Neutrophilic inflammation promotes SARS-CoV-2 infectivity and augments the inflammatory responses in airway epithelial cells.

In response to viral infection, neutrophils release inflammatory mediators as part of the innate immune response, contributing to pathogen clearance through virus internalization and killing. Pre-existing co- morbidities correlating to incidence of severe COVID-19 are associated with chronic airway neutrophilia. Furthermore, examination of COVID-19 explanted lung tissue revealed a series of epithelial pathologies associated with the infiltration and activation of neutrophils, indicating neutrophil activity in response to SARS- CoV-2 infection. To determine the impact of neutrophil-epithelial interactions on the infectivity and inflammatory responses to SARS-CoV-2 infection, we developed a co-culture model of airway neutrophilia. SARS-CoV-2 infection of the airway epithelium alone does not result in a notable pro-inflammatory response from the epithelium. The addition of neutrophils induces the release of proinflammatory cytokines and stimulates a significantly augmented pro-inflammatory response subsequent SARS-CoV-2 infection. The resulting inflammatory response is polarized with differential release from the apical and basolateral side of the epithelium. Additionally, the integrity of the epithelial barrier is impaired with notable epithelial damage and infection of basal stem cells. This study reveals a key role for neutrophil-epithelial interactions in determining inflammation and infectivity in response to SARS-CoV-2 infection.

Development of Focal Segmental Glomerulosclerosis and Thrombotic Microangiopathy in a Liver Transplant Patient on Sorafenib for Hepatocellular Carcinoma: A Case Report.

Transplant patients are at risk for hemodynamic injury and glomerular diseases such as focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathy (TMA). Calcineurin inhibitors (CNI) can cause various patterns of acute kidney injury (AKI) in transplant patients and their effects must be differentiated from kidney injury due to other agents. Transplant populations are also at risk for atypical infections and malignancies. These conditions and the agents that are used to treat them can then induce their own set of glomerular diseases. We report a patient with hepatitis C who had received an orthotopic liver transplant and then developed recurrent hepatocellular carcinoma, which was treated with the oral tyrosine kinase inhibitor (TKI) sorafenib. In a manner temporally related to the initiation of the TKI, progressive AKI and high-grade rising proteinuria were noted. A biopsy disclosed FSGS and concomitant TMA. Despite the discontinuation of the TKI and high-dose steroid treatment, the patient developed end-stage renal disease and was initiated on hemodialysis. After determining the TKI as the probable culprit, as opposed to CNIs, the patient successfully received a living related renal transplant. CNIs are used to maintain renal and hepatic allografts without the development of hematuria, significant proteinuria, or significant impairment of renal function. It is noted that the pathologic phenotype observed in this case is only the second reported case of concomitant TMA and FSGS in a sorafenib-treated patient.

European Society of Coloproctology consensus on the surgical management of intestinal failure in adults.

Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation.

Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19-23, 2013, and was preceded by a 2-day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody-mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter-observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis ("isolated v") represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d-negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

Banff 2011 Meeting report: new concepts in antibody-mediated rejection.

The 11th Banff meeting was held in Paris, France, from June 5 to 10, 2011, with a focus on refining diagnostic criteria for antibody-mediated rejection (ABMR). The major outcome was the acknowledgment of C4d-negative ABMR in kidney transplants. Diagnostic criteria for ABMR have also been revisited in other types of transplants. It was recognized that ABMR is associated with heterogeneous phenotypes even within the same type of transplant. This highlights the necessity of further refining the respective diagnostic criteria, and is of particular significance for the design of randomized clinical trials. A reliable phenotyping will allow for definition of robust end-points. To address this unmet need and to allow for an evidence-based refinement of the Banff classification, Banff Working Groups presented multicenter data regarding the reproducibility of features relevant to the diagnosis of ABMR. However, the consensus was that more data are necessary and further Banff Working Group activities were initiated. A new Banff working group was created to define diagnostic criteria for ABMR in kidneys independent of C4d. Results are expected to be presented at the 12th Banff meeting to be held in 2013 in Brazil. No change to the Banff classification occurred in 2011.

Do Doppler waveforms at the common femoral artery accurately predict iliac stenosis?

OBJECTIVE: Evaluate whether common femoral artery (CFA) Doppler waveform assessment predicted the presence of significant iliac artery stenosis as visualised on magnetic resonance angiography (MRA). METHOD: Three-year retrospective study of patients investigated using CFA Doppler waveforms and MRA. The patients were identified from vascular/radiology databases. Waveforms were reported real time as monophasic, biphasic or triphasic. Results were compared with MRA findings. RESULTS: In 76 patients, 119 waveforms were assessed. MRA demonstrated 37 iliac vessels with significant stenosis. 32 (86%) had abnormal waveforms (monophasic/biphasic), 5 were triphasic. In 82 cases where MRA showed no significant stenosis, waveforms were abnormal in 35 (43%). Abnormal CFA waveforms have sensitivity of 86% and specificity of 57%. Monophasic waveforms alone were more specific (88%) but less sensitive (57%) for predicting iliac lesions. CONCLUSION: Whilst CFA waveform morphology is a useful adjunct in detection of iliac disease, normal triphasic waveforms do not exclude iliac stenosis.

Death from metastatic donor-derived ovarian cancer in a male kidney transplant recipient.

Posttransplant malignancy developing in an allograft is an uncommon complication of organ transplantation. The tumor may represent malignant transformation of donor or recipient cells that were previously normal, metastatic malignancy of recipient origin or malignancy transmitted from organ donor to recipient. Establishing the origin of the malignancy is critical to treatment algorithms. It is generally believed allograft removal and immunosuppression withdrawal will lead to resolution of transmitted malignancies in cases where the renal allograft is the origin. We report a male patient who developed metastatic ovarian malignancy secondary to donor transmission.

Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft.

Pathologic obliterative bronchiolitis (OB)/Bronchiolitis obliterans syndrome (pathologic OB/BOS) is the major obstacle to long-term survival post-lung transplantation (LT). Our group has demonstrated that pulmonary hypertension (PH) complicates the course of chronic inflammatory lung diseases that have similarities to pathologic OB/BOS and that vascular remodeling of the bronchial circulation occurs during BOS. Consequently, we hypothesized that PH is associated with pathologic OB/BOS and may result from a vasculopathy of the allograft pulmonary circulation. We conducted a single-center, retrospective study and examined the presence of PH and vasculopathy in patients with pathologic OB/BOS. Fifty-two pathologic specimens post-LT were recovered from January 10, 1997 to January 5, 2007 and divided into two groups, those with and without pathologic OB/BOS.PH was defined as a mean pulmonary artery pressure (mPAP) > 25 mmHg by right heart catheterization (RHC) or right ventricular systolic pressure (RVSP) > or = 45 mmHg by transthoracic echocardiogram (TTE). PH was more prevalent in those LT recipients with pathologic OB/BOS (72% vs. 0%, p = 0.003). Furthermore, pulmonary arteriopathy and venopathy were more prevalent in patients with pathologic OB/BOS (84% vs. 4%, p < 0.0001, and 77% vs. 35%, p = 0.004, respectively). PH is common in LT recipients with pathologic OB/BOS and is associated with a vasculopathy of the allograft pulmonary circulation.

Phosphorylated S6 ribosomal protein: a novel biomarker of antibody-mediated rejection in heart allografts.

We tested the hypothesis that phosphorylation of S6 ribosomal protein (S6RP), a downstream target of the PI3K/Akt/mTOR pathway, is a biomarker of antibody-mediated rejection (AMR) in heart allografts. Primary cultures of human aortic and microvascular endothelial cells (EC) were treated with anti-HLA class I and class II antibodies (Ab) and cell lysates were studied for phosphorylation of S6 ribosmal protein at Serine235/236 (p-S6RP). Treatment of cultured EC with anti-class I and class II Ab stimulated S6RP phosphorylation. Immunohistochemical techniques were used to detect the level of p-S6RP in endomyocardial biopsies (n = 131) from 46 heart transplant recipients and the results were correlated with histopathological diagnosis of rejection, C4d staining, production of posttransplant anti-HLA Ab and clinical outcome. Increased phosphorylation of S6RP in endomyocardial biopsies was significantly associated with the diagnosis of AMR (p < 0.0001). No significant association between acute cellular rejection (ACR) and p-S6RP was observed. C4d staining was positively associated with both AMR and p-S6RP. Posttransplant anti-HLA class II Ab production was also significantly associated with a positive p-S6RP status in cardiac biopsies. These results indicate that p-S6RP is a useful biomarker for the diagnosis of AMR.

Instrumentation for monitoring gas exchange and metabolic rate in critically ill patients.

In the critically ill patient the monitoring of oxygen consumption (VO2) and carbon dioxide production (VCO2) can identify abnormalities in tissue perfusion and metabolism. A patient's metabolic utilization can be calculated by indirect calorimetry, once VO2 and VCO2 are measured. This paper evaluates a compact instrument designed for monitoring VO2 and VCO2 in the critically ill adult. Accuracy was measured under controlled laboratory conditions using oxygen-enriched air, PEEP, and intermittent mandatory ventilation (IMV). Accuracy averaged 1.3% for VO2 and 0.9% for VCO2 when room air was used. Accuracy was 11.7% for VO2 and 6.8% for VCO2 when 80% oxygen was used. PEEP of 30 cm H2O had little effect on accuracy. IMV at 2 breath/min (room air) resulted in an accuracy of 4.0% and 4.1% for VO2 and VCO2, respectively.

Blood-gas analyzer calibration and quality control using a precision gas-mixing instrument.

We describe a new instrument that performs on-site mixing of oxygen (O2), carbon dioxide (CO2), and nitrogen (N2) to create compositions that can replace gases from standard premixed cylinders. This instrument yields accurate and predictable gas mixtures that can be used for two-point gas calibration of blood gas/pH analyzers or for liquid tonometry of either an aqueous buffer or blood used as quality-control material on blood-gas electrodes. The desired mixture of O2, CO2, and N2 is produced by microprocessor control of the sequential open-times on three solenoid valves that meter these pure gases through a common small-bore orifice. Any combination of O2 and CO2 can be chosen by dialing the front panel thumbwheels and pressing a button. Gas chromatographic evaluation of this gas-mixing instrument demonstrates its accuracy and precision to be better than +/- 0.1% absolute full scale for O2, CO2, and N2, making this instrument calibration and tonometry.

New gas-liquid equilibration method: syringe tonometer.

This new apparatus for gas-liquid equilibration (tonometry) in a transportable vessel is designed for tonometry of blood or buffer solution in a specially designed syringe. Gas enters the syringe chamber through small holes in the tip of the syringe plunger and bubbles upward through the sample. The syringe plunger is a second chamber, which is used for warming and humidifying the gas before it enters the tonometer chamber. The entire syringe is housed in a transparent, temperature-controlled environment during equilibration. After equilibration, the sample is easily entered into a blood-gas analyzer. At most, gas-liquid O2/CO2 equilibration for 2.5 mL of buffer or blood requires less than 13 min. Comparisons with a standard thin-film tonometer show good agreement for pO2 and pCO2 over the range 0-93 kPa (0-700 mmHg) and 2-20 kPa (14-150 mmHg), respectively. The syringe tonometer eliminates contamination of the sample during transfer and transport to the analyzer, thus making tonometry more technique-independent. The apparatus is simple and easy to use, with definite advantages over existing methods of tonometry.