High-resolution breakpoint junction mapping of proximally extended D4Z4 deletions in FSHD1 reveals evidence for a founder effect.

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy clinically characterized by weakness in the facial, shoulder girdle and upper a muscles. FSHD is caused by chromatin relaxation of the D4Z4 macrosatellite repeat, mostly by a repeat contraction, facilitating ectopic expression of DUX4 in skeletal muscle. Genetic diagnosis for FSHD is generally based on the sizing and haplotyping of the D4Z4 repeat on chromosome 4 by Southern blotting (SB), molecular combing or single-molecule optical mapping, which is usually straight forward but can be complicated by atypical rearrangements of the D4Z4 repeat. One of these rearrangements is a D4Z4 proximally extended deletion (DPED) allele, where not only the D4Z4 repeat is partially deleted, but also sequences immediately proximal to the repeat are lost, which can impede accurate diagnosis in all genetic methods. Previously, we identified several DPED alleles in FSHD and estimated the size of the proximal deletions by a complex pulsed-field gel electrophoresis and SB strategy. Here, using the next-generation sequencing, we have defined the breakpoint junctions of these DPED alleles at the base pair resolution in 12 FSHD families and 4 control individuals facilitating a PCR-based diagnosis of these DPED alleles. Our resultsshow that half of the DPED alleles are derivates of an ancient founder allele. For some DPED alleles, we found that genetic elements are deleted such as DUX4c, FRG2, DBE-T and myogenic enhancers necessitating re-evaluation of their role in FSHD pathogenesis.

Health-related quality of life after a diagnosis of bladder cancer: a longitudinal survey over the first year.

OBJECTIVES: To describe the health-related quality of life (HRQoL) of patients in a prospective 12-month observational cohort study of new bladder cancer diagnoses and compare with national cancer and general population surveys. PATIENTS AND METHODS: A prospective UK study in patients with new bladder cancer diagnoses at 13 NHS Trusts. The HRQoL data were collected at 3, 6, 9 and 12 months. Questionnaires used included: the EuroQoL five Dimensions (EQ-5D), European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ)-30-item core, EORTC QLQ-24-item non-muscle-invasive bladder cancer, and EORTC QLQ-30-item muscle-invasive bladder cancer. Results were compared with the Cancer Quality of Life Survey and Health Survey for England. RESULTS: A total of 349 patients were recruited, 296 (85%) completed the first (baseline) and 233 (67%) the final survey. The patients underwent transurethral resection of bladder tumour (TURBT) ± intravesical therapy (238 patients, 80%), radical cystectomy/radiotherapy (51, 17%) or palliation (seven, 2%). At baseline, patients needing radical treatment reported worse HRQoL including lower social function (74.2 vs 83.8, P = 0.002), increased fatigue (31.5 vs 26.1, P = 0.03) and more future worries (39.2 vs 29.4, P = 0.005) than patients who underwent TURBT. Post-treatment surveys showed no change/improvements for patients who underwent TURBT but deterioration for the radically treated cohort. At final survey, reports were similar to baseline, regardless of treatment. Radically treated patients continued to report poorer HRQoL including issues with body image (23.4 vs 12.5, P = 0.007) and male sexual function (75.8 vs 40.4, P < 0.001) compared to those who underwent TURBT. Radically treated patients reported lower EQ-5D utility scores and more problems with usual activities than the general population. DISCUSSION: Patients undergoing TURBT can be reassured regarding HRQoL following treatment. However, those requiring radical treatment report greater changes in HRQoL with the need for appropriate clinical and supportive care to minimise the impact of treatments.

Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver.

Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction.

Prediction of driver variants in the cancer genome via machine learning methodologies.

Sequencing technologies have led to the identification of many variants in the human genome which could act as disease-drivers. As a consequence, a variety of bioinformatics tools have been proposed for predicting which variants may drive disease, and which may be causatively neutral. After briefly reviewing generic tools, we focus on a subset of these methods specifically geared toward predicting which variants in the human cancer genome may act as enablers of unregulated cell proliferation. We consider the resultant view of the cancer genome indicated by these predictors and discuss ways in which these types of prediction tools may be progressed by further research.

Effect of Multicomponent Home-Based Training on Gait and Muscle Strength in Older Adults After Hip Fracture Surgery: A Single Site Randomized Trial.

OBJECTIVE: To investigate the effect of 16-week home-based physical therapy interventions on gait and muscle strength. DESIGN: A single-blinded randomized controlled trial. SETTING: General community. PARTICIPANTS: Thirty-four older adults (N=34) post hip fracture were randomly assigned to either experimental group (a specific multi-component intervention group [PUSH], n=17, 10 women, age=78.6±7.3 years, 112.1±39.8 days post-fracture) or active control (a non-specific multi-component intervention group [PULSE], n=17, 11 women, age=77.8±7.8 years, 118.2±37.5 days post-fracture). INTERVENTION: PUSH and PULSE groups received 32-40 sessions of specific or non-specific multi-component home-based physical therapy, respectively. Training in the PUSH group focused on lower extremity strength, endurance, balance, and function for community ambulation, while the PULSE group received active movement and transcutaneous electrical nerve stimulation on extremities. MAIN OUTCOME MEASURES: Gait characteristics, and ankle and knee muscle strength were measured at baseline and 16 weeks. Cognitive testing of Trail Making Test (Part A: TMT-A; Part-B: TMT-B) was measured at baseline. RESULTS: At 16 weeks, both groups demonstrated significant increases in usual (P<.05) and fast (P<.05) walking speed, while there was no significant difference in increases between the groups. There was only 1 significant change in lower limb muscle strength over time (non-fractured side) between the groups, such that PUSH did better (mean: 4.33%, 95% confidence interval:1.43%-7.23%). The increase in usual and fast walking speed correlated with the baseline Trail-making Test-B score (r=-0.371, P=.037) and improved muscle strength in the fractured limb (r=0.446, P=.001), respectively. CONCLUSION: Gait speed improved in both home-based multicomponent physical therapy programs in older adults after hip fracture surgery. Muscle strength of the non-fractured limb improved in the group receiving specific physical therapy training. Specific interventions targeting modifiable factors such as muscle strength and cognitive performance may assist gait recovery after hip fracture surgery.

Oral versus Intravenous Antibiotics for Bone and Joint Infection.

BACKGROUND: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).

Rapid, robust plasmid verification by de novo assembly of short sequencing reads.

Plasmids are a foundational tool for basic and applied research across all subfields of biology. Increasingly, researchers in synthetic biology are relying on and developing massive libraries of plasmids as vectors for directed evolution, combinatorial gene circuit tests, and for CRISPR multiplexing. Verification of plasmid sequences following synthesis is a crucial quality control step that creates a bottleneck in plasmid fabrication workflows. Crucially, researchers often elect to forego the cumbersome verification step, potentially leading to reproducibility and-depending on the application-security issues. In order to facilitate plasmid verification to improve the quality and reproducibility of life science research, we developed a fast, simple, and open source pipeline for assembly and verification of plasmid sequences from Illumina reads. We demonstrate that our pipeline, which relies on de novo assembly, can also be used to detect contaminating sequences in plasmid samples. In addition to presenting our pipeline, we discuss the role for verification and quality control in the increasingly complex life science workflows ushered in by synthetic biology.

CScape-somatic: distinguishing driver and passenger point mutations in the cancer genome.

MOTIVATION: Next-generation sequencing technologies have accelerated the discovery of single nucleotide variants in the human genome, stimulating the development of predictors for classifying which of these variants are likely functional in disease, and which neutral. Recently, we proposed CScape, a method for discriminating between cancer driver mutations and presumed benign variants. For the neutral class, this method relied on benign germline variants found in the 1000 Genomes Project database. Discrimination could, therefore, be influenced by the distinction of germline versus somatic, rather than neutral versus disease driver. This motivates this article in which we consider predictive discrimination between recurrent and rare somatic single point mutations based solely on using cancer data, and the distinction between these two somatic classes and germline single point mutations. RESULTS: For somatic point mutations in coding and non-coding regions of the genome, we propose CScape-somatic, an integrative classifier for predictively discriminating between recurrent and rare variants in the human cancer genome. In this study, we use purely cancer genome data and investigate the distinction between minimal occurrence and significantly recurrent somatic single point mutations in the human cancer genome. We show that this type of predictive distinction can give novel insight, and may deliver more meaningful prediction in both coding and non-coding regions of the cancer genome. Tested on somatic mutations, CScape-somatic outperforms alternative methods, reaching 74% balanced accuracy in coding regions and 69% in non-coding regions, whereas even higher accuracy may be achieved using thresholds to isolate high-confidence predictions. AVAILABILITY AND IMPLEMENTATION: Predictions and software are available at http://CScape-somatic.biocompute.org.uk/. CONTACT: mark.f.rogers.phd@gmail.com or C.Campbell@bristol.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cervical Spine CT Can Miss Fractures in American Football Players When Protective Equipment is in Place: A Cadaver Study.

BACKGROUND: Iatrogenic worsening of spinal injury can result in significant harm to American football players and complicate management when equipment is removed in the acute setting by inexperienced personnel. Spine imaging before removal of protective equipment mitigates this risk. There is no consensus regarding the ideal timing of equipment removal or whether current diagnostic imaging modalities are effective to detect such injuries without equipment removal. Prior data suggest that CT is a diagnostic modality for this purpose; however, radiologists' accuracy in detecting fractures in the presence of protective equipment requires additional study. QUESTIONS/PURPOSES: (1) Does the introduction of American football equipment result in a significant reduction in sensitivity for cervical spine fracture detection? (2) Absent specific guidance as to parameters needed to establish diagnostic quality, can a radiologist determine whether such CTs are of diagnostic quality by subjectively relying on the ability to identify anatomic landmarks? METHODS: A pendulum device was engineered to deliver a measured axial load to the crown of cadavers to produce a variety of cervical spine fractures in 13 cadaver specimens. The cadavers were then imaged using a standardized CT protocol first without and then with protective football equipment. The images were presented to three board-certified, fellowship-trained radiologists to (1) identify all fractures from the occiput to T1 and (2) subjectively assess the diagnostic quality of the resulting CTs. A sensitivity analysis was performed against a reference standard of fractures produced by the consensus of all radiologists in this study to determine whether there was any reduction in radiologists' ability to detect fractures once football equipment was in place. RESULTS: We found that CT scans obtained with football protective equipment in place resulted in lower sensitivity in diagnosing cervical spine injuries than CT scans obtained without pads. A total of 42 fractures were identified in the reference standard, allowing for a combined 126 possible fracture identifications between the three interpreters. Without football equipment, a combined 98 fractures were identified, whereas a combined 65 fractures were identified once the equipment was introduced. Overall, the sensitivity was reduced by 26% (52% [65 of 126] versus 78% [98 of 126] [95% CI 14.8% to 37.5%]; p < 0.001). Of the 78 total CT series imaged with football equipment, 92% (72 of 78) were considered to be of diagnostic quality. However, the study radiologists failed to identify 50% (53 of 105) of fractures present in those CT images. CONCLUSION: The sensitivity of cervical spine fracture detection using CT is diminished in the setting of protective American football equipment. Future studies in live subjects with cervical spine fracture may be warranted to support these conclusions. CLINICAL RELEVANCE: These findings contradict previous studies that determined CT to be a diagnostic imaging modality to image the cervical spine through equipment. Although the interpreting radiologists consistently deemed CTs performed in the presence of helmets and shoulder pads to have subjectively diagnostic quality, numerous fractures that had been detected in the absence of equipment were missed in their presence. Furthermore, this study established that subjective approval of the appearance of an imaging study based on the ability to recognize anatomic landmarks is insufficient to reliably determine the diagnostic quality of a CT study.

Effects of transcranial direct current stimulation (tDCS) on posture, movement planning, and execution during standing voluntary reach following stroke.

BACKGROUND: Impaired movement preparation of both anticipatory postural adjustments and goal directed movement as shown by a marked reduction in the incidence of StartReact responses during a standing reaching task was reported in individuals with stroke. We tested how transcranial direct current stimulation (tDCS) applied over the region of premotor areas (PMAs) and primary motor area (M1) affect movement planning and preparation of a standing reaching task in individuals with stroke. METHODS: Each subject performed two sessions of tDCS over the lesioned hemisphere on two different days: cathodal tDCS over PMAs and anodal tDCS over M1. Movement planning and preparation of anticipatory postural adjustment-reach sequence was examined by startReact responses elicited by a loud acoustic stimulus of 123 dB. Kinetic, kinematic, and electromyography data were recorded to characterize anticipatory postural adjustment-reach movement response. RESULTS: Anodal tDCS over M1 led to significant increase of startReact responses incidence at loud acoustic stimulus time point - 500 ms. Increased trunk involvement during movement execution was found after anodal M1 stimulation compared to PMAs stimulation. CONCLUSIONS: The findings provide novel evidence that impairments in movement planning and preparation as measured by startReact responses for a standing reaching task can be mitigated in individuals with stroke by the application of anodal tDCS over lesioned M1 but not cathodal tDCS over PMAs. This is the first study to show that stroke-related deficits in movement planning and preparation can be improved by application of anodal tDCS over lesioned M1. Trial registration ClinicalTrial.gov, NCT04308629, Registered 16 March 2020-Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT04308629.

Nucleotide diversity of functionally different groups of immune response genes in Old World camels based on newly annotated and reference-guided assemblies.

BACKGROUND: Immune-response (IR) genes have an important role in the defense against highly variable pathogens, and therefore, diversity in these genomic regions is essential for species' survival and adaptation. Although current genome assemblies from Old World camelids are very useful for investigating genome-wide diversity, demography and population structure, they have inconsistencies and gaps that limit analyses at local genomic scales. Improved and more accurate genome assemblies and annotations are needed to study complex genomic regions like adaptive and innate IR genes. RESULTS: In this work, we improved the genome assemblies of the three Old World camel species - domestic dromedary and Bactrian camel, and the two-humped wild camel - via different computational methods. The newly annotated dromedary genome assembly CamDro3 served as reference to scaffold the NCBI RefSeq genomes of domestic Bactrian and wild camels. These upgraded assemblies were then used to assess nucleotide diversity of IR genes within and between species, and to compare the diversity found in immune genes and the rest of the genes in the genome. We detected differences in the nucleotide diversity among the three Old World camelid species and between IR gene groups, i.e., innate versus adaptive. Among the three species, domestic Bactrian camels showed the highest mean nucleotide diversity. Among the functionally different IR gene groups, the highest mean nucleotide diversity was observed in the major histocompatibility complex. CONCLUSIONS: The new camel genome assemblies were greatly improved in terms of contiguity and increased size with fewer scaffolds, which is of general value for the scientific community. This allowed us to perform in-depth studies on genetic diversity in immunity-related regions of the genome. Our results suggest that differences of diversity across classes of genes appear compatible with a combined role of population history and differential exposures to pathogens, and consequent different selective pressures.

Asymptomatic carotid stenosis is associated with mobility and cognitive dysfunction and heightens falls in older adults.

BACKGROUND: Atherosclerosis of the carotid bifurcation with plaque formation causes asymptomatic carotid artery stenosis (ACAS), which may also be associated with cerebral hypoperfusion. Cerebral hypoperfusion adversely affects multiple aspects of mobility and cognition. This study tests the hypothesis that community-dwelling older adults with a 50% or greater diameter-reducing ACAS will have mobility and cognitive impairments that heighten their risk for falls. METHODS: Eighty community-dwelling adults completed a mobility assessment (Short Physical Performance Battery, Berg Balance Scale, Four Square Step Test, Dynamic Gait Index, Timed Up and Go, and gait speed), self-reported physical function (Activities-Specific Balance Confidence, SF-12 Physical Function Component), and cognitive tests (Mini-Mental State Examination). Falls were recorded for the past 6 months. Standardized carotid ultrasound examination classified participants into no stenosis (<50% diameter reduction) (n = 54), moderate stenosis (50%-69%) (n = 17), and high-grade stenosis (70%-99%) (n = 9) groups. Linear and logistic regression analyses determined the associations between these measures and the degree of stenosis (three groups). RESULTS: Logistic regression analysis showed their degree of stenosis was associated with reductions in mobility (Short Physical Performance Battery [P = .008], Berg Balance Scale [P = .0008], Four Square Step Test [P = .005], DGI [P = .0001], TUG [P = .0004], gait speed [P = .02]), perceived physical function (ABC [P < .0001], SF-12 Physical Function Component [P < .0001]), and cognition (MMSE [P = .003]). Adults with moderate- and high-grade stenosis had a greater incidence of falls compared with those without stenosis (relative risk, 2.86; P = .01). Results remained unchanged after adjustment for age, sex and cardiovascular risk factors. CONCLUSIONS: ACAS is associated with impaired mobility and cognition that are accompanied with increased fall risk. These impairments increased with worsening severity.

Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation.

BACKGROUND: Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. METHODS: Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). RESULTS: No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher's exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4-83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3-83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation. DISCUSSION: These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.

Biomechanical control of paretic lower limb during imposed weight transfer in individuals post-stroke.

BACKGROUND: Stroke is a leading cause of disability with associated hemiparesis resulting in difficulty bearing and transferring weight on to the paretic limb. Difficulties in weight bearing and weight transfer may result in impaired mobility and balance, increased fall risk, and decreased community engagement. Despite considerable efforts aimed at improving weight transfer after stroke, impairments in its neuromotor and biomechanical control remain poorly understood. In the present study, a novel experimental paradigm was used to characterize differences in weight transfer biomechanics in individuals with chronic stroke versus able-bodied controls METHODS: Fifteen participants with stroke and fifteen age-matched able-bodied controls participated in the study. Participants stood with one foot on each of two custom built platforms. One of the platforms dropped 4.3 cm vertically to induce lateral weight transfer and weight bearing. Trials involving a drop of the platform beneath the paretic lower extremity (non-dominant limb for control) were included in the analyses. Paretic lower extremity joint kinematics, vertical ground reaction forces, and center of pressure velocity were measured. All participants completed the clinical Step Test and Four-Square Step Test. RESULTS: Reduced paretic ankle, knee, and hip joint angular displacement and velocity, delayed ankle and knee inter-joint timing, increased downward displacement of center of mass, and increased center of pressure (COP) velocity stabilization time were exhibited in the stroke group compared to the control group. In addition, paretic COP velocity stabilization time during induced weight transfer predicted Four-Square Step Test scores in individuals post-stroke. CONCLUSIONS: The induced weight transfer approach identified stroke-related abnormalities in the control of weight transfer towards the paretic limb side compared to controls. Decreased joint flexion of the paretic ankle and knee, altered inter-joint timing, and increased COP stabilization times may reflect difficulties in neuromuscular control during weight transfer following stroke. Future work will investigate the potential of improving functional weight transfer through induced weight transfer training exercise.

Impaired posture, movement preparation, and execution during both paretic and nonparetic reaching following stroke.

Posture and movement planning, preparation, and execution of a goal-directed reaching movement are impaired in individuals with stroke. No studies have shown whether the deficits are generally impaired or are specific to the lesioned hemisphere/paretic arm. This study utilized StartReact (SR) responses elicited by loud acoustic stimuli (LAS) to investigate the preparation and execution of anticipatory postural adjustments (APAs) and reach movement response during both paretic and nonparetic arm reaching in individuals with stroke and in age-matched healthy controls. Subjects were asked to get ready after receiving a warning cue and to reach at a "go" cue. An LAS was delivered at -500, -200, and 0 ms relative to the go cue. Kinetic, kinematic, and electromyographic data were recorded to characterize APA-reach movement responses. Individuals with stroke demonstrated systemwide deficits in posture and in movement planning, preparation, and execution of APA-reach sequence as shown by significant reduction in the incidence of SR response and impaired APA-reach performance, with greater deficits during paretic arm reaching. Use of trunk compensation strategy as characterized by greater involvement of trunk and pelvic rotation was utilized by individuals with stroke during paretic arm reaching compared with nonparetic arm reaching and healthy controls. Our findings have implications for upper extremity and postural control, suggesting that intervention should include training not only for the paretic arm but also for the nonparetic arm with simultaneous postural control requirements to improve the coordination of the APA-reach performance and subsequently reduce instability while functional tasks are performed during standing. NEW & NOTEWORTHY Our study is the first to show that nonparetic arm reaching also demonstrates impairment in posture and movement planning, preparation, and execution when performed during standing by individuals with stroke. In addition, we found compensatory trunk and pelvic rotations were used during a standing reach task for the paretic arms. The findings have clinical implications for upper extremity and postural rehabilitation, suggesting that training should include the nonparetic arms and incorporate simultaneous postural control demands.

Aging changes in protective balance and startle responses to sudden drop perturbations.

This study investigated aging changes in protective balance and startle responses to sudden drop perturbations and their effect on landing impact forces (vertical ground reaction forces, vGRF) and balance stability. Twelve healthy older (6 men; mean age = 72.5 ± 2.32 yr, mean ± SE) and 12 younger adults (7 men; mean age = 28.09 ± 1.03 yr) stood atop a moveable platform and received externally triggered drop perturbations of the support surface. Electromyographic activity was recorded bilaterally over the sternocleidomastoid (SCM), middle deltoid, biceps brachii, vastus lateralis (VL), biceps femoris (BF), medial gastrocnemius (MG), and tibialis anterior (TA). Whole body kinematics were recorded with motion analysis. Stability in the anteroposterior direction was quantified using the margin of stability (MoS). Incidence of early onset of bilateral SCM activation within 120 ms after drop onset was present during the first-trial response (FTR) for all participants. Co-contraction indexes during FTRs between VL and BF as well as TA and MG were significantly greater in the older group (VL/BF by 26%, P < 0.05; TA/MG by 37%, P < 0.05). Reduced shoulder abduction between FTR and last-trial responses, indicative of habituation, was present across both groups. Significant age-related differences in landing strategy were present between groups, because older adults had greater trunk flexion (P < 0.05) and less knee flexion (P < 0.05) that resulted in greater peak vGRFs and decreased MoS compared with younger adults. These findings suggest age-associated abnormalities of delayed, exaggerated, and poorly habituated startle/postural FTRs are linked with greater landing impact force and diminished balance stabilization. NEW & NOTEWORTHY This study investigated the role of startle as a pathophysiological mechanism contributing to balance impairment in aging. We measured neuromotor responses as younger and older adults stood on a platform that dropped unexpectedly. Group differences in landing strategies indicated age-associated abnormalities of delayed, exaggerated, and poorly habituated startle/postural responses linked with a higher magnitude of impact force and decreased balance stabilization. The findings have implications for determining mechanisms contributing to falls and related injuries.

Genomic Research and American Indian Tribal Communities in Oklahoma: Learning From Past Research Misconduct and Building Future Trusting Partnerships.

Research misconduct and consequential harms have been inflicted upon American Indian/Alaska Native communities for decades. To protect their people and culture and to retain oversight over research, many Native communities have established tribal health research and institutional review boards. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study showcases a successful, trusting research collaboration with tribal nations and academic investigators in Oklahoma. In 2006, the TODAY Study investigators proposed a modification of the study protocol to collect biological specimens from participants for genomic analyses and indefinite storage. Partnering American Indian tribal nations elected not to participate in the genomics collection and repository proposal. Reasons included 1) protection of cultural values, 2) concerns regarding community anonymity, 3) a potential threat to tribal services eligibility, 4) broad informed consent language, and 5) vague definitions of data access and usage. The nations believed the proposed genomics analyses presented a risk of harm to their people and nations without clear benefit. Since the 2006 proposal and the advancement of genomics research, many tribal communities in Oklahoma, appreciating the potential benefits of genomic research, are developing policies regarding oversight of/access to data and biological specimens to mitigate risks and provide members and communities with opportunities to participate in safe and meaningful genomic research.

FATHMM-XF: accurate prediction of pathogenic point mutations via extended features.

Summary: We present FATHMM-XF, a method for predicting pathogenic point mutations in the human genome. Drawing on an extensive feature set, FATHMM-XF outperforms competitors on benchmark tests, particularly in non-coding regions where the majority of pathogenic mutations are likely to be found. Availability and implementation: The FATHMM-XF web server is available at http://fathmm.biocompute.org.uk/fathmm-xf/, and as tracks on the Genome Tolerance Browser: http://gtb.biocompute.org.uk. Predictions are provided for human genome version GRCh37/hg19. The data used for this project can be downloaded from: http://fathmm.biocompute.org.uk/fathmm-xf/. Contact: mark.rogers@bristol.ac.uk or c.campbell@bristol.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer.

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

A Cost-Effectiveness Analysis of Isolated Meniscal Repair Versus Partial Meniscectomy for Red-Red Zone, Vertical Meniscal Tears in the Young Adult.

PURPOSE: To evaluate the cost-effectiveness of treating isolated red-red zone, vertical meniscal tears with either isolated meniscal repair (IMR) or partial meniscectomy (PM) in the young adult using conservative modeling. METHODS: A decision-analytic Markov disease progression model with a 40-year horizon was created simulating outcomes after IMR or PM for an isolated meniscal tear. Event probabilities, costs, and utilities were used for the index procedures, and the development of osteoarthritis (OA) and subsequent need for knee arthroplasty were calculated or selected from the published literature. Differences in cost, difference in quality-adjusted life years (QALYs), and the incremental cost effect ratio were calculated to determine which index procedure is most cost effective. RESULTS: Total direct costs from PM were modeled at $38,648, and the total direct costs of IMR were $23,948, resulting in a projected cost savings of $14,700 with IMR. There was a modeled gain in QALYs of 17 for PM and 21 for IMR, resulting in an increase in 4 QALYs for the IMR treatment group. This results in an incremental cost effect ratio of $3,935 per QALY, favoring IMR as the dominant procedure. CONCLUSIONS: Meniscal repair for isolated red-red zone, vertical meniscal tears was predicted to have lower direct costs and improve QALYs compared with partial meniscectomy over 40-year modeling, indicating isolated meniscal repair to be the cost-effective procedure in the treatment of an isolated meniscal tear in the young adult population. LEVEL OF EVIDENCE: Level 3: economic and decision analysis.