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.

Laryngeal Desiccation Challenge and Nebulized Isotonic Saline in Healthy Male Singers and Nonsingers: Effects on Acoustic, Aerodynamic, and Self-Perceived Effort and Dryness Measures.

OBJECTIVES: This study examined the effects of a laryngeal desiccation challenge and nebulized isotonic saline on voice production in young, healthy male singers and nonsingers. STUDY DESIGN: This is a prospective, double-blind, within-subjects experimental design. METHODS: Participants included 10 male university-trained singers and 10 age-matched nonsingers (mean age, 21.8 years; range, 18-26 years) who underwent a 30-minute oral breathing laryngeal desiccation challenge using medical grade dry air (<1% relative humidity) on two occasions in consecutive weeks. After the challenge, participants received either 3 mL or 9 mL of nebulized isotonic saline (0.9% Na+Cl-); order of administration was counterbalanced. Phonation threshold pressure (PTP), the cepstral spectral index of dysphonia (CSID) for sustained vowels and connected speech, and self-perceived vocal effort, mouth dryness, and throat dryness were measured at each recording (baseline, after challenge, and at 5, 35, and 65 minutes after treatment). RESULTS: Self-perceived effort and dryness measures increased (worsened) after desiccation challenge and decreased (improved) after nebulized treatment (P < 0.05). No consistent changes were observed for PTP or CSID over time. Overall, singers demonstrated significantly lower vocal effort and CSID as compared with nonsingers. CONCLUSIONS: Young, vocally healthy men may not experience physiologic changes in voice production associated with laryngeal desiccation and nebulized saline treatments; however, self-reported increases in vocal effort which are associated with dryness symptoms might improve with nebulized treatments. Future hydration research should consider age and sex variables.

The effects of emotional expression on vibrato.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the effect of emotional expression on several acoustic measures of vibrato, including its rate, extent, and steadiness. We hypothesized that singing a passage with emotional content would influence these variables. STUDY DESIGN: This study used a within-subjects, repeated-measures design. Singer performance under different conditions was analyzed. METHODS: Ten graduate student singers (eight women, two men) completed a series of tasks including sustained sung vowels at several pitch and loudness levels, an assigned song that was judged to have relatively neutral emotion, and a personal selection that included passages of intense emotion. Vowel tokens were extracted from the recordings and averaged for each task. Dependent measures included the mean fundamental frequency (F0), mean intensity, frequency modulation (FM) rate, FM extent, and measures of FM rate and extent variability. RESULTS: The FM rate and extent were higher and the modulation variability was lower for the more emotional song than for the sustained vowels. Mean F0 and intensity were higher for the emotional song than for the neutral song. CONCLUSIONS: Singing an emotional passage influences acoustic features of vibrato when compared with isolated, sustained vowels. The wider dynamic and pitch ranges for emotional passages only partly explain vibrato differences between emotional and neutral singing.

The acoustic effects of vowel equalization training in singers.

Vowel equalization is a technique that can be used by singers to achieve a more balanced vocal resonance, or chiaroscuro, by balancing corresponding front and back vowels, which share approximate tongue heights, and also high and low vowels by means of a more neutral or centralized lingual posture. The goal of this single group study was to quantify acoustic changes in vowels after a brief training session in vowel equalization. Fifteen young adults with amateur singing experience sang a passage and sustained isolated vowels both before and after a 15-minute training session in vowel equalization. The first two formants of the target vowels /e, i, ɑ, o, u/ were measured from microphone recordings. An analysis of variance was used to test for changes in formant values after the training session. These formant values mostly changed in a manner reflective of a more central tongue posture. For the sustained vowels, all formant changes suggested a more neutral tongue position after the training session. The vowels in the singing passage mostly changed in the expected direction, with exceptions possibly attributable to coarticulation. The changes in the vowel formants indicated that even a brief training session can result in significant changes in vowel acoustics. Further work to explore the perceptual consequences of vowel equalization is warranted.

Immune and genetic aspects of asthma, allergy and parasitic worm infections: evolutionary links.

There are important parallels in the immunobiology of allergy and asthma, and of the human host's response to parasitic worms. Th-2 immune actions with 'weep and sweep' mucosal biology are common to both - pathological in the first and protective in the second. Common up-regulating genetic variants of Th-2 immunity, notably in IL13 and STAT6, predict increased risk of asthma and allergy, but diminished intensity of infection by Ascaris and Schistosoma. Endemic exposures of humans to parasitic worms may have been one evolutionary force selecting for genetic variants that promote asthma and allergy.

Laryngeal-level amplitude modulation in vibrato.

The goal of this investigation was to test a new methodology for measuring amplitude modulation (AM) at the level of the vocal folds during vibrato in trained singers, because previous research has suggested that AM arises in large part as an acoustic epiphenomenon through an interaction of the harmonics in the laryngeal source with the resonances of the vocal tract as the fundamental frequency oscillates. A within-subjects model was used to compare vocal activity across three pitch and three loudness conditions. Seventeen female singers with a range of training and experience were recorded with a microphone and an electroglottograph (EGG). Fluctuations in the ratio of closing to opening peaks in the first derivative of the EGG signal were used as an index of laryngeal-level AM. Evidence of laryngeal AM was found to a greater or lesser extent in all the singers, and its extent was not related to the degree of training. Across singers and pitch conditions, it was more prominent at lower intensities. The differentiated EGG signal lends itself to the measurement of AM at the level of the larynx, and the extent of the modulation appears more related to the level of vocal effort than to individual singer characteristics.

PTPRC (CD45) variation and disease association studied using single nucleotide polymorphism tagging.

CD45 is a haemopoietic tyrosine phosphatase, crucial for lymphocyte signalling. Two polymorphisms (C77G and A138G), which alter CD45 isoform expression, are associated with autoimmune and infectious diseases. Using HapMap data, we show that there is substantial linkage disequilibrium across the CD45 gene (PTPRC), with similar patterns in different populations. Employing a set of single nucleotide polymorphisms, correlated with a substantial proportion of variation across this gene, we tested for association with type 1 diabetes, Graves' disease in a Japanese population, hepatitis C in UK population and tuberculin response in a Chinese population. A limited number of common haplotypes was found. Most 138G alleles are present on only one haplotype, which is associated with Graves' disease, supporting previous data that A138G is a functionally important CD45 polymorphism.

Upregulating promoter polymorphisms of RANTES relate to atopic dermatitis.

It has been reported that a functional polymorphism in the promoter of the RANTES gene (-403G/A) is associated with atopic dermatitis in a German population. Although there are several reports on the association of RANTES promoter polymorphisms (-403G/A and -28C/G) with asthma, the association of these polymorphisms with atopic dermatitis has not yet been confirmed in other populations. We therefore aimed to test whether the RANTES promoter polymorphisms relate to atopic dermatitis in a well-defined Japanese population. We conducted an association study of upregulating promoter polymorphisms of RANTES (-403G/A and -28C/G) in 389 patients with atopic dermatitis and 177 healthy control subjects. There was a significant association between the upregulating variant of RANTES -28G and atopic dermatitis, while -403A variant showed a significant association with atopic dermatitis with high IgE productivity. These results support a role for RANTES promoter polymorphisms in susceptibility to atopic dermatitis.

The next extreme sport? Subdural haematoma in a patient with arachnoid cyst after head shaking competition.

A young man, engaged in a head shaking competition presented with headache, nausea and vomiting. Imaging revealed a subdural haematoma and ipsilateral arachnoid cyst. This novel mechanism of trauma underscores the predisposition to haemorrhage in patients with arachnoid cysts, even with minor trauma. Aetiology, imaging and possible treatment options are discussed.

Polymorphisms in ADAM33 are associated with allergic rhinitis due to Japanese cedar pollen.

BACKGROUND: A recent report provided evidence that a disintegrin and metalloprotease domain 33 (ADAM33), a member of the ADAM family, is a novel susceptibility gene in asthma linked to bronchial hyper-responsiveness. However, there has been no investigation of the genetic role of ADAM33 variants in nasal allergy. OBJECTIVE: The purpose of this study was to test the association between ADAM33 polymorphisms and Japanese cedar pollinosis (JCPsis), a most common seasonal allergic rhinitis in Japan. METHODS: We conducted a case-control association study among a Japanese population, involving 95 adult individuals with JCPsis and 95 normal healthy controls. A total of 22 single-nucleotide polymorphisms (SNPs) in ADAM33 were genotyped using PCR-based molecular methods. RESULTS: Six SNPs of ADAM33 gene, three in introns (7575G/A, 9073G/A and 12540C/T) and three in the coding region (10918G/C, 12433T/C and 12462C/T), were strongly associated with JCPsis (P = 0.0002-0.022 for absolute allele frequencies) and most of the SNPs were in linkage disequilibrium with each other. A higher frequency of the common alleles of these SNPs was noted for the subjects with JCPsis in comparison with healthy controls. We also identified a haplotype associated with the disease susceptibility. In addition, associations were found between ADAM33 polymorphisms and various cedar pollinosis phenotypes including clinical severity, eosinophil counts in nasal secretion and allergen-specific IgE levels in sera, but not total serum IgE levels. CONCLUSION: These results indicate that polymorphisms in the ADAM33 gene are associated with susceptibility to allergic rhinitis due to Japanese cedar pollen, but the functional relationship still needs clarification.

Genetic variants of FcepsilonRIbeta and Il-4 and atopy in a Polish population.

BACKGROUND: Atopy results from the interaction between genetic and environmental factors. The aim of our study was to clarify the association between the FcRIint2 polymorphic variant, the Glu237Gly mutation in exon 7 of FcepsilonRIbeta and (-590 C/T) Il-4 gene promoter polymorphism with atopy in a randomized Polish sample. SUBJECTS AND METHODS: Unrelated subjects aged 18-45 years who were residents of an urban area (Lodz, Poland) were included in the study: 98 patients with asthma and/or allergic rhinitis, and 87 non-atopic, non-asthmatic controls. We used common criteria for atopy and asthma. Atopic status was determined by positive skin prick tests (SPT) and IgE levels. The severity of asthma was assessed in spirometric measurements; SPTs to house dust mite (HDM) and mixed grass pollen (MGP) were performed. Total and specific IgE were measured in each subject. Genotypic analysis was performed by PCR for FcRIint2 and (590 C/T) Il-4 gene promoter polymorphism and ARMS-PCR was performed for the Glu237Gly mutation. RESULTS: We found a statistically significant association between atopy and FcRIint2 variant polymorphism (OR = 2.96), a correlation between positive skin prick tests to MGP and raised MGP-specific IgE concentrations in patients bearing this variant (OR = 4.0). We did not observe that the FcRIint2 variant was associated with positive SPTs to HDM or high levels of HDM-specific IgE (OR = 1.0). The intronic variant of FcepsilonRIbeta was strongly correlated with elevated total serum IgE (OR = 4.74). No statistically significant association was found between atopy and the Glu237Gly mutation of FcepsilonRIbeta(OR = 1.36) or (-590 C/T) Il-4 gene promoter polymorphism (OR = 0.88). CONCLUSIONS: The results suggest that FcRIint2 polymorphism is related to atopy and may influence its development.

An asthma-associated genetic variant of STAT6 predicts low burden of ascaris worm infestation.

Th-2 immune mechanisms are involved in the pathology of asthma and in the protective immune response to parasitic worms. Common upregulating genetic variants of Th-2 immune signalling are risk factors for asthma, and we tested whether they may confer a counteradvantage in protecting against parasitic worms. We examined the intensity of infection by the parasitic worm, Ascaris lumbricoides, by microsopic counting of ascaris eggs in the stool of 614 schoolchildren from an area of endemic ascaris infection in China. We investigated the relationship between the intensity of ascaris infection and common, asthma-associated genetic variants of Th-2 and Th-1 immune signalling. Ascaris egg counts per gram of stool (epg), mean 1068 epg, ranged from barely detectable (<240 epg) to heavy (approximately 9600 epg) in a skewed distribution. Logistic regression, after exploratory discriminant analysis, showed a major association between a common genetic variant of the 3'-UTR regulatory elements of the signal transducer and transactivating factor (STAT6) (P=0.0002) and egg counts, at the 77 th centile. Linear regression after log transformation of egg counts confirmed a highly significant association with this STAT6 variant (P=0.001). Thus, a common, asthma-associated, genetic variant of the pivotal transduction and transactivating factor for Th-2 immune signalling, STAT6, predicts increased resistance to ascaris worm infection. The evolution of enhanced resistance to parasitic worm infection, through human genetic variation in Th-2 immune signalling, may represent one origin for asthma.

The rise of atopy and links to infection.

Atopy is the state of allergy to common environmental antigens. Genetic and environmental factors promote the disorder. The impressive rise in prevalence, mainly centred on socio-economically developed communities around the world, emphasizes the potent action of environmental factors in moulding this immune disorder which is characterized by inadequately restrained Th-2 immune mechanisms and IgE production. Reversing the epidemiological trend depends on our identifying the major environmental inputs and acting against these. As yet, the nature of these environmental factors remains to be clarified. Candidate factors include changes in diet, chemical air pollution and microbial exposures in developed countries. This article limits its scope to changing microbial exposures as a potential mechanism. (a) It records epidemiological data that have associated atopic status with less natural exposure to pathogens, parasites and commensal micro-organisms, but with more exposure to certain antibiotics and public health immunizations in early life. (b) It records studies in mice that support the concept that certain microbial exposures can inhibit experimental allergy. (c) It considers potential immune mechanisms for such an action, including the possibility that certain natural infections promote immune regulatory processes that can restrain atopy. It is concluded that the hypothesis that changing patterns of microbial exposure may have promoted the rise in atopy is viable, and that exciting possibilities for reversing the rise of atopy may be derived from further studies.

Low molecular weight PTP-IL-4RA interaction in atopy predisposition.

We recently described a protective effect of the low molecular weight protein tyrosine phosphatase (LMPTP) BC genotype, associated with the highest total enzymatic activity, against high serum IgE levels both in the English and the Italian populations. Here we test the hypothesis of a role of LMPTP in the negative modulation of IL-4 signal transduction checking for genetic interaction between interleukin-4 receptor alpha chain (IL-4RA) genetic polymorphisms and LMPTP polymorphism in the predisposition to high total IgE levels in the English population. We find a significant interaction between LMPTP polymorphism and the intracellular Gln/Arg polymorphism in position 551 of IL-4RA. Our data support the hypothesis of a direct or indirect biochemical interaction between LMPTP and IL-4RA resulting in different modulation of IL-4 signal transduction among joint genotypes.

Service provision of complex mutation analysis: a technical and economic appraisal using dystrophin point mutation analysis as an example.

Duchenne muscular dystrophy (DMD) results from mutations in the dystrophin gene. One-third of cases arise from point mutations, which are heterogeneous and difficult to detect. The aims of this study of dystrophin point mutation analysis were to assess its technical feasibility in a routine diagnostic laboratory, and to estimate its costs and clinical benefits. The methods used were a laboratory based study using reverse transcription-polymerase chain reaction (RT-PCR) and a protein truncation test, and a mathematical model to estimate costs and clinical benefits. None of the cases analyzed had an identifiable dystrophin deletion or duplication. They were 12 males affected with DMD and two obligate female carriers; two female carriers of known dystrophin point mutations were also analyzed. Point mutations were detected in six out of 12 males, but in none of the female carriers. Assuming a sensitivity of 50% the model predicts significant clinical benefits of point mutation analysis over linkage analysis, including a reduction in the number of prenatal diagnoses (by 0.77 per family), terminations of pregnancy (by 0.18 per family), and terminations of unaffected fetuses (by 0.16 per family). The mean cost of point mutation analysis to prevent the termination of an unaffected fetus is 6220 US dollars.

IL-4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two-locus haplotypes are more informative than individual SNPs.

The IL-4RA locus encodes for the alpha chain of the IL-4 receptor, and is both a functional and positional candidate gene for atopy and allergic disease. Recently Ober et al. have shown that the study of haplotypes at multiple loci in the IL-4RA gene could be more informative than the separate study of single nucleotide polymorphisms (SNPs). One hundred and fifty subjects affected by atopic asthma and 150 healthy control subjects were studied in the English population (Oxford district). Subjects and controls were genotyped for the Ile50Val, Ser478Pro and Gln551Arg polymorphism of the IL-4 receptor alpha chain. The distribution of haplotypes 50-478 shows a highly significant association with IgE levels. In particular, the haplotype Val50/Pro478 is much less frequent in subjects with IgE levels > 100 U mL-1 than in those with IgE levels < 100 U mL-1. Furthermore, the distribution of haplotype 50-551 shows a weak association with IgE levels that is lacking for 478-551 haplotypes. A lower frequency of the Val50/Pro478 haplotype is also observed among asthmatic subjects as compared to healthy controls. With regard to individual SNPs (50 478 and 551), no significant association has been observed with IgE levels or with asthma, thus confirming the higher informative value of the haplotype analysis as compared to separate study on SNPs.

Interleukin-4 and its alternatively spliced variant (IL-4delta2) in patients with atopic asthma.

The interleukin-4 (IL-4) splice variant (IL-4delta2) is known to antagonize many biological activities of IL-4, and this challenges our understanding of the role of IL-4 in asthma. Studies that have used nonspecific antibodies, probes, and/or primers to quantify IL-4 in clinical samples would not have distinguished the expression of IL-4 from IL-4delta2. This is the first study to examine patients with chronic asthma and atopy for IL-4delta2 mRNA in their peripheral blood mononuclear cells without antigen stimulation, using a quantitative nested reverse-transcription polymerase chain reaction (RT-PCR) protocol. The median IL-4 mRNA copy number in cells from the patients with asthma was 2.8 logs higher than in a comparator group of patients with tuberculosis (p = 0.0005) and 4.5 logs higher (p = 0.0004) than in healthy control subjects. In contrast, IL-4delta2 expression in cells from patients with asthma was similar to that seen in cells from patients with tuberculosis. Hence, the median ratio of IL-4 to IL-4delta2 was 500-fold higher in the patients with asthma when compared with either patients with tuberculosis or healthy control subjects. The relative expression of IL-4 and IL-4delta2 may be a reason for the functional diversity of Th2 cells in different clinical conditions, and a hitherto unexplored mechanism for the pulmonary pathology in patients with atopic asthma.

Use of Gore-Tex tubing as a conduit for inferior alveolar and lingual nerve repair: experience with 6 cases.

PURPOSE: This report evaluates treatment outcomes associated with the use of Gore-Tex (GT; W.L. Gore & Associates, Flagstaff, AZ) vein graft tubing as a conduit for repair of inferior alveolar nerve (IAN) and lingual nerve (LN) continuity defects. PATIENTS AND METHODS: Six patients (5 female and 1 male) with painful dysesthesia secondary to injuries of the IAN (n = 3) or LN (n = 3) underwent surgical exploration and resection of pathologic tissue. Reconstruction of the resultant continuity defects was performed using 3-mm diameter GT tubing sutured to the epineurium of the proximal and distal nerve trunks. Nerve reconstruction was performed an average of 20 months after injury (range, 4 to 48 months). Patients were tested before and after surgery with the following tests: subjective pain level using an analogue scale, sharp stimulus, touch, cold sensation, directional sense, and 2-point discrimination. RESULTS: Four patients reported no change in subjective pain level, and 2 patients had minimal decrease in pain. Two patients reported some sensation to sharp stimulus, and 1 patient was hypersensitive. Three patients responded to touch, and 3 had no response. Four patients had no response to cold sensation, and 2 had a delayed response. Only 1 patient could detect brushstroke direction. Three patients had no response to 2-point discrimination, and 3 responded at greater than 20 mm. CONCLUSIONS: Use of GT tubing in this group of patients produced poor clinical outcomes and is not recommended for nerve reconstruction of IAN and LN continuity defects.