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Purpose This study aimed to assess the real-world management of achondroplasia in Italy. Methods Two online surveys addressed to (1) parents/caregivers of individuals with achondroplasia and (2) Italian clinicians managing individuals with achondroplasia were conducted to assess real-world perspectives on achondroplasia management. Both surveys collected data on either patient or clinician demographics, details on diagnoses and referrals, disease complications, and views/experiences with limb lengthening surgery. Results In total, 42 parents/caregivers and 19 clinicians (from 18 hospitals) completed the surveys. According to parents/caregivers, achondroplasia diagnosis was most commonly made in the third trimester of gestation (55% of respondents), with a genetic test performed to confirm the diagnosis in all but one case. In contrast, the clinicians indicated that, while achondroplasia was typically suspected during the prenatal period (78%), diagnosis was more frequently confirmed postnatally (72%). Parents/caregivers reported that the greatest impact of achondroplasia-related complications occurred in their children between the ages of 2–5 years. The most significant complications were otitis, sleep apnoea, stenosis of the foramen magnum or pressure on the spinal cord, and hearing difficulties. Lengthening surgery had been presented as a treatment option to 92% of responding parents/caregivers, with 76% of clinicians viewing surgery favourably. Typically, clinicians’ reasons for suggesting limb lengthening surgery were to improve patient quality of life, increase patient autonomy and self-acceptance, improve trunk-limb disproportion, short stature and walking, and ensure that all possible treatment options had been presented to the parents/caregivers. Conclusion This survey provides insight into the real-world management of individuals with achondroplasia in Italy.

During the COVID-19 outbreak, the European Reference Network on Rare Bone Diseases (ERN BOND) coordination team and Italian rare bone diseases healthcare professionals created the “COVID-19 Helpline for Rare Bone Diseases” in an attempt to provide high-quality information and expertise on rare bone diseases remotely to patients and healthcare professionals. The present position statement describes the key characteristics of the Helpline initiative, along with the main aspects and topics that recurrently emerged as central for rare bone diseases patients and professionals. The main topics highlighted are general recommendations, pulmonary complications, drug treatment, trauma, pregnancy, children and elderly people, and patient associations role. The successful experience of the “COVID-19 Helpline for Rare Bone Diseases” launched in Italy could serve as a primer of gold-standard remote care for rare bone diseases for the other European countries and globally. Furthermore, similar COVID-19 helplines could be considered and applied for other rare diseases in order to implement remote patients’ care.

(ProQuest: ... denotes formulae and/or non-USASCII text omitted; see image).Measurements are presented of electroweak boson production using data from pp collisions at a centre-of-mass energy of ... TeV. The analysis is based on an integrated luminosity of 2.0 fb super(-1) recorded with the LHCb detector. The bosons are identified in the W arrow right mu nu and Z arrow right mu super(+) mu super(-) decay channels. The cross-sections are measured for muons in the pseudorapidity range 2.0 < eta < 4.5, with transverse momenta p sub(T) > 20 GeV/c and, in the case of the Z boson, a dimuon mass within ... GeV/c super(2). The results are ... ... ... ... ... ... ... ... where the first uncertainties are statistical, the second are systematic, the third are due to the knowledge of the LHC beam energy and the fourth are due to the luminosity determination. The evolution of the W and Z boson cross-sections with centre-of-mass energy is studied using previously reported measurements with 1.0 fb super(-1) of data at 7 TeV. Differential distributions are also presented. Results are in good agreement with theoretical predictions at next-to-next-to-leading order in perturbative quantum chromodynamics. [Figure not available: see fulltext.]

Background Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder caused by defects at the 11p15.5 imprinted region. Many cases of female monozygotic (MZ) twins discordant for BWS have been reported, but no definitive conclusions have been drawn regarding the link between epigenetic defects, twinning process, and gender. Here, we report a comprehensive characterization and follow‐up of female MZ twins discordant for BWS. Methods Methylation pattern at 11p15.5 and multilocus methylation disturbance (MLID) profiling were performed by pyrosequencing and MassARRAY in placental/umbilical cord samples and postnatal tissues. Whole‐exome sequencing was carried out to identify MLID causative mutations. X‐chromosome inactivation (XCI) was determined by HUMARA test. Results Both twins share KCNQ1OT1:TSS‐DMR loss of methylation (LOM) and MLID in blood and the epigenetic defect remained stable in the healthy twin over time. KCNQ1OT1:TSS‐DMRLOM was nonhomogeneously distributed in placental samples and the twins showed the same severely skewed XCI pattern. No MLID‐causative mutations were identified. Conclusion This is the first report on BWS‐discordant twins with methylation analyses extended to extraembryonic tissues. The results suggest that caution is required when attempting prenatal diagnosis in similar cases. Although the causative mechanism underlying LOM remains undiscovered, the XCI pattern and mosaic LOM suggest that both twinning and LOM/MLID occurred after XCI commitment.

Background Living with a disabled child has profound effects on the entire family. With a prevalence of developmental disabilities around 2,5 %, there is a considerable need to promote improvements in the health care system. Little is known about changes and adaptations in the lives of affected families and this paucity of information hinders the improvement of services. This study sought to explore the needs and changes in the everyday life of families with children suffering from rare diseases of varying severity, with and without mental disability. The aim was to measure the socio-demographic characteristics, health care problems and living conditions of a large cohort of families with an affected member. Methods A sample of 154 families was recruited between September 2011 and April 2013 to respond to a 136 item questionnaire that explored different areas of concern (diagnosis and follow-up of clinical specialists, relationship with pediatrician, rehabilitation, school, work, institutional and/or private support, child care needs and family relationships). Results All parents answered the questionnaire. They were satisfied with the services provided in particular for diagnosis and follow-up, relationships with the family pediatrician, rehabilitation services and school, regardless of the severity of condition, presence of intellectual disability (ID) or absence of diagnosis. Negative scores were reported for institutional and/or private support and family relationships in severe conditions. Conclusions The Health Care System should maintain a family-centered care and a multi-agency working, improving quality of life of families with disabled child to allow adaptation. At present these services are uncoordinated and financial support is poor, resulting in a heavy burden for these families.

BackgroundMutations in TRPV4, a gene that encodes a Ca2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear.Objectives and methodsTo examine TRPV4 mutation spectrum and phenotype−genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands.ResultsTRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations.ConclusionThe TRPV4 mutation spectrum in MD and SMDK, which showed genotype−phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

The goal of the INFN-RETINA R&D project is to develop and implement a computational methodology that allows to reconstruct events with a large number (> 100) of charged-particle tracks in pixel and silicon strip detectors at 40 MHz, thus matching the requirements for processing LHC events at the full bunch-crossing frequency. Our approach relies on a parallel pattern-recognition algorithm, dubbed artificial retina, inspired by the early stages of image processing by the brain. In order to demonstrate that a track-processing system based on this algorithm is feasible, we built a sizable prototype of a tracking processor tuned to 3 000 patterns, based on already existing readout boards equipped with Altera Stratix III FPGAs. The detailed geometry and charged-particle activity of a large tracking detector currently in operation are used to assess its performances. We report on the test results with such a prototype.

Osteogenesis imperfecta or “brittle bone disease” is a congenital disorder of connective tissue causing the bone to break easily. Around 85–90% of cases are due to autosomal dominant mutations in the genes encoding type I collagen, the major organic component of bone. Genotype–phenotype correlations have shown that quantitative defects of collagen type I lead to mild OI, whereas structural defects show a wide clinical range from mild to perinatal lethal. This may partially be explained by the type of amino acid substitution and the relative location in the domain structure. To fully understand the variability of the clinical manifestation and the underlying pathomechanisms, further investigations are required. Here we provide the first biochemical characterization of a mutation at the signal peptide cleavage site of COL1A1, a domain not yet characterized. By steady-state analysis, we observed reduced production of collagen type I. Furthermore, by pulse-chase analysis we detected delayed secretion and partial intracellular retention of collagen I. In the cellular fraction, the electrophoretic migration was abnormal; however, secreted type I collagen showed a normal migration pattern. The intracellular retention of collagen I was confirmed by immunofluorescent staining. Moreover, transmission electron microscopy of cultured fibroblasts revealed enlargement of ER cisternae. These results further support the hypothesis that mechanisms interfering with ER integrity play an important role in the pathology of severe OI.

(ProQuest: ... denotes formulae and/or non-USASCII text omitted; see image).The associated production of a Z boson or an off-shell photon gamma super( )*with a bottom quark in the forward region is studied using proton-proton collisions at a centre-of-mass energy of 7 TeV. The Z bosons are reconstructed in the Z/ gamma super( )* arrow right mu super( )+ mu super( )-final state from muons with a transverse momentum larger than 20 GeV, while two transverse momentum thresholds are considered for jets (10 GeV and 20 GeV). Both muons and jets are reconstructed in the pseudorapidity range 2.0 < eta < 4.5. The results are based on data corresponding to 1.0 fb super(-1) recorded in 2011 with the LHCb detector. The measurement of the Z+b-jet cross-section is normalized to the Z+jet cross-section. The measured cross-sections are ... ... for p sub(T)(jet) > 10 GeV, and ... ... for p sub(T)(jet) > 20 GeV. [Figure not available: see fulltext.]

Conventional, hadronic matter consists of baryons and mesons made of three quarks and a quark–antiquark pair, respectively 1 , 2 . Here, we report the observation of a hadronic state containing four quarks in the Large Hadron Collider beauty experiment. This so-called tetraquark contains two charm quarks, a u ¯ and a d ¯ quark. This exotic state has a mass of approximately 3,875 MeV and manifests as a narrow peak in the mass spectrum of D 0 D 0 π + mesons just below the D *+ D 0 mass threshold. The near-threshold mass together with the narrow width reveals the resonance nature of the state. The LHCb Collaboration reports the observation of an exotic, narrow, tetraquark state that contains two charm quarks, an up antiquark and a down antiquark.