Faculty Bibliography

Parkinson's Disease (PD) is a progressive neurological condition characterized by motor and non-motor symptoms impacting life quality. The main aim of the current study was to investigate the effect of PD on objective (i.e., working memory and semantic memory) and subjective memory (i.e., self-reported seriousness of forgetting, mnemonic usage and actual memory efficiency) controlling for the effect of depressive symptomatology. The relationship of working memory performance to gait and mobility indices was also examined, as well as the factors predicting subjective memory were explored. Fifty-four community-dwelling adults (mean age = 72.3 years, SD = 8.8) were recruited in Sardinia, an Italian island located in the Mediterranean Sea. Specifically, 27 non-demented adults with mild, early-stage PD were matched for years of education, age, and gender with a sample of healthy individuals. Participants completed a test battery assessing objective memory, subjective memory, and depressive symptoms, and an instrumental analysis of gait and functional mobility was performed. Participants with PD had poorer objective memory across all indices measured and displayed a restricted set of gait and posture impairments. Working memory performance was selectively related to gait and posture measures. Moreover, participants with PD had lower trust in their memory efficiency relative to the past than the control healthy group. Finally, 22% of the variance in seriousness of the consequences of forgetting was predicted by education and general cognitive efficiency. Overall, the present findings confirm the presence of changes in both objective and subjective memory in PD, independent from depressive symptoms.

OBJECTIVE:To identify and quantify determinants of anxiety symptoms and disorders experienced by elite athletes. DESIGN/METHODS:Systematic review and meta-analysis. DATA SOURCES/METHODS:Five online databases (PubMed, SportDiscus, PsycINFO, Scopus and Cochrane) were searched up to November 2018 to identify eligible citations. ELIGIBILITY CRITERIA FOR SELECTING STUDIES/UNASSIGNED:Articles were included if they were published in English, were quantitative studies and measured a symptom-level anxiety outcome in competing or retired athletes at the professional (including professional youth), Olympic or collegiate/university levels. RESULTS AND SUMMARY/UNASSIGNED:=0.26)-higher anxiety in athletes who had experienced one or more recent adverse life events. CONCLUSION/CONCLUSIONS:Determinants of anxiety in elite populations broadly reflect those experienced by the general population. Clinicians should be aware of these general and athlete-specific determinants of anxiety among elite athletes.

BACKGROUND:Leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein 1(LINGO-1 is a key suppressor of oligodendrocyte differentiation and axonal remyelination and regeneration. This analysis evaluated the potential benefit of opicinumab, a human monoclonal antibody against LINGO-1, vs placebo on exploratory clinical endpoints of patient-reported vision-related functioning and high-contrast visual acuity (HCVA) in RENEW participants with acute optic neuritis (AON). METHODS:Participants were randomized to 100 mg/kg opicinumab intravenous or placebo every 4 weeks (6 infusions). Assessments were conducted in the per-protocol (PP) population and included: 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), 10-item Neuro-Ophthalmic Supplement (NOS-10), and HCVA. RESULTS:The opicinumab group (n = 33) had worse mean (SD) baseline patient-reported vision-related functioning scores vs placebo (n = 36): NEI-VFQ-25 composite, 75.5 (17.6) vs 79.0 (16.6); NOS-10 composite, 63.6 (19.8) vs 69.8 (21.2), respectively. By Week 24, the placebo and opicinumab groups experienced substantial mean improvements from baseline (NEI-VFQ-25 composite, 15.17 vs 13.51 [difference (95% CI): -1.66 (-5.11 to 1.78)]; NOS-10 composite, 17.40 vs 16.04 [difference (95% CI): -1.35 (-7.38 to 4.67)]). Between-treatment differences in mean change from baseline were not significantly different at any time point. Analysis of covariance-adjusted mean recovery from baseline in HCVA at Week 24 for the affected eyes was 11.8 and 8.7 letters for placebo and opicinumab, respectively (P = 0.202). CONCLUSIONS:Most participants in the RENEW PP population demonstrated substantial recovery from baseline in patient-reported vision-related functioning and HCVA, regardless of treatment and structural damage. Average scores after recovery remained lower than those of published disease-free control groups. These results provide important information on visual function recovery in patients with AON, as measured by NEI-VFQ-25 and NOS-10.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Human fibrin hydrogels are a popular choice for use as a biomaterial within tissue engineered constructs because they are biocompatible, nonxenogenic, autologous use compatible, and biodegradable. We have recently demonstrated the ability to culture induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium on fibrin hydrogels. However, iPSCs themselves have relatively few substrate options (e.g., laminin) for expansion in adherent cell culture for use in cell therapy. To address this, we investigated the potential of culturing iPSCs on fibrin hydrogels for three-dimensional applications and further examined the use of fibrinogen, the soluble precursor protein, as a coating substrate for traditional adherent cell culture. iPSCs successfully adhered to and proliferated on fibrin hydrogels. The two-dimensional culture with fibrinogen allows for immediate adaption of culture models to a nonxenogeneic model. Similarly, multiple commercially available iPSC lines adhered to and proliferated on fibrinogen coated surfaces. iPSCs cultured on fibrinogen expressed similar levels of the pluripotent stem cell markers SSea4 (98.7% ± 1.8%), Oct3/4 (97.3% ± 3.8%), TRA1-60 (92.2% ± 5.3%), and NANOG (96.0% ± 3.9%) compared with iPSCs on Geltrex. Using a trilineage differentiation assay, we found no difference in the ability of iPSCs grown on fibrinogen or Geltrex to differentiate to endoderm, mesoderm, or ectoderm. Finally, we demonstrated the ability to differentiate iPSCs to endothelial cells using only fibrinogen coated plates. On the basis of these data, we conclude that human fibrinogen provides a readily available and inexpensive alternative to laminin-based products for the growth, expansion, and differentiation of iPSCs for use in research and clinical cell therapy applications. Stem Cells Translational Medicine 2019;8:512-521.

Mental health symptoms and disorders are common among elite athletes, may have sport related manifestations within this population and impair performance. Mental health cannot be separated from physical health, as evidenced by mental health symptoms and disorders increasing the risk of physical injury and delaying subsequent recovery. There are no evidence or consensus based guidelines for diagnosis and management of mental health symptoms and disorders in elite athletes. Diagnosis must differentiate character traits particular to elite athletes from psychosocial maladaptations.Management strategies should address all contributors to mental health symptoms and consider biopsychosocial factors relevant to athletes to maximise benefit and minimise harm. Management must involve both treatment of affected individual athletes and optimising environments in which all elite athletes train and compete. To advance a more standardised, evidence based approach to mental health symptoms and disorders in elite athletes, an International Olympic Committee Consensus Work Group critically evaluated the current state of science and provided recommendations.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

Introduction: To date, only very few series have aimed to assess the outcomes of botulinum toxin injections in patients with Parkinson's Disease (PD). The aim of this study was to assess the safety and efficacy of intradetrusor onabotulinum toxin A injections for the treatment of overactive bladder (OAB) in patients with PD.
Method(s): All PD patients who underwent intradetrusor injections of onabotulinum toxin A (BoNT-A) for storage symptoms between 2010 and 2017 were included in a retrospective study. A 100 U dose of BoNT-A (Botox, Allergan Irvine, CA) was used for the first injection in all patients. The primary endpoint was clinical success defined as any subjective improvement in OAB symptoms self-assessed by the patients four weeks after the injections.
Result(s): Out of 24 patients analyzed, 19 reported improvement of their OAB symptoms four weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in 7 patients (29.1%; p<0.001). The average post-void residual (PVR) increased significantly after the first injection from 17.6 to 125.3 ml (p<0.001). Three of the patients had to start clean intermittent catheterization (CIC) after the first injection (12.5%). Out of 49 injections in total, only five caused incomplete bladder emptying requiring the use of CIC (10.2%). Higher pre-injection PVR was significantly associated with both a lower chance of symptomatic improvement (p=0.04) and a higher risk of incomplete bladder emptying with institution of CIC (p=0.047).
Conclusion(s): Botox appeared effective in PD patients with a relatively low rate of retention requiring CIC. Higher preoperative PVR was the stronger predictor of both treatment failure and postoperative urinary retention requiring CIC while urodynamic obstruction was also associated with treatment failure in male patients. Intradetrusor injections of BoNT-A 100 U appeared as a safe and effective option in PD patients with OAB symptoms and a low PVR before the injection

A common complaint after concussion is the development of new or worsening headaches which can make it difficult or even impossible for patients to work or function in their day-to-day lives. Uncertainties associated with the complaints and a wide variety of approaches exist regarding the appropriate work-up and management of these patients. Areas of ongoing debate include the need for neuroimaging; optimal, acute, and preventative treatment; and proper counseling and expectation management. Given the wide variety of potential approaches and the lack of consensus, we sought expert opinion from around the globe on how to evaluate and manage patients with headache following concussion. Similar questions were posed to the rest of our readership in an online survey (links.lww.com/CPJ/A96), the results of which are also presented.

AIM:Femtosecond laser assisted cataract surgery is associated with pupillary constriction. This study aims to look at patient and surgical factors predisposing to abnormal pupil behaviour during FLACS. METHODS:This prospective observational study included all patients undergoing FLACS in the Princess of Wales Hospital, Bridgend, UK between February and June 2017. Pupils were measured at three time points; immediately before and after laser pre-treatment, and at the start of surgery. Pupil behaviour during surgery was noted in descriptive terms, patient demographic, co-morbidities, eye measurements, suction on time, shifting time and laser energy levels were recorded. RESULTS:Seventy-three eyes were included. Average patient age was 74.84 ± 9.1 years. Mean horizontal pupil sizes immediately before and after femto pre-treatment were 7.87 ± 0.87 mm and 7.7 ± 0.89 mm respectively (P < 0.0005). Mean horizontal pupil size at the start of surgery was 6.83 ± 1.43 mm (P < 0.0005). Short capsulotomy-pupil distance (P = 0.01), shallower anterior chamber (P = 0.0012), smaller pre-operative pupil size (P = 0.045) and longer suction on time (P = 0.0019) were significantly associated with intra-operative miosis during FLACS. Sustained mydriasis was observed in eyes in whom topical diclofenac was used within 2 h of surgery. CONCLUSIONS:FLACS can result in significant pupil miosis. Eyes particularly at risk are ones with smaller pre-operative pupils and shallower anterior chambers and those subjected to longer suction on time. Well-timed NSAIDs application could be protective against this phenomenon.