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How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

Background: Germ cell tumours (GCT) are tumours arising from primordial germ cells. Gonadal and extragonadal GCT are infrequent in childhood occurring at a rate of 2.4 cases per million children accounting for 2-3 % of paediatric malignancies with most common subtype being a matured Teratoma. Case presentation: We present a case of a 10-year-old female child who presented to the emergency department of a tertiary care centre with complaints of cough with massive expectoration of blood of approximately 200 ml in quantity which on imaging revealed a left anterior mediastinal mass which was managed by left lateral thoracotomy with a non-anatomical left sided pulmonary lobectomy which on histopathology was diagnosed to be a case of mature teratoma. Conclusion: This case report describes a unique presentation of extra-gonadal mediastinal teratoma which presented as a rare complication with rupture into the left bronchus. It emphasizes caution and a high clinical suspicion is required in managing cases of varied presentations of teratomas.

Background: The definition of ectopic ureter is an abnormal opening of the ureter (single or duplex) that does not open in the trigonal region of the bladder. In 80% of these cases, ectopic ureter is associated with complete duplication. The upper moiety of a duplex kidney is usually the origin of a ectopic ureter in most of the cases. The opening of the ectopic ureteric in females can be anywhere from bladder neck to perineum with urethra, vagina, and vestibule. Duplex kidney, also known as duplex collecting system, is a common congenital urinary system anomaly with a morbidity of about 0.8–1%. We present a unique case of a completed duplicated system with ectopic ureter opening into the uterus leading to a non-functional associated upper renal moiety of the affected side which was managed by robotic assisted segmental nephrectomy. Case presentation: We present a case of 52-year- old lady who presented to urology outpatient department with complaints of sticky white perineal discharge through vaginum associated with left sided intermittent colicky flank pain who was diagnosed to have complete duplex left moiety with ectopic insertion of the upper moiety ureter into the vagina associated with non-functioning left upper renal moiety. She was managed by robotic assisted Left sided heminephrectomy with excision of left ectopic ureter. Conclusion: Our case report thus highlights the importance of adequate evaluation of a patient to determine the anatomy and the function of the kidney to decide for the definitive management of these patients with ectopic ureter and duplex kidneys.

Although mucosal-associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set, and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Here, following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127-Klrg1+ and CD127+Klrg1- antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue. These populations remained altered from steady state for months as stable, separate MAIT cell lineages with enhanced effector programmes and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic programme, which was critical for their maintenance and IL-17A synthesis. This programme was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded antigen independently and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccination and immunotherapies.

Gossypiboma, a retained surgical sponge, is a rare complication following any surgical procedure and is primarily a result of human error. Such patients often have vague clinical presentations and the diagnosis often comes as a surprise and has serious medicolegal implications. We present a case of a 28-year-old female with a long-standing duration of 9 months with purulent discharge from the operated scar site of Lower segment caesarean section done 2 years back and then diagnosed to have a gossypiboma in the ureterovesical space causing structuring of the ipsilateral ureter which was successfully managed by Exploratory laparotomy with removal of the retained gossypiboma and right sided ureteric reimplantation.

Background: Academic trials are essential in investigating health research questions relevant to the society. Only a few leading research institutions in India have been engaged in academic trials. Thus, there is a need to understand what factors dampen the spirit of the academician in conducting academic clinical trials. Aims and Objectives: The aim of the study is to evaluate the investigator’s perception of obstacles to carrying out academic trials and to identify factors that will motivate investigators in conducting academic trials Materials and Methods: We conducted a prospective observational study in a tertiary care hospital for 6 months. Faculty members working in academic institutes were selected. A structured questionnaire was designed for the study and administered using google forms. Responses were taken on a Likert scale. Validity and reliability assessments were carried out. Mann-Whitney test was applied to assess differences between demographic groups. P 10 years of experience (P = 0.00001). Conclusion: Thus, to conclude the challenges faced by investigators were at multiple levels, most common being applying for research grants and making arrangements for the funds for payment towards participation or study-related injury. Faculty members with exposure to conducting clinical trials and with experience of more than 10 years had perceived a reduced degree of challenges.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Synthesis of chromophore (E)-2-(2-(2-(5-(2,5-bis(2-ethylhexyl)-3,6-dioxo-4-(thiophen-2-yl)-2,3,5,6 tetrahydropyrrolo [3,4-c] pyrrol-1-yl) thiophen-2-yl) vinyl)-4H-chromen-4 ylidene) malononitrile (DPP-CM-CN) has been designed and achieved in multistep reaction strategy. The experimental, photophysical and electrochemical properties along with theoretical calculations were explored. DPP-CM-CN dye was – chemically anchored on CdS nanowires (NWs) to investigate its influence on the dye-sensitized solar cell (DSSC) applications. Under the illumination of standard sunlight conditions, the photovoltaic performance of DPP-CM-CN based CdS nanowire device displayed a power conversion efficiency (PCE) of 0.38 %, which is 3.30 times higher as compared to a bare CdS nanowire (0.115 %) based DSSC device; ascribed to the dye loading time on CdS nanostructures. The present results suggest the potential ability of DPP-CM-CN to enhance DSSC device efficiency and reveal the importance of dye molecules in device fabrication, a key step towards the development of DSSC technology.

Renal stones and their management forms bread and butter for a practising urologist. Percutaneous Cystolithotripsy (PCNL) forms the workhorse in the management of large renal stones with size greater than 2 cm. Many score predictors have been described to determine stone free rates and complications related to PCNL surgery.

Colovesical fistula is an improper connection between the urinary bladder and intestinal tract. Although there are many possible causes of colonovesical fistula, Chen et al. have classified them into five main classes: congenital, traumatic, tumor, inflammatory, and other. Intestinal diverticulitis accounts for 50-70% of cases in Western countries, and nearly all of them are related to colonic or bladder fistulas. Malignant tumors (20%) rank second in Western countries as the most common cause, which are situated largely in the large intestine. Other related tumours include bladder, cervical, ovarian and prostate cancers, and non-Hodgkin's lymphoma in the small intestine. The third most prevalent cause is Crohn's disease (10%), which occurs mainly in the ileum. "Other causes" include iatrogenic injury; trauma; foreign bodies in the intestinal tract; radiotherapy; chronic appendicitis

The lean manufacturing approach is employed across several sectors to minimise waste and extend its ideas to institutional settings. The objective of this work is to provide instruction to aspiring engineers regarding the implementation and utilisation of lean tools. The machine shop of an engineering college utilised several tools, including 5S, standard work, and machine maintenance. The students were educated on the difficulties and achievements associated with the implementation of lean ideas across several tiers within the machine shop. The findings indicate that it is imperative to remove non-value-added operations, commonly referred to as Muda, in any manifestation inside the shop. A sequence of 5S audits was carried out to facilitate the enhancement of KAIZEN initiatives and uphold the shop's commitment to lean principles. The determination and assessment of the influence of lean tools on the Machine Shop were conducted through the utilisation of a questionnaire employing a five-point Likert scale. Following the implementation of lean principles, there has been a notable enhancement in several aspects. Specifically, there has been a 6.6% improvement in space utilisation, a substantial 95.12% increase in safety measures, a significant reduction of 83.3% in machine failure occurrences, and a noteworthy decrease of 80.2% in the time required for tool search.

Consumer awareness is one where the buyer could take the right decision in purchasing all types of product. Marketers in view of earning profit, neglect the interest of the consumers and this leads to exploitation of the buyers. To investigate the current scenario, this study focused on the consumer awareness in the urban and rural area towards the Fast Moving Consumer Goods (FMCG) along with the exploitation if any that existed in the market. For this purpose, 557 consumers who were using FMCG products residing in the western region of Tamilnadu were selected through cluster sampling followed by simple random sampling. To meet out the objectives, various statistical tools through SPSS 21 were applied and the result revealed that all the constructs like communication, price, labeling, promotion and unfair trade practices, if any remarkably influencing the consumer awareness. Also, labeling has a noteworthy mediating role between consumer awareness and satisfaction. But there existed a direct negative effect of consumer awareness on the satisfaction. It is suggested that marketers need to focus to fulfill all the rights of the consumers as detailed in the consumerism.

Jennifer Naftel,1,* Heena Mistry,1– 5,* Frances Ann Mitchell,4 Jane Belson,4 Mohammed Aref Kyyaly,2,4 Clair Barber,1,2 Hans Michael Haitchi,1– 3,6 Paddy Dennison,1– 3 Ratko Djukanovic,1– 3,6 Gregory Seumois,5 Pandurangan Vijayanand,2,5 Syed Hasan Arshad,1– 4,6 Ramesh J Kurukulaaratchy1– 4 1National Institute for Health Research (NIHR) Southampton Biomedical Research Centre at University Hospital Southampton NHS Foundation Trust, Southampton, UK; 2Clinical and Experimental Sciences Department, Faculty of Medicine, University of Southampton, Southampton, UK; 3Asthma, Allergy and Clinical Immunology Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 4The David Hide Asthma & Allergy Research Centre, St Mary’s Hospital, Newport, Isle of Wight, UK; 5Vijayanand Laboratory, La Jolla Institute of Immunology, San Diego, CA, 92037, USA; 6Institute for Life Sciences, University of Southampton, Southampton, UK*These authors contributed equally to this workCorrespondence: Ramesh J Kurukulaaratchy, Respiratory Medicine & Allergy, Clinical Experimental Sciences, Mailpoint 810, F-Level, South Academic Block, Southampton General Hospital, Tremona Road, Southampton, Hampshire, SO16 6YD, United Kingdom, Tel +442381 208790, Email Rjk1s07@soton.ac.ukBackground: Despite most of the asthma population having mild disease, the mild asthma phenotype is poorly understood. Here, we aim to address this gap in knowledge by extensively characterising the mild asthma phenotype and comparing this with difficult-to-treat asthma.Methods: We assessed two real-world adult cohorts from the South of England using an identical methodology: the Wessex AsThma CoHort of difficult asthma (WATCH) (n=498) and a mild asthma cohort from the comparator arm of the Epigenetics Of Severe Asthma (EOSA) study (n=67). Data acquisition included detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, plus biological samples (blood and sputum) in a subset.Results: Mild asthma is predominantly early-onset and is associated with type-2 (T2) inflammation (atopy, raised fractional exhaled nitric oxide (FeNO), blood/sputum eosinophilia) plus preserved lung function. A high prevalence of comorbidities and multimorbidity was observed in mild asthma, particularly depression (58.2%) and anxiety (56.7%). In comparison to difficult asthma, mild disease showed similar female predominance (> 60%), T2-high inflammation and atopy prevalence, but lower peripheral blood/airway neutrophil counts and preserved lung function. Mild asthma was also associated with a greater prevalence of current smokers (20.9%). A multi-component T2-high inflammatory measure was comparable between the cohorts; T2-high status 88.1% in mild asthma and 93.5% in difficult asthma.Conclusion: Phenotypic characterisation of mild asthma identified early-onset disease with high prevalence of current smokers, T2-high inflammation and significant multimorbidity burden. Early comprehensive assessment of mild asthma patients could help prevent potential later progression to more complex severe disease.Keywords: mild asthma, difficult asthma, multimorbidity, type 2 inflammation

Abstract The preferred method for disease modeling using induced pluripotent stem cells (iPSCs) is to generate isogenic cell lines by correcting or introducing pathogenic mutations. Base editing enables the precise installation of point mutations at specific genomic locations without the need for deleterious double-strand breaks used in the CRISPR-Cas9 gene editing methods. We created a bulk population of iPSCs that homogeneously express ABE8e adenine base editor enzyme under a doxycycline-inducible expression system at the AAVS1 safe harbor locus. These cells enabled fast, efficient and inducible gene editing at targeted genomic regions, eliminating the need for single-cell cloning and screening to identify those with homozygous mutations. We could achieve multiplex genomic editing by creating homozygous mutations in very high efficiencies at four independent genomic loci simultaneously in AAVS1-iABE8e iPSCs, which is highly challenging with previously described methods. The inducible ABE8e expression system allows editing of the genes of interest within a specific time window, enabling temporal control of gene editing to study the cell or lineage-specific functions of genes and their molecular pathways. In summary, the inducible ABE8e system provides a fast, efficient and versatile gene-editing tool for disease modeling and functional genomic studies.

MicroRNAs (miRNAs) are short non-coding RNAs that play crucial roles in gene regulation, exerting post-transcriptional silencing, thereby influencing cellular function, development, and disease. Traditional loss-of-function methods for studying miRNA functions, such as miRNA inhibitors and sponges, present limitations in terms of specificity, transient effects, and off-target effects. Similarly, CRISPR/Cas9-based editing of miRNAs using single guide RNAs (sgRNAs) also has limitations in terms of design space for generating effective gRNAs. In this study, we introduce a novel approach that utilizes CRISPR/Cas9 with dual guide RNAs (dgRNAs) for the rapid and efficient generation of short deletions within miRNA genomic regions. Through the expression of dgRNAs through single-copy lentiviral integration, this approach achieves over a 90% downregulation of targeted miRNAs within a week. We conducted a comprehensive analysis of various parameters influencing efficient deletion formation. In addition, we employed doxycycline (Dox)-inducible expression of Cas9 from the AAVS1 locus, enabling homogeneous, temporal, and stage-specific editing during cellular differentiation. Compared to miRNA inhibitory methods, the dgRNA-based approach offers higher specificity, allowing for the deletion of individual miRNAs with similar seed sequences, without affecting other miRNAs. Due to the increased design space, the dgRNA-based approach provides greater flexibility in gRNA design compared to the sgRNA-based approach. We successfully applied this approach in two human cell lines, demonstrating its applicability for studying the mechanisms of human erythropoiesis and pluripotent stem cell (iPSC) biology and differentiation. Efficient deletion of miR-451 and miR-144 resulted in blockage of erythroid differentiation, and the deletion of miR-23a and miR-27a significantly affected iPSC survival. We have validated the highly efficient deletion of genomic regions by editing protein-coding genes, resulting in a significant impact on protein expression. This protocol has the potential to be extended to delete multiple miRNAs within miRNA clusters, allowing for future investigations into the cooperative effects of the cluster members on cellular functions. The protocol utilizing dgRNAs for miRNA deletion can be employed to generate efficient pooled libraries for high-throughput comprehensive analysis of miRNAs involved in different biological processes.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

Urologists commonly make use of ureteral double J stents in endourology. If a DJ stent is forgotten to be removed, then complications happen in the form of encrustations, infection, migration, renal dysfunction and hydronephrosis. Ectopic pelvic Kidney is a relatively rare congenital anomaly caused by lack of ascent of the kidney. We report a very rare case of forgotten DJ stent in an ectopic kidney in a 55 years old patient with diabetes mellitus with history of left sided open pyelolithotomy done 21 months back. Redo open surgery was done to remove DJ stent along with stone removal.

Urethrocutaneous fistula (UCF) after hypospadias repair remain a frustrating Problem for all the practicing urologists. Furthermore, with the improvement in suture materials and surgical techniques, complications if they may arise also present with litigations for the urologist. We present a case of a 18 year old boy with 46 XY mixed gonadal dysgenesis who had undergone proximal hypospadias repair with Duckett’s tube urethroplasty with resultant complication of subcoronal urethrocutaneous fistula which failed first attempt at repair and resulted in two urethrocutaneous fistulas which was successfully managed by two stage Johanson’s urethroplasty.