An unusual case of chondrolysis of the hip: a possible etiology for a rare condition - a case report.

J Pediatr Orthop B. 2016 Nov;25(6):533-8

Authors: Ruiz Picazo D, Doñate Pérez F, Jiménez Ortega P, Gaspar Aparicio N

Abstract
UNLABELLED: Idiopathic chondrolysis of the hip (ICH) is a rare condition of unknown etiology, and is characterized by rapid, progressive destruction of the articular cartilage in the coxofemoral joint. This condition has an insidious onset, and is observed more commonly in female preadolescents. Patients report intense pain, motion restriction, and often present with an antalgic gait. Medical imaging techniques are required to make a differential diagnosis and biological markers for inflammation and infection should be evaluated. Avascular necrosis, septic arthritis, and juvenile idiopathic arthritis are the primary alternatives that should be precluded before making a diagnosis. Conservative treatment focuses on pain control and preservation of joint mobility. However, surgical treatment may be an option for these patients. We present a rare case of a 10-year-old boy where imaging tests and physical examination were consistent with conventional idiopathic hip chondrolysis. Following hip joint biopsy and culture, we observed the presence of bacteria originating from the mouth, which could have been responsible for the pathogenesis of ICH. This is the first report of ICH in which common bacteria of the mouth were found upon joint biopsy. In addition, with respect to the pathogenesis of hip chondrolysis, this case emphasizes that numerous factors are involved, many of which remain unknown.
LEVEL OF EVIDENCE: V.

PMID: 27243805 [PubMed - indexed for MEDLINE]

Rare Diseases on the Internet: An Assessment of the Quality of Online Information.

J Med Internet Res. 2017 Jan 18;19(1):e23

Authors: Pauer F, Litzkendorf S, Göbel J, Storf H, Zeidler J, Graf von der Schulenburg JM

Abstract
BACKGROUND: The importance of the Internet as a medium for publishing and sharing health and medical information has increased considerably during the last decade. Nonetheless, comprehensive knowledge and information are scarce and difficult to find, especially for rare diseases. Additionally, the quality of health or medical information about rare diseases is frequently difficult to assess for the patients and their family members.
OBJECTIVE: The aim of this study is to assess the quality of information on the Internet about rare diseases. Additionally, the study aims to evaluate if the quality of information on rare diseases varies between different information supplier categories.
METHODS: A total of 13 quality criteria for websites providing medical information about rare diseases were transferred to a self-disclosure questionnaire. Identified providers of information on the Internet about rare diseases were invited to fill out the questionnaire. The questionnaire contained questions about the information provider in general (eg, supplier category, information category, language, use of quality certificates, and target group) and about quality aspects that reflect the 13 quality criteria. Differences in subgroup analyses were performed using t tests.
RESULTS: We identified 693 websites containing information about rare diseases. A total of 123 questionnaires (17.7%) were completely filled out by the information suppliers. For the remaining identified suppliers (570/693, 82.3%), the questionnaires were filled out by the authors based on the information available on their website. In many cases, the quality of websites was proportionally low. Furthermore, subgroup analysis showed no statistically significant differences between the quality of information provided by support group/patient organization compared to medical institution (P=.19). The quality of information by individuals (patient/relative) was significantly lower compared to information provided by support group/patient organization (P=.001), medical institution (P=.009), and other associations and sponsoring bodies (P=.001) as well.
CONCLUSIONS: Overall, the quality of information on the Internet about rare diseases is low. Quality certificates are rarely used and important quality criteria are often not fulfilled completely. Additionally, some information categories are underrepresented (eg, information about psychosocial counseling, social-legal advice, and family planning). Nevertheless, due to the high amount of information provided by support groups, this study shows that these are extremely valuable sources of information for patients suffering from a rare disease and their relatives.

PMID: 28100442 [PubMed - indexed for MEDLINE]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/08/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Intoxication and substance use disorder to Areca catechu nut containing betel quid: A review of epidemiological evidence, pharmacological basis and social factors influencing quitting strategies.

Drug Alcohol Depend. 2017 Jul 29;179:187-197

Authors: Osborne PG, Ko YC, Wu MT, Lee CH

Abstract
AIM: We present a systematic review of substance use disorder (SUD) to Areca catechu nut (AN) and AN containing betel quid (ANcBQ) with emphasis on dependence resulting from chewing of tobacco-free ANcBQ. We examined pharmacology of intoxication and addiction, and factors influencing quitting strategies.
METHODS: Epidemiological publications of SUD were included according to PRISMA criteria. Pharmacological publications were retrieved from the PUBMED database and websites of the WHO, United Nations, and Sigma-Aldrich.
RESULTS: Nine epidemiological studies show clear evidence of abuse and dependence in tobacco-free ANcBQ and/or ANcBQ+Tobacco chewers. Dependency is greater if ANcBQ contains tobacco. In both groups higher dependency scores were positively correlated with higher frequency of chewing. Dependency on AN+Lime is associated with altered brain morphology, resting state brain activity, neurochemistry and deterioration of working spatial memory. ANcBQ contains a complex mixture of neuroactive compounds that have the potential to act directly upon all major cerebral neurotransmitter systems. Of these compounds, only arecoline (muscarinic agonist) has been the focus of limited pharmacological investigation. In animal studies, arecoline increases dopamine transmission in the mesocorticolimbic circuit and this action may be one factor contributing to ANcBQ dependency in humans. Societal and familial acceptance of ANcBQ consumption is paramount for commencement and persistence of chewing.
CONCLUSIONS: ANcBQ SUD remains an orphan disease. The limited understanding of pharmacological basis of intoxication and SUD determines there are no pharmacological replacement therapies for ANcBQ SUD. The addictive properties of ANcBQ coupled with social acceptance of ANcBQ chewing limits the effectiveness of counseling-based quitting programs.

PMID: 28787696 [PubMed - as supplied by publisher]

Inherited platelet disorders: toward DNA-based diagnosis.

Blood. 2016 Jun 09;127(23):2814-23

Authors: Lentaigne C, Freson K, Laffan MA, Turro E, Ouwehand WH, BRIDGE-BPD Consortium and the ThromboGenomics Consortium

Abstract
Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).(1) The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein-protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.

PMID: 27095789 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/08/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Depression and Hypersomnia: A Complex Association.

Sleep Med Clin. 2017 Sep;12(3):395-405

Authors: Lopez R, Barateau L, Evangelista E, Dauvilliers Y

Abstract
Hypersomnolence is a clinically defined syndrome characterized by the association of prolonged nocturnal sleep, impaired arousal quality, and sleep inertia. Hypersomnolence is the major feature of central hypersomnias and is frequently reported in various mood disorders, such as major depressive disorder, bipolar disorder, or seasonal affective disorder. Assessment of hypersomnolence is challenging in depressed patients, with objective tests often in the normal range despite a high level of sleepiness complaint. On the other hand, many patients with central hypersomnias reported depressive symptoms. The self-assessment of mood symptoms in patients with central hypersomnias may overdiagnose depression with an overlap between both conditions.

PMID: 28778237 [PubMed - in process]

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.

Am J Hum Genet. 2017 Aug 03;101(2):267-273

Authors: Edvardson S, Nicolae CM, Agrawal PB, Mignot C, Payne K, Prasad AN, Prasad C, Sadler L, Nava C, Mullen TE, Begtrup A, Baskin B, Powis Z, Shaag A, Keren B, Moldovan GL, Elpeleg O

Abstract
Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

PMID: 28777933 [PubMed - in process]

High oxygen affinity hemoglobins.

Rev Med Interne. 2017 Feb;38(2):106-112

Authors: Mangin O

Abstract
High oxygen affinity hemoglobins are responsible for rare and heterogeneous autosomic dominant genetic diseases. They cause pure erythrocytosis, sometimes accountable for hyperviscosity and thrombosis, or hemolysis. Differential diagnoses must be first ruled out. The diagnosis is based on the identification of a decreased P50, and their possible characterization by cation exchange-high performance liquid chromatography and capillary electrophoresis. Finally, genetic studies of the responsible globin chain gene will confirm the mutation. The prognosis mainly relies on the P50 decrease rate and on the hemoglobin cooperativity impairment. Disease management should be personalized, and it should primarily depend on smoking cessation and physical activity. Phlebotomy and platelet aggregation inhibitors' prescriptions can be discussed. There is no contraindication to flights, high-altitude conditions, or pregnancy. Nevertheless, blood donation must be prohibited.

PMID: 27637720 [PubMed - indexed for MEDLINE]

Role of B cells in the pathogenesis of systemic sclerosis.

Rev Med Interne. 2017 Feb;38(2):113-124

Authors: Sanges S, Guerrier T, Launay D, Lefèvre G, Labalette M, Forestier A, Sobanski V, Corli J, Hauspie C, Jendoubi M, Yakoub-Agha I, Hatron PY, Hachulla E, Dubucquoi S

Abstract
Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-β (TGF-β) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

PMID: 27020403 [PubMed - indexed for MEDLINE]

A Fast Association Test for Identifying Pathogenic Variants Involved in Rare Diseases.

Am J Hum Genet. 2017 Jul 06;101(1):104-114

Authors: Greene D, NIHR BioResource, Richardson S, Turro E

Abstract
We present a rapid and powerful inference procedure for identifying loci associated with rare hereditary disorders using Bayesian model comparison. Under a baseline model, disease risk is fixed across all individuals in a study. Under an association model, disease risk depends on a latent bipartition of rare variants into pathogenic and non-pathogenic variants, the number of pathogenic alleles that each individual carries, and the mode of inheritance. A parameter indicating presence of an association and the parameters representing the pathogenicity of each variant and the mode of inheritance can be inferred in a Bayesian framework. Variant-specific prior information derived from allele frequency databases, consequence prediction algorithms, or genomic datasets can be integrated into the inference. Association models can be fitted to different subsets of variants in a locus and compared using a model selection procedure. This procedure can improve inference if only a particular class of variants confers disease risk and can suggest particular disease etiologies related to that class. We show that our method, called BeviMed, is more powerful and informative than existing rare variant association methods in the context of dominant and recessive disorders. The high computational efficiency of our algorithm makes it feasible to test for associations in the large non-coding fraction of the genome. We have applied BeviMed to whole-genome sequencing data from 6,586 individuals with diverse rare diseases. We show that it can identify multiple loci involved in rare diseases, while correctly inferring the modes of inheritance, the likely pathogenic variants, and the variant classes responsible.

PMID: 28669401 [PubMed - indexed for MEDLINE]

Electronic Health Record Based Algorithm to Identify Patients with Autism Spectrum Disorder.

PLoS One. 2016;11(7):e0159621

Authors: Lingren T, Chen P, Bochenek J, Doshi-Velez F, Manning-Courtney P, Bickel J, Wildenger Welchons L, Reinhold J, Bing N, Ni Y, Barbaresi W, Mentch F, Basford M, Denny J, Vazquez L, Perry C, Namjou B, Qiu H, Connolly J, Abrams D, Holm IA, Cobb BA, Lingren N, Solti I, Hakonarson H, Kohane IS, Harley J, Savova G

Abstract
OBJECTIVE: Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co-occurrence patterns of medical comorbidities in ASD.
METHODS: We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children's Hospital (BCH) (N = 150) and Cincinnati Children's Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups.
RESULTS: The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children's Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters.
CONCLUSIONS: In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD.

PMID: 27472449 [PubMed - indexed for MEDLINE]

The ethical framework for performing research with rare inherited neurometabolic disease patients.

Eur J Pediatr. 2017 Mar;176(3):395-405

Authors: Giannuzzi V, Devlieger H, Margari L, Odlind VL, Ragab L, Bellettato CM, D'Avanzo F, Lampe C, Cassis L, Cortès-Saladelafont E, Cazorla ÁG, Barić I, Cvitanović-Šojat L, Fumić K, Dali CI, Bartoloni F, Bonifazi F, Scarpa M, Ceci A

Abstract
The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families.
CONCLUSION: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and information on how these rules have been applied.

PMID: 28093642 [PubMed - indexed for MEDLINE]

Activity of Pazopanib and Trabectedin in Advanced Alveolar Soft Part Sarcoma.

Oncologist. 2017 Jul 28;:

Authors: Stacchiotti S, Mir O, Le Cesne A, Vincenzi B, Fedenko A, Maki RG, Somaiah N, Patel S, Brahmi M, Blay JY, Boye K, Sundby Hall K, Gelderblom H, Hindi N, Martin-Broto J, Kosela H, Rutkowski P, Italiano A, Duffaud F, Kobayashi E, Casali PG, Provenzano S, Kawai A

Abstract
BACKGROUND: Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin.
MATERIALS AND METHODS: From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method.
RESULTS: Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months.
CONCLUSION: The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS.
IMPLICATIONS FOR PRACTICE: This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.

PMID: 28754721 [PubMed - as supplied by publisher]

'You two - There must be some mistake!'

Emerg Med Australas. 2016 Dec;28(6):758

Authors: Brown AF, Zia M, Symons P, Moore N

PMID: 27796071 [PubMed - indexed for MEDLINE]

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

Am J Hum Genet. 2017 May 04;100(5):695-705

Authors: Boycott KM, Rath A, Chong JX, Hartley T, Alkuraya FS, Baynam G, Brookes AJ, Brudno M, Carracedo A, den Dunnen JT, Dyke SOM, Estivill X, Goldblatt J, Gonthier C, Groft SC, Gut I, Hamosh A, Hieter P, Höhn S, Hurles ME, Kaufmann P, Knoppers BM, Krischer JP, Macek M, Matthijs G, Olry A, Parker S, Paschall J, Philippakis AA, Rehm HL, Robinson PN, Sham PC, Stefanov R, Taruscio D, Unni D, Vanstone MR, Zhang F, Brunner H, Bamshad MJ, Lochmüller H

Abstract
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

PMID: 28475856 [PubMed - indexed for MEDLINE]

Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis.

J Exp Med. 2016 Jul 25;213(8):1497-512

Authors: Rowe RG, Wang LD, Coma S, Han A, Mathieu R, Pearson DS, Ross S, Sousa P, Nguyen PT, Rodriguez A, Wagers AJ, Daley GQ

Abstract
For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood. In this study, we find that expression of the heterochronic factor Lin28b decreases in common myeloid progenitors during hematopoietic maturation to adulthood in mice. This decrease in Lin28b coincides with accumulation of mature let-7 microRNAs, whose biogenesis is regulated by Lin28 proteins. We find that inhibition of let-7 in the adult hematopoietic system recapitulates fetal erythroid-dominant hematopoiesis. Conversely, deletion of Lin28b or ectopic activation of let-7 microRNAs in the fetal state induces a shift toward adult-like myeloid-dominant output. Furthermore, we identify Hmga2 as an effector of this genetic switch. These studies provide the first detailed analysis of the roles of endogenous Lin28b and let-7 in the timing of hematopoietic states during development.

PMID: 27401346 [PubMed - indexed for MEDLINE]

Limb Amputation after Multiple Treatments of Tenosynovial Giant Cell Tumour: Series of 4 Dutch Cases.

Case Rep Orthop. 2017;2017:7402570

Authors: Mastboom MJL, Verspoor FGM, Gelderblom H, van de Sande MAJ

Abstract
In Tenosynovial Giant Cell Tumours (TGCT), previously named Pigmented Villonodular Synovitis (PVNS), a distinction is made between a single nodule (localized-type) and multiple nodules (diffuse-type). Diffuse-type is considered locally aggressive. Onset and extermination of this orphan disease remain unclear. Surgical resection is the most commonly performed treatment. Unfortunately, recurrences often occur (up to 92%), necessitating reoperations and adjuvant treatments. Once all treatments fail or if severe complications occur, limb amputation may become unavoidable. We describe four cases of above-knee amputation after TGCT diagnosis.

PMID: 28744388 [PubMed]

Dealing with Uncertainty and Accounting for Social Value Judgments in Assessments of Orphan Drugs: Evidence from Four European Countries.

Value Health. 2017 Jul - Aug;20(7):919-926

Authors: Nicod E, Berg Brigham K, Durand-Zaleski I, Kanavos P

Abstract
OBJECTIVES: To better understand the reasons for differences in reimbursement decisions for orphan drugs in four European countries that were not readily apparent from health technology assessment (HTA) reports and operating procedures.
METHODS: Semistructured interviews with representatives of HTA bodies in England, Scotland, Sweden, and France were conducted. An interview topic guide was developed on the basis of findings from a systematic comparison of HTA decisions for 10 orphan drugs. Qualitative thematic data analysis was applied to the interview transcripts using the framework approach.
RESULTS: Eight representatives from the four HTA bodies were interviewed between March and June 2015. Evidentiary requirements and approaches to dealing with imperfect or incomplete evidence were explored, including trial design and duration, study population and subgroups, comparators, and end points. Interviewees agreed that decisions regarding orphan drugs are made in a context of lower quality evidence, and the threshold of acceptable uncertainty varied by country. Some countries imposed higher evidentiary standards for greater clinical claims, which may be more challenging for orphan diseases. The acceptability of surrogate end points was not consistent across countries nor were the validation requirements. The most common social value judgments identified related to innovation, disease severity, and unmet need. Differences were seen in the way these concepts were defined and accounted for across countries.
CONCLUSIONS: Although agreement was seen in evidentiary requirements or preferences, there were subtle differences in the circumstances in which uncertain evidence may be considered acceptable, possibly explaining differences in HTA recommendations across countries.

PMID: 28712621 [PubMed - indexed for MEDLINE]

Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report.

Value Health. 2017 Jul - Aug;20(7):838-855

Authors: Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L

Abstract
BACKGROUND: Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals.
OBJECTIVE: To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials.
GOOD PRACTICES FOR OUTCOMES RESEARCH: This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition's natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient's perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use.
CONCLUSIONS: This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

PMID: 28712612 [PubMed - indexed for MEDLINE]