Vagus Nerve Stimulation Modulates Inflammation in Treatment-Resistant Depression Patients: A Pilot Study.

Vagal neurostimulation (VNS) is used for the treatment of epilepsy and major medical-refractory depression. VNS has neuropsychiatric functions and systemic anti-inflammatory activity. The objective of this study is to measure the clinical efficacy and impact of VNS modulation in depressive patients. Six patients with refractory depression were enrolled. Depression symptoms were assessed with the Montgomery-Asberg Depression Rating, and anxiety symptoms with the Hamilton Anxiety Rating Scale. Plasmas were harvested prospectively before the implantation of VNS (baseline) and up to 4 years or more after continuous therapy. Forty soluble molecules were measured in the plasma by multiplex assays. Following VNS, the reduction in the mean depression severity score was 59.9% and the response rate was 87%. Anxiety levels were also greatly reduced. IL-7, CXCL8, CCL2, CCL13, CCL17, CCL22, Flt-1 and VEGFc levels were significantly lowered, whereas bFGF levels were increased (p values ranging from 0.004 to 0.02). This exploratory study is the first to focus on the long-term efficacy of VNS and its consequences on inflammatory biomarkers. VNS may modulate inflammation via an increase in blood-brain barrier integrity and a reduction in inflammatory cell recruitment. This opens the door to new pathways involved in the treatment of refractory depression.

NRF2 Deficiency Attenuates Diabetic Kidney Disease in Db/Db Mice via Down-Regulation of Angiotensinogen, SGLT2, CD36, and FABP4 Expression and Lipid Accumulation in Renal Proximal Tubular Cells.

The role(s) of nuclear factor erythroid 2-related factor 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency in type 2 diabetes (T2D) db/db mice (db/dbNrf2 knockout (KO)) attenuates DKD progression through the down-regulation of angiotensinogen (AGT), sodium-glucose cotransporter-2 (SGLT2), scavenger receptor CD36, and fatty -acid-binding protein 4 (FABP4), and lipid accumulation in renal proximal tubular cells (RPTCs). Db/dbNrf2 KO mice were studied at 16 weeks of age. Human RPTCs (HK2) with NRF2 KO via CRISPR-Cas9 genome editing and kidneys from patients with or without T2D were examined. Compared with db/db mice, db/dbNrf2 KO mice had lower systolic blood pressure, fasting blood glucose, kidney hypertrophy, glomerular filtration rate, urinary albumin/creatinine ratio, tubular lipid droplet accumulation, and decreased expression of AGT, SGLT2, CD36, and FABP4 in RPTCs. Male and female mice had similar results. NRF2 KO attenuated the stimulatory effect of the Nrf2 activator, oltipraz, on AGT, SGLT2, and CD36 expression and high-glucose/free fatty acid (FFA)-stimulated lipid accumulation in HK2. Kidneys from T2D patients exhibited markedly higher levels of CD36 and FABP4 in RPTCs than kidneys from non-diabetic patients. These data suggest that NRF2 exacerbates DKD through the stimulation of AGT, SGLT2, CD36, and FABP4 expression and lipid accumulation in RPTCs of T2D.

Suspected medullary washout leading to severe polyuria following delayed cerebral ischemia: a case report.

BACKGROUND: Delayed cerebral ischemia is a clinical entity commonly encountered in patients presenting with acute neurological injury and is often complicated by dysnatremias, such as the cerebral salt wasting syndrome. In this case report, we described an exceptional case of polyuria attributed to an initial cerebral salt wasting phenomenon and iatrogenic-induced medullary washout. CASE PRESENTATION: A 53-year-old woman was admitted to our hospital for the management of a Modified Fisher scale grade 4 subarachnoid hemorrhage due to a ruptured posterior communicating aneurysm. She was initially managed with coil embolization and external ventricular drain due to secondary hydrocephalus. Throughout the course of her hospitalization, she developed severe polyuria reaching up to 40L per day. To keep up with the excessive urinary losses and maintain appropriate cerebral perfusion, fluid replacement therapy was adjusted every hour, reaching up to 1.3 L of crystalloid per hour in addition to aminergic support. An initial diagnosis of partial diabetes insipidus, followed by a cerebral salt wasting syndrome was suspected. While the urine output continued to increase, her serum urea concentration progressively decreased to a point of almost being undetectable on day 9. At that time, the presence of an interstitial medulla washout was hypothesized. Various pharmacological and non-pharmacological interventions were progressively introduced to regain normal renal homeostasis, including non-steroidal anti-inflammatory drugs, fludrocortisone, oral urea and high-protein intake. Medications were progressively weaned, and the patient was successfully discharged from the ICU. CONCLUSIONS: Cerebral salt wasting should be considered in the initial differential diagnosis of a patient presenting with polyuria in the context of acute neurological injury. Early recognition of this entity is critical to quickly implement proper management. However, as shown in this case report, the concomitance of delayed cerebral ischemia may complexify that management.

Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines.

OBJECTIVE: Colorectal cancer (CRC) is the third most diagnosed cancer, and requires surgical resection and reconnection, or anastomosis, of the remaining bowel to re-establish intestinal continuity. Anastomotic leak (AL) is a major complication that increases mortality and cancer recurrence. Our objective is to assess the causal role of gut microbiota in anastomotic healing. DESIGN: The causal role of gut microbiota was assessed in a murine AL model receiving faecal microbiota transplantation (FMT) from patients with CRC collected before surgery and who later developed or not, AL. Anastomotic healing and gut barrier integrity were assessed after surgery. Bacterial candidates implicated in anastomotic healing were identified using 16S rRNA gene sequencing and were isolated from faecal samples to be tested both in vitro and in vivo. RESULTS: Mice receiving FMT from patients that developed AL displayed poor anastomotic healing. Profiling of gut microbiota of patients and mice after FMT revealed correlations between healing parameters and the relative abundance of Alistipes onderdonkii and Parabacteroides goldsteinii. Oral supplementation with A. onderdonkii resulted in a higher rate of leaks in mice, while gavage with P. goldsteinii improved healing by exerting an anti-inflammatory effect. Patients with AL and mice receiving FMT from AL patients presented upregulation of mucosal MIP-1α, MIP-2, MCP-1 and IL-17A/F before surgery. Retrospective analysis revealed that patients with AL present higher circulating neutrophil and monocyte counts before surgery. CONCLUSION: Gut microbiota plays an important role in surgical colonic healing in patients with CRC. The impact of these findings may extend to a vast array of invasive gastrointestinal procedures.

Blood Sample Processing and Banking for Functional and Molecular Analyses.

Immune monitoring of circulating immune cells in the blood provides insight into a patient's own immune response over the course of a treatment or disease progression. Information such as whether immune cells are functional or non-functional and what specific proteins they express or secrete can be essential to understand if (and how) a treatment is working or a disease is progressing. To do so, it requires careful handling and storage of precious biological samples with the goals of obtaining a large amount of information from limited samples and minimizing future research costs by the use of banked samples. Many factors, including blood sample types, time of collection, containers used, preservatives and other additives, transport means, and length of transit time, all affect the quality of the samples and the stability of biomarkers and must be considered at the initial collection stage. An efficient study design includes provisions for further processing of the original samples, such as cryopreservation of isolated cells, purification of DNA and RNA, and preparation of specimens for genomic, immunological, and biochemical analyses. Development of standard operating procedures and quality control plans is a safeguard of the samples' quality and of the validity of the results. Here, we focus on the collection and processing of blood suitable for plasma and peripheral blood mononuclear cell (PBMC) banking, including collection, processing, and storage of samples, based on our experience.

Online Hemodiafiltration Compared to Conventional Hemodialysis in Critically Ill Patients.

Introduction: Online hemodiafiltration (HDF) has been increasingly used for improved clearance of middle molecular weight toxins. The impact of this mode of clearance is unknown in critically ill patients. We aimed to determine whether the use of HDF in acute kidney injury (AKI) is associated with lower mortality and improved kidney recovery up to 90 days after initiation of therapy. Methods: Single-center retrospective cohort study using data from 2017 to 2020 of adults with AKI who initiated intermittent renal replacement therapy (IRRT) in the intensive care unit (ICU), using either hemodialysis (HD) or HDF depending on the maintenance status of the water system without regards for patient characteristics. We assessed association with patient-events and session-events using time-dependent Cox models and general estimating equations models, respectively. Results: We included 182 adults with AKI for whom 848 IRRT sessions were performed in the ICU. The 90-day mortality rate was 43 of 182 (24.6%). There was no significant association with the use of HDF and mortality (adjusted hazard ratio [aHR]: 0.85 (0.43; 1.67) P = 0.64), kidney recovery (aHR: 1.18 (0.76; 1.84) P = 0.47), or intradialytic hypotension (adjusted odds ratio [aOR]: 0.91 confidence interval [CI]: 0.64-1.28 P = 0.58). HDF treatment was associated with a lower rate of subsequent vasopressor use (aOR: 0.60 CI: 0.36-0.99 P = 0.047) and a greater reduction of the neutrophil-to-lymphocyte ratio (NLR) following the first session (-15.0% vs. +5.1%, P = 0.047) but was also associated with increased risk of filter thrombosis during treatment (aOR: 2.42 CI: 1.67-3.50 P < 0.001). Conclusion: The use of HDF in the setting of AKI was not associated with a differential risk of mortality or kidney recovery.

Clinical Implementation of NGAL Testing to Improve Diagnostic Assessment of AKI Episodes in a Canadian Center.

Background: The differential diagnosis of acute kidney injury (AKI) episodes is often challenging. Novel AKI biomarkers have shown their utility to improve prognostic prediction and diagnostic assessment in various research populations but their implementation in standard clinical practice is still rarely reported. Objective: To report the differential diagnostic ability and associated clinical utility of the neutrophil gelatinase-associated lipocalin (NGAL) testing in a real-life setting of a heterogeneous AKI population. Design: This is a retrospective cohort study combined with a clinical audit using questionnaires distributed to consultant nephrologists following NGAL results. Setting: The first 250 consecutive patients with a confirmed AKI where an NGAL test (plasma NGAL [pNGAL] or urine NGAL [uNGAL]) was ordered from a large academic center in Montreal, Canada from January 2021 to August 2021. Patients: Patients were classified into 3 groups based on the final AKI etiology category (functional, intrarenal, and postrenal) following definitive adjudication by 2 independent nephrologists. Methods: The ability of plasma NGAL (pNGAL), urine NGAL (uNGAL), and uNGAL-to-creatinine ratio (uNGAL/Cr) to discriminate intrarenal from functional AKI etiologies was compared to standard urine chemistry (FENa) and proteinuria. A logistic regression was used to evaluate the association between intrarenal AKI and increased biomarker levels. The overall clinical utility and appreciation of the NGAL test was evaluated using a questionnaire completed prospectively by the consultant nephrologist at the time of receiving the NGAL result. The NGAL results were prospectively available to clinicians with a median time of 2.9 (1.3-7.4) hours from the initial order. Results: A total of 214 uNGAL and 44 pNGAL were ordered from 100 functional, 139 intrarenal and 11 postrenal AKI episodes after final adjudication. The discriminative ability of FENa (AUC 0.68 [95% CI: 0.61-0.75]) was lower than uNGAL (AUC 0.80 [95% CI: 0.73-0.86]) and uNGAL/Cr (AUC 0.83 [95% CI: 0.77-0.88]) but better than pNGAL (AUC 0.66 [95% CI: 0.48-0.85]). According to consultant nephrologists, the NGAL testing has led to a change in clinical management in 42% of cases. Limitations: Data reported came from a single center and NGAL was reserved for more complex cases, which limits generalizability. No biopsy has been performed for most AKI cases as the final adjudication was based on a retrospective review of the hospitalization episode. Conclusions: Neutrophil gelatinase-associated lipocalin testing can be successfully integrated as part of the diagnostic workup for AKI in clinical practice. The integration of tubular damage biomarkers to functional biomarkers can further improve the differential diagnostic assessment. However, the impact of such biomarkers on AKI management and associated outcomes still needs further validation.

Contexte: Le diagnostic différentiel des épisodes d'insuffisance rénale aiguë (IRA) pose souvent un problème. De nouveaux biomarqueurs d'IRA ont montré leur utilité pour améliorer la prédiction pronostique et l'évaluation diagnostique dans diverses populations de recherche, mais leur application dans la pratique clinique est encore peu rapportée. Objectif: Rendre compte de la capacité de diagnostic différentiel et de l'utilité clinique du test NGAL (neutrophil gelatinase-associated lipocalin) dans le contexte réel d'une population hétérogène de patients atteints d'IRA. Devis: Étude de cohorte rétrospective combinée à un audit clinique mené par l'entremise de questionnaires distribués aux néphrologues consultants à la suite du résultat NGAL. Cadre: Les 250 premiers patients consécutifs avec une IRA confirmée, pour qui un test NGAL (plasmatique [pNGAL] ou urinaire [uNGAL]) avait été demandé entre janvier et août 2021 dans un grand centre universitaire de Montréal (Canada). Sujets: Les patients ont été classés en 3 groupes selon la catégorie étiologique finale de l'IRA (fonctionnelle, intrarénale, post-rénale) après révision par deux néphrologues indépendants. Méthodologie: La capacité du pNGAL, du uNGAL et du rapport uNGAL et du rapport uNGAL sur créatinine (uNGAL/Cr) à discriminer les étiologies fonctionnelles des étiologies intrarénales a été comparée à celle des indices urinaires standard de l'urine (FENa) et de la protéinurie. Une régression logistique a servi à évaluer l'association entre l'IRA intrarénale et la hausse des taux des biomarqueurs. L'appréciation du test NGAL et son utilité clinique globale ont été évaluées à l'aide d'un questionnaire rempli prospectivement par le néphrologue consultant lors de la réception du résultat NGAL. Les résultats NGAL ont été mis à la disposition des cliniciens de manière prospective, dans un délai médian de 2,9 [1,3-7,4] heures suivant la prescription initiale. Résultats: En tout, après la révision finale, 214 tests uNGAL et 44 tests pNGAL ont été demandés à partir de 100 épisodes d'IRA fonctionnelle, 139 épisodes d'IRA intrarénale et 11 épisodes d'IRA post-rénale. La capacité discriminante du FENa (SSC: 0,68 [IC 95 %: 0,61-0,75]) était inférieure à celles du uNGAL (SSC: 0,80 [IC 95 %: 0,73-0,86]) et du rapport uNGAL/ Cr (SSC: 0,83 [IC 95 %: 0,77-0,88]), mais supérieure à celle du pNGAL (SSC: 0,66 [IC 95 %: 0,48-0,85]). Les néphrologues ont indiqué que les tests NGAL avaient entraîné un changement dans la prise en charge clinique dans 42 % des cas. Limites: Les données provenaient d'un seul centre et le test NGAL était réservé aux cas plus complexes, ce qui limite la généralisabilité. Dans la plupart des cas, aucune biopsie n'a été effectuée et le diagnostic final était basé sur un examen rétrospectif de l'hospitalisation. Conclusions: En pratique clinique, les tests NGAL peuvent être intégrés avec succès au diagnostic de l'IRA. L'intégration des biomarqueurs de lésions tubulaires aux biomarqueurs fonctionnels peut améliorer davantage l'évaluation du diagnostic différentiel. Cependant, l'impact de ces biomarqueurs sur la prise en charge de l'IRA et les résultats connexes doit encore être validé.

High Levels of MFG-E8 Confer a Good Prognosis in Prostate and Renal Cancer Patients.

Milk fat globule-epidermal growth factor-8 (MFG-E8) is a glycoprotein secreted by different cell types, including apoptotic cells and activated macrophages. MFG-E8 is highly expressed in a variety of cancers and is classically associated with tumor growth and poor patient prognosis through reprogramming of macrophages into the pro-tumoral/pro-angiogenic M2 phenotype. To date, correlations between levels of MFG-E8 and patient survival in prostate and renal cancers remain unclear. Here, we quantified MFG-E8 and CD68/CD206 expression by immunofluorescence staining in tissue microarrays constructed from renal (n = 190) and prostate (n = 274) cancer patient specimens. Percentages of MFG-E8-positive surface area were assessed in each patient core and Kaplan-Meier analyses were performed accordingly. We found that MFG-E8 was expressed more abundantly in malignant regions of prostate tissue and papillary renal cell carcinoma but was also increased in the normal adjacent regions in clear cell renal carcinoma. In addition, M2 tumor-associated macrophage staining was increased in the normal adjacent tissues compared to the malignant areas in renal cancer patients. Overall, high tissue expression of MFG-E8 was associated with less disease progression and better survival in prostate and renal cancer patients. Our observations provide new insights into tumoral MFG-E8 content and macrophage reprogramming in cancer.

MFG-E8 Reduces Aortic Intimal Proliferation in a Murine Model of Transplant Vasculopathy.

Transplant vasculopathy is characterized by endothelial apoptosis, which modulates the local microenvironment. Milk fat globule epidermal growth factor 8 (MFG-E8), which is released by apoptotic endothelial cells, limits tissue damage and inflammation by promoting anti-inflammatory macrophages. We aimed to study its role in transplant vasculopathy using the murine aortic allotransplantation model. BALB/c mice were transplanted with fully mismatched aortic transplants from MFG-E8 knockout (KO) or wild type (WT) C57BL/6J mice. Thereafter, mice received MFG-E8 (or vehicle) injections for 9 weeks prior to histopathological analysis of allografts for intimal proliferation (hematoxylin and eosin staining) and leukocyte infiltration assessment (immunofluorescence). Phenotypes of blood leukocytes and humoral responses were also evaluated (flow cytometry and ELISA). Mice receiving MFG-E8 KO aortas without MFG-E8 injections had the most severe intimal proliferation (p < 0.001). Administration of MFG-E8 decreased intimal proliferation, especially in mice receiving MFG-E8 KO aortas. Administration of MFG-E8 also increased the proportion of anti-inflammatory macrophages among graft-infiltrating macrophages (p = 0.003) and decreased systemic CD4+ and CD8+ T-cell activation (p < 0.001). An increase in regulatory T cells occurred in both groups of mice receiving WT aortas (p < 0.01). Thus, the analarmin MFG-E8 appears to be an important protein for reducing intimal proliferation in this murine model of transplant vasculopathy. MFG-E8 effects are associated with intra-allograft macrophage reprogramming and systemic T-cell activation dampening.

Risk of acute kidney injury associated with anti-pseudomonal and anti-MRSA antibiotic strategies in critically ill patients.

BACKGROUND: An increased risk of acute kidney injury (AKI) with the widely prescribed piperacillin-tazobactam(PTZ)-vancomycin combination in hospitalized patients has recently been reported, but evidence in ICU patients remain uncertain. This study evaluates the association between the exposure of various broad-spectrum antibiotic regimens with Pseudomonas and/or methicillin-resistance Staphylococcus aureus (MRSA) coverage and the risk of AKI in critically ill patients. METHODS AND FINDINGS: A retrospective cohort study based on the publicly available MIMIC-III database reporting hospitalization data from ICU patients from a large academic medical center between 2001 and 2012. Adult patients receiving an anti-pseudomonal or an anti-MRSA agent in the ICU for more than 24-hours were included. Non-PTZ anti-pseudomonal agents were compared to PTZ; non-vancomycin agents covering MRSA were compared to vancomycin; and their combinations were compared to the PTZ-vancomycin combination. The primary outcome was defined as new or worsening AKI within 7 days of the antibiotic exposure using an adjusted binomial generalized estimating equation. Overall, 18 510 admissions from 15 673 individual patients, cumulating 169 966 days of antibiotherapy were included. When compared to PTZ, exposure to another anti-pseudomonal agent was associated with lower AKI risk (OR, 0.85; 95% CI, 0.80-0.91; p < .001). When compared to vancomycin, exposure to another anti-MRSA was also associated with lower AKI risk (OR, 0.71; 95% CI, 0.64-0.80; p < .001). Finally, when compared to the PTZ-vancomycin combination, exposure to another regimen with a similar coverage was associated with an even lower risk (OR, 0.63; 95% CI; 0.54-0.73; p < .001). A sensitivity analysis of patients with high illness severity showed similar results. CONCLUSIONS: These results suggest that the risk of AKI in ICU patients requiring antibiotherapy may be partially mitigated by the choice of antibiotics administered. Further clinical trials are required to confirm these findings.

Single-dose replicating poxvirus vector-based RBD vaccine drives robust humoral and T cell immune response against SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic requires the continued development of safe, long-lasting, and efficacious vaccines for preventive responses to major outbreaks around the world, and especially in isolated and developing countries. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we characterize a temperature-stable vaccine candidate (TOH-Vac1) that uses a replication-competent, attenuated vaccinia virus as a vector to express a membrane-tethered spike receptor binding domain (RBD) antigen. We evaluate the effects of dose escalation and administration routes on vaccine safety, efficacy, and immunogenicity in animal models. Our vaccine induces high levels of SARS-CoV-2 neutralizing antibodies and favorable T cell responses, while maintaining an optimal safety profile in mice and cynomolgus macaques. We demonstrate robust immune responses and protective immunity against SARS-CoV-2 variants after only a single dose. Together, these findings support further development of our novel and versatile vaccine platform as an alternative or complementary approach to current vaccines.

Intermittent Convective Therapies in Patients with Acute Kidney Injury: A Systematic Review with Meta-Analysis.

INTRODUCTION: In critically ill patients requiring intermittent renal replacement therapy (RRT), the benefits of convective versus diffusive clearance remain uncertain. We conducted a systematic review and meta-analysis to determine the safety, clinical efficacy, and clearance efficiency of hemofiltration (HF) and hemodiafiltration (HDF) compared to hemodialysis (HD) in patients with acute kidney injury (AKI) receiving intermittent RRT. METHOD: We searched Medline, Embase, Cochrane Library, and PROSPERO. We included clinical trials and observational studies that reported the use of intermittent HF or HDF in adult patients with AKI. The following outcomes were included: mortality, renal recovery, clearance efficacy, intradialytic hemodynamic stability, circuit loss, and inflammation modulation. RESULTS: A total of 3,169 studies were retrieved and screened. Four randomized controlled trials and 4 observational studies were included (n: 615 patients). Compared with conventional HD, intermittent convective therapies had no effect on in-hospital mortality (relative risk, 1.23; 95% confidence interval (CI), 0.76-1.99), renal recovery at 30 days (RR, 0.98; 95% CI, 0.82-1.16), time-to-renal recovery (mean difference [MD], 0.77; 95% CI, -6.56 to 8.10), and number of dialysis sessions until renal recovery (MD, -1.34; 95% CI, -3.39 to 0.72). The overall quality of included studies was low, and dialysis parameters were suboptimal for all included studies. CONCLUSION: This meta-analysis suggests that there is no significant difference in short-term mortality and renal recovery in patients with severe AKI when treated with intermittent HF or HDF compared to conventional HD. This systematic review emphasizes the need for further trials evaluating optimal convective parameters in AKI patients treated with intermittent dialysis.

Exploring cannabidiol effects on inflammatory markers in individuals with cocaine use disorder: a randomized controlled trial.

Cocaine use disorder (CUD) is a major public health issue associated with physical, social, and psychological problems. Excessive and repeated cocaine use induces oxidative stress leading to a systemic inflammatory response. Cannabidiol (CBD) has gained substantial interest for its anti-inflammatory properties, safety, and tolerability profile. However, CBD anti-inflammatory properties have yet to be confirmed in humans. This exploratory study is based on a single-site randomized controlled trial that enrolled participants with CUD between 18 and 65 years, randomized (1:1) to daily receive either CBD (800 mg) or placebo for 92 days. The trial was divided into a 10-day detoxification (phase I) followed by a 12-week outpatient follow-up (phase II). Blood samples were collected from 48 participants at baseline, day 8, week 4, and week 12 and were analyzed to determine monocytes and lymphocytes phenotypes, and concentrations of various inflammatory markers such as cytokines. We used generalized estimating equations to detect group differences. Participants treated with CBD had lower levels of interleukin-6 (p = 0.017), vascular endothelial growth factor (p = 0.032), intermediate monocytes CD14+CD16+ (p = 0.024), and natural killer CD56negCD16hi (p = 0.000) compared with participants receiving placebo. CD25+CD4+T cells were higher in the CBD group (p = 0.007). No significant group difference was observed for B lymphocytes. This study suggests that CBD may exert anti-inflammatory effects in individuals with CUD.

Acute Tubulointerstitial Nephritis in a Patient on Anti-Programmed Death-Ligand 1 Triggered by COVID-19: A Case Report.

RATIONALE: Immune checkpoint inhibitors are monoclonal antibodies used in the treatment of various types of cancers. The downside of using such molecules is the potential risk of developing immune-related adverse events. Factors that trigger these autoimmune side effects are yet to be elucidated. Although any organ can potentially be affected, kidney involvement is usually rare. In this case report, we describe the first known instance of a patient being treated with an inhibitor of programmed death-ligand 1 (anti-PD-L1, a checkpoint inhibitor) who develops acute tubulointerstitial nephritis after contracting the severe acute respiratory syndrome coronavirus 2. PRESENTING CONCERNS OF THE PATIENT: A 62-year-old patient, on immunotherapy treatment for stage 4 squamous cell carcinoma, presents to the emergency department with symptoms of lower respiratory tract infection. Severe acute kidney injury is discovered with electrolyte imbalances requiring urgent dialysis initiation. Further testing reveals that the patient has contracted the severe acute respiratory syndrome coronavirus 2. DIAGNOSIS: A kidney biopsy was performed and was compatible with acute tubulointerstitial nephritis. INTERVENTIONS: The patient was treated with high dose corticosteroid therapy followed by progressive tapering. OUTCOMES: Rapid and sustained normalization of kidney function was achieved after completion of the steroid course. NOVEL FINDINGS: We hypothesize that the viral infection along with checkpoint inhibitor use has created a proinflammatory environment which led to a loss of self-tolerance to renal parenchyma. Viruses may play a more important role in the pathogenesis of autoimmunity in this patient population than was previously thought.

Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Cotransporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice.

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury, and sodium-glucose cotransporter 2 (Sglt2) expression in diabetic Akita Nrf2 -/-/Nrf2RPTC transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the SGLT2 promoter and human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-to-creatinine ratio, tubulointerstitial fibrosis, and Sglt2 expression in Akita Nrf2 -/-/Nrf2RPTC Tg mice compared with their Akita Nrf2 -/- littermates. In vitro, oltipraz or transfection of NRF2 cDNA stimulated SGLT2 expression and SGLT2 promoter activity in HK2, and these effects were inhibited by trigonelline or NRF2 siRNA. The deletion of the NRF2-responsive element (NRF2-RE) in the SGLT2 promoter abolished the stimulatory effect of oltipraz on SGLT2 promoter activity. NRF2 binding to the NRF2-RE of the SGLT2 promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.

National Preclinical Sepsis Platform: developing a framework for accelerating innovation in Canadian sepsis research.

Despite decades of preclinical research, no experimentally derived therapies for sepsis have been successfully adopted into routine clinical practice. Factors that contribute to this crisis of translation include poor representation by preclinical models of the complex human condition of sepsis, bias in preclinical studies, as well as limitations of single-laboratory methodology. To overcome some of these shortcomings, multicentre preclinical studies-defined as a research experiment conducted in two or more research laboratories with a common protocol and analysis-are expected to maximize transparency, improve reproducibility, and enhance generalizability. The ultimate objective is to increase the efficiency and efficacy of bench-to-bedside translation for preclinical sepsis research and improve outcomes for patients with life-threatening infection. To this end, we organized the first meeting of the National Preclinical Sepsis Platform (NPSP). This multicentre preclinical  research collaboration of Canadian sepsis researchers and stakeholders was established to study the pathophysiology of sepsis and accelerate movement of promising therapeutics into early phase clinical trials. Integrated knowledge translation and shared decision-making were emphasized to ensure the goals of the platform align with clinical researchers and patient partners. 29 participants from 10 independent labs attended and discussed four main topics: (1) objectives of the platform; (2) animal models of sepsis; (3) multicentre methodology and (4) outcomes for evaluation. A PIRO model (predisposition, insult, response, organ dysfunction) for experimental design was proposed to strengthen linkages with interdisciplinary researchers and key stakeholders. This platform represents an important resource for maximizing translational impact of preclinical sepsis research.

Identification of SARS-CoV-2-specific immune alterations in acutely ill patients.

Dysregulated immune profiles have been described in symptomatic patients infected with SARS-CoV-2. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of (a) patients hospitalized with acute SARS-CoV-2 infection, (b) patients of comparable age and sex hospitalized for another acute disease (SARS-CoV-2 negative), and (c) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that were similarly associated with acute SARS-CoV-2 infection and non-COVID-19-related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that were associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1+ mature/activated neutrophils, ALCAM+ monocytes, and CD38+CD8+ T cells). A subset of SARS-CoV-2-specific immune alterations correlated with disease severity, disease outcome at 30 days, and mortality. Our data provide an understanding of the immune dysregulation specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2-positive patients at risk of unfavorable outcomes and to uncover candidate molecules to investigate from a therapeutic perspective.

Estimating glomerular filtration rate in patients with acute kidney injury: a prospective multicenter study of diagnostic accuracy.

BACKGROUND: Estimating glomerular filtration rate (GFR) in acute kidney injury (AKI) is challenging, with limited data comparing estimated and gold standard methods to assess GFR. The objective of our study was to assess the performance of the kinetic estimated GFR (KeGFR) and Jelliffe equations to estimate GFR in AKI, using a radioisotopic method (technetium-diethylenetriaminepentaacetic acid) as a reference measure. METHODS: We conducted a prospective multicenter observational study in hospitalized patients with AKI. We computed the Jelliffe and KeGFR equations to estimate GFR and compared these estimations to measured GFR (mGFR) by a radioisotopic method. The performances were assessed by correlation, Bland-Altman plots and smoothed and linear regressions. We conducted stratified analyses by age and chronic kidney disease (CKD). RESULTS: The study included 119 patients with AKI, mostly from the intensive care unit (63%) and with Stage 1 AKI (71%). The eGFR obtained from the Jelliffe and KeGFR equations showed a good correlation with mGFR (r = 0.73 and 0.68, respectively). The median eGFR by the Jelliffe and KeGFR equations was less than the median mGFR, indicating that these equations underestimated the mGFR. On Bland-Altman plots, the Jelliffe and KeGFR equations displayed a considerable lack of agreement with mGFR, with limits of agreement >40 mL/min/1.73 m2. Both equations performed better in CKD and the KeGFR performed better in older patients. Results were similar across AKI stages. CONCLUSIONS: In our study, the Jelliffe and KeGFR equations had good correlations with mGFR; however, they had wide limits of agreement. Further studies are needed to optimize the prediction of mGFR with estimatation equations.

A Randomized Controlled Study to Evaluate the Safety and Reactogenicity of a Novel rVLP-Based Plant Virus Nanoparticle Adjuvant Combined with Seasonal Trivalent Influenza Vaccine Following Single Immunization in Healthy Adults 18-50 Years of Age.

Inactivated influenza vaccines efficacy is variable and often poor. We conducted a phase 1 trial (NCT02188810), to assess the safety and immunogenicity of a novel nanoparticle Toll-like receptor 7/8 agonist adjuvant (Papaya Mosaic Virus) at different dose levels combined with trivalent influenza vaccine in healthy persons 18-50 years of age. Hemagglutination-inhibition assays, antibody to Influenza A virus nucleoprotein and peripheral blood mononuclear cells for measurement of interferon-gamma ELISPOT response to influenza antigens, Granzyme B and IFNγ:IL-10 ratio were measured. The most common adverse events were transient mild to severe injection site pain and no safety signals were observed. A dose-related adjuvant effect was observed. Geometric mean hemagglutination-inhibition titers increased at day 28 in most groups and waned over time, but fold-antibody responses were poor in all groups. Cell mediated immunity results were consistent with humoral responses. The Papaya Mosaic Virus adjuvant in doses of 30 to 240 µg combined with reduced influenza antigen content was safe with no signals up to 3 years after vaccination. A dose-related adjuvant effect was observed and immunogenicity results suggest that efficacy study should be conducted in influenza antigen-naïve participants.

HSP90 Inhibitor Improves Lung Protection in Porcine Model of Donation After Circulatory Arrest.

BACKGROUND: Ischemia-reperfusion associated with prolonged warm ischemia during donation after circulatory death (DCD) induces acute lung injury. The objective of this study was to combine ex vivo lung perfusion (EVLP) and a heat shock protein-90 inhibitor (HSP90i) to recondition DCD organs and prevent primary graft dysfunction. METHODS: Pigs (55 to 65 kg) were anesthetized, ventilated, and hemodynamically monitored. Cardiac arrest was induced with potassium chloride, and animals were left nonventilated for 2 hours. Lungs were procured and perfused in an EVLP platform for 4 hours by using a cellular perfusate. In the study group, the perfusate contained HSP90i and its transport vehicle (n = 4). In the control group, the perfusate contained only the transport vehicle (n = 4). Gas exchange, airway pressures, and compliance were measured. Pulmonary edema was assessed by bronchoscopy and weight measurement. Lung biopsy samples were obtained for histologic analyses and protein expression measurements. RESULTS: The use of HSP90i reduced lung weight gain to 8.4 ± 3.4% vs 26.6 ± 6.2% in the control group (P < .05). There was reduced edema formation. The ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen at the end of EVLP was 423 ± 65 in the study group vs 339 ± 25 mm Hg in the control group, but this difference was not statistically significant. Lactate metabolism, pulmonary vascular resistance, and pulmonary arterial pressure improved during EVLP with the use of the HSP90i. CONCLUSIONS: The use of HSP90i with EVLP improves the lung reconditioning process. Further research is required to confirm whether these findings translate to benefit once transplanted and observed in vivo. Successful pharmacologic inhibitors may expand the donor pool in the context of DCD donors.