Common and uncommon mouse models of growth hormone deficiency.

Mouse models of growth hormone deficiency (GHD) have provided important tools for uncovering the various actions of GH. Nearly 100 years of research using these mouse lines has greatly enhanced our knowledge of the GH/IGF-1 axis. Some of the shared phenotypes of the five "common" mouse models of GHD include reduced body size, delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, and enhanced insulin sensitivity. Since these common mouse lines outlive their normal-sized littermates - and have protection from age-associated disease - they have become important fixtures in the aging field. On the other hand, the twelve "uncommon" mouse models of GHD described herein have tremendously divergent health outcomes ranging from beneficial aging phenotypes (similar to those described for the common models) to extremely detrimental features (such as improper development of the CNS, numerous sensory organ defects, and embryonic lethality). Moreover, advancements in next generation sequencing technologies have led to the identification of an expanding array of genes that are recognized as causative agents to numerous rare syndromes with concomitant GHD. Accordingly, this review provides researchers with a comprehensive up-to-date collection of the common and uncommon mouse models of GHD that have been used to study various aspects of physiology and metabolism associated with multiple forms of GHD. For each mouse line presented, the closest comparable human syndromes are discussed providing important parallels to the clinic.

Predictors of adherence to follow-up and treatment success in childhood obesity.

INTRODUCTION: Management of childhood obesity, based upon behavioural, physical activity and dietary guidance, usually achieves limited success and is hindered by a high attrition rate. The identification of potential predictors of either weight loss or early weight management attrition could help develop personalised management plans in order to improve patient outcomes. PATIENTS AND METHODS: We conducted a retrospective study in a cohort of 1300 patients with obesity managed in speciality clinics for up to 5 years with outpatient conservative treatment. We studied the family background and personal characteristics (demographic, behavioural, psychosocial, anthropometric and metabolic) of patients who dropped out before completing the first year of the programme and patients who achieved significant weight loss, with a separate analysis of patients who achieved substantial reductions in weight compared to the rest of the cohort. RESULTS: The mean age of the patients in the cohort was 10.46 years (SD, 3.48) the mean BMI z-score 4.01 (SD, 1.49); 52.8% of the patients were male, 53.3% were prepubertal, 75.8% were Caucasian and 19% Latin. We found a higher proportion of Latinla ethnicity and compulsive eating in the group of patients with early attrition from the weight management follow-up. In the group of patients with substantial weight loss, a greater proportion were male, there was a higher frequency of dietary intake control at home and obesity was more severe, and the latter factor was consistently observed in patients who achieved substantial weight loss at any point of the follow-up. CONCLUSIONS: Some family and personal characteristics in childhood obesity are associated with an increased risk of early withdrawal from follow-up or a greater probability of successful outcomes; however, the predictive value of these variables is limited.

New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue-nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease-causing variants; 4.4% had variants of uncertain significance. Disease-causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%-23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty-three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population.

Reduced Cortical Thickness Correlates of Cognitive Dysfunction in Post-COVID-19 Condition: Insights from a Long-Term Follow-up.

BACKGROUND AND PURPOSE: There is a paucity of data on long-term neuroimaging findings from individuals who have developed the post-coronavirus 2019 (COVID-19) condition. Only 2 studies have investigated the correlations between cognitive assessment results and structural MR imaging in this population. This study aimed to elucidate the long-term cognitive outcomes of participants with the post-COVID-19 condition and to correlate these cognitive findings with structural MR imaging data in the post-COVID-19 condition. MATERIALS AND METHODS: A cohort of 53 participants with the post-COVID-19 condition underwent 3T brain MR imaging with T1 and FLAIR sequences obtained a median of 1.8 years after Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. A comprehensive neuropsychological battery was used to assess several cognitive domains in the same individuals. Correlations between cognitive domains and whole-brain voxel-based morphometry were performed. Different ROIs from FreeSurfer were used to perform the same correlations with other neuroimaging features. RESULTS: According to the Frascati criteria, more than one-half of the participants had deficits in the attentional (55%, n = 29) and executive (59%, n = 31) domains, while 40% (n = 21) had impairment in the memory domain. Only 1 participant (1.89%) showed problems in the visuospatial and visuoconstructive domains. We observed that reduced cortical thickness in the left parahippocampal region (t(48) = 2.28, P = .03) and the right caudal-middle-frontal region (t(48) = 2.20, P = .03) was positively correlated with the memory domain. CONCLUSIONS: Our findings suggest that cognitive impairment in individuals with the post-COVID-19 condition is associated with long-term alterations in the structure of the brain. These macrostructural changes may provide insight into the nature of cognitive symptoms.

Prepubertal children with obesity have high free IGF-1 levels and accelerated growth despite reduced pappalysin levels.

BACKGROUND: Prepubertal children with obesity frequently have enhanced growth, accelerated skeletal maturation and changes in the GH-IGF axis. However, the involvement of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF bioavailability has not been studied in obesity. OBJECTIVE: We aimed to determine the effects of childhood obesity and weight reduction on serum levels of PAPP-A, PAPP-A2, STC1 and STC2 and their relationship with IGF bioavailability, growth, and other components of the GH-IGF system. PATIENTS AND METHODS: Prepubertal children with severe obesity (150, 50% males/females, age: 7.72 ± 2.05 years, BMI z-score: 4.95 ± 1.70, height z-score: 1.28 ± 1.04) were studied at diagnosis and after a minimum of 0.5 BMI z-score reduction. Two hundred and six healthy age- and sex-matched children were used as controls. RESULTS: Children with obesity had decreased serum concentrations of PAPP-A, PAPP-A2 and STC2, but increased total and free IGF-I (fIGF-I), intact IGFBP-3, ALS, IGF-II and insulin levels, with no difference in the free/total IGF-I ratio. Neither the standardized BMI nor height correlated with any biochemical parameter analyzed. A decrease in IGF-II, insulin, and ALS with an increase in IGFBP-2 and -5, STC2 and PAPP-A were observed after weight loss. CONCLUSION: Increased circulating total and free IGF-I, insulin and IGF-II may all contribute to the increased rate of prepubertal growth and bone maturation observed in children with obesity, with STC2 possibly being involved.

Effectiveness of asfotase alfa for treatment of adults with hypophosphatasia: results from a global registry.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. METHODS: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. RESULTS: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60-632 m) at baseline (n = 31) to 484 m at Month 12 (range 240-739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from - 0.72 (95% CI: - 1.23, - 0.21; n = 38) to - 1.13 (95% CI: - 1.76, - 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. CONCLUSIONS: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. REGISTRATION: NCT02306720; EUPAS13514.

[The euthanasia law and professional experiences: tensions in clinical practice]. / La ley de eutanasia y experiencias profesionales: tensiones en la práctica clínica.

OBJECTIVE: To analyze the process of assisted death provision in Catalonia and identify the main tensions, difficulties, and/or sources of discomfort related to professional practice. METHOD: A qualitative study was conducted based on interviews (n=29) and focus groups (n=19) with professionals who participated in the euthanasia process. The selection of participants combined the snowball and maximization of variability procedures, taking into account the variables of professional profile, setting, gender, age and territoriality. Intentional and theoretical sampling process. RESULTS: The assisted death process is divided into four main moments: 1) reception of the request, 2) medical-bureaucratic procedure, 3) the actual procedure, and 4) closure. At each of these moments, difficulties arise that can be a source of discomfort and have to do with the limits and tensions between the legal and moral, the conception of one's own professional role, the lack of recognition of some professional roles, stress and overload, the lack of formal and informal support, and the relationship with the patient and his/her family. The bureaucratic-administrative stress derived from a protective law, with both prior and subsequent verifying control, stands out, given that it stresses the professionals immersed in a healthcare system already under high pressure after budget cuts and the COVID-19 epidemic. CONCLUSIONS: Throughout the assisted death process, the sources of distress are diverse and of a psychological, psychosocial, and structural nature. These results may lead to interventions for psychological and peer support, information, training, institutional involvement, and burden reduction.

DNA barcodes reliably differentiate between nivicolous species of Diderma (Myxomycetes, Amoebozoa) and reveal regional differences within Eurasia.

The nivicolous species of the genus Diderma are challenging to identify, and there are several competing views on their delimitation. We analyzed 102 accessions of nivicolous Diderma spp. that were sequenced for two or three unlinked genes to determine which of the current taxonomic treatments is better supported by molecular species delimitation methods. The results of a haplotype web analysis, Bayesian species delimitation under a multispecies coalescent model, and phylogenetic analyses on concatenated alignments support a splitting approach that distinguishes six taxa: Diderma alpinum, D. europaeum, D. kamchaticum, D. meyerae, D. microcarpum and D. niveum. The first two approaches also support the separation of Diderma alpinum into two species with allopatric distribution. An extended dataset of 800 specimens (mainly from Europe) that were barcoded with 18S rDNA revealed only barcode variants similar to those in the species characterized by the first data set, and showed an uneven distribution of these species in the Northern Hemisphere: Diderma microcarpum and D. alpinum were the only species found in all seven intensively sampled mountain regions. Partial 18S rDNA sequences serving as DNA barcodes provided clear signatures that allowed for unambiguous identification of the nivicolous Diderma spp., including two putative species in D. alpinum.

Population-based Influenza and Respiratory Syncytial Virus Hospitalizations and In-hospital Mortality Rates Among Mexican Children Less Than Five Years of Age.

BACKGROUND: Population-based information regarding the impact of respiratory syncytial virus (RSV) and influenza on hospital admissions and mortality is scant for many countries. METHODS: Prospective testing of RSV and influenza virus was undertaken in patients <5 years old admitted to hospital with acute respiratory infection (ARI) between July, 2014 and June, 2015, and mortality rates for children living in 3 municipalities in the state of San Luis Potosí were calculated. RESULTS: During the 12-month study period, 790 children living in these municipalities were admitted with ARI. RSV was detected in 245 (31%) and influenza in 47 (5.9%). History of preterm birth was recorded for 112 children on admission. For children <5 years old, ARI-, RSV- and influenza-associated admission rates were 23.2, 7.2 and 1.4 (per 1000 population), respectively. The corresponding admission rates per 1000 infants <1 year old were 78, 25.2 and 4.4. Preterm infant admission rates were 2 times higher than those of term infants. Six children died; RSV was detected in 4 (66.6%) of the deceased, while no deaths were associated with influenza. ARI and RSV in-hospital mortality rates for children <5 years were 0.18 and 0.12 per 1000 population. ARI and RSV mortality rates in preterm infants were 7 and 14 times higher than in term infants, respectively. CONCLUSIONS: RSV was associated with both high admission and in-hospital mortality rates in children <5 years old. Specific interventions, such as active or passive immunization, to prevent RSV infections are required to reduce ARI-associated infant mortality.

Tasmaniomyxa umbilicata, a new genus and new species of myxomycete from Tasmania.

A new genus and species of myxomycete, Tasmaniomyxa umbilicata, is described based on numerous observations in Tasmania and additional records from southeastern Australia and New Zealand. The new taxon is characterized by an unusual combination of characters from two families: Lamprodermataceae and Didymiaceae. With Lamprodermataceae the species shares limeless sporocarps, a shining membranous peridium, an epihypothallic stalk, and a cylindrical columella. Like Didymiaceae, it has a soft, flaccid, sparsely branched capillitium, with rough tubular threads that contain fusiform nodes and are firmly connected to the peridium. Other characters of T. umbilicata that also occur in many Didymiaceae are the peridium dehiscing into petaloid lobes, the yellow, motile plasmodium, and the spores ornamented with larger, grouped and smaller, scattered warts. The transitional position of the new taxon is reflected by a three-gene phylogeny, which places T. umbilicata at the base of the branch of all lime-containing Physarales, thus justifying its description as a monotypic genus.

The Global ALPL gene variant classification project: Dedicated to deciphering variants.

BACKGROUND: Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase (TNSALP). Variants of uncertain significance (VUS) cause diagnostic delay and uncertainty amongst patients and health care providers. RESULTS: The ALPL gene variant database (https://alplmutationdatabase.jku.at/) is an open-access archive for interpretation of the clinical significance of variants reported in ALPL. The database contains coding and non-coding variants, including single nucleotide variants, insertions/deletions and structural variants affecting coding or non-coding sequences of ALPL. Each variant in the database is displayed with details explaining the corresponding pathogenicity, and all reported genotypes and phenotypes, including references. In 2021, the ALPL gene variant classification project was established to reclassify VUS and continuously assess and update genetic, phenotypic, and functional variant information in the database. For this purpose, the database provides a unique submission system for clinicians, geneticists, genetic counselors, and researchers to submit VUS within ALPL for classification. An international, multidisciplinary consortium of HPP experts has been established to reclassify the submitted VUS using a multi-step process adhering to the stringent ACMG/AMP variant classification guidelines. These steps include a clinical phenotype assessment, deep literature research including artificial intelligence technology, molecular genetic assessment, and in-vitro functional testing of variants in a co-transfection model to measure ALP residual activity. CONCLUSION: This classification project and the ALPL gene variant database will serve the global medical community, widen the genotypic and phenotypic HPP spectrum by reporting and characterizing new ALPL variants based on ACMG/AMP criteria and thus facilitate improved genetic counseling and medical decision-making for affected patients and families. The project may also serve as a gold standard framework for multidisciplinary collaboration for variant interpretation in other rare diseases.

Increased IGFBP proteolysis, IGF-I bioavailability and pappalysin levels in children with Prader-Willi syndrome.

CONTEXT: Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. OBJECTIVE: We determined serum levels of PAPP-As and STCs in association with IGF axis components in pre- and pubertal patients with PWS, also analyzing the effect of GH treatment. METHODS: Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at six months of treatment in 11 children. RESULTS: Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and higher concentrations of free IGF-I, IGFBP-5 and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. CONCLUSION: The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

The N221D variant in PCSK1 is highly prevalent in childhood obesity and can influence the metabolic profile.

OBJECTIVES: To study the prevalence and influence on metabolic profile of the prohormone-convertase-1 (PCSK1) N221D variant in childhood obesity, proven its role in the leptin-melanocortin signaling pathway as in proinsulin and other prohormone cleavage. METHODS: Transversal study of 1066 children with obesity (mean age and BMI Z-score 10.38 ± 3.44 years and +4.38 ± 1.77, respectively), 51.4 % males, 54.4 % prepubertal, 71.5 % Caucasians and 20.8 % Latinos. Anthropometric and metabolic features were compared between patients carrying the N221D variant in PCSK1 and patients with no variants found after next generation sequencing analysis of 17 genes (CREBBP, CPE, HTR2C, KSR2, LEP, LEPR, MAGEL2, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, SIM1, TBX3 and TUB) involved in the leptin-melanocortin pathway. RESULTS: No variants were found in 531 patients (49.8 %), while 68 patients carried the PCSK1 N221D variant (42 isolately, and 26 with at least one additional gene variant). Its prevalence was higher in Caucasians vs. Latinos (χ2 7.81; p<0.01). Patients carrying exclusively the PCSK1 N221D variant (n=42) showed lower insulinemia (p<0.05), HOMA index (p<0.05) and area under the curve for insulin in the oral glucose tolerance test (p<0.001) and higher WBISI (p<0.05) than patients with no variants, despite similar obesity severity, age, sex and ethnic distribution. CONCLUSIONS: The N221D variant in PCSK1 is highly prevalent in childhood obesity, influenced by ethnicity. Indirect estimation of insulin resistance, based on insulinemia could be byassed in these patients and underestimate their type 2 diabetes mellitus risk.

Clinical Profiles of Children with Hypophosphatasia Prior to Treatment with Enzyme Replacement Therapy: An Observational Analysis from the Global HPP Registry.

INTRODUCTION: To better understand the clinical profiles of children with hypophosphatasia (HPP) prior to treatment with enzyme replacement therapy (ERT). METHODS: Pretreatment demographics and medical histories of ERT-treated children (aged < 18 years) enrolled in the Global HPP Registry (2015-2020) were analyzed overall, by age at first HPP manifestation (< 6 months versus 6 months to 18 years) and by geographic region (United States/Canada, Europe, and Japan). RESULTS: Data from 151 children with HPP were analyzed. Sex distribution was balanced overall (52.3% female; 47.7% male) but differed in Japan (63.0% female; 37.0% male). Prior to ERT initiation, common manifestations were skeletal (67.5%) and extraskeletal, with the foremost being muscular (48.3%), constitutional/metabolic (47.0%), and neurologic (39.7%). A high proportion of children who first presented at < 6 months of age (perinatal/infantile period) had a history of bone deformity (59.3%) and respiratory failure (38.3%), while those aged 6 months to 18 years at first manifestation had a predominance of early loss of primary teeth (62.3%) and gross motor delay (41.0%). Japan reported a younger median age overall, the highest proportion of skeletal (80.4%) manifestations and growth impairment, while European data showed the highest proportion of muscular manifestations (70.7%). In the United States/Canada, skeletal and muscular manifestations were reported at the same frequency (57.4%). DISCUSSION/CONCLUSION: Prior to ERT, skeletal and extraskeletal manifestations were commonly reported in children with HPP, with differences by age at first HPP manifestation and geographical region. Comprehensive assessments of children with HPP are warranted prior to ERT initiation.

Bioclimatic Origin Shapes Phylogenetic Structure of Tirmania (Pezizaceae): New Species and New Record from North Africa.

The phylogenetic relationships among Tirmania were investigated using the internal transcribed spacer (ITS) and large subunit (LSU) regions of the nuclear-encoded ribosomal DNA (rDNA) and compared with morphological and bioclimatic data. The combined analyses of forty-one Tirmania samples from Algeria and Spain supported four lineages corresponding to four morphological species. Besides the two previously described taxa, Tirmania pinoyi and Tirmania nivea, here we describe and illustrate a new species, Tirmania sahariensis sp. nov., which differs from all other Tirmania by its distinct phylogenetic position and its specific combination of morphological features. We also present a first record of Tirmania honrubiae from North Africa (Algeria). Our findings suggest that restrictions imposed by the bioclimatic niche have played a key role in driving the speciation process of Tirmania along the Mediterranean and Middle East.

Impact of muscular symptoms and/or pain on disease characteristics, disability, and quality of life in adult patients with hypophosphatasia: A cross-sectional analysis from the Global HPP Registry.

Introduction: Hypophosphatasia (HPP) manifests in adults as fractures/pseudofractures, pain, muscle weakness, and other functional impairments. Better phenotypic disease characterization is needed to help recognize disability and treat patients with HPP. Methods: Baseline/pretreatment demographic, clinical characteristic, and patient-reported disability/health-related quality-of-life (HRQoL) data from adults (≥18 y) in the Global HPP Registry (NCT02306720) were stratified by presence of overt skeletal manifestations (skeletal group) versus muscular/pain manifestations without skeletal manifestations (muscular/pain group) and summarized descriptively. Disability was measured using the Health Assessment Questionnaire-Disability Index (HAQ-DI), and HRQoL using the 36-item Short Form Health Survey (SF-36v2). Results: Of 468 adults, 300 were classified into the skeletal group and 73 into the muscular/pain group. The skeletal group had a higher median age at baseline (50.1 vs 44.4 y; P=0.047) but a lower median age at first HPP manifestation (12.3 vs 22.1 y; P=0.0473), with more signs and symptoms (median, 4 vs 3; P<0.0001) and involved body systems (median, 3 vs 2; P<0.0001) than the muscular/pain group. More patients in the skeletal group required any use of mobility aids (22.6% vs 3.5%, respectively; P=0.001). Six-Minute Walk test distances walked were similar between groups. SF-36v2 and HAQ-DI scores were similar between groups for physical component summary (n=238; mean [SD]: 40.2 [11.0] vs 43.6 [11.2]; P=0.056), mental component summary (n=238; mean [SD]: 43.6 [11.3] vs 43.8 [11.8]; P=0.902), and HAQ-DI (n=239; median [minimum, maximum]: 0.4 [0.0, 2.7] vs 0.3 [0.0, 2.1]; P=0.22). Conclusion: Adults with HPP experience similar QoL impairment regardless of skeletal involvement. Registration: https://clinicaltrials.gov/ct2/show/NCT02306720 and https://www.encepp.eu/encepp/viewResource.htm?id=47907, identifier NCT02306720; EUPAS13514.

Growth and disease burden in children with hypophosphatasia.

Objective: Hypophosphatasia, an inborn error of metabolism characterized by impaired bone mineralization, can affect growth. This study evaluated relationships between anthropometric parameters (height, weight, and body mass index) and clinical manifestations of hypophosphatasia in children. Design: Data from children (aged <18 years) with hypophosphatasia were analyzed from the observational Global Hypophosphatasia Registry. Methods: Anthropometric parameters were evaluated by age group (<2 years and ≥2 years) at assessment. The frequency of hypophosphatasia manifestations was compared between children with short stature (< percentile) and those with normal stature. Results: This analysis included 215 children (54.4% girls). Short stature presented in 16.1% of children aged <2 years and 20.4% of those aged ≥2 years at assessment. Among those with available data (n = 62), height was below the target height (mean: -0.66 standard deviations). Substantial worsening of growth (mean delta height z score: -1.45; delta weight z score: -0.68) occurred before 2 years of age, while in those aged ≥2 years, anthropometric trajectories were maintained (delta height z score: 0.08; delta weight z score: 0.13). Broad-ranging hypophosphatasia manifestations (beyond dental) were observed in most children. Conclusions: Short stature was not a consistent characteristic of children with hypophosphatasia, but growth impairment was observed in those aged <2 years, indicating that hypophosphatasia might affect growth plate activity during infancy. In addition, a broad range of clinical manifestations occurred in those above and below the third percentile for height, suggesting that height alone may not accurately reflect hypophosphatasia disease burden and that weight is less affected than longitudinal growth.

Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results.

BACKGROUND: Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of life in patients with Bardet-Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet-Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522). METHODS: Patients with Bardet-Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged < 18 years or their caregiver completed the Pediatric Quality of Life Inventory (PedsQL; meaningful improvement, 4.4-point change); adults aged ≥ 18 years completed the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-Lite; meaningful improvement range, 7.7-12-point change). Descriptive outcomes were reported in patients with data both at active treatment baseline and after 52 weeks of treatment. RESULTS: Twenty patients (< 18 years, n = 9; ≥ 18 years, n = 11) reported health-related quality of life at baseline and 52 weeks. For children and adolescents, PedsQL score mean change from baseline after 52 weeks was + 11.2; all patients with PedsQL impairment at baseline (n = 4) experienced clinically meaningful improvement. In adults, IWQOL-Lite score mean change from baseline was + 12.0. Of adults with IWQOL-Lite impairment at baseline (n = 8), 62.5% experienced clinically meaningful improvement. In adults, IWQOL-Lite score was significantly correlated with changes in percent body weight (P = 0.0037) and body mass index (P = 0.0098). CONCLUSIONS: After 1 year of setmelanotide, patients reported clinically meaningful improvements across multiple health-related quality of life measures. This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. Trial Registration NCT03746522. Registered November 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03746522 .

[Care complexity and place of death in palliative home care]. / Complejidad asistencial y lugar de muerte en atención domiciliaria paliativa.

OBJECTIVE: To examine the associations between the dimensions of the HexCom care complexity model and the place of death. METHOD: Multicenter longitudinal observational study in patients with advanced illness cared for by home care support teams in Catalonia. Age, gender, type of illness, main caregiver, external support, place of death and the sub-areas of care complexity provided by HexCom were registered. A multivariate Cox regression analysis was performed. RESULTS: Participation of 1527 patients (72% oncology), cared for a median of 35 days. 45% died at home. The probability of dying at home was greater when a greater functional impairment was detected in the initial assessment (hazard ratio [HR]: 7.67; 95% confidence interval [95%CI]: 4.93-11.92), when the patient was male (HR: 1.19; 95%CI: 1.02-1.39), was over 80 years old (HR: 1.41; 95%CI: 1.20-1.66) and when care complexity was detected in relation to being in a situation of last days (HR: 2.24; 95%CI: 1.69-2.97). It was more likely not to die at home in the case of cancer (HR: 0.76; 95%CI: 0.64-0.89), or if poor external support to the family group was detected in the first evaluation (HR: 0.79; 95%CI: 0.67-0.93), or that the patient did not feel at peace with others (HR: 0.56; 95%CI: 0.40-0.79), or lack of agreement on the planning of the place of death (HR: 0.57; 95%CI: 0.48-0.68). CONCLUSIONS: The assessment of the complexity of care through the HexCom-Clin model can help to improve advance planning of decisions by incorporating among its dimensions the feeling of peace with others, the external support to the family nucleus and the degree of agreement on the place of death.