Natural History Research Articles

Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and/or early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Clonal expansion in normal tissues.

Cancer originates from a single ancestral cell that acquires a driver mutation, which confers a growth or survival advantage, followed by the acquisition of additional driver mutations by descendant cells. Recently, it has become evident that somatic cell mutations accumulate in normal tissues with aging and exposure to environmental factors, such as alcohol, smoking, and UV rays, increases the mutation rate. Clones harboring driver mutations expand with age, leading to tissue remodeling. Lineage analysis of myeloproliferative neoplasms and der(1;16)-positive breast cancer revealed that driver mutations were acquired early in our lives and that the development of cancer takes decades, unveiling the previously unknown early process of cancer development. Evidence that clonal hematopoiesis affects various diseases, including nonneoplastic diseases, highlights the potential role of the identification and functional analysis of mutated clones in unraveling unknown pathologies. In this review, we summarize the recent updates on clonal expansion in normal tissues and the natural history of cancer revealed through lineage analysis of noncancerous and cancerous tissues.

The natural history of celiac artery aneurysms.

The goal of this study was to document the natural history of celiac artery aneurysms (CAAs). Celiac artery aneurysms are rare. Existing literature is skewed towards outcomes after intervention of large, symptomatic aneurysms but the behavior of untreated CAAs is poorly understood. This is a single institution, retrospective analysis of patients with CAA diagnosed by CT imaging (2015-2019) identified through an institutional radiology database. Radiologic, demographic, and follow-up data were analyzed. The primary endpoint was the mean growth rate of CAAs. Of the 76 patients included, 86.8% were men with a mean age at presentation of 69.8years. The mean CAA diameter on index imaging was 15.4 +/- 3.8mm (range, 7-30mm). All were classified as true aneurysms and 76.3% were saccular. All patients had clinical follow-up with mean follow-up 31.2months +/- 21.6months. No patient developed symptoms or rupture. The mean radiological follow-up among 45 patients was 25.2 +/- 16.8months. Over this period, 16 CAAs (35.6%) enlarged, while 29 (64.4%) remained stable. One patient (1.3%) underwent intervention for increasing size in the setting of a chronic dissection. On multivariate analysis, age <70 was significantly associated with increased risk of aneurysm growth. In this institutional review of patients with CAAs, the majority of aneurysms remained stable in size, with no patients developing symptoms or rupture over clinical follow-up. Given the observed benign behavior of these aneurysms, guidelines that suggest conservative management of CAAs less than 2cm seems appropriate.

Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate.

: The histological characteristics and natural history of precirrhotic primary biliary cholangitis (PBC) with portal hypertension (PH) are unclear. Our aim was to clarify the prevalence, risk factors, and histological characteristics of precirrhotic PBC patients with PH. : This retrospective study compared the clinical features, histological characteristics, and response to ursodeoxycholic acid (UDCA) between the PH and non-PH groups of precirrhotic PBC patients. : Out of 165 precirrhotic PBC patients, 40 (24.2%) also had PH. According to histological stage 1, 2 and 3 disease, 5.3% (1/19), 17.3% (17/98), and 45.8% (22/48) of patients also had PH, respectively. Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation (p<0.05). In addition, patients with PH were more likely to present with symptoms of jaundice, ascites, epigastric discomfort, a poorer response to UDCA, and more decompensation events (p<0.05). High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values were risk factors for precirrhotic PBC with PH. : Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH.

Infected pancreatic necrosis-Current trends in management.

Acute necrotizing pancreatitis is a common gastrointestinal disease requiring hospitalization and multiple interventions resulting in higher morbidity and mortality. Development of infection in such necrotic tissue is one of the sentinel events in natural history of necrotizing pancreatitis. Infected necrosis develops in around 1/3rd of patients with necrotizing pancreatitis resulting in higher mortality. So, timely diagnosis of infected necrosis using clinical, laboratory and radiological parameters is of utmost importance. Though initial conservative management with antibiotics and organ support system is effective in some patients, amajority of patients still requires drainage of the collection by various modalities. Mode of drainage of infected pancreatic necrosis depends on various factors such as the clinical status of the patient, location and characteristics of collection and availability of the expertise and includes endoscopic, percutaneous and minimally invasive or open surgical approaches. Endoscopic drainage has proved to be a game changer in the management of infected pancreatic necrosis in the last decade with rapid evolution in procedure techniques, development of novel metal stent and dedicated necrosectomy devices for better clinical outcome. Despite widespread adoption of endoscopic transluminal drainage of pancreatic necrosis with excellent clinical outcomes, peripheral collections are still not amenable for endoscopic drainage and in such scenario, the role of percutaneous catheter drainage or minimally invasive surgical necrosectomy cannot be understated. In a nutshell, the management of patients with infected pancreatic necrosis involves a multi-disciplinary team including a gastroenterologist, an intensivist, an interventional radiologist and a surgeon for optimum clinical outcomes.

New records of earthworms (Clitellata: Oligochaeta) from Georgia, USA, including eight new state records

We present here new county records for 13 counties within Georgia, USA from the collections of the Georgia Museum of Natural History and the authors. These include four families, eight genera, and 23 species. Of these, eight species are new state records: Amynthas carnosus (Goto &amp; Hatai, 1899); Aporrectodea longa (Ude, 1885); Bimastos parvus (Eisen, 1874); Diplocardia deborahae Damoff &amp; Reynolds, 2017; Diplocardia gatesi Murchie, 1965; Diplocardia michaelseni Eisen, 1899; Metaphire hilgendorfi (Michaelsen, 1892); and Murchieona minuscula (Rosa, 1906). These findings are presented alongside an updated checklist for Middle Georgia building on data compiled by Reynolds (2015) to create a practical record for the region.

Hidden treasures—historical specimens from the late blight pandemic discovered in the Herbarium of the State Museum of Natural History Karlsruhe

Hidden treasures—historical specimens from the late blight pandemic discovered in the Herbarium of the State Museum of Natural History Karlsruhe

The formation of tourists’ pro-environmental behavior in natural history museum scene: A configuration analysis based on motivation–opportunity–ability theory

Tourists’ pro-environmental behavior is crucial for the sustainable growth of the tourism sector. While existing studies mainly examine the direct effects of individual factors on such behavior, there is a gap in understanding the comprehensive antecedent system that drives it. In this study, grounded in MOA theory and focused on a natural history museum scene, we developed a comprehensive framework to analyze the antecedent system of tourists’ pro-environmental behavior. We argue that the formation of this behavior in museum tourists is not a single element but a combination of three critical factors: motivation, opportunity, and ability (MOA). Using the fsQCA method to analyze data from 276 tourists, we identified four distinct pathways that promote pro-environmental behavior in museum tourists: MOA equilibrium type, motivation–ability-oriented type, motivation–opportunity-oriented type, and ability-oriented type. This study enhances our understanding of the complex interactions among various factors influencing tourists’ pro-environmental behavior and provides insightful implications for the practice of museum tourism.

Issues, Challenges and Opportunities for Economic Evaluations of Orphan Drugs in Rare Diseases: An Umbrella Review.

There are significant challenges when obtaining clinical and economic evidence for health technology assessments of rare diseases. Many of them have been highlighted in previous systematic reviews but they have not been summarised in a comprehensive manner. For all stakeholders working with rare diseases, it is important to be aware and understand these issues. The objective of this review is to identify the main challenges for the economic evaluation of orphan drugs in rare diseases. An umbrella review of systematic reviews of economic studies concerned with orphan and ultra-orphan drugs was conducted. Studies that were not systematic reviews, or on advanced therapeutic medicinal products, personalised medicines or other interventions that were not considered orphan drugs were excluded. The database searches included publications from 2010 to 2023, and were conducted in MEDLINE, EMBASE and the Cochrane library using filters for systematic reviews, and economic evaluations and models. These filters were combined with search terms for rare diseases and orphan drugs. A hand search supplemented the literature searches. The findings were reported by a compliant Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Two hundred and eighty-two records were identified from the literature searches, of which 64 were duplicates, whereas five reviews were identified from the hand search. A total of 36 reviews were included after screening against inclusion/exclusion criteria, 35 from literature searches and one from hand searching. Of those studies 1, 27 and 8 were low, moderate and high quality, respectively. The reviews highlight the scarcity of evidence for health economic parameters, for example, clinical effectiveness, costs, quality of life and the natural history of disease. Health economic evaluations such as cost-effectiveness and budget-impact analyses were scarce, and generally low-to-moderate quality. The causes were limited health economic parameters, together with publications bias, especially for cost-effectiveness analyses. The results highlighted issues around a considerable paucity of evidence for economic evaluations and few cost-effectiveness analyses, supporting the notion that a paucity of evidence makes economic evaluations of rare diseases more challenging compared with more prevalent diseases. Furthermore, we provide recommendations for more sustainable approaches in economic evaluations of rare diseases.

How to Curate and Digitize Bryozoa: Experiences at the Santa Barbara Museum of Natural History

We report on curation and digitization experiences of a large collection of Bryozoa (&gt;19,759 of estimated 38,000 lots digitized, &gt;1,000 type lots). Storage of one to two histology slides in capped glass vials and larger series in twenty-five-slot histology boxes is optimal. Bulk dry material is stored in acid-free containers (cardboard, plastic). Fluid specimens are stored in 70 percent ethanol, with small specimens housed in 20 ml scintillation vials with conical polypropylene lined screw caps. Digitizing is most effective by georeferencing immediately. Unidentified material should at least be roughly identified (family, genus) to encourage loans and ensuing expert identification. Taxonomy and nomenclature are challenging and require an experienced taxonomist. Approaches to specimen counts are discussed.

Fabry disease: a rare disorder calling for personalized medicine.

Fabry Disease (FD) is a genetic disease caused by a deficiency in the activity of lysosomal galactosidase A (α-GalA), an enzyme responsible for the catabolism of globotriaosylceramide (Gb3). Since lysosomes are present throughout the body and play a crucial role in catabolism and recycling of cytosolic compounds, FD can affect multiple organs and result in various symptoms, including renal, cardiovascular, neurological, cutaneous, and ophthalmic manifestations. Due to the nonspecific symptoms and the rarity of FD, it is often diagnosed late in life. However, introducing targeted therapies such as enzyme replacement therapy (ERT) and chaperone therapy has significantly improved FD's natural history and prognosis by restoring α-GalA enzyme activity. Despite the advancements, there are limitations to the currently available therapies, which has prompted research into new potential treatments for FD, including alternative forms of enzyme replacement therapy, substrate reduction therapy, mRNA therapy, and genetic therapy. In this review, we analyze the epidemiology, pathophysiology, and treatment of FD, with particular emphasis on promising therapeutic opportunities that could shift the treatment of this rare disease from a standardized to a personalized approach soon.

Early-life house dust mite aeroallergen exposure augments cigarette smoke-induced myeloid inflammation and emphysema in mice

BackgroundLongitudinal studies have identified childhood asthma as a risk factor for obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) where persistent airflow limitation can develop more aggressively. However, a causal link between childhood asthma and COPD/ACO remains to be established. Our study aimed to model the natural history of childhood asthma and COPD and to investigate the cellular/molecular mechanisms that drive disease progression.MethodsAllergic airways disease was established in three-week-old young C57BL/6 mice using house dust mite (HDM) extract. Mice were subsequently exposed to cigarette smoke (CS) and HDM for 8 weeks. Airspace enlargement (emphysema) was measured by the mean linear intercept method. Flow cytometry was utilised to phenotype lung immune cells. Bulk RNA-sequencing was performed on lung tissue. Volatile organic compounds (VOCs) in bronchoalveolar lavage-fluid were analysed to screen for disease-specific biomarkers.ResultsChronic CS exposure induced emphysema that was significantly augmented by HDM challenge. Increased emphysematous changes were associated with more abundant immune cell lung infiltration consisting of neutrophils, interstitial macrophages, eosinophils and lymphocytes. Transcriptomic analyses identified a gene signature where disease-specific changes induced by HDM or CS alone were conserved in the HDM-CS group, and further revealed an enrichment of Mmp12, Il33 and Il13, and gene expression consistent with greater expansion of alternatively activated macrophages. VOC analysis also identified four compounds increased by CS exposure that were paradoxically reduced in the HDM-CS group.ConclusionsEarly-life allergic airways disease worsened emphysematous lung pathology in CS-exposed mice and markedly alters the lung transcriptome.

Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy.

Finding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1-year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) in a placebo-controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles. Quantitative MRI and 31P MRS data were collected at 3T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year-1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross-sectional area (cCSA), and water T2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31P MRS indices in quadriceps or triceps surae. Analyses covered patient-control comparisons, annual change assessments via standard t-tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31P MRS, functional, strength, and clinical parameters. The quadriceps and gastrocnemius medialis muscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1-year FF increase in the quadriceps was 3.2% (P<0.001), whereas in the sirolimus group, it was 0.7% (P=0.033). Both groups experienced a significant decrease in cCSA in the quadriceps after 1year (P<0.001), with median changes of 12.6% for the placebo group and 5.5% for the sirolimus group. Differences in FF and cCSA changes between the two groups were significant (P<0.001). SRM values for FF and cCSA were 1.3 and 1.4 in the placebo group and 0.5 and 0.8 in the sirolimus group, respectively. Water T2 values were highest in the quadriceps muscles of both groups, significantly exceeding control values in both groups (P<0.001) and were higher in the placebo group than in the sirolimus group. After treatment, water T2 increased significantly only in the sirolimus group's quadriceps (P<0.01). Multiple 31P MRS indices were abnormal in patients compared to controls and remained unchanged after treatment. Significant correlations were identified between baseline water T2 and FF at baseline and the change in FF (P<0.001). Additionally, significant correlations were observed between FF, cCSA, water T2, and functional and strength outcome measures. This study has demonstrated that quantitative MRI/31P MRS can discern measurable differences between placebo and sirolimus-treated IBM patients, offering promise for future therapeutic trials in idiopathic inflammatory myopathies such as IBM.

"To honor and remember": An ethical awakening to African American remains in museums.

In 2021, amid surging activism in the Movement for Black Lives, the Smithsonian Institution's possession of the remains of thousands of African Americans drew widespread attention. In response, the Smithsonian and its National Museum of Natural History undertook a series of steps to assess these remains and to develop a policy for returning as many as possible to descendants and descendant communities, under changes that would apply to all non-Native American remains in Smithsonian collections. This paper reviews the actions taken to date and the work that is still in progress or planned. I contextualize these steps more broadly within an "ethical awakening" to African American remains that have long been present, studied, and displayed in collections across the museum community in the United States, where other institutions have faced similar challenges and changes.

Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods

BackgroundClinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported.ResultsFive pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR.ConclusionsOur findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

Giant cerebral cavernous malformation in a newborn: a rare case report and review of literature.

Cavernous malformations (CMs), also known as cavernomas or cavernous angiomas, are vascular malformations characterized by sinusoidal spaces lined by endothelial cells. Giant CMs (GCMs) are extremely rare, with limited understanding of their presentation and management. We present a case of symptomatic GCM in a newborn and review the literature on this rare entity. A 1-month-old newborn presented with focal seizures and signs of increased intracranial pressure. Imaging revealed a massive right frontal-parietal GCM, prompting surgical resection. Histopathological examination confirmed the diagnosis of cerebral cavernous malformation. The patient recovered well postoperatively with no neurological deficits. GCMs are exceedingly rare in children and have not been reported in newborns until now. Symptoms typically include seizures and mass effects. Gross total resection is the standard treatment, offering favorable outcomes. Further research is needed to understand the natural history and optimal management of GCMs, particularly in newborns, emphasizing the importance of heightened clinical awareness for timely diagnosis and appropriate management.

Are Gender Differences Important for Autoimmune Liver Diseases?

Gender Medicine has had an enormous expansion over the last ten years. Autoimmune liver diseases include several conditions, i.e., autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and conditions involving the liver or biliary tree overlapping with AIH, as well as IgG4-related disease. However, little is known about the impact of sex in the pathogenesis and natural history of these conditions. The purpose of this review is to provide an update of the gender disparities among the autoimmune liver diseases by reviewing the data published from 1999 to 2023. The epidemiology of these diseases has been changing over the last years, due to the amelioration of knowledge in their diagnosis, pathogenesis, and treatment. The clinical data collected so far support the existence of sex differences in the natural history of autoimmune liver diseases. Notably, their history could be longer than that which is now known, with problems being initiated even at a pediatric age. Moreover, gender disparity has been observed during the onset of complications related to end-stage liver disease, including cancer incidence. However, there is still an important debate among researchers about the impact of sex and the pathogenesis of these conditions. With this review, we would like to emphasize the urgency of basic science and clinical research to increase our understanding of the sex differences in autoimmune liver diseases.

New genus of Pleminiini Brunner von Wattenwyl, 1878 (Orthoptera: Tettigoniidae: Pseudophyllinae) from the Colombian Andes

The Pleminiini tribe (Pseudophyllinae: Tettigoniidae) currently comprises 51 genera and 227 valid species with a Neotropical and Afrotropical distribution. Herein, the new monotypic genus Muscuspina Mendes gen. nov. is described with a new species, Muscuspina neblina Mendes sp. nov., distributed in the Andean montane forest of Antioquia, Colombia. Maps and natural history observations are provided.

A study on the visual defensive system of the Moluo Tower Village, Western China, based on a multi-dimensional model

AbstractScientifically validating the value of rural heritage and exploring construction wisdom has emerged as a significant challenge in the study of rural settlements worldwide. Rural heritage shows significant differences according to the natural environment, history, culture, and socio-economic factors. However, the assessment of the authenticity and effectiveness of heritage values have yet to be quantified due to the difficulty in obtaining evidence directly from samples. By constructing a multi-dimensional model of villages for quantitative analysis, we proposed a multifaceted spatial visibility analysis method based on individual and combined defense structures to empirically study the remains of eight towers in Moluo village, western China. This study demonstrated that towers serve as regional defense structures and are essential for constructing a comprehensive and effective visual defensive system (VDS) in Moluo village, a typical military defense village. The effectiveness and coverage of the towers vary depending on their location, height, type, and other factors. They form a complementary and synergistic relationship, playing a dual mechanism of public and private, local and overall defense. In summary, this method enables the feasible quantification and analysis of the functional value of rural heritage through landscape visual analysis. It provides a new perspective for studying the authenticity of heritage functions.

The Natural History of Retinal Sensitivity Loss in Diabetic Macular Ischemia over One Year Evaluated by Microperimetry

Background/Objectives: This one-year prospective observational study, conducted at two centers, aimed to report the natural history of retinal sensitivity (RS) loss in diabetic macular ischemia (DMI). Methods: Patients with stable-treated proliferative diabetic retinopathy (PDR) were recruited if there was evidence of DMI on optical coherence tomography angiography, defined as a foveal avascular zone ≥ 0.5 mm2 or parafoveal capillary dropout ≥ 1 quadrant. The minimal visual acuity required for performing microperimetry (MP) was ≥54 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent 20/80). The overall RS (oRS) and pointwise sensitivity (PWS) within the 3 × 3 mm macula were assessed at baseline and twelve months. A value &lt;25 decibels (dB) was defined as impaired RS, and a decrease of 2 and 7 dB was regarded as mild and severe loss, respectively. Results: A total of 88 patients (97 eyes) were included. No statistically significant MP changes were detected at one year. However, 10% of the cohort lost oRS ≥ 2 dB, and 73% lost ≥2 dB PWS in ≥5 loci, whereas 1% lost oRS ≥ 7 dB, and 4% lost ≥7 dB PWS in ≥5 loci. The foveola and temporal parafovea were the most vulnerable to severe RS loss. Compared to their counterpart, eyes with baseline oRS ≥ 25 dB had significantly more RS loss in the macula and superior parafovea (55% versus 32% and 53% versus 28%, both p = 0.01). Conclusions: Rather than oRS loss, ≥2 dB loss in PWS in ≥5 loci is a more feasible outcome measure for clinical trials in DMI.