The central role of natural killer cells in mediating acute myocarditis after mRNA COVID-19 vaccination

BACKGROUND: Vaccine-related acute myocarditis is recognized as a rare and specific vaccine complication following mRNA-based COVID-19 vaccinations. The precise mechanisms remain unclear. We hypothesized that natural killer (NK) cells play a central role in its pathogenesis. METHODS: Samples from 60 adolescents with vaccine-related myocarditis were analyzed, including pro-inflammatory cytokines, cardiac troponin T, genotyping, and immunophenotyping of the corresponding activation subsets of NK cells, monocytes, and T cells. Results were compared with samples from 10 vaccinated individuals without myocarditis and 10 healthy controls. FINDINGS: Phenotypically, high levels of serum cytokines pivotal for NK cells, including interleukin-1β (IL-1β), interferon α2 (IFN-α2), IL-12, and IFN-γ, were observed in post-vaccination patients with myocarditis, who also had high percentage of CD57 NK cells in blood, which in turn correlated positively with elevated levels of cardiac troponin T. Abundance of the CD57 NK subset was particularly prominent in males and in those after the second dose of vaccination. Genotypically, killer cell immunoglobulin-like receptor (KIR) KIR2DL5B(-)/KIR2DS3(+)/KIR2DS5(-)/KIR2DS4del(+) was a risk haplotype, in addition to single-nucleotide polymorphisms related to the NK cell-specific expression quantitative trait loci DNAM-1 and FuT11, which also correlated with cardiac troponin T levels in post-vaccination patients with myocarditis. CONCLUSION: Collectively, these data suggest that NK cell activation by mRNA COVID-19 vaccine contributed to the pathogenesis of acute myocarditis in genetically and epidemiologically vulnerable subjects

Epigenetic Inactivation of the miR-124-1 in Haematological Malignancies

miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2′-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study

Lupus nephritis in Chinese children--a territory-wide cohort study in Hong Kong

We report a multicenter study of Chinese children in Hong Kong with systemic lupus erythematosus (SLE) nephritis. Children were included if: they fulfilled the ACR criteria, had significant proteinuria or casturia, were Chinese and younger than 19 years and had been diagnosed with SLE between January 1990 and December 2003. Investigators in each center retrieved data on clinical features, biopsy reports, treatment and outcome of these patients. There were 128 patients (eight boys, 120 girls; mean age: 11.9+/-2.8 years). About 50% presented with multisystem illness and 40% with nephritic/nephrotic symptoms. Negative anti-dsDNA antibodies were found in 6% of the patients. Renal biopsy revealed WHO Class II, III, IV and V nephritis in 13 (10%), 22 (17%), 69 (54%) and 13 (10%) patients, respectively. The clinical severity of the nephritis did not accurately predict renal biopsy findings. The follow-up period ranged from 1 to 16.5 years (mean+/-SD: 5.76+/-3.61 years). During the study five patients died (two from lupus flare, one from cardiomyopathy, two from infections). Four patients had endstage renal failure (ESRF) (one died during a lupus flare). All deaths and end-stage renal failure occurred in the Class IV nephritis group. Chronic organ damage was infrequent in the survivors. The actuarial patient survival rates at 5, 10 and 15 years of age were 95.3, 91.8, and 91.8%, respectively. For Class IV nephritis patients, the survival rates without ESRF at 5, 10, and 15 years were 91.5, 82.3 and 76%, respectively. The survival and chronic morbidity rates of the Chinese SLE children in the present study are comparable to those of other published studies.postprin

Towards a global partnership model in interprofessional education for cross-sector problem-solving

Objectives A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. Methods This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students’ data. Results We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest–posttest differences in students’ readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students’ social interaction anxiety after the IPE simulation. Conclusions The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Effects of soil structure on the mechanical properties of kaolinite clay

Behaviour of kaolinite clay is intimately related to the pore-fluid properties, such as the pH value, electrolyte concentration, ion type, and presence of organic compounds among others, because of its charged surfaces and associated interparticle electrical forces. The first part of this research focuses on the fabric formations and characterizations. The effects of pH and electrolyte concentrations on the interparticle forces and associated fabric formations were studied. Experimental results, including those from sedimentation tests, pore-size measurements, SEM images, and liquid limit tests reveal that the Coulombian attraction force dominates at low pH (pH below the isoelectric point of edge surfaces, IEPedge) and low electrolyte concentrations, which favors the formation of an opened face-to-edge fabric. At high pH (pH > IEPedge) and low electrolyte concentrations, the prevailing double layer repulsion leads to a deflocculated and dispersed fabric which tends to form a denser soil packing with particles in parallel alignment after deposition or consolidation. At high electrolyte concentrations, van der Waals' attraction overwhelms the repulsion due to a shrunk double layer, and therefore soil aggregates and a relatively opened soil packing are formed accordingly. The second part highlights the structure effects on the dynamic properties. The shear modulus and damping ratio of kaolinite with different structures, selected based on the results of fabric characterizations, were assessed by means of the Energy-Injecting Virtual Mass (EIVM) Resonant Column System. The experimental results demonstrated that the dynamic properties of kaolinite closely interrelate with interparticle forces and associated fabric arrangements. Stronger interparticle forces or higher degrees of flocculated structure lead to a greater shear modulus Gmax and lower damping ratio Dmin. The structure influence on the volumetric change and strain response under isotropic compression is apparent. Specimens with different structures have their individual consolidation lines and the merging trend is not readily seen as the isotropic confinement is up to 250 kPa. Moreover, the compressibility increases with increasing degree of flocculated structure. Anisotropic strain responses due to fabric effects can be found as well. The fabric effects on the critical-state and stress-strain behaviour are discussed in the last part based on the experimental observations of undrained shear tests. The soil structure has no apparent influence on the critical state friction angle (∅c'=27.5°), which suggests the irrelevance between the critical-stress ratio and the interparticle forces. The undrained shear strength is seemly controlled by the initial packing density rather than the interparticle forces. Differences in the effective stress path are evident. Specimens with flocculated structure show a contractive tendency until reaching the critical state, while more complicate behaviour can be observed for the specimens with dispersed structure: showing a contractive tendency initially, passing a phase-transformation state afterwards, and performing dilative shearing towards the critical state in the end. Apart from the substantial influence on the isotropic normal compression line, the soil structure also has a noticeable effect on the volumetric behaviour at critical states for the specimens under confining pressure of 100kPa

Genomic analysis of autism spectrum disorder and identification of a novel disease gene NEO1

Being a highly heritable neurodevelopmental disease, autism spectrum disorder (ASD) affects a staggering number of individuals globally with considerable impairments in social interactions and communications. With the immense clinical and genetic heterogeneity, elucidating the underlying pathogenesis of ASD is deemed to be exceedingly challenging. The advances in high throughput next-generation sequencing (NGS) and the increasing utilisation of chromosomal microarray in the recent decade result in tremendous developments in the understanding on the genetic basis of ASD. In this study, these two technologies were applied to dissect the intriguing genetic aetiology of ASD. A cohort of 68 Chinese patients from Hong Kong was recruited consisting both adult and paediatric subjects. Array comparative genomic hybridization (CGH) was performed for the cohort identifying eight clinically significant copy number variants (CNV). The overall diagnostic yield of array CGH was 11.8%. Microduplication at chromosome 16p13.11 was most frequently detected with four positive cases contributing to 5.9% of the cohort. Among the clinically significant CNV, microdeletion at chromosome 15q24 was detected in one subject and this is a recurrent genomic aberration reported in individuals with autism spectrum disorder. To decipher the culprit of ASD in this region, a targeted PCR-based enrichment method was developed using next-generation sequencing to decode all the genes in 15q24 region that listed in the Online Mendelian Inheritance in Man database. Of note, a missense variant and an intronic duplication were identified in NEO1 gene that encodes for neogenin with critical role in interneuron migration and exon guidance, the key pathways in the pathogenesis of ASD. Essentially, the missense variant c.3388C>T (p.Arg1130Cys) impaired the nuclear translocation of neogenin whereas the intronic duplication c.2204-14_2204-2dup predicted to create a cryptic lariat branch point lowering the splicing efficiency. Seemingly, these results provided the first evidence establishing the link between NEO1 and a human phenotype of autism. Apart from the identification of novel disease genes, several methods were developed to study the diverse aetiology of ASD. Notably, the link between mitochondrial disorders and autistic features is widely recognised. Using next-generation sequencing, a whole mitochondrial genome sequencing method using long-range PCR as enrichment was established. The method was validated in DNA samples extracted from blood and urine, which was deemed to be a robust and comprehensive approach to identify mitochondrial mutations. Furthermore, a targeted gene panel consisting key genes that evidently linked to autism were developed using NGS. The genes in the panel include MECP2, PTEN, NLGN3, NRXN1, CNTNAP2 and SHANK3. The method allowed simultaneous analysis of multiple ASD genes in a single analytical run. By and large, the implications of the findings from the present study can be enormous. The CNV spectrum of ASD in the Hong Kong Chinese population was delineated. NEO1 was identified to be the novel disease gene of ASD. These results certainly enhanced the understanding of the genetic basis underpinning the pathogenesis of ASD and promoted the prospect of innovative diagnostics and therapeutics.published_or_final_versionPathologyDoctoralDoctor of Philosoph