Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Early Joint Use Following Elbow Dislocation Limits Range-of-Motion Loss and Tissue Pathology in Posttraumatic Joint Contracture.

BACKGROUND: Simple elbow dislocation occurs at an incidence of 2.9 to 5.21 dislocations per 100,000 person-years, with as many as 62% of these patients experiencing long-term elbow joint contracture, stiffness, and/or pain. Poor outcomes and the need for secondary surgical intervention can often be prevented nonoperatively with early or immediate active mobilization and physical therapy. However, immobilization or limited mobilization may be necessary following trauma, and it is unknown how different periods of immobilization affect pathological changes in elbow joint tissue and how these changes relate to range of motion (ROM). The purpose of this study was to investigate the effects of varying the initiation of free mobilization on elbow ROM and histological features in an animal model of elbow posttraumatic joint contracture. METHODS: Traumatic elbow dislocation was surgically induced unilaterally in rats. Injured forelimbs were immobilized in bandages for 3, 7, 14, or 21 days; free mobilization was then allowed until 42 days after injury. Post-mortem joint ROM testing and histological analysis were performed. One-way analysis of variance was used to compare ROM data between control and injured groups, and Pearson correlations were performed between ROM parameters and histological outcomes. RESULTS: Longer immobilization periods resulted in greater ROM reductions. The anterior and posterior capsule showed increases in cellularity, fibroblasts, adhesions, fibrosis, and thickness, whereas the measured outcomes in cartilage were mostly unaffected. All measured histological characteristics of the capsule were negatively correlated with ROM, indicating that higher degrees of pathology corresponded with less ROM. CONCLUSIONS: Longer immobilization periods resulted in greater ROM reductions, which correlated with worse histological outcomes in the capsule in an animal model of posttraumatic elbow contracture. The subtle differences in the timing of ROM and capsule tissue changes revealed in the present study provide new insight into the distinct timelines of biomechanical changes as well as regional tissue pathology. CLINICAL RELEVANCE: This study showed that beginning active mobilization 3 days after injury minimized posttraumatic joint contracture, thereby supporting an immediate-motion clinical treatment strategy (when possible). Furthermore, uninjured but pathologically altered periarticular tissues near the injury location may contribute to more severe contracture during longer immobilization periods as the disease state progresses.

Factors associated with recruitment to randomised controlled trials in general practice: a systematic mixed studies review.

BACKGROUND: A common challenge for randomised controlled trials (RCTs) is recruiting enough participants to be adequately powered to answer the research question. Recruitment has been set as a priority research area in trials to improve recruitment and thereby reduce wasted resources in conducted trials that fail to recruit sufficiently. METHODS: We conducted a systematic mixed studies review to identify the factors associated with recruitment to RCTs in general practice. On September 8, 2020, English language studies were identified from MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and CENTRAL databases for published studies. NTIS and OpenGrey were searched for grey literature, and BMC Trials was hand searched. A narrative synthesis was conducted for qualitative studies and a thematic synthesis for qualitative studies. RESULTS: Thirty-seven studies met the inclusion criteria. These were of different study types (10 cross-sectional, 5 non-randomised studies of interventions, 2 RCTs, 10 qualitative and 10 mixed methods). The highest proportion was conducted in the UK (48%). The study quality was generally poor with 24 (65%) studies having major concerns. A complex combination of patient, practitioner or practice factors, and patient, practitioner or practice recruitment were assessed to determine the possible associations. There were more studies of patients than of practices or practitioners. CONCLUSIONS: For practitioners and patients alike, a trial that is clinically relevant is critical in influencing participation. Competing demands are given as an important reason for declining participation. There are concerns about randomisation relating to its impact on shared decision-making and not knowing which treatment will be assigned. Patients make decisions about whether they are a candidate for the trial even when they objectively fulfil the eligibility criteria. General practice processes, such as difficulties arranging appointments, can hinder recruitment, and a strong pre-existing doctor-patient relationship can improve recruitment. For clinicians, the wish to contribute to the research enterprise itself is seldom an important reason for participating, though clinicians reported being motivated to participate when the research could improve their clinical practice. One of the few experimental findings was that opportunistic recruitment resulted in significantly faster recruitment compared to systematic recruitment. These factors have clear implications for trial design. Methodologically, recruitment research of practices and practitioners should have increased priority. Higher quality studies of recruitment are required to find out what actually works rather than what might work. TRIAL REGISTRATION: PROSPERO CRD42018100695. Registered on 03 July 2018.

Fascicular elastin within tendon contributes to the magnitude and modulus gradient of the elastic stress response across tendon type and species.

Elastin, the main component of elastic fibers, has been demonstrated to significantly influence tendon mechanics using both elastin degradation studies and elastinopathic mouse models. However, it remains unclear how prior results differ between species and functionally distinct tendons and, in particular, how results translate to human tendon. Differences in function between fascicular and interfascicular elastin are also yet to be fully elucidated. Therefore, this study evaluated the quantity, structure, and mechanical contribution of elastin in functionally distinct tendons across species. Tendons with an energy-storing function had slightly more elastin content than tendons with a positional function, and human tendon had at least twice the elastin content of other species. While distinctions in the organization of elastic fibers between fascicles and the interfascicular matrix were observed, differences in structural arrangement of the elastin network between species and tendon type were limited. Mechanical testing paired with enzyme-induced elastin degradation was used to evaluate the contribution of elastin to tendon mechanics. Across all tendons, elastin degradation affected the elastic stress response by decreasing stress values while increasing the modulus gradient of the stress-strain curve. Only the contributions of elastin to viscoelastic properties varied between tendon type and species, with human tendon and energy-storing tendon being more affected. These data suggest that fascicular elastic fibers contribute to the tensile mechanical response of tendon, likely by regulating collagen engagement under load. Results add to prior findings and provide evidence for a more mechanistic understanding of the role of elastic fibers in tendon. STATEMENT OF SIGNIFICANCE: Elastin has previously been shown to influence the mechanical properties of tendon, and degraded or abnormal elastin networks caused by aging or disease may contribute to pain and an increased risk of injury. However, prior work has not fully determined how elastin contributes differently to tendons with varying functional demands, as well as within distinct regions of tendon. This study determined the effects of elastin degradation on the tensile elastic and viscoelastic responses of tendons with varying functional demands, hierarchical structures, and elastin content. Moreover, volumetric imaging and protein quantification were used to thoroughly characterize the elastin network in each distinct tendon. The results presented herein can inform tendon-specific strategies to maintain or restore native properties in elastin-degraded tissue.

A Remote Longitudinal Observational Study of Individuals at Genetic Risk for Parkinson Disease: Baseline Results.

Background and Objectives: To recruit and characterize a national cohort of individuals who have a genetic variant (LRRK2 G2019S) that increases risk of Parkinson disease (PD), assess participant satisfaction with a decentralized, remote research model, and evaluate interest in future clinical trials. Methods: In partnership with 23andMe, Inc., a personal genetics company, LRRK2 G2019S carriers with and without PD were recruited to participate in an ongoing 36-month decentralized, remote natural history study. We examined concordance between self-reported and clinician-determined PD diagnosis. We applied the Movement Disorder Society Prodromal Parkinson's Disease Criteria and asked investigators to identify concern for parkinsonism to distinguish participants with probable prodromal PD. We compared baseline characteristics of LRRK2 G2019S carriers with PD, with prodromal PD, and without PD. Results: Over 15 months, we enrolled 277 LRRK2 G2019S carriers from 34 states. At baseline, 60 had self-reported PD (mean [SD] age 67.8 years [8.4], 98% White, 52% female, 80% Ashkenazi Jewish, and 67% with a family history of PD), and 217 did not (mean [SD] age 53.7 years [15.1], 95% White, 59% female, 73% Ashkenazi Jewish, and 57% with a family history of PD). Agreement between self-reported and clinician-determined PD status was excellent (κ = 0.94, 95% confidence interval 0.89-0.99). Twenty-four participants had prodromal PD; 9 met criteria for probable prodromal PD and investigators identified concern for parkinsonism in 20 cases. Compared with those without prodromal PD, participants with prodromal PD were older (63.9 years [9.0] vs 51.9 years [15.1], p < 0.001), had higher modified Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor scores (5.7 [4.3] vs 0.8 [2.1], p < 0.001), and had higher Scale for Outcomes in PD for Autonomic Symptoms scores (11.5 [6.2] vs 6.9 [5.7], p = 0.002). Two-thirds of participants enrolled were new to research, 97% were satisfied with the overall study, and 94% of those without PD would participate in future preventive clinical trials. Discussion: An entirely remote national cohort of LRRK2 G2019S carriers was recruited from a single site. This study will prospectively characterize a large LRRK2 G2019S cohort, refine a new model of clinical research, and engage new research participants willing to participate in future therapeutic trials.

Genetic prediction of impulse control disorders in Parkinson's disease.

OBJECTIVE: To develop a clinico-genetic predictor of impulse control disorder (ICD) risk in Parkinson's disease (PD). METHODS: In 5770 individuals from three PD cohorts (the 23andMe, Inc.; the University of Pennsylvania [UPenn]; and the Parkinson's Progression Markers Initiative [PPMI]), we used a discovery-replication strategy to develop a clinico-genetic predictor for ICD risk. We first performed a Genomewide Association Study (GWAS) for ICDs anytime during PD in 5262 PD individuals from the 23andMe cohort. We then combined newly discovered ICD risk loci with 13 ICD risk loci previously reported in the literature to develop a model predicting ICD in a Training dataset (n = 339, from UPenn and PPMI cohorts). The model was tested in a non-overlapping Test dataset (n = 169, from UPenn and PPMI cohorts) and used to derive a continuous measure, the ICD-risk score (ICD-RS), enriching for PD individuals with ICD (ICD+ PD). RESULTS: By GWAS, we discovered four new loci associated with ICD at p-values of 4.9e-07 to 1.3e-06. Our best logistic regression model included seven clinical and two genetic variables, achieving an area under the receiver operating curve for ICD prediction of 0.75 in the Training and 0.72 in the Test dataset. The ICD-RS separated groups of PD individuals with ICD prevalence of nearly 40% (highest risk quartile) versus 7% (lowest risk quartile). INTERPRETATION: In this multi-cohort, international study, we developed an easily computed clinico-genetic tool, the ICD-RS, that substantially enriches for subgroups of PD at very high versus very low risk for ICD, enabling pharmacogenetic approaches to PD medication selection.

Upstream interventions to promote oral health and reduce socioeconomic oral health inequalities: a scoping review protocol.

INTRODUCTION: Improving oral health and reducing oral health inequalities is an important global health priority. 'Upstream interventions' are a vital part of the collective effort to reduce oral disease burdens, however it is a rather nebulous term. Furthermore, there is little evidence on the effectiveness, impact and sustainability of upstream interventions that have focused on oral health and wider public health measures that impact on oral health. The aim of this scoping review is to systematically map and synthesise evidence on the effectiveness, impact and sustainability of upstream interventions on population oral health and reducing socioeconomic oral health inequalities. METHODS AND ANALYSIS: This scoping review will be conducted in accordance with the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. A detailed search strategy will be used to conduct a comprehensive search of electronic databases: Scopus, Embase and MEDLINE, PsycINFO and CINAHL, ASSIA and Cochrane Database of Systematic Reviews. A search of grey literature will also be completed to identify relevant dissertations, governmental reports and evaluations of implemented policies. Identification and extraction of data will be performed by two pairs of reviewers. Oversight and feedback will be provided by an independent expert advisory group. ETHICS AND DISSEMINATION: This study will review published and available grey literature and does not require an ethics review. The scoping review protocol has been registered with the Open Science Framework. The final report will be circulated and disseminated through publication and feed into the work of the ongoing Lancet Commission on Oral Health. Due to the policy relevance of this work, discussions will take place with key stakeholders regarding the implications of the findings for future policy development.

Donor age and sex have limited effects on the mechanical and microstructural properties of human connective tissues.

Connective tissues, such as tendons, ligaments, and capsules, play a large role in locomotion and joint stability and are often subjected to traumatic injuries and degeneration. The purpose of this study was to evaluate if the mechanical and microstructural properties of connective tissues correlate with the age and sex of the human donor. Dissected samples were prepared for mechanical testing, consisting of 10 cycles of preconditioning, a stress-relaxation ramp and hold, and a quasi-static ramp to failure. During the testing protocol, the microstructural organization of tissues was analyzed using quantitative polarized light imaging. A linear mixed model was used to assess whether tissue type, donor age, or donor sex were significantly associated with mechanical and microstructural tissue properties. Tissue type had a significant effect on all parameters, while donor age and sex did not. Groupings by tissue type (i.e., tendon vs. ligament vs. capsule) were evident for microstructural data, with tendons having a tighter grouping and ligaments having a larger spread of values. The interaction of tissue type and age yielded a significant effect for linear modulus only (p = 0.007), with the palmaris tendon appearing to have the largest contribution to this effect. There were no significant interaction effects between sex and tissue type or donor age. Donor age appears to affect linear modulus in some, but not all, tissue types. Otherwise, age and sex do not have significant effects on the mechanical and microstructural properties of the range of connective tissues that were analyzed in this study.

Current practice trends for lacrimal gland neurotoxin in the management of epiphora-a BOPSS survey.

PURPOSE: Injection of botulinum neurotoxin A (BoNTA) to the lacrimal gland (LG) offers a simple and effective treatment in the management of epiphora. However, there is little data on current practice trends or uptake as an alternative to surgery. This study assesses current practice trends of such treatment amongst BOPSS (British Oculoplastic Surgery Society) members. METHODS: All consultant BOPSS members were invited to participate in a web-based survey which consisted of 5 questions, with a reminder invitation to participate. The role, dose, potential side effects, use as an alternative to surgical intervention, and impact on service delivery were assessed. RESULTS: Fifty-one BOPSS consultants (43% uptake) completed the survey. Ninety percent of respondents were regularly using LG BoNTA in their management of epiphora. The main indicators for considering BoNTA use were medical comorbidities and elderly patients. The mean first treatment dose of Botox® was 3.6 units (SD 1.5). Diplopia and ptosis complications were always discussed in the consent for treatment in addition to dry eye. Twenty-five percent of surgeons reported doing less conjunctivo-dacryocystorhinostomies (cDCR) due to the availability of LG BoNTA. No respondents felt that the requirement for repeated BoNTA treatments was impacting on their service delivery. CONCLUSION: Uptake of LG BoNTA in the management of epiphora is at a similar rate to all other available treatments. As a result, respondents are performing less surgical procedures, particularly cDCR in patients at higher surgical morbidity.

Recruitment for Remote Decentralized Studies in Parkinson's Disease.

BACKGROUND: Traditional in-person Parkinson's disease (PD) research studies are often slow to recruit and place unnecessary burden on participants. The ongoing COVID-19 pandemic has added new impetus to the development of new research models. OBJECTIVE: To compare recruitment processes and outcomes of three remote decentralized observational PD studies with video visits. METHODS: We examined the number of participants recruited, speed of recruitment, geographic distribution of participants, and strategies used to enhance recruitment in FIVE, a cross-sectional study of Fox Insight participants with and without PD (n = 203); VALOR-PD, a longitudinal study of 23andMe, Inc. research participants carrying the LRRK2 G2019S variant with and without PD (n = 277); and AT-HOME PD, a longitudinal study of former phase III clinical trial participants with PD (n = 226). RESULTS: Across the three studies, 706 participants from 45 U.S. states and Canada enrolled at a mean per study rate of 4.9 participants per week over an average of 51 weeks. The cohorts were demographically homogenous with regard to race (over 95%white) and level of education (over 90%with more than a high school education). The number of participants living in primary care Health Professional Shortage Areas in each study ranged from 30.3-42.9%. Participants reported interest in future observational (98.5-99.6%) and interventional (76.1-87.6%) research studies with remote video visits. CONCLUSION: Recruitment of large, geographically dispersed remote cohorts from a single location is feasible. Interest in participation in future remote decentralized PD studies is high. More work is needed to identify best practices for recruitment, particularly of diverse participants.

Cutaneous pleomorphic adenoma of the periocular region - a case series.

Mixed tumour of the skin is a rare entity also known as chondroid syringoma and pleomorphic adenoma. These usually present as slow-growing skin nodules with a smooth surface, clear boundaries, and no ulceration. Case series exist describing pleomorphic adenomas in the periocular region including the lids and orbit, separate to the more familiar lacrimal gland pleomorphic adenoma. These may arise from accessory or ectopic lacrimal gland tissue but in the eyelids are more likely to arise from sweat glands in the skin. Histopathological analysis of these lesions is important to identify complete excision, minimising recurrences and in identifying rare but potential malignant transformation. We describe the clinical features and outcomes in three cases of pleomorphic adenoma with two at the medial canthus (including one recurrence) and one in the brow region.

Phylogenetic Position of Shiraia-Like Endophytes on Bamboos and the Diverse Biosynthesis of Hypocrellin and Hypocrellin Derivatives.

The main active ingredients of the fruiting bodies of Shiraia bambusicola and Rubroshiraia bambusae are Hypocrellins, belonging perylenequinones with potential photodynamic activity against cancer and microbial diseases. However, the strains of S. bambusicola and R. bambusae do not produce hypocrellins in culture, so resource exploitation of natural products was seriously restricted. In this study, a series of novel Shiraia-like fungal endophyte strains, with varying sporulation ability and synthesizing diverse secondary metabolites, was isolated from different bamboos. Based on phylogenetic analyses and morphological characteristics of the endophytes, Pseudoshiraia conidialis gen. et sp. nov. is proposed. The secondary metabolites of different fruiting bodies and strains have been comprehensively analyzed for the first time, finding that the endophytic strains are shown not only to produce hypocrellins, but also other perylenequinonoid compounds. It was noteworthy that the highest yield of total perylenequinone production and hypocrellin A appeared in P. conidialis CNUCC 1353PR (1410.13 mg/L), which was significantly higher than any other wild type P. conidialis strains in published reports. In view of these results, the identification of Shiraia-like endophytes not only confirm the phylogenetic status of similar strains, but will further assist in developing the production of valuable natural products.

Unhealthy Behaviours and Risk of Parkinson's Disease: A Mendelian Randomisation Study.

BACKGROUND: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson's disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. OBJECTIVE: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. METHODS: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. RESULTS: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921-0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025-1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979-0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. CONCLUSION: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.

Prostaglandin analogues: A double-edged sword in orbital glaucoma disease management.

INTRODUCTION: The authors describe benefits of the recognised adverse effects of prostaglandin analogues on periocular structures in patients with unilateral proptosis and intraocular pressure rise. This case points to intentional consideration of prostaglandin analogue therapy in this selected cohort of patients with secondary ocular hypertension and proptosis. CASE DESCRIPTION: A 70-year-old gentleman who presented with a 1-week history of a red and painful right eye associated with tortuous and dilated episcleral blood vessels. Visual acuity was unaffected. A diagnosis of idiopathic orbital inflammatory disease was made by extraocular muscle biopsy. Two weeks later, the patient presented with worsening pain, reduced vision and raised intraocular pressure. The secondary ocular hypertension was successfully treated with topical preserved eye drops, including latanoprost, a prostaglandin analogue. Over 6 months, the patient developed drop intolerance and punctate keratopathy leading to therapy non-adherence. Interestingly, the patient reported improvement in periocular appearance related to prostaglandin-associated periorbitopathy. Ocular surface disease and intraocular pressures were subsequently managed with preservative-free eye drops. CONCLUSION: Secondary ocular hypertension is not an uncommon consequence of orbital disease. Prostaglandin analogue can act as a double-edged sword in the management of raised intraocular pressure by reducing eye pressure at the cost of developing adverse effects of prostaglandin-associated periorbitopathy. These adverse effects however can be beneficial in the aesthetic rehabilitation of proptosis and associated exposure keratopathy in patients with unilateral orbital disease and probably should be sought as first line treatment in those with proptosis and raised intraocular pressure.

Females and males exhibit similar functional, mechanical, and morphological outcomes in a rat model of posttraumatic elbow contracture.

Posttraumatic joint contracture (PTJC) is a debilitating condition characterized by loss of joint motion following injury. Previous work in a rat model of elbow PTJC investigated disease etiology, progression, and recovery in only male animals; this study explored sex-based differences. Rat elbows were subjected to a unilateral anterior capsulotomy and lateral collateral ligament transection followed by 42 days of immobilization and 42 days of free mobilization. Grip strength and gait were collected throughout the free mobilization period while joint mechanical testing, microcomputed tomography and histological analysis were performed postmortem. Overall, few differences were seen between sexes in functional, mechanical, and morphological outcomes with PTJC being similarly debilitating in male and female animals. Functional measures of grip strength and gait showed that, while some baseline differences existed between sexes, traumatic injury produced similar deficits that remained significantly different long-term when compared to control animals. Similarly, male and female animals both had significant reductions in joint range of motion due to injury. Ectopic calcification (EC), which had not been previously evaluated in this injury model, was present in all limbs on the lateral side. Injury caused increased EC volume but did not alter mineral density regardless of sex. Furthermore, histological analysis of the anterior capsule showed minor differences between sexes for inflammation and thickness but not for other histological parameters. A quantitative understanding of sex-based differences associated with this injury model will help inform future therapeutics aimed at reducing or preventing elbow PTJC.

The effects of physical activity, fast-mimicking diet and psychological interventions on cancer survival: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Health professionals are often asked if non-pharmacological interventions prolong life. This review aims to evaluate the effects of physical activity, fast-mimicking diet (FMD) and psychological interventions on survival in all cancers. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs). Only RCTs of physical activity, FMD and psychological interventions (including counselling, cognitive and other psychotherapies) in cancer patients that reported survival outcomes were included. DATA SOURCES: CENTRAL, MEDLINE, Embase, CINAHL, APA PsycINFO, Web of Science, ICTRP and ClinicalTrials.gov from inception to January 2020 were searched without language restrictions. The protocol was prospectively registered at PROSPERO (CRD42019160944). RESULTS: Thirty-one RCTs (9 on physical activity and 22 on psychological interventions) were included in the final analysis after evaluation of 60,207 records from our initial search. No eligible RCT on FMD was reported. RCTs on group psychological interventions (41.9 %) and in patients with breast cancer (38.7 %) were the most common. Most evaluated short-term interventions and in primary or adjuvant settings. Only one of 9 (11 %) RCTs on physical activity and 8 of 22 (36 %) RCTs on psychological interventions were associated with improved overall survival. Only group psychological interventions in breast cancer had adequate number of RCTs to allow a meta-analysis to be performed. It demonstrated a trend towards improved overall survival (HR -0.20, 95 %CI -0.49 to 0.10), particularly in RCTs that evaluated long-term (>6 months) therapies (HR -0.29, 95 %CI -0.59 to 0.01). CONCLUSION: Longer term interventions starting early in the patients' care journey in primary and adjuvant settings have shown the most promise for improving survival. Better designed RCTs including survival outcomes are particularly needed in non-breast cancers.

Radiology for medical students (1925-2018): an overview.

OBJECTIVE: Radiology has been espoused as an excellent tool for educating medical students since 1925. Advances in technology and PACS mean it has never been easier to demonstrate living anatomy and clinical pathology in exquisite detail to students. The aim of this study was to provide an overview of radiologic publications related to teaching medical students and its evolution through time. METHODS: A literature search was performed from inception to November 2018. The search strategies used both text words and relevant indexing related to "radiology", "medical students" and "curriculum". RESULTS: 3589 records were identified of which 377 were included. There was a 100 fold increase in rate of publication over time-most were expository or surveys (60%), with few truly experimental articles. Radiology was used in clinical teaching (67%) and anatomy (33%). Almost half of radiologic anatomy teaching was conducted without the input of a Radiologist. Compulsory clinical clerkships/blocks in radiology was offered infrequently (35%). Female first authorship had increased in the last decade (47%). CONCLUSION: There is a significant increase in articles published on the role of radiology in medical student teaching in the last decade. Research in this area is required in order to investigate the role of radiology in improving the modern medical students' education.

A Virtual Cohort Study of Individuals at Genetic Risk for Parkinson's Disease: Study Protocol and Design.

BACKGROUND: The rise of direct-to-consumer genetic testing has enabled many to learn of their possible increased risk for rare diseases, some of which may be suitable for gene-targeted therapies. However, recruiting a large and representative population for rare diseases or genetically defined sub-populations of common diseases is slow, difficult, and expensive. OBJECTIVE: To assess the feasibility of recruiting and retaining a cohort of individuals who carry a genetic mutation linked to Parkinson's disease (G2019S variant of LRRK2); to characterize this cohort relative to the characteristics of traditional, in-person studies; and to evaluate this model's ability to create an engaged study cohort interested in future clinical trials of gene-directed therapies. METHODS: This single-site,3-year national longitudinal observational study will recruit between 250 to 350 LRRK2 carriers without Parkinson's disease and approximately 50 with the condition. Participants must have undergone genetic testing by the personal genetics company, 23andMe, Inc., have knowledge of their carrier status, and consent to be contacted for research studies. All participants undergo standardized assessments, including video-based cognitive and motor examination, and complete patient-reported outcomes on an annual basis. RESULTS: 263 individuals living in 33 states have enrolled. The cohort has a mean (SD) age of 56.0 (15.9) years, 59% are female, and 76% are of Ashkenazi Jewish descent. 233 have completed the baseline visit: 47 with self-reported Parkinson's disease and 186 without. CONCLUSIONS: This study establishes a promising model for developing a geographically dispersed and well-characterized cohort ready for participation in future clinical trials of gene-directed therapies.