A rare partnership: patient community and industry collaboration to shape the impact of real-world evidence on the rare disease ecosystem.

People with rare lysosomal storage diseases face challenges in their care that arise from disease complexity and heterogeneity, compounded by many healthcare professionals being unfamiliar with these diseases. These challenges can result in long diagnostic journeys and inadequate care. Over 30 years ago, the Rare Disease Registries for Gaucher, Fabry, Mucopolysaccharidosis type I and Pompe diseases were established to address knowledge gaps in disease natural history, clinical manifestations of disease and treatment outcomes. Evidence generated from the real-world data collected in these registries supports multiple stakeholders, including patients, healthcare providers, drug developers, researchers and regulators. To maximise the impact of real-world evidence from these registries, engagement and collaboration with the patient communities is essential. To this end, the Rare Disease Registries Patient Council was established in 2019 as a partnership between the Rare Disease Registries and global and local patient advocacy groups to share perspectives on how registry data are used and disseminated. The Patient Council has resulted in a number of patient initiatives including patient representation at Rare Disease Registries advisory boards; development of plain language summaries of registry publications to increase availability of real-world evidence to patient communities; and implementation of digital innovations such as electronic patient-reported outcomes, and patient-facing registry reports and electronic consent (in development), all to enhance patient engagement. The Patient Council is building on the foundations of industry-patient advocacy group collaboration to fully integrate patient communities in decision-making and co-create solutions for the rare disease community.

Olfactory dysfunction is common in classical infratentorial superficial siderosis of the central nervous system.

BACKGROUND: Established features of classical infratentorial superficial siderosis (iSS) include hearing loss, impaired balance, myelopathy and, less commonly, cognitive compromise. Olfactory function may be affected but dedicated studies are lacking. This study aimed to assess the prevalence of olfactory dysfunction in iSS and correlate it with auditory and cognitive functions. METHODS: Ten participants with iSS completed the University of Pennsylvania Smell Identification Test (UPSIT). The scores were compared with population norms; regression analysis was performed to evaluate associations between the scores and hearing thresholds (3-frequency average, 3FA) or the number of cognitive domains impaired. Imaging was reviewed for haemosiderin distribution and to exclude other causes of olfactory and hearing dysfunction. RESULTS: Eight of ten participants were male; the mean (standard deviation, SD) age was 52.5 (14.5) years. Olfactory hypofunction was identified in all participants and in six (60%) was moderate or completely absent. The mean UPSIT score of 25.5 (7.8) was significantly worse than population norms (difference in means - 10.0; 95% CI - 15.6 to - 4.4). Linear regression identified an association between UPSIT and hearing thresholds (R = 0.75; p = 0.013). The score decreases by 0.157 units (95% CI - 0.31 to - 0.002; p = 0.048) per unit increase in 3FA, after adjusting for hearing loss risk factors. There was no statistically significant association between UPSIT and cognitive function (R = 0.383; p = 0.397). CONCLUSION: We report a high prevalence of olfactory dysfunction in iSS, the severity of which correlated with hearing loss. Olfaction appears to be a core feature of the iSS clinical syndrome that should be assessed routinely.

Vestibular rehabilitation in multiple sclerosis: study protocol for a randomised controlled trial and cost-effectiveness analysis comparing customised with booklet based vestibular rehabilitation for vestibulopathy and a 12 month observational cohort study of the symptom reduction and recurrence rate following treatment for benign paroxysmal positional vertigo.

BACKGROUND: Symptoms arising from vestibular system dysfunction are observed in 49-59% of people with Multiple Sclerosis (MS). Symptoms may include vertigo, dizziness and/or imbalance. These impact on functional ability, contribute to falls and significant health and social care costs. In people with MS, vestibular dysfunction can be due to peripheral pathology that may include Benign Paroxysmal Positional Vertigo (BPPV), as well as central or combined pathology. Vestibular symptoms may be treated with vestibular rehabilitation (VR), and with repositioning manoeuvres in the case of BPPV. However, there is a paucity of evidence about the rate and degree of symptom recovery with VR for people with MS and vestibulopathy. In addition, given the multiplicity of symptoms and underpinning vestibular pathologies often seen in people with MS, a customised VR approach may be more clinically appropriate and cost effective than generic booklet-based approaches. Likewise, BPPV should be identified and treated appropriately. METHODS/ DESIGN: People with MS and symptoms of vertigo, dizziness and/or imbalance will be screened for central and/or peripheral vestibulopathy and/or BPPV. Following consent, people with BPPV will be treated with re-positioning manoeuvres over 1-3 sessions and followed up at 6 and 12 months to assess for any re-occurrence of BPPV. People with central and/or peripheral vestibulopathy will be entered into a randomised controlled trial (RCT). Trial participants will be randomly allocated (1:1) to either a 12-week generic booklet-based home programme with telephone support or a 12-week VR programme consisting of customised treatment including 12 face-to-face sessions and a home exercise programme. Customised or booklet-based interventions will start 2 weeks after randomisation and all trial participants will be followed up 14 and 26 weeks from randomisation. The primary clinical outcome is the Dizziness Handicap Inventory at 26 weeks and the primary economic endpoint is quality-adjusted life-years. A range of secondary outcomes associated with vestibular function will be used. DISCUSSION: If customised VR is demonstrated to be clinically and cost-effective compared to generic booklet-based VR this will inform practice guidelines and the development of training packages for therapists in the diagnosis and treatment of vestibulopathy in people with MS. TRIAL REGISTRATION: ISRCTN Number: 27374299 Date of Registration 24/09/2018 Protocol Version 15 25/09/2019.

Osteomimetic matrix components alter cell migration and drug response in a 3D tumour-engineered osteosarcoma model.

Osteosarcoma management continues to lack the appropriate prognostic tools to assign personalised treatment. This leaves non-responders to standard care vulnerable to recurring disease and pulmonary metastases. Developing 3D in vitro disease models to serve as a test bed for personalised treatment is a promising approach to address this issue. This study describes the generation of 3D osteosarcoma models termed "tumouroids", which are geometrically compartmentalised to reproduce the bone cancer mass and its surrounding. Although the tumour microenvironment impacts osteosarcoma in many ways, this model focussed on interrogating the influence of a biomimetic matrix on tumour cell behaviour. The 3D matrix was supplemented with the bone-marrow proteins laminin, fibronectin and NuOss® bone granules. This led to increased invasion of osteosarcoma cell aggregates from within the bone-like matrix into the surrounding acellular bone marrow-like ECM. The presence of bone granules also yielded an atypical molecular profile of osteosarcoma cells, suggesting malignant metabolic reprogramming. Changes include decreased MMP-9 (p < 0.05) and increased PTEN (p < 0.05), MCP-1 (p < 0.01) and MCT-4 (p < 0.05) gene expression. This complex 3D biomimetic composition also changed cellular responses to doxorubicin, a common chemotherapeutic agent used to treat osteosarcoma, and reproduced key issues of in vivo treatment like drug penetrance and doxorubicin-induced bone toxicity. This work highlights the importance of a biomimetic matrix in 3D osteosarcoma models for both basic and translational research. STATEMENT OF SIGNIFICANCE: This study describes the generation of 3D osteosarcoma models termed "tumouroids", which are geometrically compartmentalised to reproduce the bone cancer mass and its environment. Utilising this novel model, specific parameters of osteosarcoma growth and invasion were investigated. Osteosarcoma cell lines proliferate at a slower rate, exhibit malignant metabolic reprogramming, and respond to drug intervention at lower concentrations of doxorubicin hydrochloride in matrix-complex compared to basic tumouroids. As such, this study provides evidence that the tumour microenvironment impacts osteosarcoma in many ways. The osteosarcoma tumouroid described herein may form the basis of a personalised-medicine strategy, which will allow the testing of drug effectiveness similar to that used for antibiotic selection for pathogenic bacteria.

Clinical features, microbiology and surgical outcomes of infective endocarditis: a 13-year study from a UK tertiary cardiothoracic referral centre.

BACKGROUND: Infective endocarditis (IE) causes substantial morbidity and mortality. Patient and pathogen profiles, as well as microbiological and operative strategies, continue to evolve. The impact of these changes requires evaluation to inform optimum management and identify individuals at high risk of early mortality. AIM: Identification of clinical and microbiological features, and surgical outcomes, among patients presenting to a UK tertiary cardiothoracic centre for surgical management of IE between 1998 and 2010. DESIGN: Retrospective observational cohort study. METHODS: Clinical, biochemical, microbiological and echocardiographic data were identified from clinical records. Principal outcomes were all-cause 28-day mortality and duration of post-operative admission. RESULTS: Patients (n = 336) were predominantly male (75.0%); median age 52 years (IQR = 41-67). Most cases involved the aortic (56.0%) or mitral (53.9%) valves. Microbiological diagnoses, obtained in 288 (85.7%) patients, included streptococci (45.2%); staphylococci (34.5%); Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella (HACEK) organisms (3.0%); and fungi (1.8%); 11.3% had polymicrobial infection. Valve replacement in 308 (91.7%) patients included mechanical prostheses (69.8%), xenografts (24.0%) and homografts (6.2%). Early mortality was 12.2%, but fell progressively during the study (P = 0.02), as did median duration of post-operative admission (33.5 to 10.5 days; P = 0.0003). Multivariable analysis showed previous cardiothoracic surgery (OR = 3.85, P = 0.03), neutrophil count (OR = 2.27, P = 0.05), albumin (OR = 0.94, P = 0.04) and urea (OR = 2.63, P < 0.001) predicted early mortality. CONCLUSIONS: This study demonstrates reduced post-operative early mortality and duration of hospital admission for IE patients over the past 13 years. Biomarkers (previous cardiothoracic surgery, neutrophil count, albumin and urea), predictive of early post-operative mortality, require prospective evaluation to refine algorithms, further improve outcomes and reduce healthcare costs associated with IE.

TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation.

In the adult mammalian brain, neural stem cells in the subventricular zone continuously generate new neurons for the olfactory bulb. Cell fate commitment in these adult neural stem cells is regulated by cell fate-determining proteins. Here, we show that the cell fate-determinant TRIM32 is upregulated during differentiation of adult neural stem cells into olfactory bulb neurons. We further demonstrate that TRIM32 is necessary for the correct induction of neuronal differentiation in these cells. In the absence of TRIM32, neuroblasts differentiate slower and show gene expression profiles that are characteristic of immature cells. Interestingly, TRIM32 deficiency induces more neural progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated olfactory bulb neurons of TRIM32 knockout mice. These results highlight the function of the cell fate-determinant TRIM32 for a balanced activity of the adult neurogenesis process.

The effect of virtual reality on visual vertigo symptoms in patients with peripheral vestibular dysfunction: a pilot study.

UNLABELLED: Individuals with vestibular dysfunction may experience visual vertigo (VV), in which symptoms are provoked or exacerbated by excessive or disorientating visual stimuli (e.g. supermarkets). VV can significantly improve when customized vestibular rehabilitation exercises are combined with exposure to optokinetic stimuli. Virtual reality (VR), which immerses patients in realistic, visually challenging environments, has also been suggested as an adjunct to VR to improve VV symptoms. This pilot study compared the responses of sixteen patients with unilateral peripheral vestibular disorder randomly allocated to a VR regime incorporating exposure to a static (Group S) or dynamic (Group D) VR environment. Participants practiced vestibular exercises, twice weekly for four weeks, inside a static (Group S) or dynamic (Group D) virtual crowded square environment, presented in an immersive projection theatre (IPT), and received a vestibular exercise program to practice on days not attending clinic. A third Group D1 completed both the static and dynamic VR training. Treatment response was assessed with the Dynamic Gait Index and questionnaires concerning symptom triggers and psychological state. At final assessment, significant between-group differences were noted between Groups D (p=0.001) and D1 (p=0.03) compared to Group S for VV symptoms with the former two showing a significant 59.2% and 25.8% improvement respectively compared to 1.6% for the latter. Depression scores improved only for Group S (p=0.01) while a trend towards significance was noted for Group D regarding anxiety scores (p=0.07). CONCLUSION: Exposure to dynamic VR environments should be considered as a useful adjunct to vestibular rehabilitation programs for patients with peripheral vestibular disorders and VV symptoms.

Survival of HIV-infected patients admitted to the intensive care unit in the era of highly active antiretroviral therapy.

We retrospectively studied outcomes for HIV-infected patients admitted to the intensive care unit (ICU) between January 1999 and June 2009. Patient demographics, receipt of highly active antiretroviral therapy (HAART), reason for ICU admission and survival to ICU and hospital discharge were recorded. Comparison was made against outcomes for general medical patients contemporaneously admitted to the same ICU. One hundred and ninety-two HIV-infected patients had 222 ICU admissions; 116 patients required mechanical ventilation (MV) and 43 required renal replacement therapy. ICU admission was due to an HIV-associated diagnosis in 113 patients; 37 had Pneumocystis pneumonia. Survival to ICU discharge and hospital discharge for HIV-infected patients was 78% and 70%, respectively, and was 75% and 68% among 2065 general medical patients with 2274 ICU admissions; P = 0.452 and P = 0.458, respectively. HIV infection was newly diagnosed in 42 patients; their ICU and hospital survival was 69% and 57%, respectively. From multivariable analysis, factors associated with ICU survival were patient's age (odds ratio [OR] = 0.74 [95% confidence interval (CI) = 0.53-1.02] per 10-year increase), albumin (OR = 1.05 [1.00-1.09] per 1 g/dL increase), Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR = 0.55 [0.35-0.87] per 10 unit increase), receipt of HAART (OR = 2.44 [1.01-4.94]) and need for MV (OR = 0.14 [0.06-0.36]). In the era of HAART, HIV-infected patients should be offered ICU admission if it is likely to be of benefit.

Skewed X-chromosome inactivation in Greek women with idiopathic recurrent miscarriage.

OBJECTIVES: To investigate if skewed X-chromosome inactivation (XCI) is associated with unexplained recurrent miscarriage (RM) in Greek women. METHODS: This was a prospective case-control study. A methylation-sensitive assay was used to investigate the X-inactivation pattern of women with unexplained RM and controls. RESULTS: Fifty-six of the 74 patients (75.7%) and 55 of 80 controls (68.8%) were informative. Among the informative cases, 6/56 (10.7%) women showed extreme XCI (>90%) and among the informative controls, 2/55 (3.6%) showed extreme XCI. CONCLUSIONS: In the present study, women with unexplained RM showed a statistically nonsignificant increase in skewed XCI prevalence (10.7%) compared with control women (3.6%; p = 0.271).

The impact of childhood chronic neurological diseases on Greek families.

BACKGROUND: Although the impact of childhood chronic neurological diseases (CND) on patients' psychological well-being has been increasingly addressed, little attention has been given to the influence of these conditions on family members and family functioning. The purpose of the present study was to investigate the family characteristics of Greek children suffering from CND. METHODS: A total of 52 parents of children with CND were studied by using the Family Environmental Scale (FES), the Family Burden Scale, the General Health Questionnaire (GHQ-28) and a questionnaire on the knowledge of their children's illness, their coping strategies and their satisfaction with our services. During the same period, 30 parents of hospitalized children for common paediatric illnesses completed the FES. In both groups social and demographic features were registered. Appropriate statistical processes were applied to compare the above-mentioned family groups and to study the differences between the families of children with epilepsy (n=37) and the families of children with other CND (n=15). RESULTS: Parents of children with CND discuss their problems less freely, talk less openly around home, score highly on FES subscale of Conflict and, pay more attention to ethical and religious issues and values. Furthermore, the families of children with other CND were more burdened regarding the financial state and the health status of other family members in comparison with families of children with epilepsy. In addition, families of children with epilepsy were more involved in social and recreational activities, appeared to be more knowledgeable on the availability of help in critical conditions and were more satisfied with rendered medical services, in comparison with families of children with other CND. CONCLUSION: These preliminary findings provide important information concerning the special characteristics of Greek families of children suffering from CND, which may prove especially helpful in organizing specific support services.

High intensity focused ultrasound ablation of kidney guided by MRI.

The effectiveness of magnetic resonance imaging (MRI) to monitor therapeutic protocols of high-intensity focused ultrasound (HIFU), in freshly excised pig kidney cortex is investigated. For high quality imaging, the pulse sequence fast spin echo (FSE) T1- and T2-weighted, and proton density were evaluated. For fast imaging, the pulse sequence T1-weighted fast spoiled gradient (FSPGR) was used. The main goal was to evaluate the MRI detection of large lesions (bigger than 1 cm x 1 cm x 1 cm) that is achieved by moving the transducer in a predetermined pattern. The contrast between lesion and kidney tissue is excellent with either T1-weighted or T2-weighted FSE. With T1-weighted FSE, the best contrast is observed for recovery time (TR) between 200 ms and 400 ms. With T2-weighted FSE best contrast can be achieved for echo time (TE) between 16 and 32 ms. T2-weighted FSE was proven as the best pulse sequence to detect cavitational activity. This advantage is attributed to the significant difference in signal intensity between air spaces and necrotic tissue. Air spaces appear brighter than thermal lesions. Therefore, for therapeutic protocols created using cavitational mode, T2-weighted FSE may be the optimum pulse sequence to use. The proton density pulse sequence does not provide any advantage over the T1- and T2-weighted pulse sequences. Using T1-weighted FSPGR, acquisition time as low as 5 s could be achieved. Good contrast and signal-to-noise ratio (SNR) are achieved with TR = 100 ms and flip angle between 75 to 90 degrees. The above techniques were very successful in detecting large lesion volumes.

Congenital mesoblastic nephroma associated with polyhydramnios and hypercalcemia.

Congenital mesoblastic nephroma (CMN) can present with atypical clinical and imaging findings. A premature male neonate was born to an 18-year-old woman after 33 weeks' gestation, which was complicated by polyhydramnios and placenta abruptio. A right abdominal mass was diagnosed antenatally. From the 1st day of life, the newborn had hypercalcemia with initially normal parathormone levels and polyuria for the first hours of life and normal urine output afterwards. Ultrasonographic study and magnetic resonance imaging of the abdomen showed at the upper pole of the right kidney a heterogeneous, solid, poorly defined mass, partially surrounded by a subcapsular fluid collection mimicking malignant rhabdoid tumor of the kidney. Surgical resection revealed a CMN of mixed, classic, and in areas, cellular type. One year after the resection, the patient is asymptomatic and normocalcemic. In conclusion, CMN may present with atypical clinical and imaging findings, necessitating an extensive work-up in order to exclude highly malignant renal tumors of the neonatal period.

A study of the growth-promoting and metabolic effects of growth hormone (GH) in a patient with the "growth without GH" syndrome.

The paradox of normal or even excessive growth despite a proven lack of GH is a well-known but still unexplained phenomenon that has been described in some patients following resection of a craniopharyngioma or other suprasellar tumours. However, the consequences of GH deficiency on other metabolic aspects of GH action in this syndrome have not been adequately investigated. The aim of this study was to examine whether a dissociation might exist between the growth-promoting and metabolic effects of GH. We studied a 7.1 year old boy who, after removal of a suprasellar craniopharyngioma, developed panhypopituitarism with mild hyperprolactinaemia. Despite the presence of severe GH deficiency associated with persistently low IGF-I and IGFBP-3 levels, the patient grew spontaneously at an accelerated rate for a prepubertal boy, achieving a height velocity of 9.0 cm during the first and 8.5 cm during the second post-operative year. However, other metabolic parameters of GH activity were adversely affected by the lack of GH. The maximum tubular reabsorption rate for phosphate over glomerular filtration rate ratio (2.8) was persistently low and normalized during a 4 day course of hGH administration (4.2) together with the normalization of IGF-I (from 34 microg/l to 294 microg/l), suggesting that GH-dependent renal phosphate handling is impaired in this syndrome. In addition, bone age was delayed by 1.7 years consistently with delayed skeletal maturation, whereas skinfold thickness and the waist to hip ratio were increased in comparison with normative data, suggesting increased adipose tissue mass with central fat distribution, a phenotype characteristic of GH deficiency. In conclusion, our case study suggests that, in the "growth without GH" syndrome, the excessive growth is independent of GH and dissociated from other GH-dependent metabolic effects, which are decreased.

Physical and psychosocial functioning in multiple sclerosis: descriptions, correlations, and a tentative typology.

Multiple sclerosis (MS) is a disease of great variety and ambiguity. It outcome is both multidimensional and uncertain. As part of an ongoing effort to describe and differentiate the various courses that MS can follow, 81 out-patients diagnosed with MS completed the California Psychological Inventory (CPI) and the Sickness Impact Profile (SIP) administered as a structured interview. Descriptive statistics for the SIP and the CPI are provided and examined as a function of age and sex. Correlations between health status and personality scales are reported. Increasing physical dysfunction is associated with lowered performance on a broad array of psychosocial dimensions but only among women. A cluster analysis of CPI factor scores is described and a very tentative typology of persons with MS is offered for further investigation.

Physical disability, life stress, and psychosocial adjustment in multiple sclerosis.

Eighty-one outpatients with diagnosed multiple sclerosis were studied in an effort to examine the relative contributions of physical health status, life stress, duration of illness, age, sex, marital status, and social class on various aspects of personal and interpersonal functioning. Stepwise multiple regression analyses were performed to identify the most significant discriminators of the seven psychosocial measures. Physical health status exerted the broadest influence, affecting personal efficiency and well-being, capacity for independent thought and action, self-confidence, self-reliance, and number of meaningful social contacts. Life stress was associated with lowered personal efficiency and sense of well-being. Duration of illness and the demographic variables had few or no effects on psychosocial adjustment. Discussion contrasts the present findings with others in the rehabilitation literature and specifies certain limitations of the study's design.

Stress and personal attitudes in chronic illness.

The possible relation of two stressor types (life events and illness experience) to three sets of attitudes (personal life satisfaction, self-assessed coping, and satisfaction with treatment personnel/facilities) was examined within a sample of 97 outpatients having multiple sclerosis. In addition, potential moderators of hypothesized relationships were examined (trait anxiety, age, social class, and knowledge of the disease). When attitudes were regressed on stressors and moderators, both sets of stressors exerted significant influence, though their impacts were mitigated by the moderators. This study's findings support the position that the association of attitudes with stressor exposure in chronic disease populations is contingent on demographic and psychological moderating factors.

Development of somatizing responses in multiple sclerosis.

Chronic medical illness may produce emotional stress of a variety which encourages the development of patterns of somatization. Discussed here are patterns of somatization in multiple sclerosis. The long-term uncertainty and changing nature and severity of symptoms raises the likelihood that people will become absorbed in their bodies, will demonstrate heightened responses to minor physical change, and may come to experience psychic conflict through the language of physical symptomatology. Case examples are discussed as well as recommendations for treatment.

Discussion groups for medical patients. A vehicle for improved coping.

Describing 14 professionally run discussion groups for multiple sclerosis patients, this paper delineates appropriate functions and goals of the medical discussion group. Such groups address coping activities related to affiliation with a social reference group, information seeking and, in a more limited way, consolidation of intrapsychic resources. The discussion describes the dynamic issues which arise in the groups and explores ways in which group dynamics interact with the medical format.