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Introduction/Background Whipps Cross University Hospital is a District General Hospital (DGH) in London. Children with musculoskeletal and rheumatic conditions are looked after by a paediatric multidisciplinary team (MDT). In approximately one third of cases (around 50 patients), care is shared with tertiary teams. It is widely cited in literature that patients with specialist conditions benefit from receiving specialist care. However, there are many positives of shared-care where patients also receive treatment in the local hospital. The provision of immunosuppressive treatment, regular blood monitoring, and appointments with MDT professionals (e.g. doctors/physiotherapists/ophthalmologists/community nurses) can add further complexities to shared-care. Description/Method Our objective was to identify the strengths and weaknesses of the current Paediatric Rheumatology shared-care service at our DGH and to provide an action plan for improving the service. Children and young people looked after by our DGH for a rheumatological condition, on immunosuppressants, whose care was shared with the tertiary centre were selected. Data collection was done via one-to-one telephone interviews with families based on a semi-structured questionnaire including the following four themes: 1. Views of shared care rheumatology. 2. Blood tests and the blood monitoring experience. 3. Medication related issues: obtaining, collecting and giving medication. 4. Views on transition to adult care. The questionnaire was produced jointly by a paediatric doctor, the lead paediatric pharmacist and the lead nurse for the paediatric day unit, who is involved in blood tests, blood monitoring and delivering immunosuppressant medication. The questionnaire was piloted and modified. Interviews were conducted by a doctor not involved in the routine shared-care service to encourage honest answers, and to reduce observer and investigator bias. After data collection, quantitative and qualitative analysis (thematic analysis) were performed. Strengths and weaknesses of the service were identified. Discussion/Results 20 patients met our selection criteria and all 20 responded. Questionnaires were completed between April and July 2020. On average, in the last year, patients visited their local DGH 2.5 times and their tertiary centre 2.9 times. 75% of these visits were outpatient appointments. Shared Care The following issues were identified by families through thematic analysis: 1. Proximity to home for appointments was important. The local team is responsive to their care. 2. Many appointments over both centres and missing school for appointments was a concern. 3. Local and tertiary centres don’t always share information. 4. Most families were happy to visit both hospitals. Blood Tests Blood testing was split between the GP, the local DGH, the tertiary hospital and community nurses. Blood tests were usually performed every 2-3 months. Families spoke positively about the blood testing experience. The suggested improvements were: 1. Proximity to home for blood tests to avoid missing school. 2. Better communication of results between hospitals. 3. A record of blood test results to keep at home. Medication-Related Issues 70% of our cohort were taking methotrexate, and 20% were taking biologic medications. Prescriptions were provided by the GP, the local DGH and the tertiary centre. Issues identified by families were: 1. Barriers to collecting medications (e.g. unhappy to leave the house due to COVID-19; unsure where to collect medication from; problems with obtaining prescriptions from the GP). 2. Better communication needed between hospitals about when new medication will start. 3. Patients would like to reduce the pain of the injection. 4. Methotrexate has too many side effects. Transitioning to Adult Care Most young people (60%) preferred to stay local to home and move to adult services at their local DGH, if there were to be an adolescent service with overlap between paediatric and adult services. Key learning points/Conclusion The strengths and weaknesses of shared-care rheumatology were identified by families at our DGH. Strengths were that families felt both the local and tertiary centres played a necessary role in care. Weaknesses were that families had many appointments over both centres and missing school was problematic. Some families reported communication between hospitals could be improved. The paediatric MDT proposed a list of quality improvement interventions: 1. Set up a one-stop Paediatric Rheumatology Super MDT clinic, to see the physiotherapist, ophthalmologist, paediatrician and pharmacist, if required, all in one morning. 2 one-stop clinics ran in March and May 2022. It is estimated that this super MDT clinic will save 3 to 4 DGH visits per year. 2. Obtain remote access to the tertiary hospital computer system for the local Paediatric Rheumatology team. This will improve communication between hospitals. 3. Encourage patients to view letters and results from the tertiary centre through the tertiary hospital patient app MyGOSH. This will improve timely information sharing. 4. Set up an MDT meeting with the day unit nurse and pharmacist every 2 months to discuss each patient requiring hospital prescribed medication. 5. The clinician to liaise with families around improving injection technique, and to discuss measures to mitigate side effects of medications. 6. Establish a system for posting medication to parents by pharmacy. This is in place as of August 2020 with an aim of reducing barriers to collecting medications. 7. Explore transitioning to alternative adolescent care closer to home. Our next steps will involve re-assessing if the interventions above have helped improve communication with the tertiary hospital, whether they have reduced the number of appointments, and whether medication concerns were resolved. We believe that this innovative project has improved patient access to appointments, as well as their experience of the shared-care service.

Purpose: To report a case of simultaneous chromosome 10 partial deletion and chromosome 6 partial duplication in a preterm infant. Methods: This is a retrospective case report followed with clinical observation, echocardiogram, and genetic testing. Results: A neonate with Tetralogy of Fallot, clubbed feet, low set ears, and webbed neck was found to have chromosomal abnormalities that are consistent with unbalanced translocation between chromosomes 6 and 10, resulting in a partial duplication of chromosome 6 and partial deletion of chromosome 10. Discussion: Chromosome microarray testing in a patient with multiple congenital anomalies can facilitate rapid diagnosis and treatment with the potential to improve the management of complications and subsequent development.

Emergence of SARS-CoV-2 variants of concern (VOC) with progressively increased transmissibility between humans is a threat to global public health. Omicron variant also evades immunity from natural infection or vaccines1. It is unclear whether its exceptional transmissibility is due to immune evasion or inherent virological properties.We compared the replication competence and cellular tropism of the wild type (WT) virus, D614G, Alpha, Beta, Delta and Omicron variants in ex vivo explant cultures of human bronchus and lung. Dependence on TMPRSS2 for infection was also evaluated. We show that Omicron replicated faster than all other SARS-CoV-2 in the bronchus but less efficiently in the lung parenchyma. All VOCs had similar cellular tropism as the WT. Delta was more dependent on serine protease than other VOCs tested.Our findings demonstrate that Omicron is inherently able to replicate faster than other variants known to date and this likely contributes to its inherently higher transmissibility, irrespective of its ability to evade antibody immunity. The lower replication competence of Omicron in human lung may be compatible with reduced severity but the determinants of severe disease are multifactorial. These findings provide important biological clues to the transmissibility and pathogenesis of SARS-CoV-2 VOCs.

Most aptamers targeting cell-expressed antigens are intended for in vivo application, however, these sequences are commonly generated in vitro against synthetic oligopeptide epitopes or recombinant proteins. As these in vitro analogues frequently do not mimic the in vivo target within an endogenous environment, the evolved aptamers are often prone to nonspecific binding. The presence of dead cells and cellular debris further complicate aptamer targeting, due to their high nonspecific affinities to single-stranded DNA. Despite these known limitations, assessment of cell viability and/or the removal of dead cells is rarely applied as part of the methodology during in vivo testing of aptamer binding. Furthermore, the extent and route(s) by which dead cells uptake existing aptamers remains to be determined in the literature. For this purpose, the previously reported aptamer sequences 5TR1, 5TR4, 5TRG2 and S22 - enriched against the MUC1 tumour marker of the mucin glycoprotein family - were used as model sequences to evaluate the influence of cell viability and the presence of nontarget cell-expressed protein on aptamer binding to the MUC1 expressing human cancer cell lines MCF-7, Hs578T, SW480, and SW620. From fluorescence microscopy analysis, all tested aptamers demonstrated extensive nonspecific uptake within the nuclei of dead cells with compromised membrane integrities. Using fluorescent-activated cell sorting (FACS), the inclusion of excess double-stranded DNA as a blocking agent showed no effect on nonspecific aptamer uptake by dead cells. Further nonspecific binding to cell-membrane bound and intracellular protein was evident for each aptamer sequence, as assessed by southwestern blotting and FACS. These factors likely contributed to the ∼120-fold greater binding response of the 5TR1 aptamer to dead MCF-7 cells over equivalent live cell populations. The identification of dead cells and cellular debris using viability stains and the subsequent exclusion of these cells from FACS analysis was identified as an essential requirement for the evaluation of aptamer binding specificity to live cell populations of the cancer cell lines MCF-7, Hs578T and SW480. The research findings stress the importance of dead cell uptake and more comprehensive cell viability screening to validate novel aptamer sequences for diagnostic and therapeutic application.

Background Influenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death. The host-response pathways associated with the progression to severe influenza disease are not well understood. Methods To gain insight into the disease mechanisms associated with progression to severe infection, we analyzed the leukocyte transcriptome in severe and moderate influenza patients and healthy control subjects. Pathway analysis on differentially expressed genes was performed using a topology-based pathway analysis tool that takes into account the interaction between multiple cellular pathways. The pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza. Results 107 patients (44 severe and 63 moderate influenza patients) and 52 healthy control subjects were included in the study. Severe influenza was associated with upregulation in several neutrophil-related pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (NET) formation. The degree of upregulation in neutrophil-related pathways were significantly higher in severely infected patients compared to moderately infected patients. Severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation such as CD4+ T-cell co-stimulation, CD8+ T cell and Natural Killer (NK) cells effector functions. Apoptosis pathways were also downregulated in severe influenza patients compare to moderate and healthy controls. Conclusions These findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection.

Pakistan is considered by the World Health Organization to currently have a "concentrated" HIV-1 epidemic due to a rapid rise in infections among people who inject drugs (PWID). Prevalence among the country's nearly 105,000 PWID is estimated to be 37.8% but has been shown to be higher in several large urban centers. A lack of public health resources, the common use of professional injectors and unsafe injection practices are believed to have fueled the outbreak. Here we evaluate the molecular characteristics of HIV-1 sequences (n = 290) from PWID in several Pakistani cities to examine transmission dynamics and the association between rates of HIV-1 transmission with regards to regional trends in opioid trafficking. Tip-to-tip (patristic) distance based phylogenetic cluster inferences and BEAST2 Bayesian phylodynamic analyses of time-stamped data were performed on HIV-1 pol sequences generated from dried blood spots collected from 1,453 PWID as part of a cross-sectional survey conducted in Pakistan during 2014/2015. Overall, subtype A1 strains were dominant (75.2%) followed by CRF02_AG (14.1%), recombinants/unassigned (7.2%), CRF35_AD (2.1%), G (1.0%) and C (0.3%). Nearly three quarters of the PWID HIV-1 sequences belonged to one of five distinct phylogenetic clusters. Just below half (44.4%) of individuals in the largest cluster (n = 118) did seek help injecting from professional injectors which was previously identified as a strong correlate of HIV-1 infection. Spikes in estimated HIV-1 effective population sizes coincided with increases in opium poppy cultivation in Afghanistan, Pakistan's western neighbor. Structured coalescent analysis was undertaken in order to investigate the spatial relationship of HIV-1 transmission among the various cities under study. In general terms, our analysis placed the city of Larkana at the center of the PWID HIV-1 epidemic in Pakistan which is consistent with previous epidemiological data.

Summary: Normal brain functions depend on the balanced development of excitatory and inhibitory synapses. Our knowledge of the molecular mechanisms underlying inhibitory synapse formation is limited. Neuroligin-2 (NL2), a transmembrane protein at inhibitory postsynaptic sites, is capable of initiating inhibitory synapse formation. In an effort to search for NL2 binding proteins and the downstream mechanisms responsible for inhibitory synapse development, we identify LHFPL4/GARLH4 as a major NL2 binding partner that is specifically enriched at inhibitory postsynaptic sites. LHFPL4/GARLH4 and NL2 regulate the protein levels and synaptic clustering of each other in the cerebellum. Lhfpl4/Garlh4−/− mice display profound impairment of inhibitory synapse formation as well as prominent motor behavioral deficits and premature death. Our findings highlight the essential role of LHFPL4/GARLH4 in brain functions by regulating inhibitory synapse formation as a major NL2 binding partner. : Wu et al. identify LHFPL4/GARLH4 as a major NL2 binding partner that is specifically enriched at inhibitory postsynaptic sites and regulates inhibitory synapse formation. Deletion of LHFPL4/GARLH4 in mice results in profound impairment of inhibitory synapse formation as well as prominent motor behavioral deficits and premature death. Keywords: LHFPL4/GARLH4, neuroligin-2, inhibitory synapse, GABAAR

AA5xxx series Al-Mg alloys possess good combination of high specific strength-to-weight ratio, formability and corrosion resistance, which makes them attractive to the automakers for their light weighting needs. Increasingly the automakers are demanding sustainable materials. Developing aluminum alloys with increased recycled content is becoming imperative. However, increasing the recycled content can negatively impact the overall formability and joinability of the alloy. Formability is important in the shaping of complex parts and it is a key requirement in automotive manufacturing. Similarly, the other key requirement for automotive sheet is joinability. Self-piercing riveting (SPR) technology is increasingly being used for joining. In this study, the process optimization of high recycle content AA5754 alloy’s for formability and rivetability will be discussed. Controlling the annealing heat treatment to produce optimum combination of grain size along with balanced recrystallized and rolling texture to improve the SPR joint configuration will be presented.

Omohyoid muscle syndrome is a rare cause of an X-shaped bulging lateral neck mass that occurs on swallowing. This is a diagnostic case report of a 22-year-old mixed martial arts athlete who acquired this condition.

Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers.In this study, we combined an integrated genomic analysis of 1071 individuals with

Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers.In this study, we combined an integrated genomic analysis of 1071 individuals with in vitro experiments using well-established infection models.We identified a single-gene biomarker, IFI27, which had a high prediction accuracy (91%) equivalent to that obtained by multi-gene biomarkers. In vitro studies showed that IFI27 was upregulated by TLR7 in plasmacytoid dendritic cells, antigen-presenting cells that responded to influenza virus rather than bacteria. In vivo studies confirmed that IFI27 was expressed in influenza patients but not in bacterial infection, as demonstrated in multiple patient cohorts (n=521). In a large prospective study (n=439) of patients presented with undifferentiated respiratory illness (aetiologies included viral, bacterial and non-infectious conditions), IFI27 displayed 88% diagnostic accuracy (AUC) and 90% specificity in discriminating between influenza and bacterial infections.IFI27 represents a significant step forward in overcoming a translational barrier in applying genomic assay in clinical setting; its implementation may improve the diagnosis and management of respiratory infection.

Introduction: Cardiorespiratory fitness is inversely associated with morbidity and mortality even after adjustment for traditional risk factors. The biological mechanism for the protective effect of high fitness is largely unknown. Hypothesis: We hypothesized that high fitness would be associated with larger coronary artery diameters independent of traditional risk factors. Methods: In this study, 500 men with a coronary artery calcium score (CACS) < 10 were evaluated, with 100 from each age-adjusted fitness quintile (very poor, 1-20%; poor, 21-39%; fair, 40-59%; good, 60-79%; and excellent, 80-100%). Each participant had undergone fitness assessment with an exercise treadmill test on the day of CACS. Blinded to the fitness category, one of us measured the proximal diameters of the left main (LM), left anterior descending (LAD), left circumflex (LCx), and the right coronary (RCA) arteries. Spearman correlations were calculated for the diameters of each coronary artery with treadmill time and for the sum of artery diameters with treadmill time. Linear mixed-effects regression was used to estimate the association between fitness and coronary artery diameters while adjusting for potential confounders. Results: Each coronary artery diameter (LM r=0.12, p=0.009; LAD r=0.11, p=0.02; LCx r=0.10, p=0.02; RCA r=0.18, p Conclusion: Higher fitness is positively associated with larger coronary artery diameters.

Kesterite thin film solar cell has been fabricated by chemical spray pyrolysis (CSP) of an aqueous solution followed by high temperature selenization. The pyrolysis formation of Cu2ZnSnS4 was conducted in atmospheric condition with substrate temperature of 280 °C. X-ray diffraction and Raman spectroscopy study confirmed the formation of the single phase Cu2ZnSn(S,Se)4 kesterite structure after selenization without traceable secondary phases. FESEM image shows a uniform absorber layer without carbon layer formed between CZTSSe and Mo. Power conversion efficiency of 5.1% was obtained with different amounts of selenium incorporation. Power dependent and temperature dependent photoluminescence (PL) study revealed donor-to-acceptor pairs (DAP) transition at low temperature. Severe PL quenching at temperatures above 41 K is attributed to the opening of non-radiative recombination channels from the defects associated with non-stoichiometric elemental ratio. Therefore, further enhancement of power conversion efficiency can be achieved by better control of stoichiometry. Accepted version

This thesis describes the construction of the Large Area Radio Galaxy Evolution Spectroscopic Survey (LARGESS) sample, which is designed to study the population of high- and low- excitation radio galaxies (HERGs and LERGs respectively) out to moderate redshifts (z

Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.

Troponin assays are a valuable tool in early risk stratification of patients with ischaemic sounding chest pain. However, troponin is often measured outside of this clinical context. The finding of a raised troponin value may be misinterpreted as an acute coronary syndrome leading to unnecessary and sometimes dangerous anticoagulation. This article looks at some of the considerations which need to be made when interpreting the significance of a raised troponin value.

Sub-Saharan Africa accounts for 69% of the people living with HIV globally. An estimated 1,600,000 Kenyans are living with HIV-1. Antiretroviral therapy (ART) has saved 9 million life-years in Sub-Saharan Africa. However, drug resistance mutations reduce the effectiveness of ART, and need to be monitored for effective ART. Naturally occurring primary antiretroviral drug resistance mutations have not been well analyzed in ART naive HIV+ patients in Kenya. Here we have examined protease inhibitor (PI) resistance mutations in ART naive HIV-1 seropositive women in Pumwani sex worker cohort established in Nairobi, Kenya, wherein HIV-1 infection is predominantly caused by subtypes A and D viruses. We have analyzed consensus sequences of HIV protease from 109 drug-naive patients, as a part of HIV-1 whole-genome sequencing using 454 sequencing methodology. Analysis using HIVdb program revealed a prevalence of 22% (24/109) PI resistance mutations among the study subjects. D30N (3.7%), M46I (0.9%) and V82F (0.9%) are the major mutations observed. D30N mutation is known to confer high-level resistance to nelfinavir. M46I and V82F confer resistance to indinavir, lopinavir, fosamprenavir and nelfinavir. In addition, many minor mutations were found at seven different drug resistance sites. It is important to study the implications of these mutations to the effectiveness of specific PI drug treatment. This study provides valuable data pertaining to primary drug resistance in Kenyan HIV-1 infected patients before ART became available.

A 62 year old female presented to the acute medical team with headache, fevers and enlarged axillary lymph nodes. Initial biochemical, microbiological and immunological investigations were normal. However, radiological imaging revealed that her silicone breast implants had ruptured, which may have been responsible for her presentation. A brief overview of the clinical features and management of silicone breast implant rupture is provided.

Background Sub Saharan Africa accounts for 69% of the people living with HIV globally. Antiretroviral therapy (ART) has saved 9 million life years in Sub Saharan Africa. However, drug resistance mutations reduce the effectiveness of ART, and need to be monitored for effective ART. Naturally occurring primary antiretroviral drug resistance mutations have not been well analyzed in ART naive HIV+ patients from Kenya.