Recurrent epistaxis, despite conservative therapies (i.e. nasal packing or direct vessel coagulation), is generally treated with ligation of the sphenopalatine artery (SPA). Indeed, the rationale behind SPA ligation lies in its ability to disrupt arterial blood supply to the nasal mucosa, thereby reducing the likelihood of recurrent bleeding episodes (1). Nevertheless, in some cases, nosebleeds persist despite appropriate SPA ligation, opening discussion of the anterior ethmoidal artery (AEA) contribution in recalcitrant epistaxis that, for some authors, is up to 28.8% (2). From an anatomical point of view, the AEA leaves the orbital cavity and passes the ethmoidal roof through the ethmoidal canal, before entering inside the anterior cranial fossa via the lateral lamella (3). Endocranially, the AEA gives posterior branches which vascularize the anterior cribriform plate, whereas its many trunk continues anteriorly and divides into two branches: the anterior meningeal branch, and a second vessel that enters inside the nasal fossa through the cribroethmoidal foramen located 2.86 ± 1.93 mm (range, 1-7 mm) (4) anteriorly to the first olfactory phylum, giving rise to the so-called nasal branch (NbAEA) (5).

To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males. Molecular cytogenetic analysis revealed that the deletion in this chromosomal region shares a common smallest region of overlap (SRO) of 80 kb, which contains only the WAC gene (WW-domain-containing adaptor with coiled coil). In this clinical case report, we report a 5-year-old girl, born from non-consanguineous parents, with a 10p11.22p11.21 microdeletion. She presents clinical features that overlap with other patients described in the literature, such as dysmorphic traits, speech delay, and behavioural abnormalities (hyperactivity), even though the WAC gene is not involved in the microdeletion. Our results are the first to highlight that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype but partially overlaps with the previous cases reported in the literature, even though the same genes are not involved. In particular, in this study, we speculate about the role of the WAC gene that seems to be associated with normal motor development. In fact, we found that our patient is the only one described in the literature with a large deletion in the 10p11.22p11.21 region without the involvement of the WAC gene deletion, and, interestingly, the patient did not have motor delay.

An emerging technology (ET) for laboratory medicine can be defined as an analytical method (including biomarkers) or device (software, applications, and algorithms) that by its stage of development, translation into broad routine clinical practice, or geographical adoption and implementation has the potential to add value to clinical diagnostics. Considering the laboratory medicine-specific definition, this document examines eight key tools, encompassing clinical, analytical, operational, and financial aspects, used throughout the life cycle of ET implementation. The tools provide a systematic approach starting with identifying the unmet need or identifying opportunities for improvement (Tool 1), forecasting (Tool 2), technology readiness assessment (Tool 3), health technology assessment (Tool 4), organizational impact map (Tool 5), change management (Tool 6), total pathway to method evaluation checklist (Tool 7), and green procurement (Tool 8). Whilst there are differences in clinical priorities between different settings, the use of this set of tools will help support the overall quality and sustainability of the emerging technology implementation.

The term "emerging technology" (ET) is used extensively, and there are numerous definitions offered, but to our knowledge, none specifically encompass the field of laboratory medicine. An ET definition that incorporates the overarching IFCC aim of "Advancing excellence in laboratory medicine to support healthcare worldwide" would clarify discussions. We discuss key aspects of the term "emerging technology(ies)" as it applies to laboratory medicine with a view to laying the foundations for a practical definition for the profession and propose the definition of an ET as "An analytical method or device that by virtue of its stage of development, translation into broad routine clinical practice, or geographical adoption and implementation has the potential to add value to clinical diagnostics".

An increase in the atmospheric pCO2 and temperature is expected to reduce ocean CO32− concentration, make oceans warmer and alter ocean circulation patterns. This will also affect the production and biogeographic distribution of marine calcifying organisms including coccolithophores. The lowering of oceanic CO32− is expected to interfere with the coccolithophore calcification process and cause malformation of coccoliths, whereas changes in the oceanic temperature and circulation patterns may shift their biogeographic boundaries. In this study, we have investigated Emiliania huxleyi coccolith and coccosphere size response to the wide-ranging physico-chemical conditions of the Indian sector of the Southern Ocean between latitudes 38oS and 58oS during the austral summer of 2010 (January–February). This study helps to understand the response of E. huxleyi coccolith/coccosphere morphometry and mass changes to the fluctuating temperature, salinity, CO32−, pCO2, and nutrient values. Our results show that in the Indian sector of the Southern Ocean, E. huxleyi coccoliths are larger and coccospheres are smaller in the Subtropical Zone (STZ). In contrast, coccoliths size is smaller and coccospheres size is larger in the Subantarctic Zone (SAZ), which is due to the decrease in Sea Surface Temperature, Sea Surface Salinity and increase in nutrient concentrations. In the Indian sector of the Southern Ocean, E. huxleyi shows a north-to-south morphotype shift from the heavily calcified 'Group A' (E. huxleyi morphotype A) to the weakly calcified 'Group B' (E. huxleyi morphotypes B/C, C) forms. We demonstrate that although weakly calcified E. huxleyi morphotypes (morphotypes B/C and C) comprise less mass than that of the E. huxleyi morphotype A, due to the large-sized coccospheres and numerous coccoliths per coccosphere, 'Group B' coccospheres precipitate large amount of CaCO3 in the SAZ compared to 'Group A' coccospheres located in the STZ. We have documented the presence of large E. huxleyi overcalcified coccospheres with large-sized coccoliths in the southernmost cold, high pCO2, and nutrient-rich waters which show extracellular calcite precipitation. The energy dispersive spectrometry analysis indicates the presence of a large amount of Mg in the overcalcified E. huxleyi specimens. We suspect that E. huxleyi in the colder nutrient-rich waters, with future projected changes in the carbonate chemistry, may adapt to low pH, high pCO2 conditions through extracellular Ca and Mg mineralization.

Here, we describe a case report of a Sardinian woman diagnosed as pure beta-thalassemia carrier for her anemia who underwent to alpha-thalassemia genetic testing that revealed she was heterozygous for both thalssemias. This allowed to reach a conclusive diagnosis useful for family counseling and for assess the reproductive risk.

The term frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders characterized mainly by atrophy of the frontal and anterior temporal lobes. Based on clinical presentation, three main clinical syndromes have traditionally been described: behavioral variant frontotemporal dementia (bvFTD), non-fluent/agrammatic primary progressive aphasia (nfPPA), and semantic variant PPA (svPPA). However, over the last 20 years, it has been recognized that cognitive phenotypes often overlap with motor phenotypes, either motor neuron diseases or parkinsonian signs and/or syndromes like progressive supranuclear palsy (PSP) and cortico-basal syndrome (CBS). Furthermore, FTD-related genes are characterized by genetic pleiotropy and can cause, even in the same family, pure motor phenotypes, findings that underlie the clinical continuum of the spectrum, which has pure cognitive and pure motor phenotypes as the extremes. The genotype-phenotype correlation of the spectrum, FTD-motor neuron disease, has been well defined and extensively investigated, while the continuum, FTD-parkinsonism, lacks a comprehensive review. In this narrative review, we describe the current knowledge about the genotype-phenotype correlation of the spectrum, FTD-parkinsonism, focusing on the phenotypes that are less frequent than bvFTD, namely nfPPA, svPPA, PSP, CBS, and cognitive-motor overlapping phenotypes (i.e. PPA + PSP). From a pathological point of view, they are characterized mainly by the presence of phosphorylated-tau inclusions, either 4 R or 3 R. The genetic correlate of the spectrum can be heterogeneous, although some variants seem to lead preferentially to specific clinical syndromes. Furthermore, we critically review the contribution of genome-wide association studies (GWAS) and next-generation sequencing (NGS) in disentangling the complex heritability of the FTD-parkinsonism spectrum and in defining the genotype-phenotype correlation of the entire clinical scenario, owing to the ability of these techniques to test multiple genes, and so to allow detailed investigations of the overlapping phenotypes. Finally, we conclude with the importance of a detailed genetic characterization and we offer to patients and families the chance to be included in future randomized clinical trials focused on autosomal dominant forms of FTLD.

Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10. CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations.

Bladder cancer is the 10th most common cancer type worldwide. Cystoscopy represents the gold standard for bladder cancer diagnosis, but this procedure is invasive and painful, hence the need to identify new biomarkers through noninvasive procedures. microRNAs (miRNAs) are considered to be promising diagnostic molecules, because they are very stable in biological fluids (including urine) and easily detectable. This systematic review analyses the power of urine miRNAs as bladder cancer diagnostic markers. We conducted this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 293 records related to miRNAs and their diagnostic significance in BC were retrieved from the PubMed and Embase databases. A systematic search of the literature was performed, and a total of 25 articles (N = 4054 participants) were identified and reviewed. Although many of the selected studies were of high scientific quality, the results proved to be quite heterogeneous, because we did not identify a univocal consensus for a specific miRNA signature but only isolated the signatures. We did not identify a univocal consensus for a specific diagnostic miRNA signature but only isolated the signatures, some of them with better diagnostic power compared to the others.

While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology.

Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics, allowing for the detection of sequence variants with so far unprecedented large scale, mainly in genetically heterogenous diseases, such as neurological disorders. It is a fast-moving field, where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations. Despite the as yet undiscussed advantages, however, there are still some challenges in data analysis and the interpretation of variants. In this review, we address the current state of next generation sequencing diagnostic testing for inherited human disorders, particularly giving an overview of the available high-throughput sequencing approaches; including targeted, whole-exome and whole-genome sequencing; and discussing the main critical aspects of the bioinformatic process, from raw data analysis to molecular diagnosis.

The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

Context: Maturity-onset diabetes of the young (MODY) 8 is a rare form of monogenic diabetes characterized by a mutation in CEL (carboxyl ester lipase) gene, which leads to exocrine pancreas dysfunction, followed by beta cell failure. Induced pluripotent stem cells can differentiate into functional beta cells. Thus, beta cells from MODY8 patients can be generated in vitro and used for disease modelling and cell replacement therapy. Methods: A genetic study was performed in a patient suspected of monogenic diabetes. Results: A novel heterozygous pathogenic variant in CEL (c.1818delC) was identified in the proband, allowing diagnosis of MODY8. Three MODY8-iPSC (induced pluripotent stem cell) clones were reprogrammed from skin fibroblasts of the patient, and their pluripotency and genomic stability confirmed. All 3 MODY8-iPSC differentiated into beta cells following developmental stages. MODY8-iPSC-derived beta cells were able to secrete insulin upon glucose dynamic perifusion. The CEL gene was not expressed in iPSCs nor during any steps of endocrine differentiation. Conclusion: iPSC lines from a MODY8 patient with a novel pathogenic variant in the CEL gene were generated; they are capable of differentiation into endocrine cells, and beta cell function is preserved in mutated cells. These results set the basis for in vitro modelling of the disease and potentially for autologous beta cell replacement.

The present pilot study investigates whether an abnormal miRNA profile in NIPT plasma samples can explain the finding of a low cell-free DNA (cfDNA) fetal fraction (cfDNAff) in euploid fetuses and non-obese women. Twelve women who underwent neoBona® NIPT with a normal fetal karyotype were studied. Six with a cfDNAff < 4% were matched with a control group with normal levels of cfDNAff > 4%. Samples were processed using the nanostring nCounter® platform with a panel of 800 miRNAs. Four of the maternal miRNAs, miR-579, miR-612, miR-3144 and miR-6721, had a significant abnormal expression in patients. A data filtering analysis showed that miR-579, miR-612, miR-3144 and miR-6721 targeted 169, 1, 48 and 136 placenta-specific genes, respectively. miR-579, miR-3144 and miR-6721 shared placenta-specific targeted genes involved in trophoblast invasion and migration pathways (IGF2R, PTCD2, SATB2, PLAC8). Moreover, the miRNA target genes encoded proteins localized in the placenta and involved in the pathogenesis of pre-eclampsia, including chorion-specific transcription factor GCMa, PRG2, Lin-28 Homolog B and IGFBP1. In conclusion, aberrant maternal miRNA expression in circulating plasma could be a source of dysregulating trophoblast invasion and migration and could represent a novel cause of a low cfDNAff in the sera of pregnant women at the time of NIPT analysis.

BACKGROUND Triadin is a protein expressed in cardiac and skeletal muscle that has an essential role in the structure and functional regulation of calcium release units and excitation-contraction coupling. Mutations in the triadin gene (TRDN) have been described in different forms of human arrhythmia syndromes with early onset and severe arrhythmogenic phenotype, including triadin knockout syndrome. OBJECTIVE The purpose of this study was to characterize the pathogenetic mechanism underlying a case of severe pediatric malignant arrhythmia associated with a defect in the TRDN gene. METHODS We used a trio whole exome sequencing approach to identify the genetic defect in a 2-year-old boy who had been resuscitated from sudden cardiac arrest and had frequent episodes of ventricular fibrillation and a family history positive for sudden death. We then performed in vitro functional analysis to investigate possible pathogenic mechanisms underlying this severe phenotype. RESULTS We identified a novel homozygous missense variant (p.L56P) in the TRDN gene in the proband that was inherited from the heterozygous unaffected parents. Expression of a green fluorescent protein (GFP)-tagged mutant human cardiac triadin isoform (TRISK32-L56P-GFP) in heterologous systems revealed that the mutation alters protein dynamics. Furthermore, when co-expressed with the type 2 ryanodine receptor, caffeine-induced calcium release from TRISK32-L56P-GFP was relatively lower compared to that observed with the wild-type construct. CONCLUSION The results of this study allowed us to hypothesize a pathogenic mechanism underlying this rare arrhythmogenic recessive form, suggesting that the mutant protein potentially can trigger arrhythmias by altering calcium homeostasis.

Objectives: The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 conducted a global survey to understand how biochemistry laboratories manage the operational challenges during the coronavirus disease 2019 (COVID-19) pandemic. Materials and methods: An electronic survey was distributed globally to record the operational considerations to mitigate biosafety risks in the laboratory. Additionally, the laboratories were asked to indicate the operational challenges they faced. Results: A total of 1210 valid submissions were included in this analysis. Most of the survey participants worked in hospital laboratories. Around 15% of laboratories restricted certain tests on patients with clinically suspected or confirmed COVID-19 over biosafety concerns. Just over 10% of the laboratories had to restrict their test menu or services due to resource constraints. Approximately a third of laboratories performed temperature monitoring, while two thirds of laboratories increased the frequency of disinfection. Just less than 50% of the laboratories split their teams. The greatest reported challenge faced by laboratories during the COVID-19 pandemic is securing sufficient supplies of personal protective equipment (PPE), analytical equipment, including those used at the point of care, as well as reagents, consumables and other laboratory materials. This was followed by having inadequate staff, managing their morale, anxiety and deployment. Conclusions: The restriction of tests and services may have undesirable clinical consequences as clinicians are deprived of important information to deliver appropriate care to their patients. Staff rostering and biosafety concerns require longer-term solutions as they are crucial for the continued operation of the laboratory during what may well be a prolonged pandemic.