The International Olympic Committee framework on fairness, inclusion and nondiscrimination on the basis of gender identity and sex variations does not protect fairness for female athletes.

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's "no presumption of advantage" principle disregards this reality. Studies show that transgender women (male-born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of "meaningful competition" is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case-by-case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision-making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports.

Experimental long-term diabetes mellitus alters the transcriptome and biomechanical properties of the rat urinary bladder.

Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy is widely studied. In contrast, the pathobiology of diabetic urinary bladder disease is less understood despite dysfunctional voiding being common in DM. We hypothesised that diabetic cystopathy has a characteristic molecular signature. We therefore studied bladders of hyperglycaemic and polyuric rats with streptozotocin (STZ)-induced DM. Sixteen weeks after induction of DM, as assessed by RNA arrays, wide-ranging changes of gene expression occurred in DM bladders over and above those induced in bladders of non-hyperglycaemic rats with sucrose-induced polyuria. The altered transcripts included those coding for extracellular matrix regulators and neural molecules. Changes in key genes deregulated in DM rat bladders were also detected in db/db mouse bladders. In DM rat bladders there was reduced birefringent collagen between detrusor muscle bundles, and atomic force microscopy showed a significant reduction in tissue stiffness; neither change was found in bladders of sucrose-treated rats. Thus, altered extracellular matrix with reduced tissue rigidity may contribute to voiding dysfunction in people with long-term DM. These results serve as an informative stepping stone towards understanding the complex pathobiology of diabetic cystopathy.

Transgender Women in the Female Category of Sport: Perspectives on Testosterone Suppression and Performance Advantage.

Males enjoy physical performance advantages over females within competitive sport. The sex-based segregation into male and female sporting categories does not account for transgender persons who experience incongruence between their biological sex and their experienced gender identity. Accordingly, the International Olympic Committee (IOC) determined criteria by which a transgender woman may be eligible to compete in the female category, requiring total serum testosterone levels to be suppressed below 10 nmol/L for at least 12 months prior to and during competition. Whether this regulation removes the male performance advantage has not been scrutinized. Here, we review how differences in biological characteristics between biological males and females affect sporting performance and assess whether evidence exists to support the assumption that testosterone suppression in transgender women removes the male performance advantage and thus delivers fair and safe competition. We report that the performance gap between males and females becomes significant at puberty and often amounts to 10-50% depending on sport. The performance gap is more pronounced in sporting activities relying on muscle mass and explosive strength, particularly in the upper body. Longitudinal studies examining the effects of testosterone suppression on muscle mass and strength in transgender women consistently show very modest changes, where the loss of lean body mass, muscle area and strength typically amounts to approximately 5% after 12 months of treatment. Thus, the muscular advantage enjoyed by transgender women is only minimally reduced when testosterone is suppressed. Sports organizations should consider this evidence when reassessing current policies regarding participation of transgender women in the female category of sport.

Understanding the decision to immunize: insights into the information needs and priorities of people who have utilized an online human papillomavirus (HPV) vaccine decision aid tool.

SETTING: People in Alberta are more likely to seek information about cancer prevention online than they are to have this conversation with their primary care provider. As people turn to the internet to support health decision-making, it is critical that we improve the supportiveness of the virtual health setting for cancer prevention. INTERVENTION: In 2014, the Alberta Cancer Prevention Legacy Fund launched an online HPV Decision Aid Tool to support evidence-informed decision-making in response to suboptimal uptake of the HPV (human papillomavirus) vaccine. Google Analytics data from approximately 2000 recent interactions with this tool have yielded insights into the concerns that impact people's decision-making about the vaccine. OUTCOMES: Most users of this tool are adults interested in the vaccine for themselves (69%), rather than parents considering immunizing their children (31%). No differences were found in the information-seeking behaviour of parents of girls compared with parents of boys, suggesting that mental models among those who are considering the HPV vaccine may have shifted in recent years. Concerns differed by respondent; cost was the most important concern among adults (62.0%), while parents were most concerned about vaccine safety (61.5%). Only 23% of users asked "what is HPV", suggesting that many people in Alberta now have basic knowledge about the virus. IMPLICATIONS: Results provide a real-time "pulse" on knowledge and attitudes towards HPV immunization, which informs our approach to tailoring messaging with the aim of increasing vaccine uptake in Alberta. Outcomes will provide evidence needed to inform new interventions aimed at increasing HPV immunization rates.

RéSUMé: LIEU: Les gens de l'Alberta ont plus tendance à chercher des informations sur la prévention du cancer en ligne que d'en parler avec leur fournisseur de soins de premier recours. Comme les gens se tournent de plus en plus vers Internet pour éclairer leurs décisions en matière de santé, il est essentiel d'améliorer notre soutien aux milieux de soins virtuels de prévention du cancer. INTERVENTION: En 2014, le fonds spécial de l'Alberta pour la prévention du cancer (Alberta Cancer Prevention Legacy Fund) lançait un outil en ligne d'aide à la décision axé sur le VPH (virus du papillome humain) pour favoriser la prise de décisions éclairées par les données probantes, vu le recours sous-optimal au vaccin anti-VPH. Les données sur environ 2 000 interactions récentes avec cet outil, extraites au moyen de Google Analytics, ont offert un aperçu des préoccupations qui comptent dans les décisions des gens au sujet du vaccin. RéSULTATS: La plupart des utilisateurs de l'outil sont des adultes que le vaccin intéresse pour eux-mêmes (69 %) plutôt que des parents qui songent à faire vacciner leurs enfants (31 %). Aucune différence n'a été constatée dans le comportement de recherche d'informations des parents de filles et des parents de garçons, ce qui indique que les modèles mentaux des personnes qui envisagent le vaccin anti-VPH pourraient avoir changé ces dernières années. Les préoccupations différaient selon les répondants; le coût était la préoccupation la plus importante chez les adultes en général (62 %), tandis que les parents s'inquiétaient surtout de l'innocuité du vaccin (61,5 %). Seulement 23 % des utilisateurs ont cherché « qu'est-ce que le VPH? ¼, ce qui donne à penser que beaucoup de gens en Alberta ont maintenant des connaissances de base sur le virus. CONSéQUENCES: Nos résultats permettent de prendre le « pouls ¼ en temps réel des connaissances et des attitudes à l'égard de l'immunisation contre le VPH, ce qui éclaire notre stratégie d'adaptation de nos messages en vue d'accroître le recours au vaccin en Alberta. Les résultats finaux fourniront les données probantes nécessaires pour éclairer de nouvelles interventions visant à accroître les taux d'immunisation contre le VPH.

The Effect of Pain Conditioning on Experimentally Evoked Cough: Evidence of Impaired Endogenous Inhibitory Control Mechanisms in Refractory Chronic Cough.

The pathophysiology of refractory chronic cough (RCC) is unclear. We hypothesised that endogenous inhibitory control mechanisms, such as those activated by noxiousstimuli inducing pain (conditioned pain modulation (CPM)), may be capable of inhibiting coughing and urge to cough evoked by inhaled capsaicin. Furthermore, these mechanisms may be impaired in patients with RCC.The objective was to investigate the effects of pain on cough and urge to cough (UTC) in healthy volunteers (HV) and RCC. HV and RCC patients underwent a randomised, controlled, 4-way cross-over study comparing the effect of 4 interventions on capsaicin evoked coughing and UTC. The interventions comprised immersing a hand in i) noxious cold-water, ii) warm water, iii) warm water but instructed to voluntarily supress coughing and iv) no intervention. The co-primary outcomes were numbers of evoked coughs and UTC scores.Twenty HV (mean age 50.1(±SD14.2), M:F 10:10) and 20 RCC (age 60.1(±7.9), M:F 9:11) participated. Overall, noxious cold water reduced capsaicin evoked UTC scores and cough numbers compared with warm water (1.6 (95% C.I. 1.3-2.0) versus 2.2 (1.8-2.6) p<0.001; 4.8 coughs (3.7-6.2) versus 7.9 coughs (6.7-9.5) p<0.001, respectively). HV and RCC demonstrated similar reductions in the UTC during noxious cold-water immersion, but noxious cold water and voluntary suppression interventions were less effective in RCC than HV in reducing capsaicin evoked cough (p=0.041).Endogenous inhibitory control mechanisms, specifically those activated by pain, can reduce both coughing and the UTC. Impairment of endogenous inhibitory control mechanisms may contribute to excessive coughing in RCC.

Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder.

Mutations in leucine-rich-repeats and immunoglobulin-like-domains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2, including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract.

Blood eosinophil levels as a biomarker in COPD.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder and patients respond differently to treatment. Blood eosinophils are a potential biomarker to stratify patient subsets for COPD therapy. We reviewed the value of blood eosinophils in predicting exacerbation risk and response to corticosteroid treatment in the available literature (PubMed articles in English; keywords: "COPD" and "eosinophil"; published prior to May 2017). Overall, clinical data suggest that in patients with a history of COPD exacerbations, a higher blood eosinophil count predicts an increased risk of future exacerbations and is associated with improved response to treatment with inhaled corticosteroids (in combination with long-acting bronchodilator[s]). Blood eosinophils are therefore a promising biomarker for phenotyping patients with COPD, although prospective studies are needed to assess blood eosinophils as a biomarker of corticosteroid response for this.

Single-inhaler triple therapy in symptomatic COPD patients: FULFIL subgroup analyses.

Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear. FULFIL, a phase III, randomised, double-blind study, compared 24 weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg using the Ellipta inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg using the Turbuhaler. Subgroup analyses of forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) Total score and exacerbation rates were carried out. Subgroups were defined by COPD medication at screening (ICS+LABA, BUD+FOR, ICS+LABA+LAMA, LAMA alone, tiotropium alone and LAMA+LABA), by disease severity (lung function and exacerbations) and by exacerbation history (exacerbation severity and frequency). In the intent-to-treat population (n=1810) at week 24, FF/UMEC/VI (n=911) versus BUD/FOR (n=899) improved FEV1 and SGRQ Total score and reduced mean annual exacerbation rates in all disease severity and exacerbation history subgroups. FF/UMEC/VI versus BUD/FOR improved FEV1 and SGRQ Total score in all medication subgroups and reduced mean annual exacerbation rates in all medication subgroups, except LAMA+LABA. Adverse events were similar across subgroups. These findings support the benefit of FF/UMEC/VI compared with dual ICS/LABA therapy in patients with symptomatic COPD regardless of disease severity or prior treatment and may help to inform clinical decision making.

Demographic and Clinical Characteristics of COPD Patients at Different Blood Eosinophil Levels in the UK Clinical Practice Research Datalink.

Blood eosinophil count may be a useful biomarker for predicting response to inhaled corticosteroids and exacerbation risk in chronic obstructive pulmonary disease (COPD) patients. The optimal cut point for categorizing blood eosinophil counts in these contexts remains unclear. We aimed to determine the distribution of blood eosinophil count in COPD patients and matched non-COPD controls, and to describe demographic and clinical characteristics at different cut points. We identified COPD patients within the UK Clinical Practice Research Database aged ≥40 years with a FEV1/FVC <0.7, and ≥1 blood eosinophil count recorded during stable disease between January 1, 2010 and December 31, 2012. COPD patients were matched on age, sex, and smoking status to non-COPD controls. Using all blood eosinophil counts recorded during a 12-month period, COPD patients were categorized as "always above," "fluctuating above and below," and "never above" cut points of 100, 150, and 300 cells/µL. The geometric mean blood eosinophil count was statistically significantly higher in COPD patients versus matched controls (196.6 cells/µL vs. 182.1 cells/µL; mean difference 8%, 95% CI: 6.8, 9.2), and in COPD patients with versus without a history of asthma (205.0 cells/µL vs. 192.2 cells/µL; mean difference 6.7%, 95%, CI: 4.9, 8.5). About half of COPD patients had all blood eosinophil counts above 150 cells/µL; this persistent higher eosinophil phenotype was associated with being male, higher body mass index, and history of asthma. In conclusion, COPD patients demonstrated higher blood eosinophil count than non-COPD controls, although there was substantial overlap in the distributions. COPD patients with a history of asthma had significantly higher blood eosinophil count versus those without.

The distribution of blood eosinophil levels in a Japanese COPD clinical trial database and in the rest of the world.

Background: Blood eosinophil measurements may help to guide physicians on the use of inhaled corticosteroids (ICS) for patients with chronic obstructive pulmonary disease (COPD). Emerging data suggest that COPD patients with higher blood eosinophil counts may be at higher risk of exacerbations and more likely to benefit from combined ICS/long-acting beta2-agonist (LABA) treatment than therapy with a LABA alone. This analysis describes the distribution of blood eosinophil count at baseline in Japanese COPD patients in comparison with non-Japanese COPD patients. Methods: A post hoc analysis of eosinophil distribution by percentage and absolute cell count was performed across 12 Phase II-IV COPD clinical studies (seven Japanese studies [N=848 available absolute eosinophil counts] and five global studies [N=5,397 available eosinophil counts] that included 246 Japanese patients resident in Japan with available counts). Blood eosinophil distributions were assessed at baseline, before blinded treatment assignment. Findings: Among Japanese patients, the median (interquartile range) absolute eosinophil count was 170 cells/mm3 (100-280 cells/mm3). Overall, 612/1,094 Japanese patients (56%) had an absolute eosinophil count ≥150 cells/mm3 and 902/1,304 Japanese patients (69%) had a percentage eosinophil ≥2%. Among non-Japanese patients, these values were 160 (100-250) cells/mm3, 2,842/5,151 patients (55%), and 2,937/5,155 patients (57%), respectively. The eosinophil distribution among Japanese patients was similar to that among non-Japanese patients. Within multi-country studies with similar inclusion criteria, the eosinophil count was numerically lower in Japanese compared with non-Japanese patients (median 120 vs 160 cells/mm3). Interpretation: The eosinophil distribution in Japanese patients seems comparable to that of non-Japanese patients; although within multi-country studies, there was a slightly lower median eosinophil count for Japanese patients compared with non-Japanese patients. These findings suggest that blood eosinophil data from global studies are of relevance in Japan.

Effectiveness versus efficacy trials in COPD: how study design influences outcomes and applicability.

Guidelines for chronic obstructive pulmonary disease (COPD) management are based largely on results from double-blind randomised controlled trials (RCTs) of efficacy. These trials have high internal validity and test whether a drug is efficacious, but they are conducted in highly selected populations that may differ significantly from patients with COPD seen in routine practice.We compared the baseline characteristics, healthcare use and outcomes between the Salford Lung Study (SLS), an open-label effectiveness RCT, with six recent large-scale efficacy RCTs. We also calculated the proportion of SLS patients who would have been eligible for inclusion in an efficacy RCT by applying the inclusion criteria used in efficacy trials of combination treatments.SLS patients were older, included more females and more current smokers, had more comorbidities (including asthma), and had more often experienced exacerbations prior to inclusion. In the SLS, rates of moderate or severe exacerbations, incidence of overall serious adverse events (SAEs), and SAEs of pneumonia were more frequent. A maximum of 30% of patients enrolled in the SLS would have been eligible for a phase IIIa regulatory exacerbation study.Patients in large COPD efficacy RCTs have limited representativeness compared with an effectiveness trial. This should be considered when interpreting efficacy RCT outcomes and their inclusion into guidelines.

Stability of Blood Eosinophil Count in Patients with COPD in the UK Clinical Practice Research Datalink.

Blood eosinophil counts may be predictive of corticosteroid response in chronic obstructive pulmonary disease (COPD) patients. However, little is known about measurement stability, which is important for understanding the utility of blood eosinophil counts as a potential biomarker. We evaluated the stability of blood eosinophil counts over 1 year in a population-based cohort of patients with COPD in primary care. Patients were aged ≥ 40 years with forced expiratory volume in 1 second/forced vital capacity < 0.7 and ≥ 1 blood eosinophil measurement taken during a period of stable disease within 6 months of a COPD diagnosis code recorded between January 1, 2010 and December 31, 2012. Generalized linear mixed models were fitted to log-transformed data to estimate the between-(s2between) and within-patient (s2within) variance in eosinophil count; an intra-class correlation coefficient Ri was calculated (s2between/[s2between + s2within]). A sensitivity analysis was performed from which patients who were prescribed systemic corticosteroids or antibiotics at any time during follow-up were excluded. All models were adjusted for age, gender, smoking status, and asthma history. Overall, 27,557 patients were included in the full cohort (51.5% male, mean age [standard deviation] 71.1 [10.6] years) and 54% of patients had ≥ 2 eosinophil measurements (median 2 [interquartile range 1]) during follow-up. For the full cohort, Ri = 0.64, and in the sensitivity analysis subgroup, Ri = 0.70, mainly due to a decrease in s2within. For patients with COPD in primary care, eosinophil measurements demonstrated reasonable repeatability over 1 year, which increased after exclusion of patients who were prescribed systemic corticosteroids or antibiotics.

Life Impact and Treatment Preferences of Individuals with Asthma and Chronic Obstructive Pulmonary Disease: Results from Qualitative Interviews and Focus Groups.

INTRODUCTION: The impact of asthma and chronic obstructive pulmonary disease (COPD) on individuals' lives may be substantial, yet clinical practice often focuses only on symptoms. We aimed to better understand the perspective of asthma or COPD patients and to identify condition-related burden, life impact, priorities, unmet needs, and treatment goals. METHODS: Individuals aged at least 18 years with asthma or COPD were identified by a recruitment panel via clinical referrals, support groups, consumer networks, and a patient database. Interviews were carried out individually (by telephone) or in focus groups (with no more than five participants per group). A semi-structured interview guide was used with prespecified topics, informed by a literature review, that were considered impactful in asthma or COPD (symptoms and daily-life impact, satisfaction with current treatment, important aspects of treatment, adherence, and ideal treatment). RESULTS: Overall, 72 people participated in focus groups/individual interviews (asthma n = 18/n = 21; COPD n = 15/n = 18). "Shortness of breath" was the most frequently reported symptom; however, participants discussed the life impact of their condition more than symptoms alone. Reported physical impacts included the inability to sleep and socialize, while emotional impacts included "embarrassment, stigma, and/or self-consciousness", "fear and/or panic", and "sadness, anxiety, and/or depression". Coping mechanisms for normal activities included continuing at reduced pace and avoidance. Treatment preferences centered on resolving impacts; improved sleep, "speed of action", and "length of relief" were the most frequently reported ideal treatment factors. CONCLUSION: Patients with asthma or COPD experience substantial quality of life limitations and tend to focus on these in their expressions of concern, rather than symptoms per se. Life impacts of these conditions may have implications beyond those commonly appreciated in routine practice; these considerations will be applied to a future discrete choice experiment survey. FUNDING: GSK funded study (H0-15-15502/204821).

From gene discovery to new biological mechanisms: heparanases and congenital urinary bladder disease.

We present a scientific investigation into the pathogenesis of a urinary bladder disease. The disease in question is called urofacial syndrome (UFS), a congenital condition inherited in an autosomal recessive manner. UFS features incomplete urinary bladder emptying and vesicoureteric reflux, with a high risk of recurrent urosepsis and end-stage renal disease. The story starts from a human genomic perspective, then proceeds through experiments that seek to determine the roles of the implicated molecules in embryonic frogs and newborn mice. A future aim would be to use such biological knowledge to intelligently choose novel therapies for UFS. We focus on heparanase proteins and the peripheral nervous system, molecules and tissues that appear to be key players in the pathogenesis of UFS and therefore must also be critical for functional differentiation of healthy bladders. These considerations allow the envisioning of novel biological treatments, although the potential difficulties of targeting the developing bladder in vivo should not be underestimated.

Clinical features of the urge-to-cough in patients with chronic cough.

BACKGROUND: The urge-to-cough is a consciously perceived compulsion, previously investigated in healthy volunteers inhaling irritants. We aimed to characterise the urge-to-cough and associated sensations in a group of chronic cough patients attending a specialist clinic. METHODS: 100 patients with chronic cough [mean age 60 yrs (±11.89), 71 female, median cough duration 7 yrs (IQR 11.13) completed an investigator-led survey describing aggravating and relieving factors for urge-to-cough, associated somatic sensations (quality, location, intensity) and emotions. Subjects rated each using a 5-point Likert scale (strongly disagree to strongly agree) or visual analogue scale (VAS). Cluster analysis identified groups of patients with similar patterns of responses. RESULTS: Subjects rated the severity of urge-to-cough highly (84.5 mm on VAS). The majority always cough in response to the urge-to-cough (91%), but fewer (69%) always experienced an urge-to-cough before coughing. The somatic sensations associated with the urge-to-cough were described as an irritation (86%) or tickle (73%), localised in the neck (75%). The urge-to-cough was triggered by various stimuli including smoky atmospheres (79%), talking (72%), cold temperatures (67%) and dry atmospheres (66%) and relieved by coughing (63%), and drinking (61%); in 42% nothing provided relief. Cluster analysis suggested two distinct patient groups, differing in the factors precipitating the urge-to-cough rather than quality or location of associated sensations. CONCLUSION: The unifying characteristics of patients with chronic cough are a severe urge-to-cough associated with throat irritation, consistent with sensory neuronal dysfunction of vagal afferents. Precipitants of the urge-to-cough vary though, and can be used to classify sub-groups of patients who may share similar underlying pathophysiology.

Urinary tract effects of HPSE2 mutations.

Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.

Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus.

Urofacial syndrome (UFS; previously Ochoa syndrome) is an autosomal recessive disease characterized by incomplete bladder emptying during micturition. This is associated with a dyssynergia in which the urethral walls contract at the same time as the detrusor smooth muscle in the body of the bladder. UFS is also characterized by an abnormal facial expression upon smiling, and bilateral weakness in the distribution of the facial nerve has been reported. Biallelic mutations in HPSE2 occur in UFS. This gene encodes heparanase 2, a protein which inhibits the activity of heparanase. Here, we demonstrate, for the first time, an in vivo developmental role for heparanase 2. We identified the Xenopus orthologue of heparanase 2 and showed that the protein is localized to the embryonic ventrolateral neural tube where motor neurons arise. Morpholino-induced loss of heparanase 2 caused embryonic skeletal muscle paralysis, and morphant motor neurons had aberrant morphology including less linear paths and less compactly-bundled axons than normal. Biochemical analyses demonstrated that loss of heparanase 2 led to upregulation of fibroblast growth factor 2/phosphorylated extracellular signal-related kinase signalling and to alterations in levels of transcripts encoding neural- and muscle-associated molecules. Thus, a key role of heparanase 2 is to buffer growth factor signalling in motor neuron development. These results shed light on the pathogenic mechanisms underpinning the clinical features of UFS and support the contention that congenital peripheral neuropathy is a key feature of this disorder.