Neuroimaging in Kabuki syndrome and another KMT2D-related disorder.

Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder. We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.

Novel methodology to assess the effect of contouring variation on treatment outcome.

PURPOSE: Contouring variation is one of the largest systematic uncertainties in radiotherapy, yet its effect on clinical outcome has never been analyzed quantitatively. We propose a novel, robust methodology to locally quantify target contour variation in a large patient cohort and find where this variation correlates with treatment outcome. We demonstrate its use on biochemical recurrence for prostate cancer patients. METHOD: We propose to compare each patient's target contours to a consistent and unbiased reference. This reference was created by auto-contouring each patient's target using an externally trained deep learning algorithm. Local contour deviation measured from the reference to the manual contour was projected to a common frame of reference, creating contour deviation maps for each patient. By stacking the contour deviation maps, time to event was modeled pixel-wise using a multivariate Cox proportional hazards model (CPHM). Hazard ratio (HR) maps for each covariate were created, and regions of significance found using cluster-based permutation testing on the z-statistics. This methodology was applied to clinical target volume (CTV) contours, containing only the prostate gland, from 232 intermediate- and high-risk prostate cancer patients. The reference contours were created using ADMIRE® v3.4 (Elekta AB, Sweden). Local contour deviations were computed in a spherical coordinate frame, where differences between reference and clinical contours were projected in a 2D map corresponding to sampling across the coronal and transverse angles every 3°. Time to biochemical recurrence was modeled using the pixel-wise CPHM analysis accounting for contour deviation, patient age, Gleason score, and treated CTV volume. RESULTS: We successfully applied the proposed methodology to a large patient cohort containing data from 232 patients. In this patient cohort, our analysis highlighted regions where the contour variation was related to biochemical recurrence, producing expected and unexpected results: (a) the interface between prostate-bladder and prostate-seminal vesicle interfaces where increase in the manual contour relative to the reference was related to a reduction of risk of biochemical recurrence by 4-8% per mm and (b) the prostate's right, anterior and posterior regions where an increase in the manual contour relative to the reference contours was related to an increase in risk of biochemical recurrence by 8-24% per mm. CONCLUSION: We proposed and successfully applied a novel methodology to explore the correlation between contour variation and treatment outcome. We analyzed the effect of contour deviation of the prostate CTV on biochemical recurrence for a cohort of more than 200 prostate cancer patients while taking basic clinical variables into account. Applying this methodology to a larger dataset including additional clinically important covariates and externally validating it can more robustly identify regions where contour variation directly relates to treatment outcome. For example, in the prostate case we use to demonstrate our novel methodology, external validation will help confirm or reject the counter-intuitive results (larger contours resulting in higher risk). Ultimately, the results of this methodology could inform contouring protocols based on actual patient outcomes.

Influence of Contextual Factors, Technical Performance, and Movement Demands on the Subjective Task Load Associated With Professional Rugby League Match-Play.

PURPOSE: To identify the association between several contextual match factors, technical performance, and external movement demands on the subjective task load of elite rugby league players. METHODS: Individual subjective task load, quantified using the National Aeronautics and Space Administration Task Load Index (NASA-TLX), was collected from 29 professional rugby league players from one club competing in the European Super League throughout the 2017 season. The sample consisted of 26 matches (441 individual data points). Linear mixed modeling revealed that various combinations of contextual factors, technical performance, and movement demands were associated with subjective task load. RESULTS: Greater number of tackles (effect size correlation ± 90% confidence intervals; η2 = .18 ± .11), errors (η2 = .15 ± .08), decelerations (η2 = .12 ± .08), increased sprint distance (η2 = .13 ± .08), losing matches (η2 = .36 ± .08), and increased perception of effort (η2 = .27 ± .08) led to most likely-very likely increases in subjective total task load. The independent variables included in the final model for subjective mental demand (match outcome, time played, and number of accelerations) were unclear, excluding a likely small correlation with technical errors (η2 = .10 ± .08). CONCLUSIONS: These data provide a greater understanding of the subjective task load and their association with several contextual factors, technical performance, and external movement demands during rugby league competition. Practitioners could use this detailed quantification of internal loads to inform recovery sessions and current training practices.

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study.

Importance: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. Objective: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. Design, Setting, and Participants: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. Interventions: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. Main Outcomes and Measures: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. Results: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. Conclusions and Relevance: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.

The Physiological and Perceptual Effects of Stochastic Simulated Rugby League Match Play.

PURPOSE: To examine responses to a simulated rugby league protocol designed to include more stochastic commands, and therefore require greater vigilance, than traditional team-sport simulation protocols. METHODS: Eleven male university rugby players completed 2 trials (randomized and control [CON]) of a rugby league movement simulation protocol, separated by 7 to 10 d. The CON trial consisted of 48 repeated ∼115-s cycles of activity. The stochastic simulation (STOCH) was matched for the number and types of activity performed every 5.45 min in CON but included no repeated cycles of activity. Movement using GPS, heart rate, rating of perceived exertion, and Stroop test performance was assessed throughout. Maximum voluntary contraction peak torque, voluntary activation (in percentage), and global task load were assessed after exercise. RESULTS: The mean mental demand of STOCH was higher than CON (effect size [ES] = 0.56; ±0.69). Mean sprint speed was higher in STOCH (22.5 [1.4] vs 21.6 [1.6] km·h-1, ES = 0.50; ±0.55), which was accompanied by a higher rating of perceived exertion (14.3 [1.0] vs 13.0 [1.4], ES = 0.87; ±0.67) and a greater number of errors in the Stroop test (10.3 [2.5] vs 9.3 [1.4] errors; ES = 0.65; ±0.83). Maximum voluntary contraction peak torque (CON = -48.4 [31.6] N·m and STOCH = -39.6 [36.6] N·m) and voluntary activation (CON = -8.3% [4.8%] and STOCH = -6.0% [4.1%]) was similarly reduced in both trials. CONCLUSIONS: Providing more stochastic commands, which requires greater vigilance, might alter performance and associated physiological, perceptual, and cognitive responses to team-sport simulations.

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.

PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. RESULTS: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

Infant mortality: the contribution of genetic disorders.

OBJECTIVE: To determine the proportion of infant deaths occurring in the setting of a confirmed genetic disorder. STUDY DESIGN: A retrospective analysis of the electronic medical records of infants born from 1 January, 2011 to 1 June, 2017, who died prior to 1 year of age. RESULTS: Five hundred and seventy three deceased infants were identified. One hundred and seventeen were confirmed to have a molecular or cytogenetic diagnosis in a clinical diagnostic laboratory and an additional seven were diagnosed by research testing for a total of 124/573 (22%) diagnosed infants. A total of 67/124 (54%) had chromosomal disorders and 58/124 (47%) had single gene disorders (one infant had both). The proportion of diagnoses made by sequencing technologies, such as exome sequencing, increased over the years. CONCLUSIONS: The prevalence of confirmed genetic disorders within our cohort of infant deaths is higher than that previously reported. Increased efforts are needed to further understand the mortality burden of genetic disorders in infancy.

Stochastic ordering of simulated rugby match activity produces reliable movements and associated measures of subjective task load, cognitive and neuromuscular function.

The study assesses the test-retest reliability of movement and physiological measures during a simulated rugby match that employed activities performed in a stochastic order. Twenty male rugby players (21.4 ± 2.1 y) completed two trials of a 2 × 23 min rugby movement simulation protocol during which the order of events was performed in a stochastic order, with 7-10 days between trials. Movement characteristics, heart rate (HR), RPE, maximum voluntary contraction (MVC), voluntary activation (VA%) of the quadriceps, Stroop test and subjective task load rating (NASA-TLX) were measured. The most reliable measures of external load was relative distance (typical error [TE] and CV% = 1.5-1.6 m min-1 and 1.4-1.5%, respectively), with all other movement characteristics possessing a CV% <5%. The most reliable measure of internal load, neuromuscular function and perceptual measures were for %HRmax (TE and CV% = 1.4-1.7% and 1.4-2.1%, respectively), MVC before (TE and CV% = 10.8-14.8 N·m and 3.8-4.6%, respectively), and average RPE (TE and CV% = 0.5-0.8 AU and 3.6-5.5%, respectively). The Stroop test, NASA-TLX and blood lactate produced the least reliable measures (CV% >5%). Future studies can confidently examine changes in several perceptual, neuromuscular, physiological and movement measures related to rugby activity using stochastic movements.

Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness.

BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.

BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells.

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.

Expanding the molecular-ruler process through vapor deposition of hexadecanethiol.

The development of methods to produce nanoscale features with tailored chemical functionalities is fundamental for applications such as nanoelectronics and sensor fabrication. The molecular-ruler process shows great utility for this purpose as it combines top-down lithography for the creation of complex architectures over large areas in conjunction with molecular self-assembly, which enables precise control over the physical and chemical properties of small local features. The molecular-ruler process, which most commonly uses mercaptoalkanoic acids and metal ions to generate metal-ligated multilayers, can be employed to produce registered nanogaps between metal features. Expansion of this methodology to include molecules with other chemical functionalities could greatly expand the overall versatility, and thus the utility, of this process. Herein, we explore the use of alkanethiol molecules as the terminating layer of metal-ligated multilayers. During this study, it was discovered that the solution deposition of alkanethiol molecules resulted in low overall surface coverage with features that varied in height. Because features with varied heights are not conducive to the production of uniform nanogaps via the molecular-ruler process, the vapor-phase deposition of alkanethiol molecules was explored. Unlike the solution-phase deposition, alkanethiol islands produced by vapor-phase deposition exhibited markedly higher surface coverages of uniform heights. To illustrate the applicability of this method, metal-ligated multilayers, both with and without an alkanethiol capping layer, were utilized to create nanogaps between Au features using the molecular-ruler process.

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

Influence of Knowledge of Task Endpoint on Pacing and Performance During Simulated Rugby League Match Play.

PURPOSE: To examine the influence of knowledge of exercise duration on pacing and performance during simulated rugby league match play. METHODS: Thirteen male university rugby players completed 3 simulated rugby league matches (RLMSP-i) on separate days in a random order. In a control trial, participants were informed that they would be performing 2 × 23-min bouts (separated by 20 min) of the RLMSP-i (CON). In a second trial, participants were informed that they would be performing 1 × 23-min bout of the protocol but were then asked to perform another 23-min bout (DEC). In a third trial, participants were not informed of the exercise duration and performed 2 × 23-min bouts (UN). RESULTS: Distance covered and high-intensity running were higher in CON (4813 ± 167 m, 26 ± 4.1 m/min) than DEC (4764 ± 112 m, 25.2 ± 2.8 m/min) and UN (4744 ± 131 m, 24.4 m/min). Compared with CON, high-intensity running and peak speed were typically higher for DEC in bout 1 and lower in bout 2 of the RLMSP-i, while UN was generally lower throughout. Similarly, DEC resulted in an increased heart rate, blood lactate, and rating of perceived exertion than CON in bout 1, whereas these variables were lower throughout the protocol in UN. CONCLUSIONS: Pacing and performance during simulated rugby league match play depend on an accurate understanding of the exercise endpoint. Applied practitioners should consider informing players of their likely exercise duration to maximize running.

Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome.

Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML). With rare exceptions, the spectrum of germline variants causing RASopathies does not overlap with the somatic variants identified in isolated JMML. Studies comparing these variants suggest a stronger gain-of-function activity in the JMML variants. As JMML variants have not been identified as germline defects and have a greater impact on protein function, it has been speculated that they would be embryonic lethal. Here we identified three variants, which have previously only been identified in isolated somatic JMML and other sporadic cancers, in four cases with a severe pre- or neo-natal lethal presentation of Noonan syndrome. These cases support the hypothesis that these stronger gain-of-function variants are rarely compatible with life.

The Unsuitability of Energy Expenditure Derived From Microtechnology for Assessing Internal Load in Collision-Based Activities.

This aim of this study was to examine the validity of energy expenditure derived from microtechnology when measured during a repeated-effort rugby protocol. Sixteen male rugby players completed a repeated-effort protocol comprising 3 sets of 6 collisions during which movement activity and energy expenditure (EEGPS) were measured using microtechnology. In addition, energy expenditure was estimated from open-circuit spirometry (EEVO2). While related (r = .63, 90%CI .08-.89), there was a systematic underestimation of energy expenditure during the protocol (-5.94 ± 0.67 kcal/min) for EEGPS (7.2 ± 1.0 kcal/min) compared with EEVO2 (13.2 ± 2.3 kcal/min). High-speed-running distance (r = .50, 95%CI -.66 to .84) was related to EEVO2, while PlayerLoad was not (r = .37, 95%CI -.81 to .68). While metabolic power might provide a different measure of external load than other typically used microtechnology metrics (eg, high-speed running, PlayerLoad), it underestimates energy expenditure during intermittent team sports that involve collisions.

Interrater reliability of a near-miss risk index for incident learning systems in radiation oncology.

PURPOSE: Tools for assessing the severity and risk of near-miss events in radiation oncology are few and needed. Recent work has described guidelines for the use of a 5-tier near-miss risk index (NMRI) for the classification of near-miss events. The purpose of this study was to assess the reliability of the NMRI among users in a radiation oncology department. METHODS AND MATERIALS: Reliability of the NMRI was assessed using an online survey distributed to members of a radiation oncology department. The survey contained 70 events extracted from the department's incident learning system (ILS). Survey participants rated each event using the NMRI guidelines, reported their attendance to weekly ILS meetings (used as a surrogate for familiarity with the ILS), and indicated their familiarity with the radiation oncology workflow. Interrater reliability was determined using Krippendorff's alpha. Use of the NMRI to rate actual events during 5 weekly ILS meetings was also assessed and interrater reliability determined. RESULTS: Twenty-eight survey respondents represented a wide variety of care providers. Krippendorff's alpha was calculated for the whole respondent cohort to be 0.376, indicating fair agreement among raters. Respondents who had the most participation at ILS meetings (n = 4) had moderate agreement with an alpha of 0.501. Interestingly, there were significant differences in reliability and median NMRI scores between professions. NMRI use during weekly NMRI meetings (80 events rated), participants showed moderate reliability (alpha = 0.607). CONCLUSIONS: Using the NMRI guidelines, raters from a wide variety of professions were able to assess the severity of near-miss incidents with fair agreement. Those experienced with the ILS showed better agreement, and higher agreement was seen during multidisciplinary ILS meetings. These data support the use the indices such as the NMRI for near-miss risk assessment in patient safety and prioritization of process improvements in radiation oncology.

Metrics of success: Measuring impact of a departmental near-miss incident learning system.

PURPOSE: There is a growing interest in the application of incident learning systems (ILS) to radiation oncology. The purpose of the present study is to define statistical metrics that may serve as benchmarks for successful operation of an incident learning system. METHODS AND MATERIALS: A departmental safety and quality ILS was developed to monitor errors, near-miss events, and process improvement suggestions. Event reports were reviewed by a multiprofessional quality improvement committee. Events were scored by a near-miss risk index (NMRI) and categorized by event point of origination and discovery. Reporting trends were analyzed over a 2-year period, including total number and rates of events reported, users reporting, NMRI, and event origination and discovery. RESULTS: A total of 1897 reports were evaluated (1.0 reports/patient, 0.9 reports/unique treatment course). Participation in the ILS increased as demonstrated by total events (2.1 additional reports/month) and unique users (0.5 new users/month). Sixteen percent of reports had an NMRI of 0 (none), 42% had an NMRI of 1 (mild), 25% had an NMRI of 2 (moderate), 12% had an NMRI of 3 (severe), and 5% had an NMRI of 4 (critical). Event NMRI showed a significant decrease in the first 6 months (1.68-1.42, P < .001). Trends in origination and discovery of reports were broadly distributed between radiation therapy process steps and staff groups. The highest risk events originated in imaging for treatment planning (NMRI = 2.0 ± 1.1; P < .0001) and were detected in on-treatment quality management (NMRI = 1.7 ± 1.1; P = .003). CONCLUSIONS: Over the initial 2-year period of ILS operation, rates of reporting increased, staff participation increased, and NMRI of reported events declined. These data mirror previously reported findings of improvement in safety culture endpoints. These metrics may be useful for other institutions seeking to create or evaluate their own ILS.

The Internal and External Responses to a Forward-Specific Rugby League Simulation Protocol Performed With and Without Physical Contact.

It is important to understand the extent to which physical contact changes the internal and external load during rugby simulations that aim to replicate the demands of match play. Accordingly, this study examined the role of physical contact on the physiological and perceptual demands during and immediately after a simulated rugby league match. Nineteen male rugby players completed a contact (CON) and a noncontact (NCON) version of the rugby league match-simulation protocol in a randomized crossover design with 1 wk between trials. Relative distance covered (ES = 1.27; ± 0.29), low-intensity activity (ES = 1.13; ± 0.31), high-intensity running (ES = 0.49; ± 0.34), heart rate (ES = 0.52; ± 0.35), blood lactate concentration (ES = 0.78; ± 0.34), rating of perceived exertion (RPE) (ES = 0.72; ± 0.38), and session RPE (ES = 1.45; ± 0.51) were all higher in the CON than in the NCON trial. However, peak speeds were lower in the CON trial (ES = -0.99; ± 0.40) despite unclear reductions in knee-extensor (ES = 0.19; ± 0.40) and -flexor (ES = 0.07; ± 0.43) torque. Muscle soreness was also greater after CON than in the NCON trial (ES = 0.97; ± 0.55). The addition of physical contact to the movement demands of a simulated rugby league match increases many of the external and internal demands but also results in players' slowing their peak running speed during sprints. These findings highlight the importance of including contacts in simulation protocols and training practices designed to replicate the demands of real match play.

1-Adamantanethiol as a versatile nanografting tool.

Strategies to regulate the self-assembly of adsorbates to create surface structures with molecular-scale features and organization are of broad interest to nanoscience, biochemistry, and engineering. One approach utilizes molecules with tailored intermolecular interaction strengths and topologies to direct molecular self-assembly as exemplified by the adsorption of 1-adamantanethiol molecules on Au{111} substrates. 1-Adamantanethiolate self-assembled monolayers exhibit decreased packing densities and weaker intermolecular interaction strengths than n-alkanethiolate self-assembled monolayers, which result in their complete displacement upon exposure to n-alkanethiol molecules. Herein, we explore the capabilities of the atomic force microscopy-based lithographic technique, nanografting, to fabricate chemical patterns comprised of 1-adamantanethiolate monolayers. Positive 1-adamantanethiolate patterns are generated by nanografting 1-adamantanethiol molecules into preexisting n-alkanethiolate self-assembled monolayers, and negative 1-adamantanethiolate patterns are created by nanografting n-alkanethiol molecules into preexisting 1-adamantanethiolate self-assembled monolayers. The patterned 1-adamantanethiolate regions are displaced upon exposure to solutions of n-alkanethiol molecules. This two-step nanografting-displacement strategy minimizes pattern dissolution as 1-adamantanethiol molecules do not intercalate into the preexisting self-assembled monolayer during nanografting. 1-Adamantanethiol can be utilized create high-resolution sacrificial chemical patterns with feature sizes beyond those afforded other 1-adamantanethiol patterning strategies for applications such as resists for metallic and organic structures.