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BACKGROUND: Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient's symptoms, opening new avenues for diagnosis and management. CASE PRESENTATION: We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). CONCLUSION: This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

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Biologically engineered nanomaterials give rise to unique and intriguing properties, which are not available in nature. The full-realization of such has been hindered by the lack of robust and straightforward techniques to produce the required architectures. Here a new bottomup bionano-engineering route is developed to construct nanomaterials using a guided assembly of collagen building blocks, establishing a lithographic process for three-dimensional collagen-based hierarchical micronano-architectures. By introducing optimized hybrid electro-hydrodynamic micronano-lithography exploiting collagen molecules as biological building blocks to self-assemble into a complex variety of structures, quasi-ordered mimics of metamaterials-like are constructed. The tailor-designed engineered apparatus generates the underlying substrates with vertical orientation of collagen at controlled speeds. Templating these hierarchical structures into inorganic materials allows the replication of their network into periodic metal micronano-assemblies. These generate substrates with interesting optical properties, suggesting that size-and-orientation dependent nanofilaments with varying degree of lateral order yield distinctly coloured structures with characteristic optical spectra correlated with observed colours, which varying diameters and interspacing, are attributable to coherent scattering by different periodicity of each fibrous micronano-structure. The artificial mimics display similar optical characteristics to the natural butterfly wing's structure, known to exhibit extraordinary electromagnetic properties, driving future applications in cloaking, super-lenses, photovoltaics and photodetectors.

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Metals on metal implants have long been used in arthroplasties because of their robustness and low dislocation rate. Several relatively low-corrosion metals have been used in arthroplasty, including 316L stainless steel, titanium, and cobalt-chromium-molybdenum alloy. Debris from these implants, however, has been found to cause inflammatory responses leading to unexpected failure rates approaching 10% 7 years surgery. Safety assessment of these materials traditionally relies on the use of simple two-dimensional assays, where cells are grown on the surface of the material over a relatively short time frame. It is now well-known that the composition and stiffness of the extracellular matrix (ECM) have a critical effect on cell function. In this work, we have evaluated how cobalt ions influence the assembly of type I collagen, the principle component of the ECM in bone. We found that cobalt had a significant effect on collagen matrix formation, and its presence results in local variations in collagen density. This increase in heterogeneity causes an increase in localized mechanical properties but a decrease in the bulk stiffness of the material. Moreover, when collagen matrices contained cobalt ions, there was a significant change in how the cells interacted with the collagen matrix. Fluorescence images and biological assays showed a decrease in cell proliferation and viability with an increase in cobalt concentration. We present evidence that the cobalt ion complex interacts with the hydroxyl group present in the carboxylic terminal of the collagen fibril, preventing crucial stabilizing bonds within collagen formation. This demonstrates that the currently accepted toxicity assays are poor predictors of the longer-term biological performance of a material.

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INTRODUCTION: Describing the trajectory of prodromal symptoms has obvious appeal in supporting advances towards sub-clinical intervention. Identifying clinical phenomena associated with unfavourable illness outcomes could have greater significance in explaining some heterogeneity within and between psychotic disorders and advancing understanding of pre-psychotic typologies. Few studies have assessed the continuity, if any, between prodromal phases and illness outcome one year after treatment. METHODS: We assessed 375 people with first-episode psychosis (FEP) and 215 (57.4%) were seen approximately one year later. We performed factor analysis on prodromal symptom items obtained by interview with families and participants and identified a five-factor solution. We determined whether these factors predicted non-remission from psychosis in the presence of other factors that may predict outcome including premorbid adjustment, duration of prodrome and untreated psychosis (DUP), baseline symptoms and DSM-IV diagnoses. We used random forest classification to predict the most important variables and logistic regression to identify specific predictors. RESULTS: We identified five prodromal symptom factors comprising Negative Symptoms, General Psychopathology, Reality Distortion, Strange Ideas and Irritability. Prodromal symptoms did not predict a greater risk of non-remission with the exception of Irritability and this factor was also associated with earlier age at onset, being male and a diagnosis of substance-induced psychosis. Being male, DUP and baseline positive symptoms predicted non-remission at one year. CONCLUSION: Prodromal symptoms were not linked with outcome after a year of treatment which could be explained by greater heterogeneity in illness psychopathology which may be more pronounced in broad FEP diagnoses at different stages. It could also be explained by prodromal symptoms exerting greater influence earlier in the course illness.

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BACKGROUND: This study was designed to establish a reference interval for sweat chloride for infants without evidence of cystic fibrosis (CF), aged between 5 wk and 6 wk, a time when sweat testing is an integral part of newborn screening for CF. In addition, we compared the gold standard method of sweat testing (quantitative pilocarpine iontophoresis [QPIT, coulometry]) with an emerging methodology (Macroduct [ISE]). METHODS: This was a prospective study on healthy infants at 5-6 wk of age. Sweat collection was undertaken at home on both outer thigh areas using two methods (QPIT and Macroduct ). The order of testing was randomly assigned. Filter paper samples (QPIT) were analysed using flame photometry and coulometry. Macroduct samples were analysed using ion-selective electrodes (ISE, Abbott Architect c8000, UK). RESULTS: Insufficient sweat was collected on 28 occasions with the QPIT (coulometry) method and on 31 with the Macroduct (ISE) capillary system. We achieved a 92% success rate in undertaking two sweat collections consecutively (n = 177). Sweat chloride concentrations were normally distributed with excellent limits of agreement between the two methods of sweat collection and analysis (n = 150). Median (IQR) sweat chloride was 11.2 mmol/L (8-13) with QPIT (coulometry) method with a 99.5th centile (n = 165) of 24 mmol/L. CONCLUSION: The Macroduct (ISE) capillary sweat collection system is valid in this age group. Sweat chloride concentrations above 30 mmol/L should prompt assessment in a specialist CF centre.

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We report a mother and son with an interstitial deletion of chromosome 2: del(2)(p21p22.2). Both have mildly dysmorphic facial features and learning difficulties. This phenotype contrasts with two previously described cases with a similar deletion that presented with cyclopia and alobar holoprosencephaly.

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Familial pancreatic cancer (FPC) (approximately 3% of all cases) has not been linked to defects in any specific gene. Germline inactivation of the gene LKB1/STK11 have been shown to cause Peutz-Jeghers syndrome (PJS) associated with a approximately 100-fold higher risk for the development of pancreatic cancer. We have analysed 39 index patients from European FPC families for mutations of LKB1/STK11 by sequencing of their DNA. No germline mutation was found within the complete coding region. Therefore, our results indicate that LKB1/STK11 is not altered in the germline of patients with hereditary pancreatic cancer.

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We describe a 71-year-old woman who presented to the neurology department late in life with a jerky axial dystonia due to the DYT1 GAG deletion. She recalled that her symptoms began 62 years prior to study and remained unchanged for 40 years, illustrating the broad phenotype of DYT1 idiopathic torsion dystonia.

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