Modulators of Innate Gut Immunity to Enteric Viral Infections: Murine Norovirus (MNV) as a Model

Challenged by a huge and diverse antigenic stimulus, the intestinal mucosa has developed a unique immune system that mainly functions to maintain tolerance to innocuous antigens while retaining the ability to respond swiftly to pathogenic threats. Central to this specialised immune system are the Intraepithelial Lymphocytes (IELs). These cells are uniquely located between Intestinal Epithelial Cells (IECs) ready to respond to exogenous antigens in the intestinal lumen. The intestinal immune system is constantly influenced, not only by the commensal microbiota, but also by the nutritional status of the host and the availability of certain essential micronutrients that are derived from a healthy-balanced diet. Additionally, age has a significant impact on the efficiency of gut immunity in responding to infectious pathogens, as reflected by the increased burden of gastrointestinal infections at the extremes of age. In this thesis, using the Murine Norovirus (MNV) oral infection model, I aimed to characterize intestinal mucosal antiviral-responses with specific focus on the role of IELs, the impact of aging and the influence of certain micronutrients whose effects are mediated through the Aryl Hydrocarbon Receptor (AhR). Employing different knock-out and adoptive transfer experiments, I concluded that, at least in our experimental conditions and in a viral strain-specific manner, the activated IELs are not essential and may play a minor role in the protective response against MNV infection. This work also demonstrated that various MNV virus strains activate IELs differentially and for the first time (to our knowledge) revealed distinct abilities of these different Norovirus variants to infect IECs. Recognising an impaired response in old (2-year) mice, we were also able to identify a specific defect in the IFN-Lambda response of aged IECs. Furthermore, using the model of MNV infection to investigate the role of AhR signalling, the data I generated suggested a direct link between constitutive AhR signalling and innate interferon-mediated responses. These findings have uncovered a potential preventive/therapeutic targets for enhancing anti-viral responses.IDB Cambridge International Scholarshi

Clinical Staging and Flowcytomteric CD38 and Zap 70 Prognostic Indicators in Sudanese Patients with Chronic Lymphocytic Leukemia

Background: The clinical course of chronic lymphocytic leukemia is highly variable. The determination of ZAP70 and CD38 is increasingly utilized as prognostic factor for chronic lymphocytic leukemia. The aim of conducting this study was to investigate the frequency of CD38 and ZAP70 expression among Sudanese Chronic lymphocytic leukemia (CLL) patients and to relate them to the Binet and Rai clinical staging systems. Method: A total of 93 patients (mean age; 62.29 ± 11.68, sd) were enrolled in this cross-sectional study. CD38 and ZAP70 expression levels were measured with four color flowcytometry using the cut-off values of 20% for ZAP70 and 30% for CD38 expression. Staging was assessed by using clinical examination and CBC for all patients. Data were analyzed using the Statistical Package for Social science for Windows (SPSS), version 22. Results: There were 93 CLL patients and the median age of the group was 63 years (36–95 years). About 71% of the patients presented with lymphadenopathy, 53.8% with splenomegaly, 73.1% with anemia, and 45.2% with thrombocytopenia. There was higher frequency of Binet stage C and Rai stage IV (62 [66.6%] patients and 34 [36.5%] patients, respectively). In addition, CD38 and ZAP70 showed higher frequency among Binet and Rai advance stages. ZAP70 and CD38 positivity were detected in 21 patients (22.6%) and 31 patients (33.3%), respectively. There was no statistically significant association between ZAP70 and CD38 and clinical staging systems (P-value > 0.05). Conclusion: No significant association was observed between Flowcytometric (CD38 and Zap70) Prognostic Indicators and clinical staging systems. Keywords: chronic lymphocytic Leukemia, Flowcytometry, ZAP70, CD38, clinical staging system

ZAP-70 Expression in B-Chronic Lymphocytic Leukemia in Sudanese Patients

Background: Chronic lymphocytic leukemia is the most common form of leukemia in adults. The prognostic impact of ZAP-70 in CLL has been reported in several studies. The aim of conducting this study was to investigate the prevalence of ZAP-70 in Sudanese patients with chronic lymphocytic leukemia attending Khartoum Oncology Hospital.Materials and Methods: A total of 93 newly diagnosed patients with chronic lymphocytic leukemia were enrolled in this study. Lymphadenopathy and organomegaly were assessed in all participants using clinical examination, chest radiography, and abdominal ultrasound. Full blood count was carried out by an automated hematology analyzer. ZAP-70 was evaluated using flowcytometry on peripheral blood samples. ZAP-70 was defined as positive expression at a cutoff level of 20%. Results: There were 63 (67.7%) males and 30 (32.3%) females and the median age of the group was 63 years; 68 patients (73.1%) were presented with anemia and 66(70.9%) had lymphadenopath;y. Majority of our patients 35 (37.6%) were in Rai stage IV. ZAP-70 positivity was detected in 21 patients (22.6%). There was no statistically significant association of ZAP-70 with age, sex, lymphadenopathy, organomegaly, hemoglobin concentration, total white blood cell count, platelet count and Rai staging system (p-value > 0.05). Conclusion: Only 21 patients (22.6%) were ZAP-70 positive. There was no association between ZAP-70 and the study variables. Further studies to evaluate prognostic role of ZAP-70 in Sudanese patients with chronic lymphocytic leukemia are recommended

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Development of the Simulation Model for the CoSES Laboratory Test Microgrid in Modelica

Evolution of the traditional consumer in a power system to a prosumer has posed many problems in the traditional uni-directional grid. This evolution in the grid model has made it important to study the behaviour of microgrids. This thesis deals with the laboratory microgrid setup at the Munich School of Engineering, built to assist researchers in studying microgrids. The model is built in Dymola which is a tool for the OpenModelica language. Models for the different components were derived, suiting the purpose of this study. The equivalent parameters were derived from data sheets and other simulation programs such as PSCAD. The parameters were entered into the model grid and tested at steady state, firstly. This yielded satisfactory results that were similar to the reference results from MATPOWER power flow. Furthermore, fault conditions at several buses were simulated to observe the behaviour of the grid under these conditions. Recommendations for further developing this model to include more detailed models for components, such as power electronic converters, were made at the end of the thesis

Outcomes of pediatric tracheostomy after surgery for congenital heart disease: A 20‐year experience

Abstract Objective Children with congenital heart defects (CHD) requiring cardiovascular surgery (CVS) rarely require tracheostomy placement; however the mortality rate remains high. The study aimed to analyze the incidence of tracheostomy in children with CHD, and to determine factors contributing to postoperative outcomes, decannulation rates, and mortality. Methods Retrospective case series of children ≤18 years old with CHD status post‐CVS who underwent tracheostomy placement between January 1, 2001 and December 31, 2020. Variables analyzed included demographic information, presence of comorbidities including prematurity, respiratory diseases, presence of genetic syndromes, decannulation status, type of repair (univentricular vs. biventricular), and need for cardiopulmonary bypass. Adverse events analyzed included all‐cause mortality, development of mediastinitis, fatal decannulation, and persistence of tracheocutaneous fistula. Results Fifty‐one patients were analyzed. The incidence of tracheostomy was 0.8%. Median age at tracheostomy was 5.3 months. The 5‐year survival estimate was 56.3% (95% confidence interval 43.6%, 72.6%). Age ≤6 months at the time of tracheostomy placement (p = .03), and the presence of tracheomalacia (p = .04) were factors significantly associated with 5‐year survival. Two patients (3.9%) experienced fatal decannulation, and one patient (2.0%) developed postoperative mediastinitis. The 10‐year decannulation rate estimate was 47.8% (30.5%, 63.2%). Seven patients (13.7%) had a persistent tracheocutaneous fistula. Conclusions This study corroborates high mortality rates in this population. Factors associated with improved survival were younger age at the time of tracheostomy and presence of tracheomalacia. Decannulation rates were low, but estimates improved over 10 years. Further studies are needed to determine optimal indications and timing for tracheostomy placement in this patient population. Level of Evidence

Ectopia cordis sternal cleft repair with mandibular distractors: a follow-up case report

A neonate with thoracic ectopia cordis presented following an uncomplicated delivery. A mandibular distractor was placed to bridge the sternal cleft and retracted (reverse distractor activation) over 24 days to facilitate sternal closure. Follow-up at five years postoperatively demonstrated a well-healed sternum. This novel approach to ectopia cordis repair facilitates slow, steady physiologic accommodation of the heart without hemodynamic instability or long-term complications