The Use of Social Media in Orphan Drug Development.

Clin Ther. 2017 Sep 20;:

Authors: Milne CP, Ni W

Abstract
Social media has transformed how people interact with one another through the Internet, and it has the potential to do the same for orphan drug development. Currently, social media influences the orphan drug development process in the following three ways: assisting the study of orphan diseases, increasing the awareness of orphan disease, and playing a vital role in clinical trials. However, there are some caveats to the utilization of social media, such as the need to protect patient privacy by adequately de-identifying personal health information, assuring consistent quality and representativeness of the data, and preventing the unblinding of patient group assignments. Social media has both potential for improving orphan drug development and pitfalls, but with proper oversight on the part of companies, support and participation of patients and their advocacy groups, and timely guidance from regulatory authorities, the positives outweigh the negatives for this powerful and patient-centric tool.

PMID: 28942336 [PubMed - as supplied by publisher]

Direct-to-Consumer Genetic Testing and Orphan Drug Development.

Genet Test Mol Biomarkers. 2017 Aug;21(8):456-463

Authors: Mason M, Levenson J, Quillin J

Abstract
Since the introduction of the Orphan Drug Act (ODA) in 1983, orphan drug approvals in the United States have jumped from <100 per decade to over 200 per year. This growth is widely attributed to the financial incentives the ODA gives to companies that develop these medicines, and it is likely to continue for a unique reason: partnerships between pharmaceutical firms and direct-to-consumer (DTC) genetic testing companies. This emerging trend is the subject of this article, which begins by considering how rare-disease drugs are regulated and the rising interest in nonclinical genetic testing. It then outlines how DTC companies analyze DNA and how their techniques benefit researchers and drug developers. Then, after an overview of the current partnerships between DTCs and drug developers, it examines concerns about privacy and cost brought up by these partnerships. The article concludes by contrasting the enormous positive potential of DTC-pharma relationships and their concomitant dangers, especially to consumer privacy and cost to the healthcare system.

PMID: 28696792 [PubMed - indexed for MEDLINE]

[Neuroendocrine prostate cancer: Natural history, molecular features, therapeutic management and future directions].

Bull Cancer. 2017 Sep;104(9):789-799

Authors: Campedel L, Kossaï M, Blanc-Durand P, Rouprêt M, Seisen T, Compérat E, Spano JP, Malouf G

Abstract
Neuroendocrine prostate cancer is a rare malignancy with a an adverse prognostic. Histologically, It can be pure (small cells or large cells neuroendocrine carcinoma) or mixed with a adenocarcinoma component. Rarely diagnosed de novo, neuroendocrine prostate cancer is generally associated with advanced stage disease resistant to castration. As such, this histological subtype could represent an aggressive evolution of prostatic adenocarcinoma, through the epithelio-neuroendocrine transdifferentiation mechanism (phenomenon of lineage plasticity). Nonetheless, neuroendocrine prostate cancer is a heterogeneous malignancy with multiple histopathological variants showing distinct clinical features. The broad variety of molecular analyses could help to understand the ontogeny of this histological subtype and its signaling pathways. This may also allow identifying diagnostic and prognostic biomarkers as well as potential molecular targets. However, treatment options are currently limited and consist only in platinium-based chemotherapy for advanced stage disease.

PMID: 28673439 [PubMed - indexed for MEDLINE]

7 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 2017/09/21

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.

[Alzheimer's disease from Auguste Deter to the present : Progress, disappointments and open questions].

Z Gerontol Geriatr. 2017 Sep 18;:

Authors: Pantel J

Abstract
AIM: The present article aims to provide a short overview of the discovery history, conceptual development, as well as on current neurobiological and pharmacological research questions in the field of Alzheimer's disease (AD). In view of the long hoped for but so far unachieved therapeutic breakthrough, this also includes a critical reflection of current research paradigms.
MATERIAL AND METHODS: Starting from the first case report described by Alois Alzheimer in 1906, the historical impact of his seminal discovery is reconstructed. Neurobiological research paradigms central to AD are discussed with respect to their relevance for modern biomarker-based diagnostic approaches as well as to the development of innovative disease-modifying drug therapies.
RESULTS: Originally conceived as a rare presenile form of dementia it was not until the 1970s that AD was granted an orphan disease status. The biomedical deconstruction of senility and the introduction of new research methods enabled the nosological unification of AD with the concept of senile dementia which, in turn led to a global flowering of AD research. In the 1990s the amyloid cascade hypothesis was introduced as the leading research paradigm of AD. In the following years this stimulated the development of a huge variety of innovative biomarker-based diagnostic and disease-modifying pharmacological approaches.
CONCLUSION: Against the background of the recent failures of many clinical drug trials, the relevance of the amyloid cascade hypothesis to explain the etiology of sporadic AD is increasingly being questioned. On the one hand, this leaves the question of the central etiological paradigm unresolved and on the other hand it stimulated a debate on alternative etiological models which might lead to fruitful consequences for future research strategies.

PMID: 28924872 [PubMed - as supplied by publisher]

Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.

Lancet Oncol. 2017 Aug;18(8):1022-1039

Authors: Gatta G, Capocaccia R, Botta L, Mallone S, De Angelis R, Ardanaz E, Comber H, Dimitrova N, Leinonen MK, Siesling S, van der Zwan JM, Van Eycken L, Visser O, Žakelj MP, Anderson LA, Bella F, Kaire I, Otter R, Stiller CA, Trama A, RARECAREnet working group

Abstract
BACKGROUND: Rare cancers pose challenges for diagnosis, treatments, and clinical decision making. Information about rare cancers is scant. The RARECARE project defined rare cancers as those with an annual incidence of less than six per 100 000 people in European Union (EU). We updated the estimates of the burden of rare cancers in Europe, their time trends in incidence and survival, and provide information about centralisation of treatments in seven European countries.
METHODS: We analysed data from 94 cancer registries for more than 2 million rare cancer diagnoses, to estimate European incidence and survival in 2000-07 and the corresponding time trends during 1995-2007. Incidence was calculated as the number of new cases divided by the corresponding total person-years in the population. 5-year relative survival was calculated by the Ederer-2 method. Seven registries (Belgium, Bulgaria, Finland, Ireland, the Netherlands, Slovenia, and the Navarra region in Spain) provided additional data for hospitals treating about 220 000 cases diagnosed in 2000-07. We also calculated hospital volume admission as the number of treatments provided by each hospital rare cancer group sharing the same referral pattern.
FINDINGS: Rare cancers accounted for 24% of all cancers diagnosed in the EU during 2000-07. The overall incidence rose annually by 0.5% (99·8% CI 0·3-0·8). 5-year relative survival for all rare cancers was 48·5% (95% CI 48·4 to 48·6), compared with 63·4% (95% CI 63·3 to 63·4) for all common cancers. 5-year relative survival increased (overall 2·9%, 95% CI 2·7 to 3·2), from 1999-2001 to 2007-09, and for most rare cancers, with the largest increases for haematological tumours and sarcomas. The amount of centralisation of rare cancer treatment varied widely between cancers and between countries. The Netherlands and Slovenia had the highest treatment volumes.
INTERPRETATION: Our study benefits from the largest pool of population-based registries to estimate incidence and survival of about 200 rare cancers. Incidence trends can be explained by changes in known risk factors, improved diagnosis, and registration problems. Survival could be improved by early diagnosis, new treatments, and improved case management. The centralisation of treatment could be improved in the seven European countries we studied.
FUNDING: The European Commission (Chafea).

PMID: 28687376 [PubMed - indexed for MEDLINE]

Congenital inverse Duane's retraction syndrome: A rare presentation.

Indian J Ophthalmol. 2017 May;65(5):422-423

Authors: Agarkar S, Kaduskar A

Abstract
A 12-year-old girl presented with esotropia and face turn since birth. Ocular motility examination showed restricted abduction associated with down shoot and retraction on attempted abduction characteristic of inverse Duane's retraction syndrome. To the best of our knowledge, this is one of the very few reported cases of congenital inverse Duane's retraction syndrome.

PMID: 28574005 [PubMed - indexed for MEDLINE]

A case report on a very rare variant of popliteal artery entrapment syndrome due to an enlarged fabella associated with severe knee osteoarthritis.

J Orthop Sci. 2017 Jan;22(1):164-168

Authors: Ando Y, Miyamoto Y, Tokimura F, Nakazawa T, Hamaji H, Kanetaka M, Koshiishi A, Hirabayashi K, Anamizu Y, Miyazaki T

PMID: 26740435 [PubMed - indexed for MEDLINE]

7 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 2017/09/19

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.

7 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 2017/09/19

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.

Impaired fertility and motor function in a zebrafish model for classic galactosemia.

J Inherit Metab Dis. 2017 Sep 14;:

Authors: Vanoevelen JM, Rubio-Gozalbo ME, van Erven B, Bierau J, Huang X, Berry GT, Vos R, Coelho AI

Abstract
Classic galactosemia is a genetic disorder of galactose metabolism, caused by severe deficiency of galactose-1-phosphate uridylyltransferase (GALT) enzyme activity due to mutations of the GALT gene. Its pathogenesis is still not fully elucidated, and a therapy that prevents chronic impairments is lacking. In order to move research forward, there is a high need for a novel animal model, which allows organ studies throughout development and high-throughput screening of pharmacologic compounds. Here, we describe the generation of a galt knockout zebrafish model and present its phenotypical characterization. Using a TALEN approach, a galt knockout line was successfully created. Accordingly, biochemical assays confirm essentially undetectable galt enzyme activity in homozygotes. Analogous to humans, galt knockout fish accumulate galactose-1-phosphate upon exposure to exogenous galactose. Furthermore, without prior exposure to exogenous galactose, they exhibit reduced motor activity and impaired fertility (lower egg quantity per mating, higher number of unsuccessful crossings), resembling the human phenotype(s) of neurological sequelae and subfertility. In conclusion, our galt knockout zebrafish model for classic galactosemia mimics the human phenotype(s) at biochemical and clinical levels. Future studies in our model will contribute to improved understanding and management of this disorder.

PMID: 28913702 [PubMed - as supplied by publisher]

Homozygous EEF1A2 mutation causes dilated cardiomyopathy, failure to thrive, global developmental delay, epilepsy and early death.

Hum Mol Genet. 2017 Sep 15;26(18):3545-3552

Authors: Cao S, Smith LL, Padilla-Lopez SR, Guida BS, Blume E, Shi J, Morton SU, Brownstein CA, Beggs AH, Kruer MC, Agrawal PB

Abstract
Eukaryotic elongation factor 1A (EEF1A), is encoded by two distinct isoforms, EEF1A1 and EEF1A2; whereas EEF1A1 is expressed almost ubiquitously, EEF1A2 expression is limited such that it is only detectable in skeletal muscle, heart, brain and spinal cord. Currently, the role of EEF1A2 in normal cardiac development and function is unclear. There have been several reports linking de novo dominant EEF1A2 mutations to neurological issues in humans. We report a pair of siblings carrying a homozygous missense mutation p.P333L in EEF1A2 who exhibited global developmental delay, failure to thrive, dilated cardiomyopathy and epilepsy, ultimately leading to death in early childhood. A third sibling also died of a similar presentation, but DNA was unavailable to confirm the mutation. Functional genomic analysis was performed in S. cerevisiae and zebrafish. In S. cerevisiae, there was no evidence for a dominant-negative effect. Previously identified putative de novo mutations failed to complement yeast strains lacking the EEF1A ortholog showing a major growth defect. In contrast, the introduction of the mutation seen in our family led to a milder growth defect. To evaluate its function in zebrafish, we knocked down eef1a2 expression using translation blocking and splice-site interfering morpholinos. EEF1A2-deficient zebrafish had skeletal muscle weakness, cardiac failure and small heads. Human EEF1A2 wild-type mRNA successfully rescued the morphant phenotype, but mutant RNA did not. Overall, EEF1A2 appears to be critical for normal heart function in humans, and its deficiency results in clinical abnormalities in neurologic function as well as in skeletal and cardiac muscle defects.

PMID: 28911200 [PubMed - in process]

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

Nat Neurosci. 2017 Sep;20(9):1217-1224

Authors: Lim ET, Uddin M, De Rubeis S, Chan Y, Kamumbu AS, Zhang X, D'Gama AM, Kim SN, Hill RS, Goldberg AP, Poultney C, Minshew NJ, Kushima I, Aleksic B, Ozaki N, Parellada M, Arango C, Penzol MJ, Carracedo A, Kolevzon A, Hultman CM, Weiss LA, Fromer M, Chiocchetti AG, Freitag CM, Autism Sequencing Consortium, Church GM, Scherer SW, Buxbaum JD, Walsh CA

Abstract
We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10(-6)), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10(-3)). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

PMID: 28714951 [PubMed - indexed for MEDLINE]

Neurological outcome in patients with inborn errors of metabolism submitted to hematopoietic stem cell transplantation. What should we expect?

Arq Neuropsiquiatr. 2016 Dec;74(12):949-950

Authors: Lange MC

PMID: 27991990 [PubMed - indexed for MEDLINE]

Legius syndrome: A case report.

J Dermatol. 2017 Apr;44(4):459-460

Authors: Kimura R, Yoshida Y, Maruoka R, Kosaki K, Yamamoto O

Abstract
Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss-of-function SPRED1 mutation. In Japan, a family with Legius syndrome was first described in 2015 by Sakai et al. We described a first solitary case of Legius syndrome identified by next-generation sequencing in Japan. A 37-year-old woman presented with multiple café-au-lait macules and freckles but has no other features of neurofibromatosis type 1 (NF-1). Sequencing results showed the presence of a mutation in exon 2 of SPRED1 c.70C>T, resulting in the protein at position 24 (p.Arg24X). When a dermatological clinician sees an adult patient showing only pigmented lesions and no other specifically diagnostic features of NF-1, it is important to suspect the possibility of Legius syndrome.

PMID: 28378438 [PubMed - indexed for MEDLINE]

Klippel-Trenaunay syndrome: a rare entity with anesthesia concerns.

J Clin Anesth. 2016 Dec;35:233-234

Authors: Dwivedi D, Sheshadri K, Tandon U, Chakraborty S

PMID: 27871531 [PubMed - indexed for MEDLINE]

7 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 2017/09/14

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.

Insights from early experience of a Rare Disease Genomic Medicine Multidisciplinary Team: a qualitative study.

Eur J Hum Genet. 2017 Jun;25(6):680-686

Authors: Ormondroyd E, Mackley MP, Blair E, Craft J, Knight JC, Taylor J, Taylor JC, Wilkie AO, Watkins H

Abstract
Whole-exome/whole-genome sequencing (WES/WGS) has the potential to enhance genetic diagnosis of rare disease, and is increasingly becoming part of routine clinical care in mainstream medicine. Effective translation will require ongoing efforts in a number of areas including: selection of appropriate patients, provision of effective consent, pre- and post-test genetic counselling, improving variant interpretation algorithms and practices, and management of secondary findings including those found incidentally and those actively sought. Allied to this is the need for an effective education programme for all members of clinical teams involved in care of patients with rare disease, as well as to maintain public confidence in the use of these technologies. We established a Genomic Medicine Multidisciplinary Team (GM-MDT) in 2014 to build on the experiences of earlier successful research-based WES/WGS studies, to address these needs and to review results including pertinent and secondary findings. Here we report on a qualitative study of decision-making in the GM-MDT combined with analysis of semi-structured interviews with GM-MDT members. Study findings show that members appreciate the clinical and scientific diversity of the GM-MDT and value it for education and oversight. To date, discussions have focussed on case selection including the extent and interpretation of clinical and family history information required to establish likely monogenic aetiology and inheritance model. Achieving a balance between effective use of WES/WGS - prioritising cases in a diverse and highly complex patient population where WES/WGS will be tractable - and meeting the recruitment targets of a large project is considered challenging.

PMID: 28327571 [PubMed - indexed for MEDLINE]

Internet Use by Parents of Children With Rare Conditions: Findings From a Study on Parents' Web Information Needs.

J Med Internet Res. 2017 Feb 28;19(2):e51

Authors: Nicholl H, Tracey C, Begley T, King C, Lynch AM

Abstract
BACKGROUND: Parents of children with rare conditions increasingly use the Internet to source information on their child's condition. This study reports on part of a larger study whose overall aim was to identify the Internet use by parents when seeking information on their child's rare condition, with the specific purpose of using the findings to aid in the development of a website specifically designed to meet the parents' needs. It presents findings on why these parents use the Internet, the information and support content they source, and the impact these resources have on their capacity to care for and manage their child's condition.
OBJECTIVE: To (1) ascertain parents' general Internet usage patterns, (2) identify the nature of the information parents most frequently searched for, and (3) determine the effect the Internet-sourced information had on parents of children with rare conditions.
METHODS: Data collection was conducted in 2 parts: Part 1 was a focus group interview (n=8) to inform the development of the questionnaire, and Part 2 was a questionnaire (Web- and paper-based). All respondents (N=128) completed the questionnaire using the Internet.
RESULTS: Parents frequently and habitually used the Internet and social media to gather information on their child's condition. These Web-based resources provide parents with a parent-to-parent support platform that allows them to share their experiences and information with other parents, which, the respondents considered, improved their knowledge and understanding of their child's condition. The respondents also reported that these resources positively impacted on their decision making, care, and management of their child's condition. However, they reported receiving mixed responses when wishing to engage and share with health care professionals their Internet and social media interactions and information outcomes.
CONCLUSIONS: This study adds to the emerging body of research on the Internet use by parents of children with rare conditions to source information on their child's condition. The evolving and ever increasing parent-to-parent support systems via social media are impacting on parents' capacity to manage their children. Implications for practice include health care professionals' response to this knowledge and capacity shift, and the significance of these changes when interacting with parents. The key message of this study was that parents of children with rare conditions are habitual users of the Internet to source information about their children's conditions. Social media, especially Facebook, has an increasing role in the lives of these parents for information and support. Parents' interest in information gathering and sharing includes a desire for shared dialogue with health care professionals.

PMID: 28246072 [PubMed - indexed for MEDLINE]

Experience With Direct-to-Patient Recruitment for Enrollment Into a Clinical Trial in a Rare Disease: A Web-Based Study.

J Med Internet Res. 2017 Feb 28;19(2):e50

Authors: Krischer J, Cronholm PF, Burroughs C, McAlear CA, Borchin R, Easley E, Davis T, Kullman J, Carette S, Khalidi N, Koening C, Langford CA, Monach P, Moreland L, Pagnoux C, Specks U, Sreih AG, Ytterberg S, Merkel PA, Vasculitis Clinical Research Consortium

Abstract
BACKGROUND: The target sample size for clinical trials often necessitates a multicenter (center of excellence, CoE) approach with associated added complexity, cost, and regulatory requirements. Alternative recruitment strategies need to be tested against this standard model.
OBJECTIVES: The aim of our study was to test whether a Web-based direct recruitment approach (patient-centric, PC) using social marketing strategies provides a viable option to the CoE recruitment method.
METHODS: PC recruitment and Web-based informed consent was compared with CoE recruitment for a randomized controlled trial (RCT) of continuing versus stopping low-dose prednisone for maintenance of remission of patients with granulomatosis with polyangiitis (GPA).
RESULTS: The PC approach was not as successful as the CoE approach. Enrollment of those confirmed eligible by their physician was 10 of 13 (77%) and 49 of 51 (96%) in the PC and CoE arms, respectively (P=.05). The two approaches were not significantly different in terms of eligibility with 34% of potential participants in the CoE found to be ineligible as compared with 22% in the PC arm (P=.11) nor in provider acceptance, 22% versus 26% (P=.78). There was no difference in the understanding of the trial as reflected in the knowledge surveys of individuals in the PC and CoE arms.
CONCLUSIONS: PC recruitment was substantially less successful than that achieved by the CoE approach. However, the PC approach was good at confirming eligibility and was as acceptable to providers and as understandable to patients as the CoE approach. The PC approach should be evaluated in other clinical settings to get a better sense of its potential.

PMID: 28246067 [PubMed - indexed for MEDLINE]