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Objective Emotional distress is common in both survivors and their informal caregivers following admission to a neuroscience intensive care unit (Neuro-ICU) and can negatively affect their individual recovery and quality of life. Neuro-ICU survivor-caregiver dyads can influence each other's emotional distress over time, but whether such influence emerges during dyadic treatment remains unknown. The present study involved secondary data analysis of Neuro-ICU dyads enrolled in a randomized clinical trial of a dyadic resiliency intervention, Recovering Together (RT), versus a health education attention placebo control to test dyadic similarities in emotional distress before and after treatment. Method Data were collected from 58 dyads following Neuro-ICU admission. Emotional distress (depression, anxiety, and posttraumatic stress) was assessed at baseline, 6 weeks (postintervention), and 12 weeks later. Nonindependence within survivor-caregiver dyads was examined (i.e., correlations between cross-sectional symptoms and changes in symptoms over time); mutual influence of emotional functioning over time (i.e., "partner effects") was examined using cross-lagged path analyses. Results There were strong, positive cross-sectional correlations between survivor and caregiver distress at postintervention and follow-up and between changes in survivor and caregiver distress from baseline to postintervention and postintervention to follow-up. There were no partner effects. Conclusions Neuro-ICU survivors and their informal caregivers show similar changes in emotional distress after treatment. These findings highlight the potential benefits of intervening on both survivor and caregiver distress following Neuro-ICU admission. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Digital Pathology (DP) is a platform which has the potential to develop a truly integrated and global pathology community. The generation of DP data at scale creates novel challenges for the histopathology community in managing, processing, and governing the use of these data. The current understanding of, and confidence in, the legal and ethical aspects of DP by pathologists is unknown. We developed an electronic survey (e‐survey) comprising of 22 questions, which was developed with input from the Royal College of Pathologists (RCPath) Digital Pathology Working Group. The e‐survey was circulated via e‐mail and social media (Twitter) through the RCPath Digital Pathology Working Group network, RCPath Trainee Committee network, the Pathology image data Lake for Analytics, Knowledge and Education (PathLAKE) digital pathology consortium, National Pathology Imaging Co‐operative (NPIC), local contacts, and to the membership of both The Pathological Society of Great Britain and Ireland and the British Division of the International Academy of Pathology (BDIAP). Between 14 July 2020 and 6 September 2020, we collected 198 responses representing a cross section of histopathologists, including individuals with experience of DP research. We ascertained that in the UK, DP is being used for diagnosis, research, and teaching, and that the platform is enabling data sharing. Our survey demonstrated that there is often a lack of confidence and understanding of the key issues of consent, legislation, and ethical guidelines. Of 198 respondents, 82 (41%) did not know when the use of digital scanned slide images would fall under the relevant legislation and 93 (47%) were ‘Not confident at all’ in their interpretation of consent for scanned slide images in research. With increasing uptake of DP, a working knowledge of these areas is essential but histopathologists often express a lack of confidence in these topics. The need for specific training in these areas is highlighted by the findings of this study.

Thyroid abnormalities are well reported following childhood treatment for Hodgkin Lymphoma (HL). Limited information exists for adult patients and after modern treatments. We analyzed risks of thyroid disorders in 237 female participants treated at the Royal Marsden Hospital 1970-2015. Multivariable analyses of risk according to treatment and time-related factors, survival analyses, and Cox regression modeling were undertaken. Overall, 33.8% of patients reported thyroid disorders (hypothyroidism 30.0% and thyroid nodules 6.8%). Cumulative prevalence was 42.9% by 40 years follow-up. Risks were greatest after supradiaphragmatic radiotherapy (RR = 5.0, p

Tumor evolution drives tumor progression, therapeutic resistance, and metastasis. Therefore, new predictive medicine strategies that adapt with a tumor are needed to improve patient outcomes. The techniques used in weather prediction are mathematically proven to enable prediction of evolving systems, and thus provide a framework for a new predictive medicine paradigm for cancer.

Meningiomas are the most common primary intracranial tumour in adults1. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas2. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified. Multi-omics datasets are integrated to generate a unified and clinically informed molecular classification of meningiomas.

Modern agent-based models (ABM) and other simulation models require evaluation and testing of many different parameters. Managing that testing for large scale parameter sweeps (grid searches), as well as storing simulation data, requires multiple, potentially customizable steps that may vary across simulations. Furthermore, parameter testing, processing, and analysis are slowed if simulation and processing jobs cannot be shared across teammates or computational resources. While high-performance computing (HPC) has become increasingly available, models can often be tested faster with the use of multiple computers and HPC resources. To address these issues, we created the Distributed Automated Parameter Testing (DAPT) Python package. By hosting parameters in an online (and often free) “database”, multiple individuals can run parameter sets simultaneously in a distributed fashion, enabling ad hoc crowdsourcing of computational power. Combining this with a flexible, scriptable tool set, teams can evaluate models and assess their underlying hypotheses quickly. Here, we describe DAPT and provide an example demonstrating its use.

There is growing awareness of the need for mathematics and computing to quantitatively understand the complex dynamics and feedbacks in the life sciences. Although individual institutions and research groups are conducting pioneering multidisciplinary research, communication and education across fields remains a bottleneck. The opportunity is ripe for using education research principles to develop new mechanisms of cross-disciplinary training at the intersection of mathematics, computation and biology. In this paper we present a case study which describes the efforts of one computational biology lab to rapidly prototype, test, and refine a mentorship infrastructure for undergraduate research experiences in alignment with the computational apprenticeship theoretical framework. We describe the challenges, benefits, and lessons learned, as well as the utility of the computational apprenticeship framework in supporting computational/math students learning and contributing to biology, and biologists in learning computational methods. We also explore implications for undergraduate classroom instruction, and cross-disciplinary scientific communication.

People and water intersect in the movement of sediment downstream in rivers. Social processes and geomorphological processes become entangled as each system moves in ways that trigger corresponding responses from the other. Long-term dialectical relationships emerge that span multiple human generations. The power of sediment and water to change physical environments is in constant tension with the power of human actions informed by social, cultural, legal, economic and engineering imperatives. The Pacific Rim gold rushes that began in the mid-nineteenth century provide an opportunity to examine how the interplay of people, water and sediment unfolds over historic time. The mass discharge of mining sediment in California and Victoria that began over 150 years ago was a catastrophic human alteration of river systems. Subsequently, mining sediment has had a long and complex entanglement with society and rivers in both regions and continues to be an active agent in reshaping riparian environments. Mining sediments also have a toxic legacy as associated contaminants, including mercury and arsenic, that are discharged into waterways and dispersed in windblown dust. The changes to river systems caused by gold mining committed societies and rivers to new trajectories of mutual engagement. Anthropogenically induced sedimentation that resulted from mining is an issue that will continue to impact watersheds for generations to come.

Objective The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site‐centric therapeutic trials in Parkinson’s disease and generate novel insights. The value of this approach has never been more evident than during the current COVID‐19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow‐up of clinical trial participants, (2) compare changes in smartphone‐based assessments, online patient‐reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson’s disease disability and progression. Methods Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele‐Health Outcomes in Multiyear Extensions of Parkinson’s Disease trials (AT‐HOME PD), a two‐year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone‐based assessments of motor function and socialization, and patient‐reported outcomes online. Results From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study’s smartphone application and 161 (71%) have completed patient‐reported outcomes on the online platform. Interpretation It is feasible to conduct a large‐scale, international virtual observational study following the completion of participation in brick‐and‐mortar clinical trials in Parkinson’s disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow‐up of clinical trial participants and design of future clinical trials.

We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs—personalized checklists—are used during annual wellness visits with the patient’s PCP. A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.

Objective To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. Methods Twenty ALS subjects were randomized to placebo and mexiletine 300 mg or 600 mg daily for 4 weeks and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results RMT was unchanged with 4 weeks of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (p=0.039). Reductions of motor evoked potential (MEP) amplitude (p=0.013) and accommodation half-time (p=0.002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 weeks on mexiletine. Conclusions The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine. This article is protected by copyright. All rights reserved.

This paper conceptually draws the connections between complexity theory and employee engagement. Instead of the tendency to adhere to a binary, dichotomous approach, complexity theory helps move employee engagement forward as a process that is rooted in multiplicity, intricacy, and variance. This approach provides a more sustainable future for employee engagement scholarship by reimagining the ways in which scholars investigate the phenomenon. In providing future research suggestions rooted in complexity, scholarship and practice can transition away from prescriptive, normalized processes and solutions for employee engagement to welcome various approaches that lead to more fluid and organic understanding. The goal is to set a standard of encouraging employee engagement scholars to challenge how they explore employee engagement and to welcome new and innovative ways of examining the phenomenon to provide a sustainable and enriching scholarly conversation.

POINTS CLES L’obesite est une maladie chronique complexe dans laquelle la graisse corporelle anormale ou excessive (adiposite) nuit a la sante, augmente le risque de complications medicales a long terme et reduit la duree de vie[1][1]. Les etudes epidemiologiques definissent l’obe

Aim Cutaneous abscesses are one of the most common acute general surgery presentations. This study aimed to understand the current practice in the management of cutaneous abscesses in the United Kingdom (UK), once the decision has been made that acute surgical incision and drainage (I&D) is required. Method General surgeons from across the UK were surveyed on their opinions on the optimum management of cutaneous abscesses. Outcomes measured included anaesthesia, incision technique, antibiotic administration, departmental abscess pathways, and post-drainage management. A combination of Likert scales, multiple-choice questions, and short answer questions were used. Comparisons were made of Likert scales between regions using a two-sample independent t-test. The survey was peer reviewed and distributed through the Association of Coloproctology of Great Britain and Ireland (ACPGBI) network between April and June 2018. Results Sixty-one responses were collected from surgeons throughout the UK. Of these respondents, 69% indicated that cutaneous abscesses would always or usually require a General Anaesthetic (GA) for treatment, and 82% indicated that abscesses were at least sometimes not treated until the next day due to a lack of resources. While 79% of surgeons stated that pus swabs are always or are usually taken, 44% of respondents never or rarely chased the results. The main indications for giving antibiotics were sepsis/systemically unwell patients, and cellulitis. 31% of responding centres had an abscess management protocol, and 82% of respondents confirmed that they would always pack the abscess wound post-operatively. Conclusion ‘Incision and drainage’ is currently the most widely used technique for the surgical management of cutaneous abscess. However, this study demonstrates the significant variability in the use of anaesthesia, antibiotics, packing and the use of protocols to guide and streamline patient management., Highlights • There are no current NICE guidelines specifically covering cutaneous abscess management. • There is significant practice variation in the management of cutaneous abscesses across the UK. • Wound packing is still commonplace, despite guidelines recommending that there is evidence that it should be avoided. • New recommendations on the use of antibiotics whilst treating cutaneous abscesses are yet to be taken up by most surgeons. • Surgically managed cutaneous abscesses in the UK are preferably managed under a general anaesthetic.

PURPOSE Many patients with cancer, often those with rare cancers such as sarcomas, travel long distances to access expert care. The COVID-19 pandemic necessitated widespread changes in delivery of cancer care, including rapid adoption of telemedicine-based care. We aimed to evaluate the impact of telemedicine on patients, clinicians, and care delivery at the Royal Marsden Hospital (RMH) Sarcoma Unit during the pandemic. METHODS Data were extracted from patient records for all planned outpatient appointments at the RMH Sarcoma Unit from March 23 to April 24, 2020. Patients and clinicians completed separate questionnaires to understand their experiences. RESULTS Of 379 planned face-to-face appointments, 283 (75%) were converted to telemedicine. Face-to-face appointments remained for patients who needed urgent start of therapy or performance status assessment. Patients lived on average > 1.5 hours from RMH. Patient satisfaction (n = 108) with telemedicine was high (mean, 9/10), and only 48% (n = 52/108) would not want to hear bad news using telemedicine. Clinicians found telemedicine efficient, with no associated increased workload, compared with face-to-face appointments. Clinicians indicated lack of physical examination did not often affect care provision when using telemedicine. Most clinicians (n = 17; 94%) believed telemedicine use was practice changing; congruently, 80% (n = 86/108) of patients desired some telemedicine as part of their future care, citing reduced cost and travel time. CONCLUSION Telemedicine can revolutionize delivery of cancer care, particularly for patients with rare cancers who often live far away from expert centers. Our study demonstrates important patient and clinician benefits; assessment of longer-term impact on patient outcomes and health care systems is needed.

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

The prospect of a widely available severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine is an increasingly high priority for an effective response to the coronavirus disease 2019 (COVID-19) pandemic and an area of intense interest and attention for professionals, politicians, and the public alike. The understandable desire for such a vaccine has led to significant discussion and even some planning for the possibility of human challenge studies (HCS) as a tool for accelerating the process for identifying, testing, and developing an effective vaccine (1⇓–3). Proponents of human challenge studies suggest that they will accelerate the time to approved vaccines. But the facts don’t support those claims. Image credit: Shutterstock/REDPIXEL.PL. Typically, undertaking HCS in vaccine development requires that the disease for which a challenge would be introduced either has an available rescue therapy to treat those who become infected or the disease is known to be self-limiting. There is no rescue therapy for SARS-CoV-2 infection, and proponents of HCS have claimed that the infection is likely to be self-limiting and mild in young, healthy volunteers based on current understanding of the infection. If accurate, the basic requirements for undertaking an HCS could be met if conducted with that population. Proponents further argue that such HCS are ethically acceptable in the current pandemic. Most critically, they contend that these studies are likely to speed the development of effective vaccines. But based on our assessment of these arguments, we disagree. We believe it is unethical to move forward with such trials at the current time. Whereas proponents of these studies suggest that such studies will accelerate the time to approved vaccines, the facts fail to support these claims. HCS to address SARS-CoV-2 face unacceptable ethics challenges, and, further, undertaking them would do a disservice to the public by … [↵][1]1To whom correspondence may be addressed. Email: jeffkahn{at}jhu.edu. [1]: #xref-corresp-1-1

Higher serum urate concentration is associated with decreased risk of Parkinson’s disease (PD) as well as slower disease progression, but its relationship with severity of PD remains unclear. This study investigated whether changes in serum urate concentration over 5 years were associated with disease progression assessed by MDS-UPDRS Part III score, Hoehn and Yahr stage, or DaTscan imaging. Average serum urate concentration was stable over time and change in serum urate concentration did not correlate with worsening of measures of PD progression. These results suggest that serum urate concentration is not a monitoring biomarker of PD progression in early stages.

Background Spinal manipulation may reduce migraine frequency, but effects of multimodal chiropractic care on migraine frequency have not been evaluated. Methods We conducted a pilot randomized controlled trial comparing multimodal chiropractic care + enhanced usual care (MCC+) versus enhanced usual care alone (EUC) among adult women with episodic migraine. EUC was comprised of usual medical care and migraine education literature. MCC+ participants received 10 sessions of chiropractic care over 14 weeks. Primary aims evaluated feasibility of recruitment, retention, protocol adherence, and safety. Change in migraine days was a secondary aim. Results Of 422 patients screened, 61 were randomized over 20 months. Fifty-seven (93%) completed daily migraine logs during the intervention, 51 (84%) completed final follow-up, and 45 (74%) completed all assessments. Twenty-four of 29 MCC+ participants (83%) attended > 75% of the chiropractic sessions. Ninety-eight non-serious adverse events were reported by 26 participants (43%) with 39 events among 11 EUC participants and 59 events among 15 MCC+ participants. MCC+ participants experienced greater reductions in migraine days (−2.9 days for MCC+ vs. −1.0 days for EUC, difference = −1.9; 95% confidence interval: −3.5, −0.4). Conclusions Pre-specified feasibility criteria were not met, but deficits were remediable. Preliminary data support a definitive trial of MCC+ for migraine. Trial Registration This study is registered at Clinicaltrials.gov (NCT03177616).

Digital pathology enables computational analysis algorithms to be applied at scale to histological images. An example is the identification of immune cells within solid tumours. Image analysis algorithms can extract precise cell locations from immunohistochemistry slides, but the resulting spatial coordinates, or point patterns, can be difficult to interpret. Since localisation of immune cells within tumours may reflect their functional status and correlates with patient prognosis, novel descriptors of their spatial distributions are of biological and clinical interest. A range of spatial statistics have been used to analyse such point patterns but, individually, these approaches only partially describe complex immune cell distributions. In this study, we apply three spatial statistics to locations of CD68+ macrophages within human head and neck tumours, and show that images grouped semi-quantitatively by a pathologist share similar statistics. We generate a synthetic dataset which emulates human samples and use it to demonstrate that combining multiple spatial statistics with a maximum likelihood approach better predicts human classifications than any single statistic. We can also estimate the error associated with our classifications. Importantly, this methodology is adaptable and can be extended to other histological investigations or applied to point patterns outside of histology.

ObjectiveTo identify markers of resistance to developing Parkinson disease (PD) among LRRK2 mutation carriers (LRRK2+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation.MethodsPlasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2−/PD+, and 65 LRRK2−/UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between LRRK2 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with p value corrections for multiple comparisons.ResultsPlasma caffeine concentration was lower in patients with PD vs UC (p < 0.001), more so among LRRK2+ carriers (by 76%) than among LRRK2− participants (by 31%), with significant interaction between LRRK2 and PD status (p = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in LRRK2+/PD+ compared to LRRK2+/UC with significant interaction effect with the LRRK2+ mutation (p < 0.001).ConclusionsMetabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic LRRK2 mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among LRRK2 mutation carriers.

Objective: To report our experience with intramedullary fixation and osteosynthesis of the tibia with suprapatellar approach and semiextended positioning. Methods: This study retrospectively assessed 6 patients with tibial fracture treated with suprapatellar intramedullary nail fixation and osteosynthesis from September 2015 to September 2018. Results: There was acceptable bone fixation. Mean healing time was 6 months (range: 4-10 months). Postoperative pain was assessed using a visual analog scale, and the knee was divided into 9 quadrants to help locate the specific site of pain; all participants reported that pain was located at distal quadrants. Knee function was completely restored. Conclusion: Suprapatellar approach with the knee in the semiextended position is a good surgical technique for extra-articular proximal tibial fractures or those associated with soft tissue involvement at the conventional infrapatellar entry site. Thus, this analysis led us to believe that the technique should also be applicable to middle diaphyseal fractures or fractures in general, regardless of their location. Level of Evidence IV, Therapeutic Studies; Case Series.

KEY POINTS Obesity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan.[1][1] Epidemiologic studies define obesity using the body mass index (BMI; weight/height2), which can stratify

Since establishment of the Global Polio Eradication Initiative* in 1988, polio cases have declined >99.9% worldwide; extensive use of live, attenuated oral poliovirus vaccine (OPV) in routine childhood immunization programs and mass campaigns has led to eradication of two of the three wild poliovirus (WPV) serotypes (types 2 and 3) (1). Despite its safety record, OPV can lead to rare emergence of vaccine-derived polioviruses (VDPVs) when there is prolonged circulation or replication of the vaccine virus. In areas with inadequate OPV coverage, circulating VDPVs (cVDPVs) that have reverted to neurovirulence can cause outbreaks of paralytic polio (2). Immunodeficiency-associated VDPVs (iVDPVs) are isolated from persons with primary immunodeficiency (PID). Infection with iVDPV can progress to paralysis or death of patients with PID, and excretion risks seeding cVDPV outbreaks; both risks might be reduced through antiviral treatment, which is currently under development. This report updates previous reports and includes details of iVDPV cases detected during July 2018-December 2019 (3). During this time, 16 new iVDPV cases were reported from five countries (Argentina, Egypt, Iran, Philippines, and Tunisia). Alongside acute flaccid paralysis (AFP) surveillance (4), surveillance for poliovirus infections among patients with PID has identified an increased number of persons excreting iVDPVs (5). Expansion of PID surveillance will facilitate early detection and follow-up of iVDPV excretion among patients with PID to mitigate the risk for iVDPV spread. This will be critical to help identify all poliovirus excretors and thus achieve and maintain eradication of all polioviruses.

We describe the phenotype of a patient with extensive aortic, carotid, and abdominal dissections. The proband was found to have a heterozygous deletion of exons 21–34 in MYLK, which is a rare finding, as deletions in this gene have been infrequently reported. We describe this finding following detection in a proband with an extensive history of aortic, carotid, and abdominal dissections. Neoteric molecular modeling techniques to help determine the impact of this deletion on protein function indicated loss of function due to lack of any kinase domain. We also provide the electrostatics calculations from the wild type and mutant variant. Through a combined multiomic approach of clinical, functional, and protein informatics, we arrive at a data fusion for determination of pathogenicity embedded within the genetic code for this particular genetic variant, which, as a platform, continues to broaden its scope across the field of variants of uncertain significance classification.

Femtosecond lasers at fixed wavelengths above 1,000 nm are powerful, stable and inexpensive, making them promising sources for two-photon microscopy. Biosensors optimized for these wavelengths are needed for both next-generation microscopes and affordable turn-key systems. Here we report jYCaMP1, a yellow variant of the calcium indicator jGCaMP7 that outperforms its parent in mice and flies at excitation wavelengths above 1,000 nm and enables improved two-color calcium imaging with red fluorescent protein-based indicators. jYCaMP1, a yellow variant of the calcium indicator jGCaMP7, enables fast multicolor two-photon imaging at excitation wavelengths above 1,000 nm for use with popular ytterbium-doped fiber and modelocked semiconductor lasers.

Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson's disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these 'reduced risk' factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference -125 mg/day, p < 0.001) but not in females (mean difference -30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference -0.46 mg/dL, p = 0.017) and females (mean difference -0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.

An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease. Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls. We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p

Background Insomnia and low iron stores are common in children with autism spectrum disorders, and low iron stores have been associated with sleep disturbance. Methods We performed a randomized placebo-controlled trial of oral ferrous sulfate to treat insomnia in children with autism spectrum disorders and low normal ferritin levels. Twenty participants who met inclusion criteria and whose insomnia did not respond to sleep education were randomized to 3 mg/kg/day of ferrous sulfate (n = 9) or placebo (n = 11) for three months. Results Iron supplementation was well tolerated, and no serious adverse events were reported. Iron supplementation improved iron status (+18.4 ng/mL active versus −1.6 ng/mL placebo, P = 0.044) but did not significantly improve the primary outcome measures of sleep onset latency (−11.0 minutes versus placebo, 95% confidence interval −28.4 to 6.4 minutes, P = 0.22) and wake time after sleep onset (−7.7 minutes versus placebo, 95% confidence interval −22.1 to 6.6 min, P = 0.29) as measured by actigraphy. Iron supplementation was associated with improvement in the overall severity score from the Sleep Clinical Global Impression Scale (−1.5 points versus placebo, P = 0.047). Changes in measures of daytime behavior did not differ between groups. Conclusion This trial demonstrated no improvement in primary outcome measures of insomnia in subjects treated with ferrous sulfate compared with placebo. Interpretation was limited by low enrollment.

To examine effects of a virtual mind–body group for adolescents with neurofibromatoses (NF1 and NF2; Resilient Youth with Neurofibromatosis; RY-NF) on multiple resiliency factors against a health education attention control (Health Education for Youth with Neurofibromatosis; HE-NF) using data from a randomized controlled trial. Specifically, our research question was whether adolescents randomized to the RY-NF (versus the HE-NF) would have greater improvements in resiliency factors at post-intervention and whether these gains would be maintained at 6-month follow-up. Adolescents with NF (n = 51; M age 12–17) were randomly assigned to RY-NF (n = 27) or HE-NF (n = 24). Resiliency factors (mindfulness, coping, gratitude, optimism, and social support) were collected at baseline, post-intervention (88%), and 6-month follow-up (82%). Participation in the RY-NF was associated with greater pre-to-post improvements in gratitude (Mdifference = 4.38; 95% CI—0.52–8.23; p = .027) and mindfulness (Mdifference= 9.41; 95% CI 4.40–14.42.; p

A joint Kazakh-British archaeological initiative undertook a survey and excavation of the city of Kuik-Mardan, one of the largest of the seventy or so known settlements in the Otrar oasis on the Syr-Darya river, Kazakhstan. Several complimentary field techniques were employed including unmanned aerial vehicle photomapping and an extensive programme of radiometric dating. The radiocarbon dates obtained are the first for any city in the oasis and allow more confident interpretations of the experience of the city to be ventured. Also undertaken was a geoarchaeological investigation of the surrounding irrigation and water supply canal system. Key results include its wholesale destruction during the 6th to 7th century and the form of the later occupation of the city.

ObjectivesTo investigate the relationship between total and ionised calcium concentrations in dogs with ionised hypercalcaemia and to evaluate how albumin influences this relationship.MethodsInitially, a reference interval for ionised and total calcium was established using a large population of healthy adult dogs. Our teaching hospital clinical database was searched to identify adult dogs with ionised hypercalcaemia between 2012 and 2017, a time frame when the same sample handling and analysis protocols were in place as for the healthy reference interval population. The relationship between ionised and total calcium concentrations was then compared in the ionised hypercalcaemia population.ResultsBased on biochemical analysis of 351 healthy adult dogs, a reference interval of 1.18 to 1.53 mmol/L for ionised calcium and 2.24 to 2.85 mmol/L for total calcium was established. Using these reference intervals, 63 dogs with ionised hypercalcaemia were identified, of which 23 did not have a total hypercalcaemia. Only seven of the 23 dogs with ionised hypercalcaemia and total calcium below the upper limit of the reference interval had hypoalbuminemia. The majority of dogs with ionised hypercalcemia and normal total calcium had a modest increase in ionised calcium.Clinical SignificanceIf relying on total calcium alone, more than one third of dogs with ionised hypercalcaemia will be classified as normocalcaemic and the majority of these dogs had normal serum albumin.

Unnecessary antimicrobial treatment promotes the emergence of resistance. Early confirmation that a blood culture is negative could shorten antibiotic courses. The Cognitor Minus test, performed on blood culture samples after 12 hours incubation has a negative predictive value (NPV) of 99.5%. The aim of this study was to determine if earlier confirmation of negative blood culture result would shorten antibiotic treatment. Paired blood cultures were taken in the Critical Care Unit at a teaching hospital. The Cognitor Minus test was performed on one set >12 hours incubation but results kept blind. Clinicians were asked after 24 and 48 hours whether a result excluding bacteraemia or fungaemia would affect decisions to continue or stop antimicrobial treatment. Over 6 months, 125 patients were enrolled. The median time from start of incubation to Cognitor Minus test was 27.1 hours. When compared to 5 day blood culture results from both the control and test samples, Cognitor Minus gave NPVs of 99% and 100% respectively. Test results would have reduced antibiotic treatment in 14% (17/119) of patients at 24 and 48 hours (24% at either time) compared with routine blood culture. The availability of rapid tests to exclude bacteraemia may be of benefit in antimicrobial stewardship.

Purpose Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. Methods From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. Results The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. Conclusion Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Background Personalized diet counselling, as part of lifestyle change programs for cardiometabolic risk conditions (combinations of prediabetes or type 2 diabetes, hypertension, dyslipidemia and high waist circumference) has been shown to reduce progression to type 2 diabetes overall. To identify key process of care measures that could be linked to changes in diet, we undertook a secondary analysis of a Canadian pre-post study of lifestyle treatment of metabolic syndrome (MetS). Diet counselling process measures were documented and association with diet quality changes after 3 months were assessed. Results of the primary study showed 19% reversal of MetS after 1 year. Methods Registered dietitians (RDs) reported on contact time, specific food behaviour goals (FBG), behaviour change techniques (BCT; adapted from the Michie CALO-RE taxonomy) and teaching resources at each contact. Diet quality was measured by 2005 Canadian Healthy Eating Index (HEI-C) and assessed for possible associations with individual BCT and FBG. Results Food behaviour goals associated with improved HEI-C at 3 months were: poultry more than red meat, increased plant protein, increased fish, increased olive oil, increased fruits and vegetables, eating breakfast, increased milk and alternatives, healthier fats, healthier snacks and increased nuts, with an adverse association noted for more use (> 2 times/ 3 months) of the balanced meal concept (F test; p 3 times/3 months) was associated with poorer HEI-C at 3 months (F test; p = 0.007). Only self-monitoring, feedback on performance and focus on past success were associated with improved HEI-C. Conclusions These results identify key aspects of process that impact diet quality. Documentation of both FBG and BCT is highly relevant in diet counselling and a summary diet quality score is a promising target for assessing short-term counselling success.

It takes great effort to manually or semi-automatically convert free-text phenotype narratives (e.g., morphological descriptions in taxonomic works) to a computable format before they can be used in large-scale analyses. We argue that neither a manual curation approach nor an information extraction approach based on machine learning is a sustainable solution to produce computable phenotypic data that are FAIR (Findable, Accessible, Interoperable, Reusable) (Wilkinson et al. 2016). This is because these approaches do not scale to all biodiversity, and they do not stop the publication of free-text phenotypes that would need post-publication curation. In addition, both manual and machine learning approaches face great challenges: the problem of inter-curator variation (curators interpret/convert a phenotype differently from each other) in manual curation, and keywords to ontology concept translation in automated information extraction, make it difficult for either approach to produce data that are truly FAIR. Our empirical studies show that inter-curator variation in translating phenotype characters to Entity-Quality statements (Mabee et al. 2007) is as high as 40% even within a single project. With this level of variation, curated data integrated from multiple curation projects may still not be FAIR. The key causes of this variation have been identified as semantic vagueness in original phenotype descriptions and difficulties in using standardized vocabularies (ontologies). We argue that the authors describing characters are the key to the solution. Given the right tools and appropriate attribution, the authors should be in charge of developing a project's semantics and ontology. This will speed up ontology development and improve the semantic clarity of the descriptions from the moment of publication. In this presentation, we will introduce the Platform for Author-Driven Computable Data and Ontology Production for Taxonomists, which consists of three components: a web-based, ontology-aware software application called 'Character Recorder,' which features a spreadsheet as the data entry platform and provides authors with the flexibility of using their preferred terminology in recording characters for a set of specimens (this application also facilitates semantic clarity and consistency across species descriptions); a set of services that produce RDF graph data, collects terms added by authors, detects potential conflicts between terms, dispatches conflicts to the third component and updates the ontology with resolutions; and an Android mobile application, 'Conflict Resolver,' which displays ontological conflicts and accepts solutions proposed by multiple experts. a web-based, ontology-aware software application called 'Character Recorder,' which features a spreadsheet as the data entry platform and provides authors with the flexibility of using their preferred terminology in recording characters for a set of specimens (this application also facilitates semantic clarity and consistency across species descriptions); a set of services that produce RDF graph data, collects terms added by authors, detects potential conflicts between terms, dispatches conflicts to the third component and updates the ontology with resolutions; and an Android mobile application, 'Conflict Resolver,' which displays ontological conflicts and accepts solutions proposed by multiple experts. Fig. 1 shows the system diagram of the platform. The presentation will consist of: a report on the findings from a recent survey of 90+ participants on the need for a tool like Character Recorder; a methods section that describes how we provide semantics to an existing vocabulary of quantitative characters through a set of properties that explain where and how a measurement (e.g., length of perigynium beak) is taken. We also report on how a custom color palette of RGB values obtained from real specimens or high-quality specimen images, can be used to help authors choose standardized color descriptions for plant specimens; and a software demonstration, where we show how Character Recorder and Conflict Resolver can work together to construct both human-readable descriptions and RDF graphs using morphological data derived from species in the plant genus Carex (sedges). The key difference of this system from other ontology-aware systems is that authors can directly add needed terms to the ontology as they wish and can update their data according to ontology updates. a report on the findings from a recent survey of 90+ participants on the need for a tool like Character Recorder; a methods section that describes how we provide semantics to an existing vocabulary of quantitative characters through a set of properties that explain where and how a measurement (e.g., length of perigynium beak) is taken. We also report on how a custom color palette of RGB values obtained from real specimens or high-quality specimen images, can be used to help authors choose standardized color descriptions for plant specimens; and a software demonstration, where we show how Character Recorder and Conflict Resolver can work together to construct both human-readable descriptions and RDF graphs using morphological data derived from species in the plant genus Carex (sedges). The key difference of this system from other ontology-aware systems is that authors can directly add needed terms to the ontology as they wish and can update their data according to ontology updates. The software modules currently incorporated in Character Recorder and Conflict Resolver have undergone formal usability studies. We are actively recruiting Carex experts to participate in a 3-day usability study of the entire system of the Platform for Author-Driven Computable Data and Ontology Production for Taxonomists. Participants will use the platform to record 100 characters about one Carex species. In addition to usability data, we will collect the terms that participants submit to the underlying ontology and the data related to conflict resolution. Such data allow us to examine the types and the quantities of logical conflicts that may result from the terms added by the users and to use Discrete Event Simulation models to understand if and how term additions and conflict resolutions converge. We look forward to a discussion on how the tools (Character Recorder is online at http://shark.sbs.arizona.edu/chrecorder/public) described in our presentation can contribute to producing and publishing FAIR data in taxonomic studies.

IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Biodiversity data is obtained by a variety of methodological approaches—including observation surveys, environmental sampling and biological object collection—employing diverse sample processing protocols and data transformations. While complete and accurate accounts of these data-generating processes are important to enable integration and informed reuse of data, the structure and content of published biodiversity data currently are often shaped by specific application goals. For example, data publishers that export specimen-based data from collection management systems for inclusion in aggregations like those in the Global Biodiversity Information Facility (GBIF) must frequently relax their internal models and produce unnatural joins to fit GBIF’s occurrences-based data structure. Third-party assertions over these aggregated data therefore assume the risk of irreproducibility or concept drift. Here we introduce process- and state-based representation of object histories as the main organizing principle for data about specimens and samples in Digital Information System for Natural History Data (DINA, Glöckler et al. 2020)-compliant collection management software (Fig. 1). Specimens, samples and objects in general are subjected to a variety of processes, including planned actions involving the object, e.g., collecting, preparing, subsampling, loaning. Object states are any particular mode of being of an object at a certain point in time. For example, any one intermediate step in preparing a collected specimen for long-term conservation in a collection would constitute an individual object state. An object’s history is the entire chain of these interrelated processes and states. We argue that using object histories as main conceptual modeling paradigm in DINA offers the generality required to accommodate a diverse, open set of use cases in biodiversity data representation, yet also offers the versatility to serve as basis for use-case specific data aggregation and presentation. Specifically, a representation based on object histories provides a coherent structure for documenting individual processes and states for any given object and for linking this documentation (e.g., textual descriptions or images pertaining to a given process or state), a natural representational structure of the real-world sequence of processes an object participates in and for the data generated in these processes (e.g., a DNA-extraction procedure and sequence information generated on its basis), a straightforward structure to link data about related objects (e.g., tissue samples, the biological specimen a bone is derived from) in a network of connected object histories. a coherent structure for documenting individual processes and states for any given object and for linking this documentation (e.g., textual descriptions or images pertaining to a given process or state), a natural representational structure of the real-world sequence of processes an object participates in and for the data generated in these processes (e.g., a DNA-extraction procedure and sequence information generated on its basis), a straightforward structure to link data about related objects (e.g., tissue samples, the biological specimen a bone is derived from) in a network of connected object histories. The approach is designed to be embedded in DINA’s modular application architecture, so that information on object histories can be accessed via corresponding APIs either through its own interfaces (Fig. 2) or by integration with external web services (Fig. 3). Viewing collection management tasks as part of object histories also informs delineation of modules to support these tasks with specialized functions and interfaces. It also admits the use of persistent, dereferencable identifiers for individual processes and states in object histories and for linking their representations to elements in ontologies and controlled vocabularies. In this contribution to the symposium, DINA's object histories as a main organizing principle for collection object data will be discussed and the utility of using it in the context of modular application architecture, data federation, and data integration in projects like BiCIKL will be illustrated.

Background Stress and negative emotions contribute to atrial fibrillation (AF). Mind-body practices decrease stress and negative emotions and may reduce AF episodes and improve quality of life for patients with AF. Objective We examined the effects of a multimodal mind-body program, the SMART Program, on AF-related quality of life in patients with paroxysmal AF (PAF). Methods In this randomized, waitlist-controlled pilot trial, 18 subjects with PAF participated in an 8-week SMART Program delivered online immediately or 3 months later. Validated measures were completed at baseline and at 3 and 6 months (waitlist group only). Results Comparing pre- vs post-program scores among all 18 participants, subjects reported improvement in AF-related quality of life (Cohen's d=0.75, P = .005) and depression (d = 0.50, P = .05) but not anxiety (d = 0.35, P = .16). Subjects also reported improvements in AF symptom severity (P = .026), distress (P = .014), positive affect (P = .003), and ability to cope with stress (P = .001). Compared to waitlist control subjects, those in the immediate group reported improvement in positive affect (d = 1.20, P = .021) and coping with stress (d = 1.36, P = .011) after participating in the program. Conclusion The SMART Program, delivered virtually, may enhance positive emotions and coping with stress as well as decrease negative emotions and AF symptoms. These results warrant a larger trial to better understand the potential benefits of such programs for patients with PAF.

Background The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. Methods Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates’ correction. Results Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. Conclusions This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Burkitt lymphoma is a rare, highly aggressive non-Hodgkin lymphoma with increasing incidence. Here we present a 26-year-old man with a history of a recent root canal who presented with 2 days of black, tarry stools, persistent tooth pain, and 2 weeks of fatigue, night sweats, and a 20-pound weight loss. He developed massive hematemesis while hospitalized and an esophagogastroduodenoscopy revealed innumerable, doughnut-shaped masses with central umbilication throughout the stomach, which were also the source of bleeding. Targeted biopsies revealed Burkitt lymphoma. After prompt chemotherapy treatment, repeat endoscopy showed complete resolution of all gastric masses, and the mucosa appeared normal.

Summary Organoid model systems recapitulate key features of mammalian tissues and enable high throughput experiments. However, the impact of these experiments may be limited by manual, non-standardized, static or qualitative phenotypic analysis. OrgDyn is an open-source and modular pipeline to quantify organoid shape dynamics using a combination of feature- and model-based approaches on time series of 2D organoid contour images. Our pipeline consists of (i) geometrical and signal processing feature extraction, (ii) dimensionality reduction to differentiate dynamical paths, (iii) time series clustering to identify coherent groups of organoids and (iv) dynamical modeling using point distribution models to explain temporal shape variation. OrgDyn can characterize, cluster and model differences among unique dynamical paths that define diverse final shapes, thus enabling quantitative analysis of the molecular basis of tissue development and disease. Availability and Implementation https://github.com/zakih/organoidDynamics (BSD 3-Clause License). Supplementary information Supplementary data are available at Bioinformatics online.

Mobilisation of large volumes of bedrock, regolith and soil has long been a characteristic feature of metal mining. Prior to the 20th century this was most efficiently achieved through harnessing the motive power of water. Large-scale water use in mining produced waste sands, gravels and silts that were flushed downstream, triggering changes in stream and floodplain morphology and function. During the 19th century the shift from artisanal to industrialised mining resulted in a rapid increase in the scale and extent of environmental change. This paper presents results from a multi-disciplinary research program investigating the environmental effects of 19th-century gold mining on waterways in south-eastern Australia. Archaeological and geospatial landscape survey are combined with historical data modelling and geomorphological analysis to examine the extractive processes that produced sediment in headwater regions and how this influenced fluvial processes operating on downstream waterways and floodplains. Our case study of the Three Mile-Hodgson Creek system on the Ovens (Beechworth) goldfield in north-east Victoria indicates that miners mobilised up to 7.3 million m3 of sediment in this small catchment alone. Results of the research suggest that tailings dams and sludge channels in this catchment are important archaeological evidence for early attempts to manage industrial waste.

A team-based 12-month lifestyle program for the treatment of metabolic syndrome (MetS) (involving physicians, registered dietitians (RDs), and kinesiologists) was previously shown to reverse MetS in 19% of patients (95% confidence interval, 14% to 24%). This work evaluates changes in nutrient intake and diet quality over 12 months (n = 205). Individualized diet counselling was provided by 14 RDs at 3 centres. Two 24-h recalls, the Canadian Healthy Eating Index (HEI-C), and the Mediterranean Diet Score (MDS) were completed at each time point. Total energy intake decreased by 145 ± 586 kcal (mean ± SD) over 3 months with an additional 76 ± 452 kcal decrease over 3–12 months. HEI-C improved from 58 ± 15 to 69 ± 12 at 3 months and was maintained at 12 months. Similarly, MDS (n = 144) improved from 4.8 ± 1.2 to 6.2 ± 1.9 at 3 months and was maintained at 12 months. Changes were specific to certain food groups, with increased intake of fruits, vegetables, and nuts and decreased intake of “other foods” and “commercial baked goods” being the most prominent changes. There was limited change in intake of olive oil, fish, and legumes. Exploratory analysis suggested that poorer diet quality at baseline was associated with greater dietary changes as assessed by HEI-C. Novelty Multiple dietary assessment tools provided rich information on food intake changes in an intervention for metabolic syndrome. Improvements in diet were achieved by 3 months and maintained to 12 months. The results provide a basis for further dietary change implementation studies in the Canadian context.

ObjectiveTo investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.MethodsThe Safety of Urate Elevation in Parkinson’s Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1–7.0 mg/dL) or moderate (7.1–8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.ResultsInosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson’s Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = −0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = −0.44; p = 0.006). No significant associations were observed in men.ConclusionsInosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.Clinicaltrials.gov identifierNCT00833690.Classification of evidenceThis study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

Presentation du projet LEADER: outil prototype de formation dans le domaine des sciences de l'information- cette formation devant etre integree au curriculum des etudiants de toute discipline (physique, ingenierie...)

Objectives: We recently found that metformin attenuated weight gain due to mixed dopamine and serotonin receptor antagonists, commonly termed atypical antipsychotics, in children and adolescents with autism spectrum disorder (ASD). Previous studies have found that genetic variation predicts response to metformin in diabetes. In this study, we aimed to assess whether response to metformin for weight gain in this population is associated with variants in five genes previously implicated in metformin response in diabetes. Methods: Youth with ASD who experienced significant weight gain while taking mixed receptor antagonist medications were randomly assigned to metformin or placebo for 16 weeks, followed by open-label metformin treatment for 16 weeks. In the 53 participants with available DNA samples, we used a linear, mixed model analysis to assess response in the first 16 weeks of metformin treatment, whether in the randomized or open-label period, based upon genotypes at polymorphisms in five genes previously associated with metformin response in diabetes: ATM, SLC2A2, MATE1, MATE2, and OCT1. Results: In the primary analysis, both ATM and OCT1 showed significant effects of genotype on change in body mass index z-scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. Conclusion: As has been shown for metformin treatment in diabetes, genetic variation may predict response to metformin for weight gain in youth with ASD treated with mixed receptor antagonists. Further work is needed to replicate these findings and evaluate whether they can be used prospectively to improve outcomes.