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Background/aims Individuals who are severely disabled from stroke (survivors of severely disabling stroke) experience poorer outcomes compared to those who are less disabled from stroke. However, there is a paucity of evidence describing current therapy practice in the management of severely disabling stroke. The aim of the study was to describe intervention and outcome measure use by physiotherapists and occupational therapists in the rehabilitation of physical function of survivors of severely disabling stroke. Methods A mixed-methods survey was conducted, involving an online questionnaire and follow-up interviews. Survey participants were UK-based physiotherapists and occupational therapists with experience treating stroke. Questionnaire data were analysed with descriptive and inferential statistics. Interview data were analysed using content analysis. Results A total of 452 therapists (59% physiotherapists) responded to the questionnaire. Out of the respondents, 18 self-selected therapists participated in follow-up interviews to explain questionnaire data. Whole body positioning, training of upper limb handling and positioning, and sitting balance practice were the most frequently used interventions. Inpatient-based therapists performed more active rehabilitation interventions, whereas community-based therapists performed more training and education. The Barthel Index, Modified Rankin Scale and National Institutes for Health Stroke Scale were the most frequently used outcome measures. Outcome measure use was generally low and was more likely to be completed when it was part of a national audit. Reasons for low outcome measure use were perceived lack of time and insensitivity to detect clinical change. Conclusions A variety of interventions and outcome measures are used in the rehabilitation of survivors of severely disabling stroke. There is a need to evaluate the effectiveness of frequently used interventions and identify outcome measures that are sensitive to the needs of survivors of severely disabling stroke.

Eric Mack defends a version of John Locke’s proviso. Mack applies his proviso to original appropriations, uses, and systems of private property. His proviso precludes severely disabling the world-interactive powers of others. Mack specifically warns against using concrete features of the natural world as a baseline for determine whether the proviso has been violated. While his proviso is plausible, I argue that he cannot. eschew employing the receptivity of the natural, unowned world to the extent that he suggests. We cannot determine whether one’s powers are disabled or diminished without knowing how receptive the world would be to those powers had a system of private property not arisen. The upshot of this paper is that the requirements of a well-formulated proviso is an empirical matter.

Tendon adhesion formation describes the development of fibrotic tissue between the tendon and its surrounding tissues, which commonly occurs as a reaction to injury or surgery. Its impact on function and quality of life varies from negligible to severely disabling, depending on the affected area and extent of adhesion formed. Thus far, treatment options remain limited with prophylactic anti-inflammatory medications and revision surgeries constituting the only tools within the doctors' armamentarium - neither of which provides reliable outcomes. In this review, the authors aim to collate the current understanding of the pathophysiological mechanisms underlying tendon adhesion formation, highlighting the significant role ascribed to the inflammatory cascade in accelerating adhesion formation. The bulk of this article will then be dedicated to critically appraising different therapeutic structures like nanoparticles, hydrogels and fibrous membranes fabricated by various cutting-edge technologies for adhesion formation prophylaxis. Emphasis will be placed on the role of the fibrous membranes, their ability to act as drug delivery vehicles as well as the combination with other therapeutic structures (e.g., hydrogel or nanoparticles) or fabrication technologies (e.g., weaving or braiding). Finally, the authors will provide an opinion as to the future direction of the prevention of tendon adhesion formation in view of scaffold structure and function designs.

Introduction: Congenital proximal radio-ulnar synostosis is a rare congenital anomaly of the upper extremity which is severely disabling as it causes severe pronation deformity. So the aim of this study was to assess the efficacy of proximal radioulnar derotational osteotomy followed by internal fixation for the treatment of congenital radioulnar synostosis.Materials and Method: Between June 2018 and April 2020, 11 patients with CRUS who underwent derotational osteotomy at the proximal radioulnar synostosis site were evaluated. There were 7 boys and 4 girls. The mean age at the time of surgery was 10.5 years (range, 2 to 13) years. The forearm was derotated to the goal position (20 degrees of supination to 10 degrees of pronation) using plates for internal fixation and plaster splints for external immobilization. Pre- and postoperative positions of the forearm were recorded; forearm function was evaluated based on the classification system proposed by Failla et al.Results: The mean follow-up duration was 6 months. The mean initial pronation deformity was 65.0 ± 5.2 (55 to 80) degrees. The mean correction achieved was 75.27 ± 5.25 (50 to 90) degrees, resulting in a mean final position of 9.45 ± 3.25 degrees of supination (20 degrees of supination to 10 degrees of pronation). Based on the Failla classification system, 7 forearms were rated as good, 4 were rated as fair preoperatively. At the final follow-up, 9 forearms were rated as excellent and 2 were rated as good. All patients achieved bone union after 10 weeks. Post-operative period was uneventful and no complications were seen.Conclusion: Proximal radioulnar derotational osteotomy followed by plate fixation is a safe and feasible procedure with a low complication rate. The technique can effectively improve the function of the forearm.

Introduction: Cluster headache [CH] is a severely disabling trigeminal autonomic cephalalgia [TAC]. Approximately 1 in 1,000 adults are affected by CH. Calcitonin gene-related peptide [CGRP] is an ...

Background Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a rare but severely disabling variant within the spectrum of trigeminal autonomic cephalalgia lacking evidence-based treatment. Case We report a case of chronic SUNCT in a 67-year-old man refractory to various guideline-conforming treatment attempts responding excellently to galcanezumab. Conclusions This case report indicates that monoclonal antibodies against calcitonin gene-related peptide, specifically galcanezumab, might be a treatment option for SUNCT warranting further investigation.

Objectives/hypothesis Respiratory laryngeal dystonia (RLD) is poorly understood and rarely reported in the literature. Patients have atypical laryngeal movement resulting in airway obstruction. This motion is neurogenic in nature, is constant while awake, nonepisodic, and non-trigger dependent. Given its rarity, it is often misdiagnosed for inducible laryngeal obstruction; however, it is refractory to medical and behavioral management. Although this condition has been addressed in the literature, this report is the largest case series characterizing presenting symptomology, multimodal treatment outcomes, and longitudinal course of these patients, and proposes a set of diagnostic criteria to aid in clinical identification of RLD patients. Our objectives were to characterize RLD clinically and offer diagnostic guidelines to clinicians. Study design A prospective case series with a retrospective analysis at a tertiary referral center. Methods A review of clinical records and videostroboscopic analysis of 16 patients treated for respiratory laryngeal dystonia from October 2005 to October 2018 was performed. Results Sixteen patients with respiratory laryngeal dystonia were included. The common features of this group were persistent, nonepisodic dyspnea and stridor with laryngoscopic evidence of paradoxical vocal fold motion. Our patients had no structural neurologic abnormalities. These patients typically failed respiratory retraining therapy and medical management of laryngeal irritants. In our series, 100% of patients underwent respiratory retraining therapy, 68.8% received laryngeal botulinum toxin injection, and 31.3% required tracheostomy. Conclusions RLD is a rare and challenging condition. The disorder can be severely disabling, and treatment options appear limited. A multidisciplinary approach may be helpful. Some patients responded to laryngeal botulinum injection and medical management, whereas others required tracheostomy for symptom control. Laryngoscope, 2020.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and severely disabling autosomal dominant disease that is yet to be clearly understood. The purpose of this review is to present recent literature on pathophysiology, clinical features, diagnosis and treatment of FOP.FOP is characterized by congenital great toe deformity and progressive heterotopic ossifications in connective tissue. Heterotopic ossifications occur after painful flare-ups that can arise spontaneously or can be triggered by minor trauma. Each flare-up ultimately causes restriction of related-joint, and along with the others eventually leads to immobility. Death is usually caused by pulmonary complications because of chest wall involvement. The causative gene of FOP is activin A receptor type 1 (ACVR1), a bone morphogenetic protein-signalling component, which normally acts to inhibit osteoblastogenesis. The treatment of FOP is still preventive and supportive.Although there are still gaps in the underlying mechanism of FOP, effective treatment options, such as potential pharmacologic targets and cell-based therapies are promising for the future. Some of these were tested without a clinical trial setting, and are currently in the process of evidence-based research.

Because of the demographic shift and the increased proportion of patients surviving acute critical illnesses, the number of people living with severely disabling chronic diseases and, consequently, the demand for rehabilitation are expected to increase sharply over time. As underscored by the World Health Organization, there is substantial evidence that the provision of inpatient rehabilitation in specialized rehabilitation units to people with complex needs is effective in fostering functional recovery, improving health-related quality of life, increasing independence, reducing institutionalization rate, and improving prognosis. Recent studies in the real world setting reinforce the evidence that patients with ischemic heart disease or stroke benefit from rehabilitation in terms of improved prognosis. In addition, there is evidence of the effectiveness of rehabilitation for the prevention of functional deterioration in patients with complex and/or severe chronic diseases. Given this evidence of effectiveness, rehabilitation should be regarded as an essential part of the continuum of care. Nonetheless, rehabilitation still is underdeveloped and underused. Efforts should be devoted to foster healthcare professional awareness of the benefits of rehabilitation and to increase referral and participation.

Background It is reported that in New Zealand financially disadvantaged adolescents are less likely to access orthodontic treatment than the more affluent in society. Objectives The aim of the study was to investigate the attitudes of a group of New Zealand orthodontists towards the current fee-for-service model of treatment funding. A second aim was to explore orthodontists’ perceptions of how the affordability of orthodontic treatment affects low socio-economic families. Methods As part of the project, 11 volunteer orthodontists were interviewed. A subsequent content analysis of the collected data was performed. Results Most participants reported that parents would feel inadequate if they were unable to secure orthodontic treatment for their child; however, some participants also indicated that it was common for parents to ‘go without’ to fund their child’s treatment. Most participants maintained that the government should only fund treatment for severely disabling malocclusions but not other treatments due to the limited health budget and orthodontic treatment being primarily considered for aesthetic reasons. Some participants reported that if the government funded orthodontic treatment, it would result in over subscription and compromised standards of care. Conclusion Despite some low socio-economic families being unable to access orthodontic treatment because of the expense, the current fee-for-service model may be the best method for delivering high standards of orthodontic care.

Myelopathy is a broad term used to describe a heterogeneous group of disorders that affects the spinal cord; the focus of this article will be a subgroup of these disorders with an autoimmune and inflammatory-based pathology. Symptoms typically develop over hours or days and then worsen over a matter of days to weeks, but sometimes can have a more insidious or subacute presentation, which can make the diagnosis more puzzling. Despite relatively low incidence rates, almost a third of affected patients are left with severely disabling symptoms. Prompt recognition of the underlying etiology is essential so that a specific targeted therapy can be implemented for optimal outcomes. The authors discuss a systematic approach to immune-mediated myelopathies, with a focus on the unique characteristics of each that may aid in diagnosis.

There are limited data on endovascular treatment (EVT) for anterior cerebral artery (ACA) occlusions. This review focuses on aspects related to ACA EVT: ACA anatomy, clinical and imaging findings, prognosis of ACA stroke, and ACA thrombectomy techniques. The ACA anatomy, and the regions supplied by the ACA, are highly variable; frequent anatomical variants include azygos ACA, triplicated ACA and fenestrations of the anterior communicating artery. ACA occlusions can be classified based on occlusion location, their continuity with other vessel occlusions (isolated ACA occlusion vs ACA occlusion as part of a carotid T occlusion) and etiology (primary—spontaneous ACA occlusion, vs secondary—spontaneous or iatrogenic due to clot fragmentation/migration). Symptoms of ACA stroke differ in severity and nature due to large inter-individual variations in territorial ACA blood supply. Generally, ACA strokes are severely disabling, and the typical clinical hallmark is a motor deficit of the contralateral lower extremity. Advanced imaging (CT perfusion, multiphase CT angiography) increases the likelihood of the correct diagnosis of ACA stroke and should be obtained on routine basis.Available data for ACA EVT suggest its feasibility and safety while clinical outcomes are often unfavorable with conservative management. Therefore, the potential benefit of EVT seems obvious. An optimized endovascular approach for ACA thrombectomy comprises the development and use of smaller and softer devices that can be delivered through small microcatheters with an optimized vector of force. Ultimately, generating high-level evidence for ACA EVT from randomized trials remains warranted.

Purpose of review Neurotoxicity from antineoplastic treatment remains a challenge in oncology. Cancer treatment-induced central nervous system (CNS) injury can be therapy-limiting, severely disabling, and even fatal. While emerging cancer immunotherapies have revolutionized oncology during the past decade, their immunomodulatory properties can cause immune-related adverse effects (IRAE) across organ systems, including the nervous system. Central neurologic IRAEs from chimeric antigen receptor T cells (CAR-T) and immune checkpoint inhibitors (ICPI) are challenging complications of such therapies.We aim to provide clinicians with a comprehensive review of the relevant forms of CAR-T and ICPI-associated CNS toxicity, focusing on clinical features of such complications, diagnostic workup, predictive biomarkers, and management considerations in affected patients. Recent findings Unique forms of CAR-T and ICPI-related CNS toxicity have been characterized in the recent literature. CAR-T-related neurotoxicity is common and clinically well delineated. ICPI-related CNS toxicity is relatively rare but includes a heterogenous spectrum of severe and diagnostically challenging conditions. While putative risk factors, neurotoxicity biomarkers, imaging correlates and treatment strategies have been put forward, development of tailored diagnostic and management consensus guidelines awaits further clinical investigation. Summary As CAR-T and ICPI become more widely adopted, early recognition, documentation, and management of immunotherapy-related CNS toxicity are of paramount importance in the clinical setting.

Oromandibular dystonia (OMD) is a severely disabling disorder with limited available therapies. Current oral medications for OMD are ineffective and may pose further risks of aspiration particularly in combination states of jaw and tongue dystonia. We advocate the use of Botulinum neurotoxin (BoNT) injection with proper muscle site selection and dosing as the most effective treatment in OMD clinically. Targeting muscle for injection should involve not only an astute clinical examination and understanding the patient’s history, but perhaps also guided by instrumentation. Based on our previous and present case series, we present specific localization techniques for BoNT in OMD patients subsequent to methodical patient selection, proper BoNT reconstitution and conversion. We believe adequate knowledge and appropriate technique will give our patients greatest benefit and will minimize risk of adverse events following treatment.

Summary:. Rheumatoid lymphedema is a rare but severely disabling condition caused by reduced lymphatic drainage. Most treatment methods are conservative and may lead to the exacerbation of lymphedema. Lymphatic venous anastomosis (LVA) is an effective treatment for lymphedema after surgery involving the lymphatic system, such as lymph node dissection for cancer treatment. LVA has not been used to treat rheumatoid lymphedema. We present a case of rheumatoid lymphedema treated with surgical procedures, including LVA. Following LVA, objective and subjective symptom relief was noted, along with decreased swelling and pain in the affected area. The postoperative course was uneventful. LVA for the treatment of rheumatoid lymphedema may provide definitive clinical improvements.

Parkinson's disease (PD) is an incurable, progressive neurological condition, with symptoms impacting movement, walking, and posture that eventually become severely disabling. Advanced PD (aPD) has a significant impact on quality-of-life (QoL) for patients and their caregivers/families. Levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of advanced levodopa-responsive PD with severe motor fluctuations and hyper-/dyskinesia when available combinations of therapy have not given satisfactory results.To determine the cost-effectiveness of LCIG vs standard of care (SoC) for the treatment of aPD patients.A Markov model was used to evaluate LCIG vs SoC in a hypothetical cohort of 100 aPD patients with severe motor fluctuations from an Irish healthcare perspective. Model health states were defined by HoehnYahr (HY) scale-combined with amount of time in OFF-time-and death. SoC comprised of standard oral therapy ± subcutaneous apomorphine infusion and standard follow-up visits. Clinical efficacy, utilities, and transition probabilities were derived from published studies. Resource use was estimated from individual patient-level data from Adelphi 2012 UK dataset, using Irish costs, where possible. Time horizon was 20 years. Costs and outcomes were discounted at 4%. Both one-way and probabilistic sensitivity analyses were conducted.The incremental cost-effectiveness ratio for LCIG vs SOC was €26,944/quality adjusted life year (QALY) (total costs and QALYs for LCIG vs SoC: €537,687 vs €514,037 and 4.37 vs 3.49, respectively). LCIG is cost-effective at a payer threshold of €45,000. The model was most sensitive to health state costs.LCIG is a cost-effective treatment option compared with SoC in patients with aPD.

Complex regional pain syndrome (CRPS) is a severely disabling condition that typically develops after an inciting traumatic event. Ketamine infusion in subanesthetic dose provides sustained analgesia in selected cases of CRPS. In general, ketamine treatment does not significantly affect electrolyte or water balance. Here, we report a case of a CRPS patient on intrathecal baclofen pump developing syndrome of inappropriate antidiuretic hormone release (SIADH) during ketamine infusion. Prophylactic treatment with intravenous loop diuretics was successful in preventing the development of SIADH during ketamine infusion during subsequent infusions in this case.

Background Migraine is a common and severely disabling neurological disorder affecting millions of patients in Europe. Despite the availability of evidence-based national and international guidelines, the management of migraine patients often remains poor, which is often attributed to a low availability of headache specialists. The aim of this study was to investigate the adherence to national guidelines and to assess the possible potential of optimized therapy regimens in migraine patients. Methods We collected data of migraine patients presenting to our out-patient clinic via standardized questionnaires regarding headache, diagnostics and experience with previous treatments. We also assessed the efficacy of treatment started by our center. Results 1,935 migraine patients were included between 2010 and 2018. In the 12 months before consulting our headache clinic 89.5% of the patients had consulted a general practitioner and 74.9% had consulted a neurologist because of their migraine. Nevertheless, 50% of the patients underwent unnecessary diagnostics and 34.2% had not been treated according to evidence-based treatment guidelines. Out of 1,031 patients who had not been prescribed a preventative treatment 627 (60.8%) had in average 3 or more migraine attacks per month and thus qualified for a preventative treatment. These patients missed in the 3 months prior to consultation on average 5 work or school days. Initiating a preventative treatment was effective in 71.2% of the patients, that provided follow-up data. Conclusions Our data suggest, that many migraine patients to this day do not receive state-of-the-art therapy. Adherence to national and international European guidelines could improve the outcome in migraine patients. Future research should try to answer why guidelines are not followed.

Background: Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling painful disease challenging to treat. This multicenter, randomized, double-blind placebo-controlled trial examined the efficacy of intramuscular (i.m.) neridronate in CRPS-1 patients. Methods: A total of 78 patients diagnosed with CRPS-1 (aged 59.5 ± 10.3, 66.7% female) were randomly assigned to 25 mg (i.m.) neridronate ( N = 41) given once daily for 16 consecutive days or placebo control ( N = 37). Efficacy was assessed after 30 days using a visual analogue scale (VAS) pain score and the number of patients achieving ⩾50% reduction in VAS score. Change in clinical signs and symptoms, quality of life (QoL) using Short Form Health Survey (SF-36) and the McGill Pain Questionnaire were also assessed. Results: After 30 days, VAS score decreased significantly to a greater extent in neridronate-treated patients versus placebo (31.9 ± 23.3 mm versus 52.3 ± 27.8 mm, p = 0.0003). Furthermore, the proportion of patients achieving a VAS reduction of ⩾50% was greater in the neridronate group (65.9% versus 29.7%, p = 0.0017). Clinical signs and symptoms were improved significantly in the neridronate group versus placebo for edema (72.5% versus 79.9%, p = 0.03), pain during motion (70% versus 83.3%, p = 0.0009), allodynia (20% versus 63.3%, p = 0.0004), and hyperalgesia (20% versus 56.7%, p = 0.0023). Whereas no difference was observed for QoL measures using the SF-36 questionnaire, three of the four pain variables using the McGill Pain Questionnaire improved significantly in the neridronate group. No serious drug-related adverse events were reported during the study. Conclusion: In patients with acute CRPS-1, i.m. injections of 25 mg neridronate were associated with clinically relevant benefit compared with placebo controls. Trial registration: EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001156-28

Adequate ligament balancing has a tremendous impact on successful total knee arthroplasty. In case of instability, severely disabling symptoms require revision surgery. Here we present a case of early total knee arthroplasty failure due to secondary valgus laxity, which was successfully treated with medial collateral ligament (MCL) reconstruction. For anatomical MCL reconstruction, a flattened semitendinosus autograft was used to reconstruct the superficial medial collateral and the posterior oblique ligament.

Idiopathic clubfoot has a tremendous worldwide prevalence. If left untreated, the deformity has severely disabling effects on mobility and quality of life. Given its prevalence and significance, numerous studies are published on this condition every year. In this article, we attempt to highlight important themes and findings of studies published on idiopathic clubfoot over the past 3 years.

Purpose To provide a review of the diagnostic criteria, pathophysiology, and potential treatments of the complications of migraine as identified by the International Classification of Headache Disorders 3β, with the exception of status migrainosus. Method Migraine with aura may be associated with the onset of rare, but significantly disabling neurological symptoms. This review provides an overview of the associated complications that may arise from migraine with aura. Conclusion The complications of migraine that arise from migraine aura are infrequently encountered in clinical practice; however, they can be severely disabling for patients. As these conditions are encountered, thorough diagnostic evaluation is necessary. In some cases, it may be difficult to find a consistently reliable therapeutic option for these patients; however, as more cases enter the literature, a greater understanding of these conditions and how to treat them may arise.

Cancers of the head and neck region are a severely disabling group of diseases with no method for early detection. Analysis of exhaled breath volatile organic compounds shows promise as biomarkers for early detection and disease monitoring. This article reviews breath analysis in the setting of head and neck cancer, with a practical focus on breath sampling techniques, detection technologies and valid data analysis methods. Title and abstract keyword searches were conducted on PubMed and Embase databases to identify English language studies without a time-period limitation. The main inclusion criteria were human studies comparing head and neck cancer patients to healthy controls using exhaled breath analysis. Multiple breath collection techniques, three major detection technologies and multiple data analysis methods were identified. However, the variability in techniques and lack of methodological standardization does not allow for adequate study replication or data pooling. Twenty-two volatile organic compounds identified in five studies have been reported to discriminate head and neck cancer patients from healthy controls. Breath analysis for detection of head and neck cancer shows promise as a non-invasive detection tool. However, methodological standardization is paramount for future research study design to provide the potential for translating these techniques into routine clinical use.

Hemarthroses and muscle bleeds are well-known and well-documented complications in pediatric and young adult hemophilia patients. In contrast, deep bleeds in atypical locations can be a diagnostic challenge, since clinicians and radiologists are often unfamiliar with their clinical and radiological features. Some atypical bleeds, however, can be life-threatening or severely disabling, highlighting the need for prompt, accurate diagnosis. Rare bleeds include central nervous system bleeds (including intracranial and spinal hematomas), urogenital bleeds, intra-abdominal bleeds (mesenteric and gastrointestinal wall hematomas) and pseudo tumors in unusual locations like the sinonasal cavities. Because clinical assessment can be difficult, clinicians and radiologists should be aware of the possibility of these rare complications in their hemophilia patients, so that they can avoid unnecessary invasive diagnostic and surgical procedures and institute prompt, appropriate treatment. The purpose of this review is to illustrate the imaging features of bleeds that occur in rare locations in young (i.e., children and young adults) patients with hemophilia to make the reader more familiar with these conditions.

Background Bone Marrow Oedema Syndrome (BMES) is a severely disabling pain syndrome without a definite treatment well established. Objectives The aim of this monocentric prospective trial was to test the efficacy and the safety of the amino-bisphosphonate neridronate in patients with BMES administered in two different schedules. Methods one hundred seventy-three patients with BMES at various joints were consecutively assigned to I.V. infusion of 100 mg neridronate given four times over 10 days (Group A) or alternatively to I.V. infusion of 100 mg every 21 days over 63 days (Group B). At baseline (T0) and after 90 days from the first infusion we performed a MRI (T2). We assessed a 0–100 mm pain VAS in each patient at T0, at the day of the last infusion (T1: day 10 for group A and day 63 for group B) and at T2. Primary outcome was to evaluate the MRI changes, secondary endpoint was the VAS change. Results we observed a significant improvement in MRI with the resolution of bone marrow oedema present at T0 (p 0.1). Conclusions In patients with BMES, the infusions of neridronate 100 mg every 21 days over 3 months or alternately every 3 days over 10 days are associated with clinically relevant and persistent benefits without significant differences between the two treatment-schedules. These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice BMES Disclosure of Interest None declared

Many clinical trials using gene therapy have shown significant therapeutic benefits and exceptional safety records. Increasing evidence is verifying the long sought-after promise that gene therapy will genetically 'cure' some severely disabling diseases. In particular, the first gene therapy bioproduct for RPE65-associated Leber's congenital amaurosis, which was approved by the US Food and Drug Administration in 2017, has provided tremendous encouragement to the field of gene therapy. Recent developments in genome editing technologies have significantly advanced our capability to precisely engineer genomes in eukaryotic cells. Programmable nucleases, particularly the CRISPR/Cas system, have been widely adopted in studies applying genome engineering therapy to ocular diseases with the hope of managing these diseases. In this review article, we summarize the current approaches that have been developed in the area of gene therapy for ocular disease. We also discuss the challenges and opportunities facing gene therapy for ocular diseases, as well as its prospects.

Depression can be a severely disabling condition, which affects a substantial proportion of the population. People with chronic depression now have available to them a therapy that is demonstrating promise as an evidence-based psychological treatment. In this article a description and explanation of cognitive behavioural analysis system of psychotherapy (CBASP) in the treatment of chronic depression will be presented. The aim of this article is to provide information and explanation of CBASP that will equip mental health nurses with sufficient understanding of the treatment and related processes. This overview will equip mental health nurses with the knowledge for them to appreciate when to refer someone for this therapy.

Nonunions of the proximal femur may be severely disabling when they occur in active individuals [1, 2], although elderly people may live reasonably normal lives with nonunions of the upper extremity long bones (e.g., clavicle, humerus, and forearm). Femoral nonunions, however, are more frequently painful and may preclude weightbearing on the affected extremity. If, however, pain is minimal or nonexistent and occurring within a nonambulatory individual, nonoperative management is the treatment of choice.

Acquired brain injury (ABI) is known to be severely disabling. On average, 40% of employees return to work (RTW) within two years after injury. There is, however, limited research on what might contribute to successful RTW.To examine factors that might impact the time-to first RTW for patients with ABI, participating in a RTW-program.The study was designed as a cohort study of patients on sick leave due to mild or moderate ABI (n = 137). The mean age of the patients was 51 years, and 58% were men. The most common diagnoses were stroke (75%) and traumatic brain injury (12%). Data were collected through questionnaires, and combined with register data on sickness absence. Survival analyses were used to analyse the effect of different variables on time to first RTW (full or partial), at one- and two-year follow-up.Generally, women (HR = 0.447; CI: 0.239-0.283) had higher RTW-rates than men, and patients with non-comorbid impairments returned to work earlier than patients with multiple impairments. Although not statistically significant, receiving individual consultations and participating in group-sessions were generally associated with a delayed RTW at both follow-up-times. The only service-related factor significantly associated with delayed RTW was meetings with the social insurance office (HR = 0.522; CI: 0.282-0.965), and only at one-year follow-up.Women and patients with non-comorbid impairments returned to work earlier than men and patients with multiple impairments. There seems to be an association between intense and long-lasting participation in the RTW program and prolonged time-to first-RTW, even after controlling for level of cognitive impairments and comorbidity. Implications for Rehabilitation Acquired brain injury (ABI) is known to be severely disabling, and persons with ABI often experience difficulties in regard to returning to work. This study provides information on prognostic factors that might contribute to return to work (RTW) for patients with acquired brain injury, both at the individual level, but also in regard to service and timing characteristics. Knowledge about such factors provide rehabilitation professionals with information about effective service components that might help patients with ABI to RTW, and thus makes it possible to adapt and adjust the services to the patient's situation. Furthermore, having more knowledge on factors that contribute to RTW gives clinics the opportunity to select patients that might benefit the most from these services, thereby making them more effective.

Pulmonary arterial hypertension (PAH) is a severely disabling disorder characterized by elevated pulmonary artery pressure ultimately leading to right heart failure and death. Treatment options have significantly increased over the past decade. Intravenous prostacyclins remain the treatment of choice for advanced PAH, leading to long-term clinical benefits and improved survival. Their administration requires a high level of nursing competency and presents considerable challenges for patients and caregivers. This article reviews the characteristics of currently available intravenous prostacyclins and provides a practical guide for nurses who may have had limited exposure to intravenous prostacyclins and their unique dosing, side effects, and titration characteristics.

Migraine is a common neurological disorder and can be severely disabling during attacks. The highest prevalence occurs between the ages of 25 and 55 years. Prior studies have found that migraine occurs together with other illnesses at a greater coincidental rate than is seen in the general population. These occurrences are called "comorbidities". To delineate the comorbidities of migraine is important, because it can help improve treatment strategies and the understanding of the possible pathophysiology of migraine.

Gait impairment in Parkinson's Disease (PD) is often severely disabling, yet frequently remains refractory to treatment. The locus coeruleus (LC) has diffuse noradrenergic projections that are thought to play a role in gait function. Enhancement of norepinephrine transmission may improve gait in some PD patients. We hypothesized that the severity of PD pathology, and more specifically, Lewy bodies and neuronal loss in the LC, would correlate with the severity of gait dysfunction in PD.Autopsy data from 51 patients, collected through the Morris K. Udall Parkinson's Disease Research Center, were correlated with clinical gait-related measures, including individual Unified Parkinson's Disease Rating Scale (UPDRS) Part II and III questions, total UPDRS Part III scores, and timed up-and-go speed (TUG).Neither the presence nor degree of Lewy body pathology in the LC on autopsy was associated with a higher UPDRS part III gait score. LC tau deposition and frontal Lewy body deposition were not correlated with any of the assessed gait measures. The degree of Lewy body pathology, independent of Braak stage, was positively associated with the severity of motor symptoms overall (UPDRS Part III total score).Neither the degree of Lewy body nor tau pathology in the LC is associated with severity of gait disorders in PD. This finding may have implications for targeted noradrenergic therapies in patients with refractory gait disorders.

The authors evaluated management of illness, including access to specialist mental health care, among people identified by general practitioners as clinically depressed.Australian primary care practitioners recruited in 2009 completed case reports and collected self-report assessments from five to seven consecutively presenting patients whom they identified as having clinical depression.Among 735 patients with clinical depression, 55% met criteria for major depressive syndrome, 86% reported clinically significant sleep disturbance, and 47% had been depressed for more than 12 months. Most (77%) were prescribed antidepressants, and 30% were prescribed anxiolytics or hypnotics. Patients under shared care with specialist mental health care providers (42%) had more severe, chronic, and recurrent conditions but no demographic advantages.Depressed patients of general practitioners often had chronic, recurrent, and moderately to severely disabling conditions, but fewer than half received specialist care. Access to specialist care, however, appeared to be based on clinical need, with little inequity in sociodemographic characteristics observed.

Headache, particularly migraine, is the commonest neurological problem with which patients present to general practitioners and neurologists. Episodic migraine affects up to 18% of women and 6% of men. Acute migraine attacks can be severely disabling and chronic migraine is even more disabling. Of the mental and neurological disorders, migraine ranks eighth worldwide in terms of disability. Migraine is one of the primary headaches and may occur with or without aura. Differentiation from other severe primary headaches, such as cluster headache, is important for management. The vast majority of patients with migraine can be satisfactorily helped and treated. This involves acute and prophylactic drug therapy and management of triggers. In patients with migraine, medication overuse headache and chronic migraine need to be identified and treated.

We present a case series of 6 patients who developed persistent depersonalization disorder in adolescence after consuming cannabis. In 2 of these cases, the illness course was severely disabling. Within the growing body of literature that investigates the effects of cannabis use on mental health, the association between cannabis and depersonalization disorder is widely neglected. We review the clinical characteristics of this disorder and summarize the neurobiological evidence relating it to cannabis use. This case series extends awareness about the potentially detrimental effect of cannabis use in young individuals beyond its well-documented relationship with psychosis and other psychological sequelae.

Tremor secondary to multiple sclerosis (MS) can be severely disabling but remains understudied. The development of brief, acceptable patient-reported measures of tremor could facilitate further study. We aimed to assess the criterion and construct validity of the Tremor and Coordination Scale (TACS) used by the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. Forty-four patients with MS completed the TACS and Performance Scales and underwent a neurologic examination (Expanded Disability Status Scale; EDSS) and evaluation with the Multiple Sclerosis Functional Composite (MSFC). We assessed criterion and construct validity with Spearman rank correlations between the TACS and the following measures: EDSS, Nine-Hole Peg Test (NHPT) of the MSFC, age, body-mass index (BMI), the hand function and mobility domains of the Performance Scales, and the Physical and Mental Composite Scores of the 36-item Short Form Health Status Survey (SF-36). The median (interquartile range; IQR) score on the TACS was 1 (0.5–2.0). The TACS correlated moderately with the cerebellar Functional System Score (FSS) (r = 0.51; 95% confidence interval [CI], 0.24–0.70) and with the NHPT (r = −0.51; 95% CI, −0.70 to −0.29). The TACS correlated with the hand (r = 0.60; 95% CI, 0.36–0.76) and mobility (r = 0.56; 95% CI, 0.31–0.73) domains of the Performance Scales. The TACS did not correlate significantly with age (r = −0.11; 95% CI, −0.40 to 0.19) or BMI (r = 0.15; 95% CI, −0.15 to 0.43). These findings support the criterion and construct validity of the TACS. Further evaluation is needed to establish the test-retest reliability of the scale and its responsiveness to change.

Nephrogenic systemic fibrosis (NSF), originally described as “scleromyxedema-like cutaneous disease,” is an entity that has emerged recently in patients with renal dysfunction.1 NSF is a rare but severely disabling disease that manifests as fibrosis of skin and viscera. Numerous reports have highlighted an association between NSF and gadolinium (Gd)-based contrast agents (GBCAs) used for magnetic resonance imaging. The exact mechanisms underlying this association are still under investigation.2,3 There were apparently no reports of NSF prior to 1997, when the first cases were described.1 Clinical Pharmacology & Therapeutics (2011) 89 6, 920–923. doi:10.1038/clpt.2010.346

Primary generalized dystonia presents mainly at a young age and commonly is severely disabling. The authors report the long-term follow-up (mean, 73 months; range, 50-101 months) of 5 pediatric patients (mean age at surgery 13 years; range, 8-16 years) undergoing globus pallidus internus deep brain stimulation. Mean improvement in the Burke-Fahn-Marsden movement score was 67.4% (range, 47.0%-87.5%), 75.4% (range, 61.5%-91.7%), and 83.5% (range, 72.0%-93.3%) at 3 months, 12 months, and long-term follow-up (>36 months), respectively. Hardware problems (electrode dislocation/breakage of extension cable, and imminent perforation of extension cable) were observed in 2 patients (operative revision without sequelae). Except for mild dysarthria in 2 patients, no other therapy-related morbidity was observed. The authors found globus pallidus internus stimulation to offer a very effective and safe therapy in pediatric patients with primary dystonia. Early neurosurgical intervention seems to be crucial to prevent irreversible impairment of motor function.

Macrophagic myofasciitis and chronic fatigue syndrome are severely disabling conditions which may be caused by adverse reactions to aluminium-containing adjuvants in vaccines. While a little is known of disease aetiology both conditions are characterised by an aberrant immune response, have a number of prominent symptoms in common and are coincident in many individuals. Herein, we have described a case of vaccine-associated chronic fatigue syndrome and macrophagic myofasciitis in an individual demonstrating aluminium overload. This is the first report linking the latter with either of these two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in this individual. This case has highlighted potential dangers associated with aluminium-containing adjuvants and we have elucidated a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events which are associated with autoimmune conditions including chronic fatigue syndrome and macrophagic myofasciitis.

Rheumatoid arthritis is prevalent in the UK and can be severely disabling. Gail Burbage explores its diagnosis and management and the practice nurse's role in patient care

Human onchocerciasis is a severely disabling filarial disease that is endemic in 28 African countries, six Latin American countries and Yemen. The disease causes a high burden of blindness and visual loss, along with itching and other severe dermal manifestations. It constitutes a significant obstacle to socio-economic development in highly endemic riverine areas, where the Simulium blackflies that act as vectors breed. Onchocerciasis has been subject to control efforts for more than 50 years, initially mainly through vector control but since 1988, with free access to ivermectin (Mectizan), also through large-scale chemotherapy. The Onchocerciasis Control Programme in West Africa operated successfully from 1974 to 2002 in 11 countries, covering the worst savannah foci of the disease through vector control and, in its later stages, also through ivermectin distribution. The African Programme for Onchocerciasis Control was established in 1995, to cover the remaining endemic areas in Africa, with the sustainable annual distribution of ivermectin by 2010 its main goal. Meanwhile, the Onchocerciasis Elimination Program for the Americas is making rapid progress in the virtual regional elimination of the disease through ivermectin distribution, which is achievable primarily because the vectors in the western hemisphere are less efficient than those elsewhere. The global elimination of onchocerciasis as a public-health problem is now within reach but this will require long-term strategies to secure the great gains made so far, through ivermectin treatment and local vector control. Research is needed to define the optimal approaches with the existing tools and to intensify the development of alternative strategies, such as macrofilaricidal drugs for wide-scale use.

The use of stimulation electrodes implanted in the brain to control severely disabling neurological and psychiatric conditions is an exciting and fast emerging area of neuroscience. An excellent example is Parkinson's disease (PD), in which tens of thousands of patients have now been implanted with stimulation electrodes. Patients with PD underwent deep brain stimulation (DBS) at the level of the thalamus, globus pallidus internus, subthalamic nucleus, pedunculopontine nucleus and prelemniscal radiation. The results of these interventions revealed that each target has its own specific stimulation-related positive and negative effects. Clinicians can choose their DBS target based on the situation of their individual PD patients. In the authors' opinion, patient-specific targeting should be preferred over disease-specific targeting. In this review, the authors give an overview of the targets that have been used for DBS in PD and discuss patient-specific targeting.

The International Fibrodysplasia Ossificans Progressiva (FOP) Association was, founded by patient Jeannie Peeper in June of 1988 to educate patients, doctors, and the public about FOP: to raise funds and provide a patient base to support medical research into FOP: and to support patients with FOP and their families by providing a network of communication to help end the isolation that accompanies this rare and severely disabling condition.

Although palmoplantar psoriasis can be severely disabling, there are very few large clinico-epidemiological studies on this condition. Our purpose was to study the morphology and pattern of lesions in Indian patients with palmoplantar psoriasis and to elucidate the role of occupation in the incidence/localization of these lesions. All patients attending our Psoriasis Clinic from 1993 to 2000 were screened for palmoplantar lesions and their demographic characteristics, occupation and the exact localization of the lesions were noted. Out of 3,065 patients screened, 532 had palm and/or sole involvement. Plantar lesions were seen in 91.9% and palmar lesions in 55.6% of these patients. Four distinct patterns of lesion localization were noted on the palms and 5 patterns on the soles. Almost half of the men involved in regular manual labor had palmar lesions restricted to areas exposed to pressure, whereas only a quarter of other men had this type of lesion pattern. All patients with unilateral palmar lesions had them on their dominant hand and these patients were involved in regular manual labor. In our patients, the prevalence of plantar lesions was much higher than that of palmar lesions. The possible role of occupational trauma in lesion localization in Indian patients with palmoplantar psoriasis is discussed.

Achondroplasia, Duchenne muscular dystrophy, and osteogenesis imperfecta are among the most frequent rare genetic disorders affecting the musculoskeletal system in children. Rare genetic disorders are severely disabling and can have substantial impacts on families, children, and on healthcare systems. This literature review aims to classify, summarize and compare these non-medical impacts of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

The aim of this study is to describe the clinical features of powered wheelchair users with severely disabling multiple sclerosis (MS) and explore the problematic clinical features influencing prescription.Retrospective review of electronic and case note records of recipients of electric-powered indoor/outdoor powered wheelchairs (EPIOCs) attending a specialist wheelchair service between June 2007 and September 2008. Records were reviewed by a consultant in rehabilitation medicine, data systematically extracted and entered into a computer database. Further data were entered from clinical records. Data were extracted under three themes; demographic, diagnostic, clinical and wheelchair factors.Records of 28 men mean age 57 (range 37-78, SD 12) years and 63 women mean age 57 (range 35-81, SD 11) years with MS were reviewed a mean of 64 (range 0-131) months after receiving their wheelchair. Twenty two comorbidities, 11 features of MS and 8 features of disability were thought to influence wheelchair prescription. Fifteen users were provided with specialised seating and 46 with tilt-in-space seats.Our findings suggest that people with severe MS requiring an EPIOC benefit from a holistic assessment to identify problematic clinical features that influence the prescription of the EPIOC and further medical and therapeutic interventions.People with multiple sclerosis (MS), referred for an EPIOC, require a full clinical assessment to identify problematic clinical features that are potentially treatable and/or can be accommodated through specialised seating and tilt. The beneficial effects of TIS should be considered for all EPIOC users with MS and particularly for those with comorbidity Poorly controlled spasticity, when identified in people with MS, should be managed through positioning in the chair, pressure-relieving cushion and referral for medical management.

Health-related quality of life (HRQoL) assessments are increasingly used to evaluate treatment effects and to shape the delivery of value based care. Valid generic and disease specific tools are available for quantifying HRQoL in patients with non-toxic goitre. However, few studies have applied these validated instruments to assess HRQoL in patients with benign non-toxic goitre. Limited evidence suggests that patients with non-toxic goitre have HRQoL impairments in multiple HRQoL domains. While the HRQoL-impact of non-toxic goitre may be small relative to other severely disabling medical conditions, treatment is almost exclusively elected for HRQoL indications. Thus better quantification of HRQoL, particularly at better (or more favorable) levels where many patients score, is essential. Web and mobile technologies have eased the ability to deliver surveys to patients. Routine consideration of HRQoL provides the opportunity to monitor the impact of treatment on the outcomes most meaningful for patients and the opportunity to help shape the delivery of value based health care.

Valproate is an important but uncommon cause of drug induced parkinsonism in the elderly. The development of symptoms after valproate onset is unpredictable, and severity of symptoms is unrelated to plasma levels. However, though the majority of cases improve after drug cessation, parkinsonian symptoms can persist and should prompt investigation into underlying degenerative parkinsonism, as valproate can unmask idiopathic Parkinson’s disease in susceptible individuals. This case describes a patient on chronic valproate therapy developing a severely disabling akinetic-rigid syndrome, only partially reversed on stopping valproate. We hypothesise that an increase in valproate dosage unmasked clinically silent Parkinson’s disease. The patient made an excellent recovery following cessation of valproate and commencement of dopaminergic therapy.

International audience; Predominantly occurring in developing parts of the world, Buruli ulcer is a severely disabling mycobacterium infection which often leads to extensive necrosis of the skin. While the exact route of transmission remains uncertain, like many tropical diseases, associations with climate have been previously observed and could help identify the causative agent's ecological niche. In this paper, links between changes in rainfall and outbreaks of Buruli ulcer in French Guiana, an ultraperipheral European territory in the northeast of South America, were identified using a combination of statistical tests based on singular spectrum analysis, empirical mode decomposition and cross-wavelet coherence analysis. From this, it was possible to postulate for the first time that outbreaks of Buruli ulcer can be triggered by combinations of rainfall patterns occurring on a long (i.e., several years) and short (i.e., seasonal) temporal scale, in addition to stochastic events driven by the El Niño-Southern Oscillation that may disrupt or interact with these patterns. Long-term forecasting of rainfall trends further suggests the possibility of an upcoming outbreak of Buruli ulcer in French Guiana.

Introduction: Paraneoplastic neurological syndromes (PNSs) are severely disabling conditions that are associated with cancer. Well-characterized onconeural antibodies (Abs) are, by definition, virtually exclusively present in patients with cancer and include anti-Hu, Yo, CV2, Ri, Ma2, amphiphysin and antidelta/notchlike epidermal growth factor-related receptor (DNER; Tr). More recently, a second group of antineuronal Abs has been described that are found in both patients with and without cancer. Areas covered: This review is focused on putative Tcellmediated immunopathogenetic mechanisms and treatment of PNS associated with well-characterized onconeural Abs. As of December 2013, only uncontrolled open-label clinical trials, retrospective case series and case reports were detected in the literature. Six clinical studies in HuPNS reported the effect of immunotherapy on functional outcome. Expert opinion: When taken together, these six studies showed an improvement of one point or more on the modified Rankin scale (mRS) in 11% (7/61) of patients. In Yo-PNS, 8% (2/26) of patients improved on the mRS. PNS with other well-characterized onconeural Abs also responded poorly to immunotherapies. Potential new immunotherapies include natalizumab, fingolimod, alemtuzumab and a combination of rituximab with cyclophosphamide.