Exploring an objective measure of overactivity in children with rare genetic syndromes.

BACKGROUND: Overactivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex, although has been predominantly assessed using questionnaire techniques. Threats to the precision and validity of questionnaire data may undermine existing insights into this behaviour. Previous research indicates objective measures, namely actigraphy, can effectively differentiate non-overactive children from those with attention-deficit hyperactivity disorder. This study is the first to examine the sensitivity of actigraphy to overactivity across rare genetic syndromes associated with intellectual disability, through comparisons with typically-developing peers and questionnaire overactivity estimates. METHODS: A secondary analysis of actigraphy data and overactivity estimates from The Activity Questionnaire (TAQ) was conducted for children aged 4-15 years with Smith-Magenis syndrome (N=20), Angelman syndrome (N=26), tuberous sclerosis complex (N=16), and typically-developing children (N=61). Actigraphy data were summarized using the M10 non-parametric circadian rhythm variable, and 24-hour activity profiles were modelled via functional linear modelling. Associations between actigraphy data and TAQ overactivity estimates were explored. Differences in actigraphy-defined activity were also examined between syndrome and typically-developing groups, and between children with high and low TAQ overactivity scores within syndromes. RESULTS: M10 and TAQ overactivity scores were strongly positively correlated for children with Angelman syndrome and Smith-Magenis syndrome. M10 did not substantially differ between the syndrome and typically-developing groups. Higher early morning activity and lower evening activity was observed across all syndrome groups relative to typically-developing peers. High and low TAQ group comparisons revealed syndrome-specific profiles of overactivity, persisting throughout the day in Angelman syndrome, occurring during the early morning and early afternoon in Smith-Magenis syndrome, and manifesting briefly in the evening in tuberous sclerosis complex. DISCUSSION: These findings provide some support for the sensitivity of actigraphy to overactivity in children with rare genetic syndromes, and offer syndrome-specific temporal descriptions of overactivity. The findings advance existing descriptions of overactivity, provided by questionnaire techniques, in children with rare genetic syndromes and have implications for the measurement of overactivity. Future studies should examine the impact of syndrome-related characteristics on actigraphy-defined activity and overactivity estimates from actigraphy and questionnaire techniques.

Artificial gauge fields in the t-z mapping for optical pulses: Spatiotemporal wave packet control and quantum Hall physics.

We extend the t-z mapping of time-dependent paraxial optics by engineering a synthetic magnetic vector potential, leading to a nontrivial band topology. We consider an inhomogeneous 1D array of coupled optical waveguides and show that the wave equation describing paraxial propagation of optical pulses can be recast as a Schrödinger equation, including a synthetic magnetic field whose strength can be controlled via the spatial gradient of the waveguide properties across the array. We use an experimentally motivated model of a laser-written array to demonstrate that this synthetic magnetic field can be engineered in realistic setups and can produce interesting physics such as cyclotron motion, a controllable Hall drift of the pulse in space or time, and propagation in chiral edge states. These results substantially extend the physics that can be explored within propagating geometries and pave the way for higher-dimensional topological physics and strongly correlated fluids of light.

Blood-brain barrier remodeling in an organ-on-a-chip device shows Dkk1 to be a regulator of early metastasis.

Brain metastases are the most lethal progression event, in part because the biological processes underpinning brain metastases are poorly understood. There is a paucity of realistic models of metastasis, as current in vivo murine models are slow to manifest metastasis. We set out to delineate metabolic and secretory modulators of brain metastases by utilizing two models consisting of in vitro microfluidic devices: 1) a blood brain niche (BBN) chip that recapitulates the blood-brain-barrier and niche; and 2) a migration chip that assesses cell migration. We report secretory cues provided by the brain niche that attract metastatic cancer cells to colonize the brain niche region. Astrocytic Dkk-1 is increased in response to brain-seeking breast cancer cells and stimulates cancer cell migration. Brain-metastatic cancer cells under Dkk-1 stimulation increase gene expression of FGF-13 and PLCB1. Further, extracellular Dkk-1 modulates cancer cell migration upon entering the brain niche.

Profiles of autism characteristics in thirteen genetic syndromes: a machine learning approach.

BACKGROUND: Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes. METHODS: Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n = 154, Cri du Chat n = 75, Cornelia de Lange n = 199, fragile X n = 297, Prader-Willi n = 278, Lowe n = 89, Smith-Magenis n = 54, Down n = 135, Sotos n = 40, Rubinstein-Taybi n = 102, 1p36 deletion n = 41, tuberous sclerosis complex n = 83 and Phelan-McDermid n = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n = 254). Self-help skills were included as an additional predictor. RESULTS: Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader-Willi, Rubinstein-Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith-Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy. LIMITATIONS: The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups. CONCLUSIONS: These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID.

Distal radius malunion: outcomes following an ulnar shortening osteotomy.

PURPOSE: Positive ulnar variance following a distal radius malunion can lead to ulnar-sided wrist pain, loss of grip strength, and distal radioulnar joint impingement. The primary aim of this study is to describe upper limb-specific functional outcomes following ulnar shortening osteotomy (USO) for ulnar-sided wrist pain associated with malunion of the distal radius. METHODS: We retrospectively identified 40 adult patients from a single centre over a 9-year period that had undergone an USO for symptomatic malunion of the distal radius. The primary outcome was the patient-rated wrist evaluation (PRWE). Secondary outcomes were the QuickDASH, EQ-5D-5L, complications, and net promoter score (NPS). RESULTS: Outcomes were available for 37 patients (93%). The mean age was 56 years and 25 patients were female (68%). At a mean follow-up of 6 years (range 1-10 years) the median PRWE was 11 (IQR 0-29.5), the median QuickDASH 6.8 (IQR 0-29.5), and the median EQ-5D-5L index was 0.88 (IQR 0.71-1). The NPS was 73. Complications occurred in nine patients (24%) and included non-union (n = 4), early loss of fixation requiring revision surgery (n = 1), superficial wound infection (n = 2), neurological injury (n = 1), and further surgery for symptomatic hardware removal (n = 1). CONCLUSIONS: For patients with a symptomatic distal radius malunion where the predominant deformity is ulnar positive variance, this study has demonstrated that despite 1 in 4 patients experiencing a complication, USO can result in excellent patient reported outcomes with high levels of satisfaction. LEVEL OF EVIDENCE: III (Cohort Study).

CCP4 Cloud for structure determination and project management in macromolecular crystallography.

Nowadays, progress in the determination of three-dimensional macromolecular structures from diffraction images is achieved partly at the cost of increasing data volumes. This is due to the deployment of modern high-speed, high-resolution detectors, the increased complexity and variety of crystallographic software, the use of extensive databases and high-performance computing. This limits what can be accomplished with personal, offline, computing equipment in terms of both productivity and maintainability. There is also an issue of long-term data maintenance and availability of structure-solution projects as the links between experimental observations and the final results deposited in the PDB. In this article, CCP4 Cloud, a new front-end of the CCP4 software suite, is presented which mitigates these effects by providing an online, cloud-based environment for crystallographic computation. CCP4 Cloud was developed for the efficient delivery of computing power, database services and seamless integration with web resources. It provides a rich graphical user interface that allows project sharing and long-term storage for structure-solution projects, and can be linked to data-producing facilities. The system is distributed with the CCP4 software suite version 7.1 and higher, and an online publicly available instance of CCP4 Cloud is provided by CCP4.

A Community-Integrated Geographic Information System Study of Air Pollution Exposure Impacts in Colfax, LA.

A community-integrated geographic information systems (CIGIS) study assimilating qualitative and quantitative information about human exposures and health was conducted in Colfax, Louisiana, which hosts a commercial open burn/open detonation thermal treatment (TT) facility that destroys waste from Superfund sites, explosives, military ordnances, and propellants. Fifty-eight percent of residents identified as Black, and median annual income was $16,318, with 90% of the population living below the poverty line. We conducted oral history interviews of twenty-nine residents and mined public records to document the community's experiences. Interviews focused on themes of Colfax's history, changing community fabric, resident health, and air pollution. The oral histories and public comments by community members provided information about lived experiences, including several health conditions, toleration of noise and vibration, property damage, and resulting changes to activity levels. These statements provided insight into the extent of suffering experienced by the local community. We also ran dispersion models for dates in 2020 when the waste stream composition, mass, and burn/smoldering times were provided in the facility's public records. The dispersion models placed the air pollution at the homes of residents during some of the time, and waste stream records from the TT facility agree with community testimony about health effects based on the known health effects of those compounds. CIGIS integration of our community-based qualitative data and maps with quantitative air pollution dispersion model output illustrated alignment between community complaints of impacts to health and property, known toxicological information about waste stream compounds, and dispersion model output.

Modern Approach to the Neck Mass.

Neck mass is a common first sign of malignancy in adult patients. Timely diagnosis can prevent disease progression. Initial evaluation of a neck mass includes creating a plan for obtaining further diagnostic information such as through imaging and tissue diagnosis. Fine-needle aspiration (FNA) can be done with or without ultrasound (US) guidance and is commonly done as an alternative to core biopsy and open biopsy. The accuracy of US-guided FNA has been shown to supersede that of palpation-guided FNA. Moreover, in-office US-guided FNA has become more accessible over time and can improve time to diagnosis.

Refining the Behavioral Phenotype of Angelman Syndrome: Examining Differences in Motivation for Social Contact Between Genetic Subgroups.

Angelman syndrome (AS) is caused by loss of information from the 15q11.2-13 region on the maternal chromosome with striking phenotypic difference from Prader-Willi syndrome in which information is lost from the same region on the paternal chromosome. Motivation for social contact and sensory seeking behaviors are often noted as characteristics of the phenotype of AS and it has been argued that the strong drive for social contact supports a kinship theory interpretation of genomic imprinting. In this study we developed an experimental paradigm for quantifying the motivation for social contact in AS and examined differences across the genetic subtypes that cause AS [deletion, imprinting centre defect (ICD), uniparental disomy and UBE3A mutation]. Using single case experimental designs we examined the rate of acquisition of behavioral responses using operant learning paradigms for 21 children with AS whilst systematically varying the nature of social and sensory reinforcement. Variability in rates of acquisition was influenced by the nature of rewarding stimuli. Across the total sample both sensory stimuli and social contact could increase the rate of rewarded behavior with difference between children in the most effective reward. A striking difference in the rewarding properties of social contact across genetic subtypes was evidenced by non-deletion genetic causes of AS showing significantly higher rates of responding than the deletion cause in the social reinforcement paradigm. The results indicate that reinforcer assessment can beneficially inform behavioral interventions and that within syndrome variability in the behavioral phenotype of AS is likely driven by genetic difference. The non-deletion cause of AS, and particularly the ICD group, may be the optimal group for further study of genomic imprinting.

Patient-reported outcomes after corrective osteotomy for a symptomatic malunion of the distal radius.

AIMS: The primary aim of this study was to describe patient satisfaction and health-related quality of life (HRQoL) following corrective osteotomy for a symptomatic malunion of the distal radius. METHODS: We retrospectively identified 122 adult patients from a single centre over an eight-year period who had undergone corrective osteotomy for a symptomatic malunion of the distal radius. The primary long-term outcome was the Patient-Rated Wrist Evaluation (PRWE) score. Secondary outcomes included the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, the EQ-5D-5L score, complications, and the Net Promoter Score (NPS). Multivariate regression analysis was used to determine factors associated with the PRWE score. RESULTS: Long-term outcomes were available for 89 patients (72%). The mean age was 57 years (SD 15) and 68 were female (76%). The median time from injury to corrective osteotomy was nine months (interquartile range (IQR) 6 to 13). At a mean follow-up of six years (1 to 11) the median PRWE score was 22 (IQR 7 to 40), the median QuickDASH score was 11.4 (IQR 2.3 to 31.8), and the median EQ-5D-5L score was 0.84 (IQR 0.69 to 1). The NPS was 69. Multivariate regression analysis showed that the presence of an associated ulnar styloid fracture was the only significant independent factor associated with a worse PRWE score when adjusting for confounding variables (p = 0.004). CONCLUSION: We found that corrective osteotomy for malunion of the distal radius can result in good functional outcomes and high levels of patient satisfaction. However, the presence of an ulnar styloid fracture may adversely affect function. Level of Evidence: III (cohort study). Cite this article: Bone Joint J 2020;102-B(11):1542-1548.

Reply to "Comment on: A Systematic Review of Organic Versus Conventional Food Consumption: Is There a Measurable Benefit on Human Health? Nutrients 2020, 12, 7".

We would like to thank Di Renzo et al [...].

New Concepts of Chronic Pain and the Potential Role of Complementary Therapies.

CONTEXT: The mechanisms of chronic pain involve complex neuroplastic changes at all 3 orders of neurons involved in the transmission of pain as well as changes in the descending inhibitory pathway. Although traditional pharmaceutical therapies have some efficacy, substantial scope exists for a new model of individualized therapy, tailored to the specific response of each patient. Because changes occur at all levels of the pain pathway, successful treatment may require a combination of therapies with different mechanisms of action. OBJECTIVE: The research team intended to examine the potential changes within the peripheral nervous system (PNS) and central nervous system (CNS) of patients with chronic pain and to propose a model of chronic pain treatment involving multimodal, complementary therapies for individualized treatment targeting multiple sites along the pain pathway. DESIGN: The research team performed a review of the literature in the field. SETTING: The study took place in the School of Health and Human Sciences at Southern Cross University (Lismore, New South Wales, Australia). INTERVENTIONS: A growing body of evidence supports the use of a variety of complementary therapies to treat chronic pain, including curcumin, capsaicin, vitamin D, omega-3 fatty acids, lipoic acid, acupuncture, yoga, meditation, and mindfulness meditation. These therapies vary with respect to the mechanisms by which they act and the potential areas of effect along the pain pathway. RESULTS: The literature review showed a number of complementary therapies may be efficacious in reducing chronic pain and/or the need for analgesics, which may offer a reduced adverse effect profile. These therapies include curcumin, capsaicin, vitamin D, omega-3 fatty acids, lipoic acid, acupuncture, yoga, meditation, and mindfulness meditation. Response rates to treatment are likely to vary between people and within therapies. CONCLUSIONS: The available evidence suggests that efficacious complementary therapies exist that target all 3 orders of neurons and, therefore, the authors recommend multimodal individualized treatment for each patient. There is high interindividual variability between patients in responses to treatments.

Evaluation of the IAEA-TRS 483 protocol for the dosimetry of small fields (square and stereotactic cones) using multiple detectors.

The IAEA TRS 483 protocol1 for the dosimetry of small static fields in radiotherapy was used to calculate output factors for the Elekta Synergy linac at the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). Small field output factors for both square and circular fields were measured using nine different detectors. The "corrected" output factors (ratio of detector readings multiplied by the appropriate correction factor from the protocol) showed better consistency compared to the "uncorrected" output factors (ratio of detector readings only), with the relative standard deviation decreasing by approximately 1% after the application of the relevant correction factors. Comparisons relative to an arbitrarily chosen PTW 60019 microDiamond detector showed a reduction of maximal variation for the corrected values of approximately 3%. A full uncertainty budget was prepared to analyze the consistency of the output factors. Agreement within uncertainties between all detectors and field sizes was found, except for the 15 mm circular field. The results of this study show that the application of IAEA TRS 4831 when measuring small fields will improve the consistency of small field measurements when using multiple detectors contained within the protocol.

A Systematic Review of Organic Versus Conventional Food Consumption: Is There a Measurable Benefit on Human Health?

The current review aims to systematically assess the evidence related to human health outcomes when an organic diet is consumed in comparison to its conventional counterpart. Relevant databases were searched for articles published to January 2019. Clinical trials and observational research studies were included where they provided comparative results on direct or indirect health outcomes. Thirty-five papers met the criteria for inclusion in the review. Few clinical trials assessed direct improvements in health outcomes associated with organic food consumption; most assessed either differences in pesticide exposure or other indirect measures. Significant positive outcomes were seen in longitudinal studies where increased organic intake was associated with reduced incidence of infertility, birth defects, allergic sensitisation, otitis media, pre-eclampsia, metabolic syndrome, high BMI, and non-Hodgkin lymphoma. The current evidence base does not allow a definitive statement on the health benefits of organic dietary intake. However, a growing number of important findings are being reported from observational research linking demonstrable health benefits with organic food consumption. Future clinical research should focus on using long-term whole-diet substitution with certified organic interventions as this approach is more likely to determine whether or not true measurable health benefits exist.

Systematic review of musculoskeletal injuries in professional golfers.

OBJECTIVE: The distribution of injuries affecting professional golfers is yet to be fully understood. We performed a systematic review of the clinical literature to establish the epidemiology of musculoskeletal injuries affecting professional golfers. DESIGN: Systematic review. DATA SOURCES: Searched databases in July 2018 were PubMed, SPORTDiscus and Embase. ELIGIBILITY CRITERIA: Published observational research articles relating to the incidence or prevalence of musculoskeletal injuries in professional golfers, which were written in the English language and not restricted by age or gender. RESULTS: Of the 1863 studies identified on the initial search, 5 studies were found to satisfy the inclusion criteria for analysis. The mean age of the golfers in these studies was 34.8 (±3.6) years. The gender of patients in included studies compromised 72% males and 28% females. Four studies reported that lumbar spine injuries were the most common (range 22%-34%). Excluding injuries to the spine (lumbar, thoracic and cervical), the hand/wrist was the next most common region of injury (range 6%-37%). The quality of the studies was relatively poor with no study satisfying >50% of the quality assessment tool questions and only one study giving a clear definition of how they defined injury. CONCLUSION: There is a paucity of well-designed epidemiological studies evaluating musculoskeletal injuries affecting professional golfers. Injuries to the spine are the most frequently affected region, followed by the hand/wrist. This study has identified targeted areas of future research that aims to improve the management of injuries among professional golfers.

Survey of 5 mm small-field output factor measurements in Australia.

The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) held a comparison exercise in April 2016 where participants came to ARPANSA and measured the output factor of a nominal 5 mm cone attached to the ARPANSA Elekta Synergy (Elekta, Crawley, UK) linear accelerator. The goal of the exercise was to compare the consistency and methods used by independent medical physicists in measuring small-field output factors. ARPANSA provided a three-dimensional scanning tank for detector setup and positioning, but the participants were required to measure the output factor with their own detectors. No information regarding output factors previously measured was supplied to participants to make each result as independent as possible. Fifteen groups travelled to ARPANSA bringing a wide range of detectors and methods. A total of 30 measurements of the output factor were made. The standard deviation of the measurements (excluding one expected outlier from an uncorrected ionization chamber measurement) was 3.6%. The results provide an insight into the consistency of small-field dosimetry being performed in Australia and New Zealand at the present time.