International consensus on the non-pharmacological and non-surgical management of osteoporotic vertebral fractures.

We identified a knowledge gap in the non-pharmacological and non-surgical management of osteoporotic vertebral fractures. MAIN RESULTS: This international consensus process established multidisciplinary biopsychosocial recommendations on pain, nutrition, safe movement, and exercise for individuals with acute and chronic vertebral fractures. SIGNIFICANCE: These recommendations will guide clinical practice and inform interventions for future research. PURPOSE: To establish international consensus on recommendations for the non-pharmacological and non-surgical management of osteoporotic vertebral fractures. METHODS: We adopted a five-step modified Delphi consensus process: (1) literature search and content analysis, (2) creation of the survey, (3) selection of the expert panel, (4) first round of the rating process, and (5) second round of the rating process. The first round included 49 statements and eight open-ended questions; the second round included 30 statements. Panelists were asked to rate their agreement with each of the statements using a 9-point scale, with the option to provide further comments. Consensus for each statement was determined by counting the number of panelists whose rating was outside the 3-point region containing the median. RESULTS: We invited 76 people with degree in medicine, physiotherapy, kinesiology, and experience in the management of osteoporotic vertebral; 31 (41%) and 27 (36%) experts agreed to participate to the first and the second round, respectively. The mean percentage agreement after the first and second rounds was 76.6% ± 16.0% and 90.7% ± 6.5%, respectively. We established consensus on recommendations on pain, early satiety, weight loss, bracing, safe movement, and exercise for individuals with acute and chronic vertebral fractures. CONCLUSION: Our international consensus provides multidisciplinary biopsychosocial recommendations to guide the management of osteoporotic vertebral fractures and inform interventions for future research.

Sublimation in bright spots on (1) Ceres.

The dwarf planet (1) Ceres, the largest object in the main asteroid belt with a mean diameter of about 950 kilometres, is located at a mean distance from the Sun of about 2.8 astronomical units (one astronomical unit is the Earth-Sun distance). Thermal evolution models suggest that it is a differentiated body with potential geological activity. Unlike on the icy satellites of Jupiter and Saturn, where tidal forces are responsible for spewing briny water into space, no tidal forces are acting on Ceres. In the absence of such forces, most objects in the main asteroid belt are expected to be geologically inert. The recent discovery of water vapour absorption near Ceres and previous detection of bound water and OH near and on Ceres (refs 5-7) have raised interest in the possible presence of surface ice. Here we report the presence of localized bright areas on Ceres from an orbiting imager. These unusual areas are consistent with hydrated magnesium sulfates mixed with dark background material, although other compositions are possible. Of particular interest is a bright pit on the floor of crater Occator that exhibits probable sublimation of water ice, producing haze clouds inside the crater that appear and disappear with a diurnal rhythm. Slow-moving condensed-ice or dust particles may explain this haze. We conclude that Ceres must have accreted material from beyond the 'snow line', which is the distance from the Sun at which water molecules condense.

[The antagonistic function of the heart muscle sustains the autoregulation according to Frank and Starling : Part I: Structure and function of heart muscle]. / Die antagonistische Funktion des Herzmuskels unterstützt die Autoregulation nach Frank-Starling : Teil I: Struktur und Funktion des Herzmuskels.

In the tradition of Harvey and according to Otto Frank the heart muscle structure is arranged in a strictly tangential fashion hence all contractile forces act in the direction of ventricular ejection. In contrast, morphology confirms that the heart consists of a 3-dimensional network of muscle fibers with up to two fifths of the chains of aggregated myocytes deviating from a tangential alignment at variable angles. Accordingly, the myocardial systolic forces contain, in addition to a constrictive also a (albeit smaller) radially acting component. Using needle force probes we have correspondingly measured an unloading type of force in a tangential direction and an auxotonic type in dilatative transversal direction of the ventricular walls to show that the myocardial body contracts actively in a 3-dimensional pattern. This antagonism supports the autoregulation of heart muscle function according to Frank and Starling, preserving ventricular shape, enhances late systolic fast dilation and attenuates systolic constriction of the ventricle wall. Auxotonic dilating forces are particularly sensitive to inotropic medication. Low dose beta-blocker is able to attenuate the antagonistic activity. All myocardial components act against four components of afterload, the hemodynamic, the myostructural, the stromatogenic and the hydraulic component. This complex interplay critically complicates clinical diagnostics. Clinical implications are far-reaching (see Part II, https://doi.org/10.1007/s00059-018-4735-x).

Making the Most of Mealtimes (M3): effect of eating occasions and other covariates on energy and protein intake among Canadian older adult residents in long-term care.

BACKGROUND: Food intake varies among long-term care (LTC) residents and, as a result, some residents are at risk for protein-energy malnutrition and its consequences, such as sarcopenia. The present study aimed to determine whether eating occasions, as well as other factors that may vary with eating occasions (e.g. family/volunteer presence), were associated with energy and protein intake at meals and snacks. METHODS: The present study comprised a secondary analysis of the cross-sectional Making the Most of Mealtimes study, including 630 residents (median age 88.00 years, range 62-107 years; 197 males) from 32 Canadian LTC homes. An analysis of variance compared protein and energy intake at meals and snacks. Mixed repeated measures linear regression testing for meal and relevant covariates (e.g. family/volunteer presence) was also conducted. RESULTS: Energy and protein intake was significantly associated with eating occasions (F = 44.31, P < 0.001; F = 12.72, P < 0.001), with the greatest energy intake at breakfast, and the greatest protein intake at dinner. Regression analysis confirmed these findings when considering other factors. Covariates associated with higher intake included: being male (+79 kcal; +3.4 g protein), living on a dementia care unit (+39 kcal; +2.1 g protein) and family/volunteer presence at meals (+58 kcal; +2.5 g protein). Intake was lowest in the oldest age group (-59 kcal; -3.6 g protein) and for those sometimes requiring eating assistance (-36 kcal; -2.0 g protein). CONCLUSIONS: Energy and protein intake appears to be associated with eating occasions. Based on these exploratory findings, LTC homes may consider providing more protein-dense foods at breakfast. Protein and energy dense snacks could also be used more extensively to support intake.

Dark material on Vesta from the infall of carbonaceous volatile-rich material.

Localized dark and bright materials, often with extremely different albedos, were recently found on Vesta's surface. The range of albedos is among the largest observed on Solar System rocky bodies. These dark materials, often associated with craters, appear in ejecta and crater walls, and their pyroxene absorption strengths are correlated with material brightness. It was tentatively suggested that the dark material on Vesta could be either exogenic, from carbon-rich, low-velocity impactors, or endogenic, from freshly exposed mafic material or impact melt, created or exposed by impacts. Here we report Vesta spectra and images and use them to derive and interpret the properties of the 'pure' dark and bright materials. We argue that the dark material is mainly from infall of hydrated carbonaceous material (like that found in a major class of meteorites and some comet surfaces), whereas the bright material is the uncontaminated indigenous Vesta basaltic soil. Dark material from low-albedo impactors is diffused over time through the Vestan regolith by impact mixing, creating broader, diffuse darker regions and finally Vesta's background surface material. This is consistent with howardite-eucrite-diogenite meteorites coming from Vesta.

Patient-reported dietetic care post hospital for free-living patients: a Canadian Malnutrition Task Force Study.

BACKGROUND: Transitions out of hospital can influence recovery. Ideally, malnourished patients should be followed by someone with nutrition expertise, specifically a dietitian, post discharge from hospital. Predictors of dietetic care post discharge are currently unknown. The present study aimed to determine the patient factors independently associated with 30-days post hospital discharge dietetic care for free-living patients who transitioned to the community. METHODOLOGY: Nine hundred and twenty-two medical or surgical adult patients were recruited in 16 acute care hospitals in eight Canadian provinces on admission. Eligible patients could speak English or French, provide their written consent, were anticipated to have a hospital stay of ≥2 days and were not considered palliative. Telephone interviews were completed with 747 (81%) participants using a standardised questionnaire to determine whether dietetic care occurred post discharge; 544 patients discharged to the community were included in the multivariate analyses, excluding those who were admitted to nursing homes or rehabilitation facilities. Covariates during and post hospitalisation were collected prospectively and used in logistic regression analyses to determine independent patient-level predictors. RESULTS: Dietetic care post discharge was reported by 61/544 (11%) of participants and was associated with severe malnutrition [Subjective Global Assessment category C: odd's ratio (OR) 2.43 (1.23-4.83)], weight loss post discharge [(OR 2.86 (1.45-5.62)], comorbidity [(OR 1.09 (1.02-1.17)] and a dietitian consultation on admission [(OR 3.41 (1.95-5.97)]. CONCLUSIONS: Dietetic care post discharge occurs in few patients, despite the known high prevalence of malnutrition on admission and discharge. Dietetic care in hospital was the most influential predictor of post-hospital care.

Complementary Response of Static Spin-Stripe Order and Superconductivity to Nonmagnetic Impurities in Cuprates.

We report muon-spin rotation and neutron-scattering experiments on nonmagnetic Zn impurity effects on the static spin-stripe order and superconductivity of the La214 cuprates. Remarkably, it was found that, for samples with hole doping x≈1/8, the spin-stripe ordering temperature T_{so} decreases linearly with Zn doping y and disappears at y≈4%, demonstrating a high sensitivity of static spin-stripe order to impurities within a CuO_{2} plane. Moreover, T_{so} is suppressed by Zn in the same manner as the superconducting transition temperature T_{c} for samples near optimal hole doping. This surprisingly similar sensitivity suggests that the spin-stripe order is dependent on intertwining with superconducting correlations.

Too Fit To Fracture: outcomes of a Delphi consensus process on physical activity and exercise recommendations for adults with osteoporosis with or without vertebral fractures.

UNLABELLED: An international consensus process resulted in exercise and physical activity recommendations for individuals with osteoporosis. Emphasis was placed on strength, balance, and postural alignment. Rather than providing generic restrictions, activity should be encouraged while considering impairments, fracture risk, activity history, and preference, and guidance on spine sparing techniques should be provided. INTRODUCTION: The objectives of this study were to establish expert consensus on key questions posed by patients or health care providers regarding recommended assessment domains to inform exercise prescription, therapeutic goals of exercise, and physical activity and exercise recommendations for individuals with osteoporosis or osteoporotic vertebral fracture. METHODS: The Too Fit To Fracture expert panel identified researchers and clinicians with expertise in exercise and osteoporosis and stakeholder groups. We delivered a modified online Delphi survey (two rounds) to establish consensus on assessment, exercise, and physical activities for three cases with varying risk (osteoporosis based on bone mineral density; 1 spine fracture and osteoporosis; multiple spine fractures, osteoporosis, hyperkyphosis, and pain). Duplicate content analyses of free text responses were performed. RESULTS: Response rates were 52% (39/75) and 69% (48/70) for each round. Key consensus points are the following: (a) Current physical activity guidelines are appropriate for individuals with osteoporosis without spine fracture, but not for those with spine fracture; (b) after spine fracture, physical activity of moderate intensity is preferred to vigorous; (c) daily balance training and endurance training for spinal extensor muscles are recommended for all; (d) providing guidance on spine-sparing techniques (e.g., hip hinge) during activities of daily living or leisure, considering impairments, fracture risk, activity history, and preference, is recommended rather than providing generic restrictions (e.g., lifting <10 lbs, no twisting), but for those with vertebral fracture, especially in the presence of pain, multiple fractures, or hyperkyphosis, the risks of many activities may outweigh the benefits-physical therapist consultation is recommended. Examples of spine-sparing techniques and exercise prescription elements are provided. CONCLUSIONS: Our recommendations guide health care providers on assessment, exercise prescription, and safe movement for individuals with osteoporosis.

Barriers to food intake in acute care hospitals: a report of the Canadian Malnutrition Task Force.

BACKGROUND: Poor food intake is common in acute care patients and can exacerbate or develop into malnutrition, influencing both recovery and outcome. Yet, research on barriers and how they can be alleviated is lacking. The present study aimed to (i) describe the prevalence of food intake barriers in diverse hospitals and (ii) determine whether patient, care or hospital characteristics are associated with the experience of these barriers. METHODS: Patients (n = 890; 87%) completed a validated questionnaire on barriers to food intake, including perceptions of food quality, just before their discharge from a medical or surgical unit in each of 18 hospitals across Canada. Scores were created for barrier domains. Associations between these barriers and selected patient characteristics collected at admission or throughout the hospital stay and site characteristics were determined using bivariate analyses. RESULTS: Common barriers were being interrupted at meals (41.8%), not being given food when a meal was missed (69.2%), not wanting ordered food (58%), loss of appetite (63.9%) and feeling too sick (42.7%) or tired (41.1%) to eat. Younger patients were more likely (P < 0.0001) to report being disturbed at meals (44.6%) than older patients (33.9%) and missing a meal for tests (39.0% versus 31.0%, P < 0.05). Patients who were malnourished, women, those with more comorbidity, and those who ate <50% of the meal reported several barriers across domains. CONCLUSIONS: The present study confirms that barriers to food intake are common in acute care hospitals. This analysis also identifies that specific patient subgroups are more likely to experience food intake barriers. Because self-reported low food intake in hospital was associated with several barriers, it is relevant to consider assessing, intervening and monitoring barriers to food intake during the hospital stay.

Risk factors associated with adverse outcome following extracorporeal life support: analysis from 360 consecutive patients.

OBJECTIVE: Risk factors for adverse outcome after extracorporeal life support (ECLS) are yet to be defined. For this purpose, we reviewed our institutional data from more than a decade, focusing on patients with ECLS. METHODS: Between December 2001 and June 2013, 360 consecutive cardiac surgical patients received ECLS for post-cardiotomy cardiogenic shock, with high mortality risk despite optimal conventional therapy. Patient demographics, clinical characteristics, ECLS-related morbidity, as well as in-hospital and long-term mortality were analysed. Multivariate logistic regression analysis was performed to identify independent predictors of adverse outcome (failed ECLS weaning, in-hospital mortality). RESULTS: The mean age was 62±17 years, 76% were male and the mean preoperative ejection fraction was 35±16%. ECLS was established through peripheral (90%) or central thoracic cannulation. The mean duration of ECLS was 7±1 days. Intra-aortic balloon pumps were implanted in 22% of the patients. ECLS weaning was successful in 58% and 30% could be discharged from hospital. The main cause of death was sepsis (69%). Overall, major cerebrovascular events occurred in 12% (bleeding 3%, embolic 9%), limb ischaemia in 13%, gastrointestinal complications in 16% and renal replacement therapy in 61%. Independent risk factors for adverse outcome were prior cardiorespiratory resuscitation (OR: 4.1, 95%CI: 0.34-4.21, p=0.04), pH <7.1 (OR: 2.8, 95%CI: 0.45-3.28, p=0.01), serum lactate >120 mg/dL (OR: 2.6, 95%CI: 0.75-2.96, p< 0.01), norepinephrine dosage >0.5 µg/kg/min (OR: 2.4, 95%CI: 0.35-2.92, p=0.02) and age >75 years (OR: 2.0, 95%CI: 0.41-2.88, p=0.02). Kaplan Meier estimates for long-term survival were 26±3% at one year and 22±2% at five years. CONCLUSION: ECLS therapy offers one-year survival to one quarter of patients with an otherwise fatal prognosis. Procedural mortality is low and morbidity at the implantation site typically moderate. Thus, prolonged metabolic deterioration in combination with high-dose vasopressor support prior to ECLS therapy should be avoided, particularly in younger patients.

Too Fit To Fracture: a consensus on future research priorities in osteoporosis and exercise.

UNLABELLED: An international consensus process identified the following research priorities in osteoporosis and exercise: study of exercise in high-risk cohorts, evaluation of multimodal interventions, research examining translation into practice and a goal to examine fracture outcomes. INTRODUCTION: To identify future research priorities related to exercise for people with osteoporosis with and without osteoporotic spine fracture via international consensus. METHODS: An international expert panel and representatives from Osteoporosis Canada led the process and identified opinion leaders or stakeholders to contribute. A focus group of four patient advocates identified quality of life, mobility, activities of daily living, falls, bone mineral density, and harms as outcomes important for decision-making. Seventy-five individuals were invited to participate in an online survey asking respondents to define future research priorities in the area of osteoporosis and exercise; the response rate was 57%. Fifty-five individuals from seven countries were invited to a half-day consensus meeting; 60% of invitees attended. The results of the online survey, knowledge synthesis activities, and results of the focus group were presented. Nominal group technique was used to come to consensus on research priorities. RESULTS: Research priorities included the study of exercise in high-risk cohorts (e.g., ≥ 65 years, low BMD, moderate/high risk of fracture, history of osteoporotic vertebral fractures, hyperkyphotic posture, functional impairments, or sedentary), the evaluation of multimodal interventions, research examining translation into practice, and a goal to examine fracture outcomes. The standardization of outcomes or protocols that could be evolved into large multicentre trials was discussed. CONCLUSIONS: The research priorities identified as part of the Too Fit To Fracture initiative can be used to inform the development of multicentre collaborations to evaluate and implement strategies for engaging individuals with osteoporosis in a safe and effective exercise.

Too Fit To Fracture: exercise recommendations for individuals with osteoporosis or osteoporotic vertebral fracture.

SUMMARY: A consensus process was conducted to develop exercise recommendations for individuals with osteoporosis or vertebral fractures. A multicomponent exercise program that includes balance and resistance training is recommended. INTRODUCTION: The aim was to develop consensus on exercise recommendations for older adults: (1) with osteoporosis and (2) with osteoporotic vertebral fracture(s). METHODS: The Grading of Recommendations Assessment, Development, and Evaluation method was used to evaluate the quality of evidence and develop recommendations. Outcomes important for decision making were nominated by an expert panel and patient advocates. They included falls, fractures, bone mineral density (BMD), and adverse events for individuals with osteoporosis/vertebral fractures, and pain, quality of life, and function for those with vertebral fracture. Meta-analyses evaluating the effects of exercise on the outcomes were reviewed. Observational studies or clinical trials were reviewed when meta-analyses were not available. Quality ratings were generated, and informed the recommendations. RESULTS: The outcome for which evidence is strongest is falls. Point estimates of the effects of exercise on falls, fractures, and BMD vary according to exercise type. There is not enough evidence to quantify the risks of exercise in those with osteoporosis or vertebral fracture. Few trials of exercise exist in those with vertebral fracture. The exercise recommendations for exercise in individuals with osteoporosis or osteoporotic vertebral fracture are conditional. The panel strongly recommends a multicomponent exercise program including resistance and balance training for individuals with osteoporosis or osteoporotic vertebral fracture. The panel recommends that older adults with osteoporosis or vertebral fracture do not engage in aerobic training to the exclusion of resistance or balance training. CONCLUSIONS: The consensus of our international panel is that exercise is recommended for older adults with osteoporosis or vertebral fracture, but our recommendations are conditional.

Negative oxygen isotope effect on the static spin stripe order in superconducting La(2-x)Ba(x)CuO(4) (x=1/8) observed by muon-spin rotation.

Large negative oxygen-isotope (^{16}O and ^{18}O) effects (OIEs) on the static spin-stripe-ordering temperature T_{so} and the magnetic volume fraction V_{m} were observed in La_{2-x}Ba_{x}CuO_{4}(x=1/8) by means of muon-spin-rotation experiments. The corresponding OIE exponents were found to be α_{T_{so}}=-0.57(6) and α_{V_{m}}=-0.71(9), which are sign reversed to α_{T_{c}}=0.46(6) measured for the superconducting transition temperature T_{c}. This indicates that the electron-lattice interaction is involved in the stripe formation and plays an important role in the competition between bulk superconductivity and static stripe order in the cuprates.

Providing quality nutrition care in acute care hospitals: perspectives of nutrition care personnel.

BACKGROUND: Malnutrition is common in acute care hospitals worldwide and nutritional status can deteriorate during hospitalisation. The aim of the present qualitative study was to identify enablers and challenges and, specifically, the activities, processes and resources, from the perspective of nutrition care personnel, required to provide quality nutrition care. METHODS: Eight hospitals participating in the Nutrition Care in Canadian Hospitals study provided focus group data (n = 8 focus groups; 91 participants; dietitians, dietetic interns, diet technicians and menu clerks), which were analysed thematically. RESULTS: Five themes emerged from the data: (i) developing a nutrition culture, where nutrition practice is considered important to recovery of patients and teams work together to achieve nutrition goals; (ii) using effective tools, such as screening, evidence-based protocols, quality, timely and accurate patient information, and appropriate and quality food; (iii) creating effective systems to support delivery of care, such as communications, food production and delivery; (iv) being responsive to care needs, via flexible food systems, appropriate menus and meal supplements, up to date clinical care and including patient and family in the care processes; and (v) uniting the right person with the right task, by delineating roles, training staff, providing sufficient time to undertake these important tasks and holding staff accountable for their care. CONCLUSIONS: The findings of the present study are consistent with other work and provide guidance towards improving the nutrition culture in hospitals. Further empirical work on how to support successful implementation of nutrition care processes is needed.

Strong pressure dependence of the magnetic penetration depth in single crystals of the heavy-fermion superconductor CeCoIn5 studied by muon spin rotation.

In the tetragonal heavy fermion system CeCoIn(5) the unconventional superconducting state is probed by means of muon spin rotation. The pressure dependence (0-1 GPa) of the basal-plane magnetic penetration depth (λ(a)), the penetration depth anisotropy (γ = λ(c)/λ(a)) and the temperature dependence of 1/λ(i)(2) (i = a, c) were studied in single crystals. A strong decrease of λ(a) with pressure was observed, while γ and λ(i)(2)(0)/λ(i)(2)(T) are pressure independent. A linear relationship between 1/λ(a)(2)(270 mK) and T(c) was also found. The large decrease of λ(a) with pressure is the signature of an increase of the number of superconducting quasiparticles by a factor of about 2.

Muon-spin rotation measurements of an unusual vortex-glass phase in the layered superconductor Bi2.15Sr1.85CaCu2O8+δ.

Muon-spin rotation measurements, performed on the mixed state of the classic anisotropic superconductor Bi(2.15)Sr(1.85)CaCu(2)O(8+δ), obtain quantities directly related to two- and three-body correlations of vortices in space. A novel phase diagram emerges from such local probe measurements of the bulk, revealing an unusual glassy state at intermediate fields which appears to freeze continuously from the equilibrium vortex liquid but differs both from the lattice and the conventional high-field vortex glass state in its structure.

Morphology and dynamics of the upper cloud layer of Venus.

Venus is completely covered by a thick cloud layer, of which the upper part is composed of sulphuric acid and some unknown aerosols. The cloud tops are in fast retrograde rotation (super-rotation), but the factors responsible for this super-rotation are unknown. Here we report observations of Venus with the Venus Monitoring Camera on board the Venus Express spacecraft. We investigate both global and small-scale properties of the clouds, their temporal and latitudinal variations, and derive wind velocities. The southern polar region is highly variable and can change dramatically on timescales as short as one day, perhaps arising from the injection of SO2 into the mesosphere. The convective cells in the vicinity of the subsolar point are much smaller than previously inferred, which we interpret as indicating that they are confined to the upper cloud layer, contrary to previous conclusions, but consistent with more recent study.

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.

Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly.

Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15-250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a 'position effect' has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients.