What to consider when pseudohypoparathyroidism is ruled out: IPPSD and differential diagnosis

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright''s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes

Reconstruction and simulation of neocortical microcircuitry

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm3 containing ∼31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ∼8 million connections with ∼37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies

European Specifications for Value-based Pre-Commercial Procurement of Innovative ICT for Empowerment and Self-management of Diabetes Mellitus Patients

Current demographic changes require a paradigm shift in the delivery of health and social services. Wide-scale implementation of validated ICT support to clinicians and patients is essential to ensure the quality of services to future generations of citizens. Healthcare providers from four European regions - Turkey, Portugal, Campania and Murcia- have joined forces to procure an innovative ICT solution for patient empowerment and self-management for patients with diabetes mellitus. The procurement is in the form of a joint pre-commercial procurement (PCP) of Research & Development, with participation by EU industry in competitive phases of development. The PCP is part of the EU-funded project ProEmpower, which is currently in the prototype testing phase. The challenge faced by the procurers was to jointly define specifications for the envisioned solution that reflect the needs of all four regions. After an intensive year of consultations with procurers' experts - clinicians, IT staff, procurement specialists - ProEmpower launched a call for tender with the defined specifications, which reflect the unmet needs across the procuring regions with regards to improving management of diabetes mellitus supported by ICT. This paper presents the ProEmpower specifications, which can be easily adapted to the local conditions of any procuring region in Europe and beyond. The specifications thus represent a valuable source for any new development of ICT-supported diabetes management

Developing a digital environment for the management of chronic conditions: The proempower experience of a Horizon 2020 PCP for type 2 diabetes

Demographic change represents the most significant challenge of the 21st century. The aging population around the world will foster a consequent change in labor markets, wealth distribution, request of goods and services, as well as social and healthcare needs. The number of survivors to once deadly conditions, as well as the age associated increase in degenerative chronic conditions will represent a severe stress to our systems, that will not be sustainable any longer. At the same time, longevity might become an opportunity for the re-organization of services, leading to a new era of opportunities for economic and social prosperity. These challenges require a strong interdisciplinary approach in the identification of unmet needs, and new social, health and technological solutions, that are demand-driven and user-oriented. ICT is going to be the key to many of these revolutionary services. The European Community has proposed a new grant instrument to foster the collaboration between public administration and ICT industry for purchasing Research and Development services in order to develop a novel Information and Communication Technology solution, called Pre Commercial Procurement. ProEmpower is such a project aimed to enable patients to early diagnosis, daily management, and clinical data collection for people with type 2 diabetes. The project goes through a call for tenders issued by a consortium of four public procurers, that jointly defined a set of requirements and use cases, in collaboration with end-users, for the development of innovative solutions This manuscript describes the process that has led to the selection of two solutions that will be tested by end users in the four regions

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations