Obesity associated with attenuated tissue immune cell responses in COVID-19

Obesity is common and associated with more severe COVID-19, proposed to be in part related to an adipokine-driven pro-inflammatory state. Here we analysed single cell transcriptomes from bronchiolar lavage in three adult cohorts, comparing obese (Ob, body mass index (BMI) >30m2) and non-obese (N-Ob, BMI <30m2). Surprisingly, we found that Ob subjects had attenuated lung immune/inflammatory responses in SARS-CoV-2 infection, with decreased expression of interferon (IFN), IFN{gamma} and tumour necrosis factor (TNF) alpha response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Analysis of peripheral blood immune cells in an independent adult cohort showed a similar, but less marked, reduction in type I IFN and IFN{gamma} response genes, as well as decreased serum IFN, in Ob patients with SARS-CoV-2. Nasal immune cells from Ob children with COVID-19 also showed reduced enrichment of IFN and IFN{gamma} response genes. Altogether, these findings show blunted tissue immune responses in Ob COVID-19 patients, with clinical implications.

Mapping interindividual dynamics of innate immune response at single-cell resolution

Common genetic variants modulate the cellular response to viruses and are implicated in a range of immune pathologies, including infectious and autoimmune diseases. The transcriptional antiviral response is known to vary between infected cells from a single individual, yet how genetic variants across individuals modulate the antiviral response (and its cell-to-cell variability) is not well understood. Here, we triggered the antiviral response in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-seq. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), the first statistical approach designed to identify dynamic eQTLs across a transcriptional trajectory of cell populations, without aggregating single-cell data into pseudo-bulk. This allows us to uncover the underlying architecture and variability of antiviral response across responding cells, and to identify more than two thousands eQTLs modulating the dynamic changes during this response. Many of these eQTLs colocalise with risk loci identified in GWAS of infectious and autoimmune diseases. As a case study, we focus on a COVID-19 susceptibility locus, colocalised with the antiviral OAS1 splicing QTL. We validated it in blood cells from a patient cohort and in the infected nasal cells of a patient with the risk allele, demonstrating the utility of GASPACHO to fine-map and functionally characterise a genetic locus. In summary, our novel analytical approach provides a new framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.

The local and systemic response to SARS-CoV-2 infection in children and adults

While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in paediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatric versus adult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data1 as a highly granular reference for the study of immune responses in airways and blood in children.

The cellular immune response to COVID-19 deciphered by single cell multi-omics across three UK centres

The COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well as economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling of over 800,000 peripheral blood mononuclear cells from a cohort of 130 patients with COVID-19. Our cohort, from three UK centres, spans the spectrum of clinical presentations and disease severities ranging from asymptomatic to critical. Three control groups were included: healthy volunteers, patients suffering from a non-COVID-19 severe respiratory illness and healthy individuals administered with intravenous lipopolysaccharide to model an acute inflammatory response. Full single cell transcriptomes coupled with quantification of 188 cell surface proteins, and T and B lymphocyte antigen receptor repertoires have provided several insights into COVID-19: 1. a new non-classical monocyte state that sequesters platelets and replenishes the alveolar macrophage pool; 2. platelet activation accompanied by early priming towards megakaryopoiesis in immature haematopoietic stem/progenitor cells and expansion of megakaryocyte-primed progenitors; 3. increased clonally expanded CD8+ effector:effector memory T cells, and proliferating CD4+ and CD8+ T cells in patients with more severe disease; and 4. relative increase of IgA plasmablasts in asymptomatic stages that switches to expansion of IgG plasmablasts and plasma cells, accompanied with higher incidence of BCR sharing, as disease severity increases. All data and analysis results are available for interrogation and data mining through an intuitive web portal. Together, these data detail the cellular processes present in peripheral blood during an acute immune response to COVID-19, and serve as a template for multi-omic single cell data integration across multiple centers to rapidly build powerful resources to help combat diseases such as COVID-19.

Clinical practice guidelines for the management of biliary tract cancers 2019: the 3rd English edition / 中华消化外科杂志

The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014. In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as grade 1 (strong) or grade 2 (weak) according to the concepts of the grading of recommendations assessment, development, and evaluation system. The 31 CQs covered the six topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, and (6) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded. This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.

Endocuff-Assisted versus Cap-Assisted Colonoscopy Performed by Trainees: A Retrospective Study

Background/Aims@#The adenoma detection rate (ADR) of screening colonoscopies performed by trainees is often lower than that of colonoscopies performed by experts. The effcacy of cap-assisted colonoscopy (CAC) in adenoma detection is well documented, especially that of CACs performed by trainees. Endocuff, a new endoscopic cap, is reportedly useful for adenoma detection; however, no trials have compared the effcacy of Endocuff-assisted colonoscopy (EAC) and CAC conducted by trainees. Therefore, the present study retrospectively compared the effcacy between EAC and CAC in trainees. @*Methods@#This was a single-center, retrospective study involving 305 patients who underwent either EAC or CAC performed by three trainees between January and December 2018. We evaluated the ADR, mean number of adenomas detected per patient (MAP), cecal intubation rate, cecal intubation time, and occurrence of complications between the EAC and CAC groups. @*Results@#The ADR was significantly higher in the EAC group than in the CAC group (54.3% vs. 37.3%, p=0.019), as was the MAP (1.36 vs. 0.74, p=0.003). No significant differences were found between the groups with respect to the cecal intubation rate or cecal intubation time. No major complications occurred in either group. @*Conclusions@#Our results suggest that EAC exhibits increased ADR and MAP compared to CAC when performed by trainees.

Comparison of Continuous Epidural Analgesia, Patient-Controlled Analgesia with Morphine, and Continuous Three-in-One Femoral Nerve Block on Postoperative Outcomes after Total Hip Arthroplasty

BACKGROUND: Postoperative pain relief can be achieved with various modalities. However, there are only few reports that have analyzed postoperative analgesic techniques in total hip arthroplasty patients. The aim of this retrospective study was to compare the postoperative outcomes of three different analgesic techniques after total hip arthroplasty. METHODS: We retrospectively reviewed the influence of three analgesic techniques on postoperative rehabilitation after total hip arthroplasty in 90 patients divided into three groups (n = 30 patients per group). Postoperative analgesia consisted of continuous epidural analgesia (Epi group), patient-controlled analgesia with morphine (PCA group), or a continuous femoral nerve block (CFNB group). We measured the following parameters relating to postoperative outcome: visual analog scale scores, the use of supplemental analgesia, side effects, length of the hospital stay, plasma D-dimer levels, and the Harris hip score. RESULTS: Each group had low pain scores with no significant differences between the groups. The PCA group had a lower frequency of supplemental analgesia use compared to the Epi and CFNB groups. Side effects (nausea/vomiting, inappetence) and day 7 D-dimer levels were significantly lower in the CFNB group (p < 0.05). There were no significant differences between the groups in terms of the length of the hospital stay or the Harris hip score. CONCLUSIONS: Although there were no clinically significant differences in outcomes between the three groups, the CFNB provided good pain relief which was equal to that of the other analgesics with fewer side effects and lower D-dimer levels in hospitalized patients following total hip arthroplasty.

Ross Operation for a Case of Secondary Aortic Regurgitation due to Infective Endocarditis / 日本心臓血管外科学会雑誌

A 6-year-old boy was admitted with infective endocarditis and aortic regurgitation. Clinical signs of infection were severe. The leukocyte count was 13, 100/μl and the C-reactive protein (CRP) was elevated to 17.2mg/dl. Blood culture was positive for <i>Staphylococcus aureus</i>. Echocardiography showed a vegetation 3mm in diameter on the aortic valve, and a perforation of the right coronary cusp with moderate aortic regurgitation. With antibiotic therapy, clinical signs and laboratory data of infection improved at an early stage. We decided to operate after his complete recovery from infection. Laboratory data normalized completely in 6 weeks, but echocardiography demonstrated aneurysmal change of the right coronary sinus and severe aortic regurgitation. The Ross operation was performed on the 44th day. At operation, it was noted that the non-coronary cusp was destroyed completely leaving only strings of fibrous tissue. A perforation of 3mm in diameter was also found on the right coronary cusp. There was a mural aneurysm near the right coronary orifice without abscess formation in the surrounding structure. A pulmonary autograft was transplanted to the aortic root after resection of the destroyed aortic cusps, aortic root and the mural aneurysm. The right ventricular outflow tract was reconstructed using an autologous pericardium as a posterior wall and the Monocusp ventricular outflow patch (MVOP) #22 as an anterior transannular patch. The postoperative course was uneventful. Postoperative echocardiography revealed no aortic regurgitation.

A Successful Case of Sutureless Pulmonary Artery Plasty Using Autologous Tissue for Severe Pulmonary Stenosis after a Rastelli Operation / 日本心臓血管外科学会雑誌

An 11-year-old boy, who underwent a Rastelli operation using a 14mm artificial graft and left pulmonary artery (PA) plasty with an autologous pericardium patch 7 years previously, had severe recurrent left pulmonary stenosis. Reoperation was performed including right ventricular outflow tract reconstruction and left PA plasty. The PA at the most stenotic site was only 2mm in diameter; it was enlarged to 10mm by good exposure and an incision on the pulmonary intima. A bovine pericardium patch with a handmade ePTFE valve was sutured onto the autologous tissue not onto the pulmonary intima to avoid restenosis and in expectation of the growth of the pulmonary orifice. On postoperative 3-D CT, the left pulmonary artery was patent and 9mm in diameter. Pulmonary scintigraphy showed an improvement in the left pulmonary perfusion. This sutureless technique was useful in this case of severe pulmonary stenosis.

Ruptured Abdominal Aortic Aneurysm in a Very Elderly Patient / 日本心臓血管外科学会雑誌

Surgical mortality associated with ruptured abdominal aneurysm remains high, especially in elderly patients, despite recent progress in improved patient management. We present the successful salvage of a 90-year-old woman with ruptured abdominal aortic aneurysm. She was transferred from another hospital because of severe abdominal and back pain and pulsatile abdominal tumor. One hour after admission, shock suddenly developed. We diagnosed her illness as ruptured abdominal aneurysm on enhanced CT scan. Emergency surgery was performed. The hematoma surrounding the aneurysm occupied the retroperitoneal space below the level of the diaphragm (Fitzgerald III). Aortic cross clamp was quickly performed below the level of the diaphragm approaching from the lesser omentum. After controlling bleeding, the site of the aortic cross clamping was changed to the infrarenal aorta. The aneurysm was resected and replaced by a knitted Dacron Y-graft (albumin coated). Duration of surgery was 5 hours and 5 minutes. Blood loss was 6200ml. After surgery, artificial ventilation was required for ten days to avoid hypoxemia. On the 5th postoperative day disseminated intravascular congulation (DIC) developed but she recovered. On the 30th postoperative day, she was discharged. Advanced age may not be an absolute contraindication for surgical treatment even in cases of rupture.