Causes of Sudden Unexpected Death in Childhood: Autopsy Findings from a Specialist Centre

OBJECTIVES: To investigate the aetiologies of sudden unexpected death from natural causes in children aged 1-18 years by retrospective examination of autopsy records from a single centre. MATERIALS AND METHODS: The post-mortem findings from 548 children (1996-2015) were examined. Details were entered into an established research database and categorized according to >400 pre-defined criteria. RESULTS: There were 265 previously apparently healthy children and 283 with pre-existing, potentially life-limiting, conditions. There were more males than females (M:F 1.4:1), and deaths were more frequent in the winter. Infection was commonest accounting for 43% of all deaths. Non-infectious diseases were identified as cause of death in 28%, and 29% of all deaths were unexplained. There was no significant difference in the proportions of deaths in each category between the previously healthy children and those with pre-existing conditions. CONCLUSION: Sudden unexpected death is a rare presentation of death in childhood and those with pre-existing conditions may be more at risk. Standardisation of the post-mortem procedure in such cases may result in more ancillary investigations performed as routine and may reduce the number of cases that are 'unexplained'

Biosynthesis of the modified tetrapyrroles: the pigments of life

Modified tetrapyrroles are large macrocyclic compounds, consisting of diverse conjugation and metal chelation systems and imparting an array of colors to the biological structures that contain them. Tetrapyrroles represent some of the most complex small molecules synthesized by cells and are involved in many essential processes that are fundamental to life on Earth, including photosynthesis, respiration, and catalysis. These molecules are all derived from a common template through a series of enzyme-mediated transformations that alter the oxidation state of the macrocycle, and also modify its size, side chain composition, and the nature of the centrally chelated metal ion. The different modified tetrapyrroles include chlorophylls, hemes, siroheme, corrins (including vitamin B12), coenzyme F430, heme d1 and bilins. After nearly a century of study, almost all of the more than 90 different enzymes that synthesize this family of compounds are now known, and expression of reconstructed operons in heterologous hosts has confirmed that most pathways are complete. Aside from the highly diverse nature of the chemical reactions catalyzed, an interesting aspect of comparative biochemistry is to see how different enzymes and even entire pathways have evolved to perform alternative chemical reactions to produce the same end products in the presence and absence of oxygen. Although there is still much to learn, our current understanding of tetrapyrrole biogenesis represents a remarkable biochemical milestone that is summarized in this review

Fabrication of Nanometer and Micrometer Scale Protein Structures by Site-Specific Immobilization of Histidine-Tagged Proteins to Aminosiloxane Films with Photoremovable Protein-Resistant Protecting Groups

The site-specific immobilization of histidine-tagged proteins to patterns formed by far-field and near-field exposure of films of aminosilanes with protein-resistant photolabile protecting groups is demonstrated. After deprotection of the aminosilane, either through a mask or using a scanning near-field optical microscope, the amine terminal groups are derivatized first with glutaraldehyde and then with N-(5-amino-1-carboxypentyl)iminodiacetic acid to yield a nitrilo triacetic acid (NTA) terminated surface. After complexation with Ni2+, this surface binds histidine-tagged GFP and CpcA-PEB in a site-specific fashion. The chemistry is simple and reliable, and leads to extensive surface functionalization. Bright fluorescence is observed in fluorescence microscopy images of micrometer- and nanometer-scale patterns. X-ray photoelectron spectroscopy is used to study quantitatively the efficiency of photodeprotection and the reactivity of the modified surfaces. The efficiency of the protein binding process is investigated quantitatively by ellipsometry and by fluorescence microscopy. We find that regions of the surface not exposed to UV light bind negligible amounts of His-tagged proteins, indicating that the oligo(ethylene glycol) adduct on the nitrophenyl protecting group confers excellent protein resistance; in contrast, exposed regions bind His-GFP very effectively, yielding strong fluorescence that is almost completely removed on treatment of the surface with imidazole, confirming a degree of site-specific binding in excess of 90%. This simple strategy offers a versatile generic route to the spatially selective site-specific immobilization of proteins at surfaces

Machine learning forecasting for COVID-19 pandemic-associated effects on paediatric respiratory infections

OBJECTIVE: The COVID-19 pandemic and subsequent government restrictions have had a major impact on healthcare services and disease transmission, particularly those associated with acute respiratory infection. This study examined non-identifiable routine electronic patient record data from a specialist children's hospital in England, UK, examining the effect of pandemic mitigation measures on seasonal respiratory infection rates compared with forecasts based on open-source, transferable machine learning models. METHODS: We performed a retrospective longitudinal study of respiratory disorder diagnoses between January 2010 and February 2022. All diagnoses were extracted from routine healthcare activity data and diagnosis rates were calculated for several diagnosis groups. To study changes in diagnoses, seasonal forecast models were fit to prerestriction period data and extrapolated. RESULTS: Based on 144 704 diagnoses from 31 002 patients, all but two diagnosis groups saw a marked reduction in diagnosis rates during restrictions. We observed 91%, 89%, 72% and 63% reductions in peak diagnoses of 'respiratory syncytial virus', 'influenza', 'acute nasopharyngitis' and 'acute bronchiolitis', respectively. The machine learning predictive model calculated that total diagnoses were reduced by up to 73% (z-score: -26) versus expected during restrictions and increased by up to 27% (z-score: 8) postrestrictions. CONCLUSIONS: We demonstrate the association between COVID-19 related restrictions and significant reductions in paediatric seasonal respiratory infections. Moreover, while many infection rates have returned to expected levels postrestrictions, others remain supressed or followed atypical winter trends. This study further demonstrates the applicability and efficacy of routine electronic record data and cross-domain time-series forecasting to model, monitor, analyse and address clinically important issues

ICTV Virus Taxonomy Profile: Herpesviridae 2021

Members of the family Herpesviridae have enveloped, spherical virions with characteristic complex structures consisting of symmetrical and non-symmetrical components. The linear, double-stranded DNA genomes of 125–241 kbp contain 70–170 genes, of which 43 have been inherited from an ancestral herpesvirus. In general, herpesviruses have coevolved with and are highly adapted to their hosts, which comprise many mammalian, avian and reptilian species. Following primary infection, they are able to establish lifelong latent infection, during which there is limited viral gene expression. Severe disease is usually observed only in the foetus, the very young, the immunocompromised or following infection of an alternative host. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Herpesviridae, which is available at ictv.global/report/herpesviridae

The genetics of virus particle shape in equine influenza A virus

Background Many human strains of influenza A virus produce highly pleomorphic virus particles that at the extremes can be approximated as either spheres of around 100 nm diameter or filaments of similar cross-section but elongated to lengths of many microns. The role filamentous virions play in the virus life cycle remains enigmatic. Objectives/Methods Here, we set out to define the morphology and genetics of virus particle shape in equine influenza A virus, using reverse genetics and microscopy of infected cells. Results and Conclusions The majority of H3N8 strains tested were found to produce filamentous virions, as did the prototype H7N7 A/eq/Prague/56 strain. The exception was the prototype H3N8 isolate, A/eq/Miami/63. Reassortment of equine influenza virus M genes from filamentous and non-filamentous strains into the non-filamentous human virus A/PR/8/34 confirmed that segment 7 is a major determinant of particle shape. Sequence analysis identified three M1 amino acid polymorphisms plausibly associated with determining virion morphology, and the introduction of these changes into viruses confirmed the importance of two: S85N and N231D. However, while either change alone affected filament production, the greatest effect was seen when the polymorphisms were introduced in conjunction. Thus, influenza A viruses from equine hosts also produce filamentous virions, and the major genetic determinants are set by the M1 protein. However, the precise sequence determinants are different to those previously identified in human or porcine viruses

Effect of Particle Size on Droplet Infiltration into Hydrophobic Porous Media As a Model of Water Repellent Soil

The wettability of soil is of great importance for plants and soil biota, and in determining the risk for preferential flow, surface runoff, flooding,and soil erosion. The molarity of ethanol droplet (MED) test is widely used for quantifying the severity of water repellency in soils that show reduced wettability and is assumed to be independent of soil particle size. The minimum ethanol concentration at which droplet penetration occurs within a short time (≤10 s) provides an estimate of the initial advancing contact angle at which spontaneous wetting is expected. In this study, we test the assumption of particle size independence using a simple model of soil, represented by layers of small (0.2–2 mm) diameter beads that predict the effect of changing bead radius in the top layer on capillary driven imbibition. Experimental results using a three-layer bead system show broad agreement with the model and demonstrate a dependence of the MED test on particle size. The results show that the critical initial advancing contact angle for penetration can be considerably less than 90° and varies with particle size, demonstrating that a key assumption currently used in the MED testing of soil is not necessarily valid

Comparison of two modern vaccines and previous influenza infection against challenge with an equine influenza virus from the Australian 2007 outbreak

During 2007, large outbreaks of equine influenza (EI) caused by Florida sublineage Clade 1 viruses affected horse populations in Japan and Australia. The likely protection that would be provided by two modern vaccines commercially available in the European Union (an ISCOM-based and a canarypox-based vaccine) at the time of the outbreaks was determined. Vaccinated ponies were challenged with a representative outbreak isolate (A/eq/Sydney/2888-8/07) and levels of protection were compared. A group of ponies infected 18 months previously with a phylogenetically-related isolate from 2003 (A/eq/South Africa/4/03) was also challenged with the 2007 outbreak virus. After experimental infection with A/eq/Sydney/2888-8/07, unvaccinated control ponies all showed clinical signs of infection together with virus shedding. Protection achieved by both vaccination or long-term immunity induced by previous exposure to equine influenza virus (EIV) was characterised by minor signs of disease and reduced virus shedding when compared with unvaccinated control ponies. The three different methods of virus titration in embryonated hens’ eggs, EIV NP-ELISA and quantitative RT-PCR were used to monitor EIV shedding and results were compared. Though the majority of previously infected ponies had low antibody levels at the time of challenge, they demonstrated good clinical protection and limited virus shedding. In summary, we demonstrate that vaccination with current EIV vaccines would partially protect against infection with A/eq/Sydney/2888-8/07-like strains and would help to limit the spread of disease in our vaccinated horse population

Myeloid Neoplasms with t(5;12) and ETV6-ACSL6 Gene Fusion, Potential Mimickers of Myeloid Neoplasm with PDGFRB Rearrangement: Case Report with Imatinib Therapy and Review of the Literature

We report the second case of ETV6-ACSL6 associated myeloproliferative neoplasm that has received a full course of imatinib therapy. The patient was a 51-year-old previously healthy man who presented with three months of worsening dyspnea and was found to have a white count of 216,000/cmm, of which 84% were eosinophil lineage. Cytogenetic analysis revealed a t(5;12)(q31~33;p13). FISH was negative for PDGFRB rearrangement but additional FISH testing demonstrated an ACSL6 rearrangement. ETV6-ACSL6 gene fusion is a rare abnormality that most often presents as a myeloproliferative-type disorder with prominent eosinophilia or basophilia. Review of the literature yielded a total of 11 previous cases. This gene fusion results in a t(5;12)(q31~33;p13) that mimics the t(5;12) found in ETV6-PDGFRB neoplasms. Identification of the fusion genes involved in t(5;12) in eosinophilia-associated myeloproliferative disorders is crucial to direct an effective treatment plan. In particular, while tyrosine kinase inhibitor therapy is effective in patients with PDGFRB rearrangement, there is little information on imatinib efficacy in patients with ETV6-ACSL6 gene fusion. Our patient was found to be nonresponsive to imatinib therapy