Kidney Injury Molecule-1 Signalling in Ischemic Acute Kidney Injury and Phagocytosis

Acute kidney injury (AKI) is defined by the rapid loss of kidney function due to tissue damage. It affects 10-30 % of hospitalized patients and is independently associated with increased morbidity and mortality. Ischemia-reperfusion injury (IRI) is the most common pathoetiological mechanism of AKI, whereby tissue injury is mediated by reactive oxygen species. Ischemic AKI leads to the rapid upregulation of a transmembrane protein, kidney injury molecule-1 (KIM-1) on the apical membrane of proximal tubular epithelial cells (TECs). Previous work from our group and others demonstrated that the extracellular domain of KIM-1 specifically binds to phosphatidylserine on apoptotic cells, thereby transforming KIM-1-expressing TECs into semi-professional phagocytes for apoptotic corpses. The pathophysiological role of KIM-1 in AKI and relevant signalling mechanisms have not yet been elucidated. Using an in vivo model of AKI in mice genetically deficient in Kim-1, we reveal that Kim-1 expression protects mice from tissue damage and renal dysfunction after AKI. To uncover the signalling pathways downstream of KIM-1 in TECs, we performed protein-protein interaction studies to uncover two signalling partners, the alpha subunit of the heterotrimeric G12 protein (Gα12), and the dynein light chain protein (Tctex-1). We provide evidence that KIM-1 interacts with both Gα12 and Tctex-1, using co-immunoprecipitation, GST-pull down and confocal microscopy co-localization studies. We show that KIM-1 upregulation during IRI suppresses endogenous Gα12 activation and down-stream effectors. Further, we reveal that KIM-1-inhibition of Gα12, and the down-stream mediator RhoA, are crucial for TEC-mediated clearance of apoptotic cells. Tctex-1 is bound to KIM-1 during the early stages of phagocytosis becoming dissociated at later stages. Here, siRNA mediated studies informed us that Tctex-1 expression is necessary for phagocytic uptake of apoptotic cells. Finally, given our data showing that TECs isolated from Kim-1-deficient mice were virtually incapable of phagocytosis, it can be inferred that our findings regarding Gα12 and Tctex-1 do not solely apply to phagocytosis by KIM-1, but to all other mechanisms of uptake of apoptotic cells by TECs. In summary, our results suggest an important protective role of KIM-1 in ischemic AKI that is mediated via non-phagocytic and phagocytic mechanisms. The work described in this thesis provides several novel mechanistic insights into the functional role of KIM-1 and suggest potential therapeutic targets for future development

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

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

Acute abdomen revealing abdominal tuberculosis complicated by a proximal jejunal perforation: Case report

Abdominal tuberculosis (TB) remains a significant health concern globally, particularly in regions with high endemicity such as North Africa and Morocco. Despite advances in diagnostic modalities, the nonspecific presentation of abdominal TB poses challenges for timely diagnosis and management. Here, we report a case of abdominal TB in a critically state of a young man from Morocco, presenting with acute abdominal pain and signs of sepsis. Radiological investigations revealed features suggestive of intestinal perforation complicating peritoneal TB. Urgent laparotomy confirmed the diagnosis, yet the patient succumbed to advanced sepsis postoperatively. This case underscores the complexity of abdominal TB diagnosis and management, necessitating a high index of suspicion and multidisciplinary collaboration. With evolving surgical techniques and ongoing research efforts, optimizing strategies for early detection and treatment of abdominal TB remains imperative, particularly in endemic regions

Effect of vinyl acetate effluent in reducing heat of hydration of concrete

Waste generation especially in surface coating industries is a potential pollutant to the environment globally. Waste disposal in the form of recycling or reused has gained some recognition as a raw material in many kind of interested fields. This study is therefore, aimed at utilizing Vinyl acetate effluent generated from manufacturing process of paint as polymer modifier in concrete. The research highlights the influence of Vinyl acetate effluent on setting time and control of heat of hydration in concrete. Three specimens containing 0%, 2.5% and 5% of Vinyl acetate effluent by weight of cement were prepared in cubic moulds. The temperature rises due to heat of hydration in all mixes were recorded. Finding shows that incorporating Vinyl acetate effluent considerably delayed the setting time in cement paste and reduced the total temperature rise in polymer modified concrete. Therefore, addition of Vinyl acetate effluent polymer in concrete may improve the properties of concrete to some extent particularly in mass concrete production