Background: Mycosis fungoides (MF) and S & eacute;zary syndrome (SS) are common sub-types of cutaneous T-cell lymphoma that primarily affect the skin but may spread to the lymph nodes, viscera and blood. The symptom burden may compromise health- related quality of life (HRQL). The phase 3 MAVORIC study (Clini calTr ials. gov iden-tifier NCT01728805) in patients with relapsed/refractory MF/SS reported improved HRQL with mogamulizumab compared with vorinostat.Objectives: Use baseline (pre-treatment) data from the MAVORIC study to describe the symptom burden of MF/SS and identify characteristics associated with worse HRQL.Methods: Data were from 372 adults with stage IB-IVB histologically confirmed relapsed/ refractory MF or SS. Associations between demographic and medical his-tory variables and worse HRQL (Skindex-29, ItchyQol and Functional Assessment of Cancer Therapy - General [FACT-G]) were determined by regression models.Results: In the cohort of 372 adults, 70% were white; 42% were female; mean age was 63 (SD 13.0) years. Fifty-five per cent had MF and 45% had SS; 77% had ad-vanced (stage IIB-IV) disease, involving the skin in all patients and the blood and/or nodes in 66%. HRQL scores showed impairment versus normative means (where available), with the greatest impact on Symptoms and Emotions in the Skindex-29, Functioning in the ItchyQol, and Functional Wellbeing in the FACT-G. In regression analysis, worse HRQL across all domains and total score was associated with being female and younger, worse mSWAT score and worse itch for the Skindex-29 (n = 352), and being female, younger, Black/African American, worse performance status and worse itch for the ItchyQol (n = 369). Associations across domains and total score were not found for the FACT-G. Associations between domains and demographic/medical history were seen for all instruments.Conclusions: The symptoms of advanced MF/SS compromise all HRQL domains. Treatment goals and therapeutic choice should be informed by individual patients' disease burden.

Mycosis fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas (CTCLs) associated with a wide range of symptoms, including severe pruritis and other morbidities. In the phase 3 MAVORIC trial (NCT01728805), mogamulizumab, a first-in-class defucosylated humanized IgG1-kappa monoclonal antibody that selectively binds to C-C chemokine receptor 4, significantly improved progression-free survival compared to vorinostat in patients with relapsed or refractory MF or SS and health-related quality of life (HRQoL). The objectives of the PROSPER study (NCT05455931) are to evaluate patient-reported changes in key patient-reported symptoms of disease, fatigue, and HRQoL following initiation of mogamulizumab treatment. Changes in caregiver HRQoL and real-world treatment patterns will also be assessed.

Inaccurate taxonomy can lead to species in need of conservation being overlooked, which makes revisionary systematics crucially important for imperilled groups. The freshwater mussel genus Alasmidonta is one such group in need of study. Here, we take a multilocus phylogenetic approach to assess species-level taxonomy of Alasmidonta and test monophyly of this genus. Phylogenetic inference resulted in polyphyly of Alasmidonta. Lasmigona, which was included to test monophyly of Alasmidonta, was also polyphyletic. Species delimitation methods disagreed about whether Alasmidonta arcula, Alasmidonta triangulata and Alasmidonta undulata are distinct species, but all delimitation methods agreed that Alasmidonta harbours an undescribed species that would be considered Alasmidonta varicosa under current taxonomy. Given conflict among species delimitation methods and geographical separation, we maintain the current taxonomy for A. arcula and A. triangulata. The undescribed species is restricted to rivers of the Uwharrie Mountains region in North Carolina, USA that flow into the Pee Dee River from the east and can be distinguished morphologically from A. varciosa by higher and wider placed adductor mussels and a hooked pseudocardinal tooth. We offer insights into how supraspecific taxonomy of subtribe Alasmidontina might be resolved and formally describe the lineage from the Uwharrie Mountains region as Uwharrie elktoe, Alasmidonta uwharriensis sp. nov.

BackgroundX-Linked Hypophosphataemia (XLH) is a rare, progressive, lifelong, hereditary renal tubule phosphate-wasting disorder characterised by a pathological increase in fibroblast growth factor 23 concentration/activity.1 Despite XLH being increasingly recognised as a chronic progressive disease, there are few data documenting its natural history or the impact of treatment on patient outcomes.2 The International XLH Registry was established to address this lack of information on XLH to help inform future clinical management. The Registry will collect data to characterise the treatment, burden of disease, disease progression and long-term outcomes of XLH.ObjectivesTo provide an overview and status update of the International XLH Registry as of 31 December 2021.MethodsThe International XLH Registry (NCT03193476) was initiated in August 2017, aims to recruit 1,200 children and adults with XLH, and will run for 10 years. This Registry is an international, multicentre, non-interventional data collection programme and will provide the largest single dataset representing children and adults with XLH. To be eligible for inclusion in the registry, patients must meet all the following criteria:1) Male or female subjects of all ages; 2) Diagnosis of XLH with clinical, radiological, biochemical and/or genetic findings consistent with XLH. The Registry captures any treatment details and clinical outcome variables in patients with XLH and patients are followed for as long as informed consent (and assent, where applicable) and regulatory permissions are maintained. Only data collected during standard routine examinations are recorded within the Registry, and no specific examinations/data entries are mandated.Parameters collected at baseline included demographics, medical and treatment history, and clinical presentation data. The conduct of the International XLH Registry is overseen by 17 Steering Committee physician members representing the region.ResultsAs of 31 December 2021, 1,043 subjects diagnosed with XLH were enrolled from 88 hospital sites in 19 countries. The geographic distribution of subjects is as follows: Belgium n=29, Bulgaria n=7, Czech Republic n=8, Denmark n=23, France n=267, Germany n=79, Hungary n=11, Ireland n=5, Israel n=21, Italy n=88, The Netherlands n=26, Norway n=23, Portugal n=9, Slovakia n=5, Slovenia n=3, Spain n=55, Sweden n=43, Switzerland n=17, and the UK n=324. A further 30 sites are yet to enrol (including sites in Austria and Latvia). Overall, 400 adults (18–29y, n=116; 30–39y, n=81; 40–49y, n=95; 50–59y, n=58; ≥60y, n=50) and 620 paediatric subjects (<5y, n=138; 5–12y, n=321; 13–17y, n=161) have been enrolled (date of birth not reported, n=23). The majority of enrolled subjects are female (648 (62.1%), with 372 male (35.7%) and 23 for whom sex was not reported (2.2%). The quantity of data from the patients included in this Registry will enable ongoing snapshot and prospective analyses to be conducted over the coming years to answer research questions and inform clinical practice.ConclusionThis International XLH Registry forms the largest dataset of subjects with XLH collected to date. Patients have been recruited from a wide geographical region and baseline demographics are consistent with a hereditary X-linked dominant disease. Information collected during the 10-year Registry duration will generate real-world evidence to help inform clinical practice throughout the region, with the aim of improving the care and quality of life of adults and children living with this debilitating disease.References[1]Haffner D, et al. Nat Rev Nephrol 2019;15(7):435–455.[2]Padidela R, et al. Orphanet J Rare Dis. 2020; 15:172.AcknowledgementsAuthors acknowledge the contribution of all International XLH Registry Steering Committee members, and all the investigators participating in the International XLH Registry.Disclosure of InterestsGema Ariceta Speakers bureau: I have received honoraria for lectures, presentations, or educational events from Alexion Pharmaceuticals, Recordati Rare Disease, Advicenne, Chiesi, Kyowa Kirin, Consultant of: I have participated on Advisory Boards for Alexion Pharmaceuticals, Advicenne, Chiesi, Dicerna, and Alnylam., Jonathan Liu Employee of: Employee of Kyowa Kirin International, Angela Williams Employee of: Employee of Kyowa Kirin International, Sue Wood Employee of: Employee of Kyowa Kirin International, Dirk Schnabel Speakers bureau: I received an honorarium from various companies for scientific lectures (i.e. Ascendis, BioMarin, Ferring Pharma, Hexal / Sandoz, Ipsen Pharma, Kyowa Kirin, Merck Serono, Novo Nordisk), Consultant of: BioMarin, Kyowa Kirin

Health Technology Assessments (HTA) often require that the impact of a treatment is modelled over a lifetime. However, clinical trials typically follow patients for a limited duration, and lifelong impact of a treatment may not be captured. X-Linked Hypophosphatemia (XLH) is a lifelong renal phosphate-wasting disorder characterised by chronic hypophosphatemia and osteomalacia, causing growth impairment and skeletal deformities in childhood; additional morbidities are evident in adulthood, including osteoarthritis, enthesopathy and fractures/pseudofractures. Burosumab targets the pathophysiology , as evidenced in a phase 3 trial in adults (UX023-CL303/NCT02526160). An elicitation exercise was used to extrapolate the observed intermediate trial results to clinically meaningful long-term outcomes, for the purpose of demonstrating the hypothesised lifetime impact of burosumab when treatment is initiated in adulthood. Expert elicitation, guided by HTA guidelines, was used to assess the hypothesised lifetime impact of treatment with burosumab initiated in adults on a variety of pre-specified morbidities that typically develop in adults. Opinions were sought from 7 international expert physicians treating adults with XLH and one dental expert via teleconferences and completion of a questionnaire. There was a high degree of agreement that initiation of treatment with burosumab during adulthood would be expected to stop the development of hypophosphatemia-mediated morbidities e.g., fractures/pseudofractures. For others, there was agreement that burosumab initiation during adulthood was unlikely to favourably affect long-term outcomes, e.g., osteoarthritis. There was less consensus of the potential impact of treatment for other morbidities (e.g., enthesopathy) when started post-epiphyseal fusion. The findings were used to inform causal links, structure and assumptions of an economic model of burosumab treatment initiated in adults with XLH. Expert elicitation to inform clinical hypotheses about the lifetime impact of a new treatment, given the known disease mechanisms and intermediate outcomes, can be used to inform the structure of an economic model.

X-linked hypophosphataemia (XLH) is a rare, phosphate wasting disease. The resultant chronic hypophosphatemia and osteomalacia lead to the development of musculoskeletal morbidities in adulthood, causing pain, stiffness, impaired physical function/mobility. A phase 3 study of burosumab (UX023-CL303) has demonstrated a treatment benefit, as measured using the Western Ontario and McMaster Universities Arthritis (WOMAC) Index. This is supported by a phase 3b, open-label extension study (BUR02). This study presents a post-hoc analysis utilising both studies. UX023-CL303 comprised a 24-week, randomised double-blind, placebo-controlled period and 72-week open-label treatment extension period. European subjects were invited to continue treatment in BUR02, with those who had interim dosing of burosumab between end of UX023-CL303 and start of BUR02 contributing to the analysis. A validated algorithm was used to map the WOMAC responses to a preference-based utility score. Utility change over time was estimated using asymptotic models fitted to the placebo data to week 24 from UX023-CL303, and the burosumab data to week 48 from BUR02. In UX023-CL303 observations were available for 131 subjects at 24 weeks and 59 subjects at 96 weeks, and for 22 subjects at BUR02 baseline. UX023-CL303 baseline mean utility score was 0.44 (SD: 0.22). At week 24, subjects randomised to burosumab had a statistically significant improvement in utility compared to placebo (difference between arms: 0.05, 95% CI: 0.02 to 0.09). Improvements were predicted for burosumab-treated patients compared to placebo using an asymptotic model at year 1 (0.11, 95% CI: 0.08 to 0.15), 2 (0.16, 95% CI: 0.13 to 0.19) and 3 (0.17, 95% CI: 0.13 to 0.21). Treatment with burosumab led to improvements in symptoms and function for adults with XLH in the phase 3 study. This is reflected in improvements in utility at 24 weeks. These improvements were predicted to continue and be maintained longer term.

Disease experience for people living with chronic diseases has changed dramatically with improvements in health utility. It remains unclear, however, the extent to which improvements in health utility leads to gains in work productivity and role functioning. This systematic literature review aimed to explore the relationship between health utility and work productivity or role functioning across chronic diseases. Diseases selected were chronic and severe (based on health utility weights in range 0.50 to 0.70). Records from a structured search conducted in MEDLINE, Embase and PsycINFO were reviewed against inclusion criteria and assessed for study quality/relevance. Articles published from 2000 – February 2021 and available in English were considered. Studies included a measure of health utility (e.g., EQ-5D) and productivity or role function (e.g., employment status, presenteeism and absenteeism). Study quality was assessed in terms of design, analysis approach, missing data and evidence of bias. The search identified 876 records; 244 underwent full review, and 34 of the highest quality studies were extracted. Only 4 longitudinal studies were identified. Studies included different diseases including multiple sclerosis, rheumatoid arthritis, and stroke. Weighted mean health utilities of 0.79 were observed for employed (full/part time) people with a chronic disease, compared with 0.71 for part time employed, 0.61 for those unemployed/not in work, and 0.62 for those incapable of working. These associations held in studies controlling for potential confounders (e.g., age, symptom severity etc). Values corresponded to approximately a 5% increase in employment per 0.1 unit increase in health utility value. There is limited longitudinal research among people with chronic diseases exploring how changes in health utility may lead to changes in work productivity and role functioning. However, the findings suggest that amongst people with a chronic and severe disease, better health states are expected to be associated with higher productivity.

TIO is a rare condition in which benign tumors secrete excess fibroblast growth factor 23 (FGF23), resulting in phosphate wasting and hypophosphatemia, compromising muscle and bone structure, and causing pain and fatigue. A valid and reliable patient-reported outcome (PRO) measure is required to evaluate the impact of treatment on TIO-associated pain and fatigue. This study evaluated the item/scale properties, reliability, validity, and sensitivity to change of the BFI and BPI-SF in adults with TIO and analyzed meaningful change thresholds. Data were from two Phase 2 studies of the FGF23-blocking antibody burosumab in adults with TIO – the largest prospective dataset to date (n=27; 48% female; age 33–73yrs). The BFI and BPI-SF item responses were well distributed across the scale but with slight floor effects. Both instruments had high Cronbach’s alphas (0.972–0.955 [BFI] and 0.949–0.954 [BPI-SF]) suggesting item redundancy. Test–retest reliability was adequate based on stability according to the 6-minute walk test (6MWT) (intraclass correlation coefficients 0.505–0.753 and 0.724–0.809, respectively). Multi-trait analysis supported the relevance of each instrument’s domain structure in TIO (item–scale correlations ≥0.77 for BFI, ≥0.65 for BPI-SF). Both instruments had good convergent validity with each other, and with the Short-Form 36 V2. For known groups validity, scores differed in a logical direction for the 6MWT and sit-to-stand test, but small samples hindered significance testing. There was some indication that the BFI and BPI-SF detect change over time in TIO. Conservative estimates for meaningful change thresholds are 1.5 points for the BFI and 1.4 points for the BPI-SF (distribution-based method). Analysis based on subgroups was exploratory given small samples but indicated test–retest reliability, known groups validity, and responsiveness. The BFI and BPI-SF are appropriate measures to evaluate the effects of treatment on pain and fatigue in TIO studies.

TIO is a rare condition in which benign tumors secrete excess fibroblast growth factor 23 (FGF23), resulting in phosphate wasting and hypophosphatemia, compromising muscle and bone structure and impacting function and wellbeing. A valid and reliable measure is required to evaluate the impact of treatment on health-related quality of life (HRQL). This study evaluated the item/scale properties, reliability, validity, and sensitivity to change of the SF-36 in adults with TIO and established meaningful change thresholds.

The southeastern United States is home to some of the richest biodiversity in the world. Over the last 200 years, however, rapid industrialization and urbanization have threatened many natural areas, including freshwater habitats. River impoundments have also rapidly altered freshwater habitats, often resulting in species extirpation or extinction. The Coosa River in Alabama experienced one of the largest faunal declines in modern history after impoundment, making it an ideal system for studying how invertebrate species are affected by reservoir creation. One such species, the Rough Hornsnail, Pleurocera foremani, is an endangered freshwater snail in the family Pleuroceridae. We sampled all known localities of P foremani and used 2bRAD-seq to measure genetic diversity. We assessed riverscape genomic patterns across the current range of P foremani and measured gene flow within and between impoundments. We also investigated the degree to which P foremani displays an isolation by distance pattern and conforms to broad hypotheses that have been put forth for population genetics of riverine species like the Mighty Headwater Hypothesis that predicts greater genetic diversity in headwater reaches compared with mainstem populations. Like most other freshwater species, a pattern of isolation by distance was observed in P foremani. We also found that Coosa River dams are a barrier to gene flow, and genetic fragmentation of P foremani is likely to increase. However, gene flow appeared common within reservoirs and tributaries. Additionally, we found that spatial genetic structure of P foremani deviates from what is expected under the Mighty Headwaters Hypothesis, adding to a growing body of research suggesting that the majority of genetic diversity in low-dispersing gastropods is found in mainstem populations.

TIO is a rare condition in which benign tumors secrete excess fibroblast growth factor 23 (FGF23), resulting in phosphate wasting and hypophosphatemia, compromising muscle and bone structure and impacting function and wellbeing. A valid and reliable measure is required to evaluate the impact of treatment on health-related quality of life (HRQL). This study evaluated the item/scale properties, reliability, validity, and sensitivity to change of the SF-36 in adults with TIO and established meaningful change thresholds. Data were from two Phase 2 studies that evaluated the FGF23-blocking antibody burosumab in adults with TIO – the largest prospective dataset to date (n=27; 48% female; age 33–73 years). Item responses for the SF-36 V2 were well distributed across the scale, with slight floor and ceiling effects. Cronbach’s alpha was ≥0.70 for all eight domains. Item–total correlations were ≥0.40 except for “vigorous activity” and “tired” in the Physical Functioning domain. For stability according to the 6-minute walk test (6MWT), intraclass correlation coefficients for test–retest were ≥0.75 for four domains and ≥0.40 for the other three. Multi-trait analysis supported the relevance of the domain structure in TIO (item–scale correlations ≥0.40 for all items except vigorous activity), with good support for convergent validity with the Brief Fatigue Inventory, Brief Pain Inventory Short-Form, and 6MWT. For known groups validity, scores differed in a logical direction for the 6MWT but small samples hindered significance testing. There was some indication that the SF-36 detects change over time in TIO. The change thresholds determined were in line with thresholds provided in the SF-36 user manual. Analyses based on subgroups were exploratory because of small samples but indicated test–retest reliability, known groups validity, and responsiveness. The SF-36 is an appropriate measure to evaluate the effects of treatment on HRQL in TIO studies.

XLH is a rare genetic, lifelong, progressive bone disorder. Adults with XLH typically experience multiple symptoms including fatigue, bone and joint pain, and stiffness. A valid and reliable patient-reported outcome (PRO) measure is required to evaluate the impact of treatment on XLH-associated fatigue. This study evaluated the item/scale properties, reliability, validity, and sensitivity to change of the BFI in adults with XLH and established meaningful change/responder thresholds. Data from a Phase 3 multicenter, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of burosumab in adults with XLH (n = 134; 65% female; median [range] age 40 [18–65] years) were analysed. Item responses were well distributed across the scale. Item-scale correlations were good for both Fatigue Interference (0.85–0.92) and Global Fatigue (0.72–0.90). In known-groups analysis, the BFI discriminated between groups differing in pain and 6-minute walk test (6MWT) distance, but not between those needing/not needing mobility assistance during the 6MWT. There was moderate support for convergent validity, with the strongest correlations with the BPI Pain Interference and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) pain scores. Fatigue Interference and Global Fatigue both had high internal consistency reliability (α=0.94). When the Patient Global Impression of Improvement (PGI-I) was used to define stability, all intraclass coefficients indicated moderate or high test–retest reliability. Responsiveness analyses provided strong support that the BFI detects change over time when using the PGI-I to define change groups, but evidence was weaker when the 6MWT was used. Recommended responder thresholds were −1.5 for Worst Fatigue and −1.2 for Fatigue Interference and Global Fatigue. These analyses confirm the reliability, validity, and responsiveness of the BFI in adults with XLH and provide responder thresholds supporting use of this PRO to evaluate the effects of treatment interventions in XLH clinical studies.

On October 4th , 2019, an angler caught and released a single northern snakehead (Channa argus) in a private pond in Gwinnett County, Georgia, USA. Pictures of the specimen were reported to the Georgia Department of Natural Resources, Wildlife Resources Division, Fisheries Management Section (DNR), and subsequent investigations by the DNR including electrofishing and rotenone surveys resulted in the capture and removal of 34 individuals from the area. Genetic analyses of fin clips from 33 specimens indicated the population consisted of a combination of juveniles from a breeding pair of captured adults and other unsampled adults. This discovery constitutes the first record of this non-native species in Georgia, and the results demonstrate how genetic analyses can facilitate effective understanding of invasion dynamics during rapid response operations.

A European, prospective, multi-centre, mixed-methods observational study is in development to investigate treatment transition and disease experience in adolescents with X-Linked Hypophosphatemia (XLH), a rare, genetic life-long phosphate-wasting disorder. To ensure robustness, feasibility and patient-centricity of study design, a UK patient-public involvement (PPI) project was undertaken. During June 2020, four adolescents (14-18 years), recruited via patient group XLH UK, underwent 1:1 semi-structured 60-minute telephone interviews (following informed consent). Participants described their experience of known symptoms and impacts of XLH identified from the literature and burosumab trials (pain, stiffness, mobility and physical function, tiredness/fatigue, sleep, emotional wellbeing) and then prioritised their importance for measurement. The acceptability of proposed methods for data capture (e.g. use of wearables, smartphone app), recruitment, and retention of participants was also discussed. Responses were summarised narratively in MS Excel to aid future study design. The interference of pain, stiffness and tiredness/fatigue on daily physical activities were identified as key endpoints, alongside modifications to daily activities and socialising for symptom management. Mild symptoms were reported by most participants, either due to effective treatment or reduced activity during COVID-19. One participant was more concerned with emotional wellbeing, relating to self-confidence, and favoured its measurement in studies. No-one reported problematic sleep. All were willing to participate in a 12-month study, answering one daily question using a phone app and wearing a wrist-device daily to capture activity, although night-time use was less acceptable. Recruitment via social media and doctors was perceived as optimal and compensatory monetary vouchers were favoured. This PPI project identified patient-relevant endpoints of pain, stiffness and fatigue/ tiredness to be examined according to their interference of daily physical activities or socialising. Measurement using wearables and smartphones was viewed as acceptable and feasible for adolescents with XLH, which may therefore relieve burden on the healthcare system.