ABSTRACT
Machine vision technology has taken huge leaps in recent years, and is now becoming an integral part of various intelligent systems, including autonomous vehicles and robotics. Usually, visual information is captured by a frame-based camera, converted into a digital format and processed afterwards using a machine-learning algorithm such as an artificial neural network (ANN)1. The large amount of (mostly redundant) data passed through the entire signal chain, however, results in low frame rates and high power consumption. Various visual data preprocessing techniques have thus been developed2-7 to increase the efficiency of the subsequent signal processing in an ANN. Here we demonstrate that an image sensor can itself constitute an ANN that can simultaneously sense and process optical images without latency. Our device is based on a reconfigurable two-dimensional (2D) semiconductor8,9 photodiode10-12 array, and the synaptic weights of the network are stored in a continuously tunable photoresponsivity matrix. We demonstrate both supervised and unsupervised learning and train the sensor to classify and encode images that are optically projected onto the chip with a throughput of 20 million bins per second.
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BACKGROUND: The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so new vaccination strategies are needed in this population. METHODS: Adult SOT recipients from 9 transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. Patients were randomized (1:1:1) to a MF59-adjuvanted or a high-dose vaccine (intervention), or a standard vaccine (control), with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least 1 vaccine strain at 28 days postvaccination. Secondary outcomes included polymerase chain reaction-confirmed influenza and vaccine reactogenicity. RESULTS: A total of 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n = 198; MF59-adjuvanted, n = 205; high-dose, n = 195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs standard vaccine, 0.20; 97.5% confidence interval [CI], .12-1); P < .001; difference in high-dose vs standard vaccine, 0.24 [95% CI, .16-1]; P < .001; difference in MF59-adjuvanted vs standard vaccine, 0.17 [97.5% CI, .08-1]; P < .001). Influenza occurred in 6% of the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. CONCLUSIONS: In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT03699839.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Organ Transplantation , Adult , Humans , Influenza, Human/prevention & control , Switzerland , Antibodies, Viral , Polysorbates/adverse effects , Squalene/adverse effects , Adjuvants, Immunologic , Hemagglutination Inhibition Tests , Organ Transplantation/adverse effectsABSTRACT
BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. METHODS: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection. CLINICAL TRIALS REGISTRATION: NCT02538172.
Subject(s)
Cytomegalovirus Infections , Organ Transplantation , Humans , Cytomegalovirus , Antiviral Agents/therapeutic use , Monitoring, Immunologic , Cytomegalovirus Infections/diagnosis , Transplant Recipients , Organ Transplantation/adverse effects , Ganciclovir/therapeutic useABSTRACT
BACKGROUND: Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients. METHODS: The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m2 and 89 mL/min per 1·73 m2, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996. FINDINGS: Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m2 per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death. INTERPRETATION: In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. FUNDING: Swiss National Science Foundation.
Subject(s)
Acidosis , COVID-19 , Kidney Transplantation , Adult , Humans , Male , Female , Adolescent , Sodium Bicarbonate/therapeutic use , Bicarbonates/therapeutic use , Switzerland , Kidney Transplantation/adverse effects , Single-Blind Method , Double-Blind Method , SARS-CoV-2 , Acidosis/drug therapy , Acidosis/etiology , Treatment OutcomeABSTRACT
OBJECTIVES: Peripheral venoarterial extracorporeal membrane oxygenation (ECMO) with femoral access is obtained through unilateral or bilateral groin cannulation. Whether one cannulation strategy is associated with a lower risk for limb ischemia remains unknown. We aim to assess if one strategy is preferable. DESIGN: A retrospective cohort study based on the Extracorporeal Life Support Organization registry. SETTING: ECMO centers worldwide included in the Extracorporeal Life Support Organization registry. PATIENTS: All adult patients (≥ 18 yr) who received peripheral venoarterial ECMO with femoral access and were included from 2014 to 2020. INTERVENTIONS: Unilateral or bilateral femoral cannulation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of limb ischemia defined as a composite endpoint including the need for a distal perfusion cannula (DPC) after 6 hours from implantation, compartment syndrome/fasciotomy, amputation, revascularization, and thrombectomy. Secondary endpoints included bleeding at the peripheral cannulation site, need for vessel repair, vessel repair after decannulation, and in-hospital death. Propensity score matching was performed to account for confounders. Overall, 19,093 patients underwent peripheral venoarterial ECMO through unilateral ( n = 11,965) or bilateral ( n = 7,128) femoral cannulation. Limb ischemia requiring any intervention was not different between both groups (bilateral vs unilateral: odds ratio [OR], 0.92; 95% CI, 0.82-1.02). However, there was a lower rate of compartment syndrome/fasciotomy in the bilateral group (bilateral vs unilateral: OR, 0.80; 95% CI, 0.66-0.97). Bilateral cannulation was also associated with lower odds of cannulation site bleeding (bilateral vs unilateral: OR, 0.87; 95% CI, 0.76-0.99), vessel repair (bilateral vs unilateral: OR, 0.55; 95% CI, 0.38-0.79), and in-hospital mortality (bilateral vs unilateral: OR, 0.85; 95% CI, 0.81-0.91) compared with unilateral cannulation. These findings were unchanged after propensity matching. CONCLUSIONS: This study showed no risk reduction for overall limb ischemia-related events requiring DPC after 6 hours when comparing bilateral to unilateral femoral cannulation in peripheral venoarterial ECMO. However, bilateral cannulation was associated with a reduced risk for compartment syndrome/fasciotomy, lower rates of bleeding and vessel repair during ECMO, and lower in-hospital mortality.
Subject(s)
Catheterization, Peripheral , Compartment Syndromes , Extracorporeal Membrane Oxygenation , Adult , Humans , Extracorporeal Membrane Oxygenation/methods , Retrospective Studies , Hospital Mortality , Catheterization, Peripheral/methods , Risk Factors , Ischemia/etiology , Femoral ArteryABSTRACT
PMT is a protein toxin produced by Pasteurella multocida serotypes A and D. As causative agent of atrophic rhinitis in swine, it leads to rapid degradation of the nasal turbinate bone. The toxin acts as a deamidase to modify a crucial glutamine in heterotrimeric G proteins, which results in constitutive activation of the G proteins and permanent stimulation of numerous downstream signaling pathways. Using a lentiviral based genome wide CRISPR knockout screen in combination with a lethal toxin chimera, consisting of full length inactive PMT and the catalytic domain of diphtheria toxin, we identified the LRP1 gene encoding the Low-Density Lipoprotein Receptor-related protein 1 as a critical host factor for PMT function. Loss of LRP1 reduced PMT binding and abolished the cellular response and deamidation of heterotrimeric G proteins, confirming LRP1 to be crucial for PMT uptake. Expression of LRP1 or cluster 4 of LRP1 restored intoxication of the knockout cells. In summary our data demonstrate LRP1 as crucial host entry factor for PMT intoxication by acting as its primary cell surface receptor.
Subject(s)
Heterotrimeric GTP-Binding Proteins , Pasteurella multocida , Animals , Swine , Low Density Lipoprotein Receptor-Related Protein-1/genetics , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Carrier Proteins/metabolism , Clustered Regularly Interspaced Short Palindromic Repeats , Pasteurella multocida/genetics , Pasteurella multocida/metabolism , Heterotrimeric GTP-Binding Proteins/genetics , Heterotrimeric GTP-Binding Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolismABSTRACT
PURPOSE OF REVIEW: The aim of this review is to discuss the concept of renal functional reserve (RFR) and its potential relevance in clinical practice. RECENT FINDINGS: The RFR is a measure of the change in glomerular filtration rate (GFR) from baseline to a peak value when the kidney is stimulated to increase its function. This concept has a strong physiologic basis in nephrology and the presence, magnitude or absence of RFR capacity may have prognostic significance in many clinical scenarios where individuals are at risk of hyperfiltration or kidney dysfunction. Unlike in other medical specialties, where organ reserve function is reliably measurable and used routinely, measurement of RFR in nephrology has not been integrated into clinical care. Methodologic challenges including standardization of methods to stimulate GFR and the ability of measures of GFR to discriminate acute dynamic changes in GFR upon kidney stimulation have hampered the robustness and use of RFR measurements in research and clinical care. SUMMARY: Given the emergence of many new disease-modifying therapies in nephrology, it is imperative that we move forward and develop more robust tools to further our understanding of kidney physiology and pathophysiology, such as the RFR, which should be integrated into research and clinical care to support optimal personalization of therapeutic kidney care strategies.
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Nephrology , Humans , Kidney , Glomerular Filtration Rate/physiologyABSTRACT
Uncertainties on the intensive care unit (ICU) regarding the eligibility of a patient to be a potential deceased organ donor may prevent their referral and enrolment in the pathway for organ donation. Healthcare staff may exclude potential donors for medical reasons, which are no longer applicable. Hence, Swisstransplant implemented a digital donor evaluation tool (DET) in 2021, which allows the local hospital's organ donation coordinator to send a direct request to medical advisors (MA) of the organ procurement organization before excluding potential donors. All 156 requests entered in 2022 were analyzed. 117 patients (75.0%) were primarily accepted by the MA as potential donors. Of those 60 patients (51.3%) became actual organ donors. Main reasons for using the DET were questions regarding malignancies (n = 33, 21.2%), infectious diseases (n = 35, 22.4%) and age/co-morbidities (n = 34, 21.8%). The average age of the actual "DET donor" compared to the regularly enrolled, actual "Non-DET donor" was 65.3 ± 15.8 vs. 56.8 ± 17.5 years, respectively (p = 0.008). On average 1.9 ± 1.1 organs compared to 3.2 ± 1.3 organs were retrieved from DET vs. Non-DET donors. In summary, this new digital donor evaluation tool supports reporting and facilitates eligibility decisions in uncertain, complex donor cases, potentially increasing the number of organ donations.
Subject(s)
Intensive Care Units , Tissue Donors , Tissue and Organ Procurement , Humans , Middle Aged , Male , Female , Aged , Tissue and Organ Procurement/methods , Adult , Donor Selection/methods , Organ TransplantationABSTRACT
BACKGROUND: Infection-associated hemolytic uremic syndrome (IA-HUS), most often due to infection with Shiga toxin-producing bacteria, mainly affects young children. It can be acutely life-threatening, as well as cause long-term kidney and neurological morbidity. Specific treatment with proven efficacy is lacking. Since activation of the alternative complement pathway occurs in HUS, the monoclonal C5 antibody eculizumab is often used off-label once complications, e.g., seizures, occur. Eculizumab is prohibitively expensive and carries risk of infection. Its utility in IA-HUS has not been systematically studied. This systematic review aims to present, summarize, and evaluate all currently available data regarding the effect of eculizumab administration on medium- to long-term outcomes (i.e., outcomes after the acute phase, with a permanent character) in IA-HUS. METHODS: PubMed, Embase, and Web of Science were systematically searched for studies reporting the impact of eculizumab on medium- to long-term outcomes in IA-HUS. The final search occurred on March 2, 2022. Studies providing original data regarding medium- to long-term outcomes in at least 5 patients with IA-HUS, treated with at least one dose of eculizumab during the acute illness, were included. No other restrictions were imposed regarding patient population. Studies were excluded if data overlapped substantially with other studies, or if outcomes of IA-HUS patients were not reported separately. Study quality was assessed using the ROBINS-I tool for risk of bias in non-randomized studies of interventions. Data were analyzed descriptively. RESULTS: A total of 2944 studies were identified. Of these, 14 studies including 386 eculizumab-treated patients met inclusion criteria. All studies were observational. Shiga toxin-producing E. coli (STEC) was identified as the infectious agent in 381 of 386 patients (98.7%), effectively limiting the interpretation of the data to STEC-HUS patients. Pooling of data across studies was not possible. No study reported a statistically significant positive effect of eculizumab on any medium- to long-term outcome. Most studies were, however, subject to critical risk of bias due to confounding, as more severely ill patients received eculizumab. Three studies attempted to control for confounding through patient matching, although residual bias persisted due to matching limitations. DISCUSSION: Current observational evidence does not permit any conclusion regarding the impact of eculizumab in IA-HUS given critical risk of bias. Results of randomized clinical trials are eagerly awaited, as new therapeutic strategies are urgently needed to prevent long-term morbidity in these severely ill patients. SYSTEMATIC REVIEW REGISTRATION NUMBER: OSF Registries, MSZY4, Registration DOI https://doi.org/10.17605/OSF.IO/MSZY4 .
Subject(s)
Antibodies, Monoclonal, Humanized , Escherichia coli Infections , Hemolytic-Uremic Syndrome , Shiga-Toxigenic Escherichia coli , Child , Humans , Child, Preschool , Hemolytic-Uremic Syndrome/microbiology , Kidney , Escherichia coli Infections/complications , Shiga Toxins/therapeutic useABSTRACT
OBJECTIVES: The prostatic urethral lift (PUL) has been used as a minimally invasive surgery for benign prostatic hyperplasia (BPH) since April 2022 in Japan. This study evaluated the initial outcomes and surgical techniques of PUL for BPH. METHODS: In this prospective, single-center study, indications were based on the proper use guidelines for PUL in Japan. Preoperative patient status, postoperative progress at 1 and 3 months, and perioperative complications were evaluated. The surgical technique was changed twice, and the subgroup analysis and technique were evaluated. RESULTS: Of the 50 patients who underwent surgeries performed by a single surgeon, the median age and prostate volume were 71 years and 42.0 mL, respectively. Furthermore, the median operative time and number of implants used were 20 min and 5, respectively. No postoperative fever or severe hematuria requiring reoperation occurred. All patients were discharged from the hospital the day following the PUL, as scheduled. Postoperative International Prostate Symptom Score, quality of life score, maximum flow rate, and postvoid residual volume at 1 and 3 months were significantly improved compared with the preoperative values. A significant improvement in maximum flow rate was observed in the subgroup analysis from 1 month postoperatively in the group with an anterior channel creation focus. CONCLUSIONS: PUL is effective and safe in cases with prostate volumes of <100 mL. Lifting the bladder neck is important for opening an anterior prostatic urethral channel and improving urinary function during the early postoperative period.
Subject(s)
Prostatic Hyperplasia , Quality of Life , Urethra , Humans , Male , Prostatic Hyperplasia/surgery , Aged , Prospective Studies , Japan/epidemiology , Urethra/surgery , Treatment Outcome , Middle Aged , Aged, 80 and over , Prostate/surgery , Prostate/pathology , Minimally Invasive Surgical Procedures/methods , Minimally Invasive Surgical Procedures/adverse effects , Operative Time , Postoperative Complications/etiology , Postoperative Complications/epidemiologyABSTRACT
Steviol and isosteviol were prepared from the commercially available sweetener stevioside and converted into lipophilic F16 hybrids. Their cytotoxicity was determined in SRB assays and showed to depend on both the substitution pattern of the aromatic substituent as well as on the spacer length. Therefore, compound 25 held an IC50 (A2780) of 180 nM, thus surpassing the activity of comparable rhodamine hybrids. Several of the compounds were also able to overcome drug resistance in the A2780/A2780cis model. Extra staining experiments showed a similar subcellular accumulation pattern of the F16 hybrids as a well-established mitocan, hence proving preferential mitochondrial accumulation but also some other accumulation in other cellular areas.
Subject(s)
Diterpenes, Kaurane , Ovarian Neoplasms , Female , Humans , Cell Line, Tumor , MitochondriaABSTRACT
During early development, juvenile animals need to acquire a diverse behavioural repertoire to interact with their environment. The ontogeny of animal behaviour, is paced by the motivation to improve, e.g. internal clocks, and limited by external constraints, e.g. weather conditions. We here evaluate how naive Egyptian vultures (Neophron percnopterus) improve in locomotor performance, measured as daily maximum displacement, prior to their first migration under three different time constraint regimes: we compared wild hatched vultures, migrating one month after fledging, with captive-hatched vultures, released in spring four months or in winter nine months before migration. We found that the time until migration paced the development of movement behaviour: wild birds rapidly increased displacement distances within the first two weeks after fledging, while spring and winter released vultures delayed movement increases by two and four months, respectively. Under relaxed time constraints captive-hatched vultures displayed diverse functional forms of performance enhancements and therefore great variability in individual ontogeny of movement behaviour. While weather conditions in winter could limit flight movements, some birds indeed moved immediately after their release, indicating that weather may not be limiting. Our findings promote the idea that relaxed ecological constraints could uncover hidden phenotypic flexibility in ontogeny, which could present a greater potential for adaptability under environmental change than currently expected.
Subject(s)
Birds , Falconiformes , Animals , Animals, WildABSTRACT
Animal movement behaviours are shaped by diverse factors, including resource availability and human impacts on the landscape. We generated home range estimates and daily movement rate estimates for 149 giraffe (Giraffa spp.) from all four species across Africa to evaluate the effects of environmental productivity and anthropogenic disturbance on space use. Using the continuous time movement modelling framework and a novel application of mixed effects meta-regression, we summarized overall giraffe space use and tested for the effects of resource availability and human impact on 95% autocorrelated kernel density estimate (AKDE) size and daily movement. The mean 95% AKDE was 359.9 km2 and the mean daily movement was 14.2 km, both with marginally significant differences across species. We found significant negative effects of resource availability, and significant positive effects of resource heterogeneity and protected area overlap on 95% AKDE size. There were significant negative effects of overall anthropogenic disturbance and positive effects of the heterogeneity of anthropogenic disturbance on daily movements and 95% AKDE size. Our results provide unique insights into the interactive effects of resource availability and anthropogenic development on the movements of a large-bodied browser and highlight the potential impacts of rapidly changing landscapes on animal space-use patterns.
Subject(s)
Ecosystem , Giraffes , Humans , Animals , Anthropogenic Effects , Movement , AfricaABSTRACT
This is a report from a one-week workshop held in Athens, Greece in July of 2022. The workshop aimed to identify emerging concepts relevant to the fundamentals of immune regulation and areas for future research. Theories of immune regulation emphasize the role of T cell help or co-stimulation (signal 2). The workshop participants considered how new data on the characteristics of agonist antigens, the role of the antigen receptor signals (signal 1) in driving fate decisions, the effect of energetics on immunity and a better understanding of class-control in the immune response, may impact theories of immune regulation. These ideas were discussed in the context of tumour immunology, autoimmunity, pregnancy and transplantation. Here we present the discussions as a narrative of different viewpoints to allow the reader to join the conversation. These discussions highlight the evolving understanding of the nature of specific antigen recognition and how both antigen-specific and non-specific mechanisms impact immune responses.
Subject(s)
Antigens , T-Lymphocytes , Humans , AutoimmunityABSTRACT
Immune-responsiveness to SARS-CoV-2 mRNA vaccination is reduced in kidney transplant recipients (KTRs). Previous reports point to a role of mycophenolic acid (MPA). Our observational cohort study included all KTRs at University Hospital Zurich receiving two SARS-CoV-2 mRNA vaccine doses more than 6 months post-transplantation, who were assessed by measuring anti-spike immunoglobulin G (IgG). We applied principles of therapeutic drug monitoring (TDM) to correlate MPA exposure and lymphocyte counts with SARS-CoV-2 IgG. MPA trough levels differ largely among KTRs with a median of 3.1 mg/L (range 0.7-9.5 mg/L). 34 of 84 KTRs (40%) developed positive SARS-CoV-2 IgG after two vaccine doses. KTRs who developed positive SARS-CoV-2 IgG showed significantly higher eGFR (p < 0.001), lower MPA trough levels (p < 0.001) and higher CD19+ lymphocytes (p < 0.001). MPA trough levels <2.5 mg/l and CD19+ lymphocytes >40/µl identify KTRs with seroconversion. Upon logistic regression, MPA trough levels <2.5 mg/L were associated with a 7-fold (CI 95%: 1.589-29.934) and ciclosporin use with a 6-fold (CI 95%: 1.148-30.853) increase in the odds of seroconversion. Our study indicates that immune-responsiveness to SARS-CoV-2 mRNA vaccines correlates with MPA exposure measured by MPA trough level but argues against a class effect of MPA. TDM-guided MPA dosing may be a strategy to increase seroconversion rate.
Subject(s)
COVID-19 , Kidney Transplantation , Humans , COVID-19 Vaccines , Mycophenolic Acid/therapeutic use , SARS-CoV-2 , Drug Monitoring , COVID-19/prevention & control , Transplant Recipients , Immunoglobulin G , Antibodies, ViralABSTRACT
BACKGROUND: Before the availability of mRNA vaccines, many transplant centers chose to significantly reduce maintenance immunosuppression in kidney transplant recipients (KTRs) with SARS-CoV-2 infection. The extent to which this increases the risk of allosensitization is unclear. METHODS: In this observational cohort study, we analyzed 47 KTRs from March 2020 to February 2021 who underwent substantial reduction of maintenance immunosuppression during SARS-CoV-2 infection. KTRs were followed at 6 and 18 months concerning the development of de novo donor-specific anti-HLA (human leukocyte antigen) antibodies (DSA). The HLA-derived epitope mismatches were calculated using the predicted indirectly recognizable HLA-epitopes (PIRCHE-II) algorithm. RESULTS: In total, 14 of 47 KTRs (30%) developed de novo HLA antibodies after the reduction of maintenance immunosuppression. KTRs with higher total PIRCHE-II scores and higher PIRCHE-II scores for the HLA-DR locus were more likely to develop de novo HLA antibodies (p = .023, p = .009). Furthermore, 4 of the 47 KTRs (9%) developed de novo DSA after reduction of maintenance immunosuppression, which were exclusively directed against HLA-class II antigens and also showed higher PIRCHE-II scores for HLA-class II. The cumulative mean fluorescence intensity of 40 KTRs with preexisting anti-HLA antibodies and 13 KTRs with preexisting DSA at the time of SARS-CoV-2 infection remained stable after the reduction of maintenance immunosuppression (p = .141; p = .529). CONCLUSIONS: Our data show that the HLA-derived epitope mismatch load between donor and recipient influences the risk of de novo DSA development when immunosuppression is temporarily reduced. Our data further suggest that reduction in immunosuppression should be made more cautiously in KTRs with high PIRCHE-II scores for HLA-class II antigens.
Subject(s)
COVID-19 , Kidney Transplantation , Humans , Epitopes , Kidney Transplantation/adverse effects , Graft Rejection/prevention & control , Histocompatibility Testing , SARS-CoV-2 , HLA Antigens , Antibodies , Tissue Donors , Immunosuppression Therapy , Histocompatibility Antigens Class II , Transplant Recipients , Graft SurvivalABSTRACT
Repulsive guidance molecules (RGMs) are cell surface proteins that regulate the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. They control fundamental biological processes, such as migration and differentiation by direct interaction with the Neogenin (NEO1) receptor and function as coreceptors for the bone morphogenetic protein (BMP)/growth differentiation factor (GDF) family. We determined crystal structures of all three human RGM family members in complex with GDF5, as well as the ternary NEO1-RGMB-GDF5 assembly. Surprisingly, we show that all three RGMs inhibit GDF5 signaling, which is in stark contrast to RGM-mediated enhancement of signaling observed for other BMPs, like BMP2. Despite their opposite effect on GDF5 signaling, RGMs occupy the BMP type 1 receptor binding site similar to the observed interactions in RGM-BMP2 complexes. In the NEO1-RGMB-GDF5 complex, RGMB physically bridges NEO1 and GDF5, suggesting cross-talk between the GDF5 and NEO1 signaling pathways. Our crystal structures, combined with structure-guided mutagenesis of RGMs and BMP ligands, binding studies, and cellular assays suggest that RGMs inhibit GDF5 signaling by competing with GDF5 type 1 receptors. While our crystal structure analysis and in vitro binding data initially pointed towards a simple competition mechanism between RGMs and type 1 receptors as a possible basis for RGM-mediated GDF5 inhibition, further experiments utilizing BMP2-mimicking GDF5 variants clearly indicate a more complex mechanism that explains how RGMs can act as a functionality-changing switch for two structurally and biochemically similar signaling molecules.
Subject(s)
Cell Adhesion Molecules, Neuronal/metabolism , GPI-Linked Proteins/metabolism , Growth Differentiation Factor 5/metabolism , Hemochromatosis Protein/metabolism , Nerve Tissue Proteins/metabolism , Bone Morphogenetic Protein 2/metabolism , Bone Morphogenetic Protein 2/ultrastructure , Cell Adhesion Molecules, Neuronal/ultrastructure , Crystallography, X-Ray , GPI-Linked Proteins/ultrastructure , Growth Differentiation Factor 5/ultrastructure , Hemochromatosis Protein/ultrastructure , Membrane Proteins/metabolism , Membrane Proteins/ultrastructure , Nerve Tissue Proteins/ultrastructure , Protein Domains , Recombinant Proteins/metabolism , Recombinant Proteins/ultrastructure , Signal TransductionABSTRACT
INTRODUCTION: There is increasing evidence for extracorporeal cardiopulmonary resuscitation (ECPR) as a rescue therapy for selected patients in refractory cardiac arrest (CA). Besides patient selection, the control of reperfusion parameters is of eminent importance. Especially in out-of-hospital CA, monitoring and individualized, targeted reperfusion remains a great challenge for emergency personnel. The CARL® system is designed to enable an early control of a variety of reperfusion parameters and to pursue a targeted reperfusion strategy in ECPR. CASE PRESENTATION: We report the first 10 ECPR applications of the CARL® system in Regensburg, Germany. Early blood gas analysis, oxygen titration and pressure monitoring were feasible and enabled an individualized and targeted reperfusion strategy in all patients. After suffering from refractory CA and prolonged resuscitation attempts, five out of the first 10 patients survived and were successfully discharged from the hospital (CPC one on hospital discharge). CONCLUSION: Application of the CARL® system contributed to early monitoring and control of reperfusion parameters. Whether targeted ECPR may have the potential to improve outcomes in refractory OHCA remains the subject of future investigations.
Subject(s)
Cardiopulmonary Resuscitation , Extracorporeal Membrane Oxygenation , Out-of-Hospital Cardiac Arrest , Humans , Out-of-Hospital Cardiac Arrest/therapy , Reperfusion , Oxygen , Retrospective StudiesABSTRACT
BACKGROUND: Adverse neurological events during extracorporeal membrane oxygenation (ECMO) are common and may be associated with devastating consequences. Close monitoring, early identification and prompt intervention can mitigate early and late neurological morbidity. Neuromonitoring and neurocognitive/neurodevelopmental follow-up are critically important to optimize outcomes in both adults and children. OBJECTIVE: To assess current practice of neuromonitoring during ECMO and neurocognitive/neurodevelopmental follow-up after ECMO across Europe and to inform the development of neuromonitoring and follow-up guidelines. METHODS: The EuroELSO Neurological Monitoring and Outcome Working Group conducted an electronic, web-based, multi-institutional, multinational survey in Europe. RESULTS: Of the 211 European ECMO centres (including non-ELSO centres) identified and approached in 23 countries, 133 (63%) responded. Of these, 43% reported routine neuromonitoring during ECMO for all patients, 35% indicated selective use, and 22% practiced bedside clinical examination alone. The reported neuromonitoring modalities were NIRS (n = 88, 66.2%), electroencephalography (n = 52, 39.1%), transcranial Doppler (n = 38, 28.5%) and brain injury biomarkers (n = 33, 24.8%). Paediatric centres (67%) reported using cranial ultrasound, though the frequency of monitoring varied widely. Before hospital discharge following ECMO, 50 (37.6%) reported routine neurological assessment and 22 (16.5%) routinely performed neuroimaging with more paediatric centres offering neurological assessment (65%) as compared to adult centres (20%). Only 15 (11.2%) had a structured longitudinal follow-up pathway (defined followup at regular intervals), while 99 (74.4%) had no follow-up programme. The majority (n = 96, 72.2%) agreed that there should be a longitudinal structured follow-up for ECMO survivors. CONCLUSIONS: This survey demonstrated significant variability in the use of different neuromonitoring modalities during and after ECMO. The perceived importance of neuromonitoring and follow-up was noted to be very high with agreement for a longitudinal structured follow-up programme, particularly in paediatric patients. Scientific society endorsed guidelines and minimum standards should be developed to inform local protocols.
Subject(s)
Brain Injuries , Extracorporeal Membrane Oxygenation , Humans , Adult , Child , Extracorporeal Membrane Oxygenation/adverse effects , EuropeABSTRACT
1,5-Diazacyclooctane was prepared by a simple synthetic sequence and coupled to pentacyclic triterpenoic acids oleanolic acid, ursolic acid, betulinic acid, platanic acid, and asiatic acid; these amides were activated with oxalyl chloride and reacted with rhodamine B or rhodamine 101 to yield conjugates. The conjugates were screened in SRB assays with various human breast cancer cell lines (MDA-MB-231, HS578T, MCF-7, and T47D) and found to exert cytotoxic activity even at a low concentration. Therefore, for an asiatic acid rhodamine 101 conjugate (28), an IC50 = 0.60 nM was determined and found to induce apoptosis in MDA-MB-231 and HS578T cells. Extra experiments showed the compound to act as a mitocan and to induce inhibition of proliferation or growth arrest in MDA-MB-231 cells at lower doses followed by an induction of apoptosis at higher doses. Furthermore, differential responses to proliferation inhibition and apoptosis induction may explain differential sensitivity of mammary cell lines to compound 28.