal under dry conditions. Terephthalate fluorescent probe data showed that under wet conditions, irradiation of white hair with UVA produced significant amounts of hydroxyl radicals. Pre-treatment of hair with NAC reduced the number of •OH radicals produced by natural white hair compared to an untreated control. In contrast to the EPR result, white hair doped with copper ions produced significantly higher levels of •OH radicals under wet conditions. It appears that the ability of copper ions to catalyse the photogeneration free radicals in hair is highly dependent on water content. Photoyellowing data showed a benefit for oxalic acid but no difference for NAC and an increase in yellowing for EDTA. CONCLUSION: The micro-EPR and terephthalate fluorescent probe methods are both effective techniques to study production of free radicals by hair exposed to UV light under wet and dry conditions, respectively. Both assays are simple methods for determining the effectiveness of potential protective hair treatments against UV damage, but because they assess free radical damage under dry vs wet conditions, the chemistry created on UV exposure is different. This gives insights into mechanism of action, but results may not be consistent between the two methods for actives added for reduction of UV damage. NAC pre-treatment did reduce free radical generation in UV-exposed hair under both wet and dry conditions. Photoyellowing data are more complicated as it is a less direct measure of UV damage and is highly dependent on irradiation source. Using UVB irradiation is experimentally convenient but may not be appropriate, because UVB wavelengths comprise only 0.3% of terrestrial sunlight. The photochemistry of hair exposed to sunlight involves concurrent photobleaching and photoyellowing processes and is far more complex. Under UVB irradiation conditions, oxalic acid showed a yellowing benefit.

OBJECTIF: Étudier les effets de l'ajout d'un métal redox, d'un cuivre, d'antioxydants et de chélateurs de métaux sur la formation de radicaux libres dans les cheveux naturels blancs de Caucasiens, exposés par la suite à des rayons  à ultraviolets. Trois méthodes différentes, la résonance paramagnétique électronique (RPE), une sonde fluorescente pour la formation de radicaux hydroxyles (téréphtalate) et le photojaunissement dû aux radicaux libres ont été utilisées. Ces méthodes ont utilisé différentes sources d'UV et de conditions de réaction, et peuvent par conséquent donner un aperçu des différents mécanismes d'action qui se produisent lors de l'oxydation des cheveux aux UV. Par ailleurs, cette étude montre comment les antioxydants et les chélateurs peuvent être analysés en vue de déterminer s'ils peuvent protéger les cheveux contre les dommages causés par les UV. RÉSULTATS: Les trois méthodes ont donné des résultats quelque peu différents, ce qui illustre l'importance des conditions de réaction et de la longueur d'onde sur les mécanismes photochimiques, ainsi que l'efficacité des additifs influençant ces réactions. Les résultats de la RPE ont montré que le traitement préalable par N-acétylcystéine (NAC) éliminait l'intensité du signal en raison de la présence du soufre et des radicaux libres de carbone dans les cheveux blancs, avant et après l'exposition aux rayons UVB. Le dopage des cheveux avec des ions de cuivre n'a eu aucun effet sur l'intensité du signal RPE en condition sèche. Les données des sondes fluorescentes de téréphtalate ont montré qu'en conditions humides, l'irradiation des cheveux blancs avec des UVA produisait d'importantes quantités de radicaux hydroxyles. Le traitement préalable des cheveux par N-acétylcystéine a réduit le nombre de radicaux hydroxyles produits par les cheveux blancs naturels comparé à un témoin non traité. Contrairement au résultat de la RPE, les cheveux blancs dopés avec des ions de cuivre ont produit des concentrations beaucoup plus élevées de radicaux hydroxyles en conditions humides. Il apparaît que la capacité des ions de cuivre à catalyser les radicaux libres photogénérés dans les cheveux dépend fortement de la teneur en eau. Les données relatives au photojaunissement ont démontré un avantage pour l'acide oxalique, aucune différence pour la N-acétylcystéine et une augmentation du jaunissement pour l'EDTA. CONCLUSION: Les méthodes de sonde fluorescente micro-RPE et téréphtalate sont deux techniques efficaces d'étude de la production de radicaux libres sur les cheveux exposés aux rayons ultraviolets en conditions humides et sèches, respectivement. Les deux tests sont des méthodes simples pour déterminer l'efficacité d'éventuels traitements de protection contre les dommages causés par les UV, mais étant donné qu'ils évaluent les dommages causés par les radicaux libres dans des conditions sèches ou humides, la réaction chimique créée lors de l'exposition aux UV est différente. Cela permet de mieux comprendre le mécanisme d'action, mais les résultats peuvent ne pas être cohérents entre les deux méthodes en raison des substances actives ajoutées pour réduire les dommages causés par les UV. Le traitement préalable par N-acétylcystéine a réduit la génération de radicaux libres dans les cheveux exposés aux UV en conditions humides et sèches. Les données de photojaunissement sont plus complexes, étant donné qu'il s'agit d'une mesure moins directe des dommages causés par les UV et qu'elles dépendent fortement de la source d'irradiation. L'utilisation de l'irradiation aux UVB est convenable d'un point de vue expérimental, mais peut ne pas être appropriée, car les longueurs d'onde UVB ne représentent que 0,3 % du rayonnement solaire terrestre. La photochimie de cheveux exposés à la lumière du soleil implique des processus de photoblanchiment et de photojaunissement concomitants, et est bien plus complexe. Dans des conditions d'irradiation aux UVB, l'acide oxalique a présenté un avantage en matière de jaunissement.

An introduction to clinical trial design.

Clinicians and other decision makers in healthcare use results from clinical trials to inform practice. Interpretation of clinical trial results can be challenging, as weaknesses in trial design, data collection, analysis or reporting, can compromise the usefulness of results. A good working knowledge of clinical trial design is essential to expertly interpret and determine the validity and generalizability of the results. This manuscript will give a brief overview of clinical trial design including the strengths and limitations of various approaches. The focus will be on confirmatory clinical trials.

Maternal and fetal genetic contribution to gestational weight gain.

BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Surgical Resection Does Not Improve Survival in Multifocal Intrahepatic Cholangiocarcinoma: A Comparison of Surgical Resection with Intra-Arterial Therapies.

BACKGROUND: Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection. METHODS: A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy. RESULTS: Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56-4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23-6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242). CONCLUSION: Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.

Effectiveness of Hepatic Artery Infusion (HAI) Versus Selective Internal Radiation Therapy (Y90) for Pretreated Isolated Unresectable Colorectal Liver Metastases (IU-CRCLM).

BACKGROUND: In the era of modern effective systemic chemotherapy, the comparative effectiveness of hepatic artery infusion (HAI) versus selective internal radiation therapy (yttrium-90 [Y90]) for pretreated patients with isolated unresectable colorectal liver metastasis (IU-CRCLM) remains unknown. This study sought to compare the overall survival (OS) after HAI versus Y90 for IU-CRCLM patients treated with modern chemotherapy and to perform a cost analysis of both regional methods. METHODS: This study retrospectively reviewed patients receiving HAI or Y90 in combination with modern chemotherapy as second-line therapy for IU-CRCLM. Overall survival was calculated from the time of IU-CRCLM diagnosis. Uni- and multivariate models were constructed to identify independent predictors of survival. RESULTS: The inclusion criteria were met by 97 patients (48 HAI patients and 49 Y90 patients). Both groups were similar in terms of age, gender, body mass index (BMI), synchronous disease, carcinoembryonic antigen (CEA), liver tumor burden, and chemotherapy-related characteristics including use of biologics and lines of chemotherapy (all p > 0.05). The HAI group had a better OS than the Y90 group (31.2 vs. 16.3 months; p < 0.001). A trend toward reduced cost favored the HAI group (median, $29,479 vs. $39,092; p = 0.296). The multivariate analysis showed that receipt of HAI (hazard ratio 0.465) and number of chemotherapy lines (HR 0.797) were associated with improved OS from the date of IU-CRCLM diagnosis. CONCLUSIONS: This is the first study to evaluate the comparative effectiveness of HAI versus Y90 in the era of modern chemotherapy, and the findings suggests that HAI is associated with better survival than Y90 for patients with pretreated IU-CRCLM.

Minimally invasive liver resection for primary and metastatic liver tumors: influence of age on perioperative complications and mortality.

BACKGROUND: As minimally invasive technique becomes more popular, an increasing number of elderly patients were considered for minimally invasive liver resection (MILR). Limited physiologic reserve remains a major concern, which frequently leads surgeons to recommend nonresectional alternatives. We sought to evaluate complications and outcomes of elderly patients undergoing MILR. METHODS: Eight hundred and thirty-one patients who underwent MILR were classified into groups A, B, and C based on age [(< 70, n = 629), (70-79, n = 148), (≥ 80, n = 54) years old, respectively]. RESULTS: Gender distribution, BMI, and cirrhotic status were comparable among all groups. Groups B and C had higher MELD (p = 0.047) and ASA (p = 0.001) scores. Operative time (170, 157, 152 min; p = 0.64) and estimated blood loss (145, 130, 145 ml; p = 0.95) were statistically equal. Overall postoperative complications were greater in groups B and C (12.9 and 9.3 vs. 6.5%, respectively). Complications in group C were all minor. Clavien-Dindo grade III-IV complications were higher in group B when compared to group A (6.8 vs. 2.7%, p = 0.43). There was no significant difference in cardiopulmonary complications, thromboembolic events, ICU admissions, and transfusion rates seen in groups B and C when compared to group A. Duration of hospital stay was statistically longer in groups B and C (3.6, 3.5 vs. 2.5 days, p = 0.0012). 30- and 90-day mortality rates were comparable among the groups, irrespective of age. CONCLUSIONS: In spite of greater preoperative comorbidities and ASA score, there was no significant increase in postoperative morbidity after minimally invasive liver resection in patients ≥ 70 years of age.

Trends in time-loss injuries during the 2011-2016 South African Rugby Youth Weeks.

Youth rugby is a popular sport in South Africa (SA) with a high injury incidence. The annual SA Rugby Youth Week tournaments attract the top age-group players in the country providing a sample of players for reliable injury surveillance. The aim of the study was to analyze the changes in time-loss injury rates at the SA Rugby Youth Week tournaments between 2011 and 2016, differences between age-groups, and to investigate associated injury risk factors. All confirmed time-loss injuries at the 4 age-group tournaments (under-13, under-16, and 2 under-18) from 2011 to 2016 were recorded. Injury incidence densities (IID) for years, tournaments, and injury risk factors were calculated and Poisson regression analyses were performed to determine differences. Time-loss injuries (n = 494) were reported over 24 240 exposure hours, with an overall IID of 20.4 (18.6-22.2) injuries per 1000 player hours. The year 2013 had a significantly lower IID compared to 2011. Injury risk decreased with increasing age; under-13 and under-16 had significantly higher IID compared to under-18 Craven Week. Tackling was the phase of play at highest risk, with an IID of 7.4 (6.3-8.5) injuries per 1000 player hours. Central/peripheral nervous system (CNS/PNS) and, therefore, the head/neck were the most commonly occurring injuries/location injured. In conclusion, within the SA Rugby tournament structure, the older players had a decreased rate of injury. The tackle event was still the phase of play with the highest injury incidence regardless of age. This increase in incidence is largely due to an increase in CNS/PNS injuries.