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Background. In islet transplantation, the use of dynamic hypothermic preservation techniques is a current challenge. This study compares the efficacy of 3 pancreas preservation methods: static cold storage, hypothermic machine perfusion (HMP), and oxygenated HMP. Methods. A standardized human pancreas split model was employed using discarded organs from both donation after brain death (n = 15) and donation after circulatory death (DCD) (n = 9) donors. The pancreas head was preserved using static cold storage (control group), whereas the tail was preserved using the 3 different methods (study group). Data on donor characteristics, pancreas histology, isolation outcomes, and functional tests of isolated islets were collected. Results. Insulin secretory function evaluated by calculating stimulation indices and total amount of secreted insulin during high glucose stimulation (area under the curve) through dynamic perifusion experiments was similar across all paired groups from both DCD and donation after brain death donors. In our hands, islet yield (IEQ/g) from the pancreas tails used as study groups was higher than that of the pancreas heads as expected although this difference did not always reach statistical significance because of great variability probably due to suboptimal quality of organs released for research purposes. Moreover, islets from DCD organs had greater purity than controls (P ≤ 0.01) in the HMP study group. Furthermore, our investigation revealed no significant differences in pancreas histology, oxidative stress markers, and apoptosis indicators. Conclusions. For the first time, a comparative analysis was conducted, using a split model, to assess the effects of various preservation methods on islets derived from pancreas donors. Nevertheless, no discernible variances were observed in terms of islet functionality, histological attributes, or isolation efficacy. Further investigations are needed to validate these findings for clinical application.

Transparent exopolymer particles (TEP) and Coomassie stainable particles (CSP), two prominent classes of gel−like particles in the ocean primarily produced by phytoplankton, play crucial roles in ecological and biogeochemical processes, influencing microbial nutrition, growth, and particle aggregation. The distribution of these particles is intricately linked to the spatiotemporal dynamics of phytoplankton. Mesoscale cyclonic eddies (CEs) are known to stimulate phytoplankton growth and influence particle transport, but their effects on TEP and CSP remain to be determined. In the Eastern Tropical North Atlantic (ETNA), we examined three CEs: one off the Mauritanian coast during summer (Mau), one offshore during winter (Sal), and another near Brava island during winter. Mau and Brava CEs were in their intensification/maturity phase, while the Sal CE was in its decay phase. Both TEP and CSP concentrations correlated with primary productivity, but TEP increased with chlorophyll−a concentration, whereas elevated CSP coincided also with the highest abundance of pico−nanophytoplankton (

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery.

Background and aimsHuman islet preparations designated for research exhibit diverse insulin-secretory profiles. This study aims to assess the impact of donor- and isolation-related factors on in vitro islet secretory function.MethodsA retrospective analysis of 46 isolations from 23 pancreata discarded for clinical transplantation was conducted. In vitro islet secretory function tests were performed on Day 1 and Day 7 of culture. Linear mixed-effects models (LMMs) were employed to investigate the relationships between various predictors characterizing the patient and donor characteristics as well as the isolation effectiveness and two functional outcomes including the islet stimulation index (SI) and area under the insulin curve (AUC). Fixed effects were introduced to represent the main effects of each predictor, and backward elimination was utilized to select the most significant fixed effects for the final model. Interaction effects between the timepoint (Day 7 vs. Day 1) and the predictors were also evaluated to assess whether predictors were associated with the temporal evolution of SI and AUC. Fold-change (Fc) values associated with each predictor were obtained by exponentiating the corresponding coefficients of the models, which were built on log-transformed outcomes.ResultsAnalysis using LMMs revealed that donor body mass index (BMI) (Fc = 0.961, 95% CI = 0.927–0.996, p = 0.05), donor gender (female vs. male, Fc = 0.702, 95% CI = 0.524–0.942, p = 0.04), and donor hypertension (Fc = 0.623, 95% CI = 0.466–0.832, p=

Mesoscale eddies modulate the ocean's physical, chemical, and biological properties. In cyclonic eddies (CEs), nutrient upwelling can stimulate primary production by phytoplankton. Yet, how this locally enhanced autotrophic production affects heterotrophy and consequently the metabolic balance between the synthesis and the consumption of dissolved organic matter (DOM) remains largely unknown. To fill this gap, we investigated the horizontal and vertical variability in auto- and heterotrophic microbial activity (biomass production and respiration) within a CE that formed off Mauritania and along the ∼ 900 km zonal corridor between Mauritania and the Cape Verde islands in the Eastern Tropical North Atlantic (ETNA). Our results show how the physical disturbances caused by the CE affected the biomass distribution of phyto- and bacterioplankton and their metabolic activities. The injection of nutrients into the sunlit surface resulted in enhanced autotrophic pico- and nanoplankton abundance and generally increased autotrophic activity as indicated by chlorophyll a (Chl a) concentration, primary production (PP), and extracellular release rates. However, the detailed eddy survey also revealed an uneven distribution of these variables with, for example, the highest Chl a concentrations and PP rates occurring near and just beyond the CE's periphery. The heterotrophic bacterial activity was similarly variable. Optode-based community respiration (CR), bacterial respiration (BR) estimates, and bacterial biomass production (BP) largely followed the trends of PP and Chl a. Thus, a submesoscale spatial mosaic of heterotrophic bacterial abundance and activities occurred within the CE that was closely related to variability in autotrophic production. Consistent with this, we found a significant positive correlation between concentrations of semi-labile dissolved organic carbon (SL-DOC; here the sum of dissolved hydrolysable amino acids and dissolved combined carbohydrates) and BR estimates. Extracellular release of carbon as indicated by primary production of dissolved organic carbon (PPDOC) was variable with depth and laterally and not always sufficient to compensate the bacterial carbon demand (BCD: BR + BP), with PPDOC accounting for between 28 % and 110 % of the BCD. Bacterial growth efficiency (BGE: BP / BCD) ranged between 1.7 % and 18.2 %. We estimated the metabolic state to establish whether the CE was a source or a sink of organic carbon. We showed that the CE carried a strong autotrophic signal in the core (PP / CR > 1). Our results suggest that submesoscale (0–10 km) processes lead to highly variable metabolic activities in both photoautotrophic and heterotrophic microorganisms. Overall, we revealed that the CEs not only trap and transport coastal nutrients and organic carbon to the open ocean but also stimulate phytoplankton growth, generating freshly produced organic matter during westward propagation. This drives heterotrophic processes and may contribute to the previously observed net heterotrophy in open Atlantic surface waters.

BackgroundThe COBE 2991 cell processor, commonly used for pancreatic islet isolation, is no longer distributed in Europe, leading to a search for alternative purification procedures with equivalent efficacy. The aim of this study was to evaluate the efficacy of an alternative method based on the discontinuous purification of islets.MethodsThe conventional isolation procedure using a standard continuous islet purification with COBE 2991 of n = 4 human pancreas was compared to n = 8 procedures using a discontinuous purification with a “bottle” method from donors of similar characteristics. Islet equivalents, purity, and dynamic glucose-stimulated insulin secretion were evaluated.ResultsA similar islet yield was obtained using continuous vs. discontinuous purification methods (76,292.5 ± 40,550.44 vs. 79,625 ± 41,484.46 islet equivalents, p = 0.89). Islets from both groups had similar purity (78.75% ± 19.73% vs. 55% ± 18.16%, p = 0.08) and functionality both in terms of stimulation index (3.31 ± 0.83 vs. 5.58 ± 3.38, p = 0.22) and insulin secretion (1.26 ± 0.83 vs. 1.53 ± 1.40 mean AUC, p = 0.73). Moreover, the size of the islets was significantly larger in the discontinuous vs. continuous purification group (19.2% ± 10.3% vs. 45.4% ± 18.8% of islets less than 100 µm, p = 0.0097 and 23.7% ± 5.3% vs. 15.6% ± 5.8% of 200–250 µm islet size, p = 0.03).ConclusionCompared to the conventional purification procedure, discontinuous purification with a bottle method shows similar results with regard to isolation yield and islet secretory function. Furthermore, this alternative technique allows for obtaining larger islets.

Objective: Evidence regarding the role of cellular immunity in protecting against COVID-19 is emerging. To better assess immune status, simple and robust assays measuring specific T-cell responses associated with humoral responses are needed. We aimed to evaluate the Quan-T-Cell SARS-CoV-2 test for measuring cellular immune responses in vaccinated healthy and immunosuppressed subjects. Methods: T-cell responses were assessed in healthy vaccinated and unvaccinated and unexposed healthcare workers to determine the sensitivity and specificity of the EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test performed on vaccinated kidney transplant recipients (KTRs). Results: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity (87.2%) and specificity (92.3%) at the calculated 147 mIU/mL cutoff, with an 88.33% accuracy. In KTRs, specific cellular immunity was lower than the antibody response; however, those with a positive IGRA result produced as much IFN-γ as healthy individuals. Conclusions: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity and specificity for the detection of specific T-cell responses against the SARS-CoV-2 spike protein. These results present an additional tool for better management of COVID-19, especially in vulnerable populations.

Purpose Hypertension is a common cardiovascular co-morbidity after kidney transplantation and contributes to shortened graft and patient survival outcomes. However, by contrast with adherence to immunosuppressive drugs, adherence to antihypertensive treatment in kidney transplant recipients has been seldom explored. The aim of the current study was to assess adherence to antihypertensive drugs in kidney transplant recipients from the Cliniques Universitaires Saint-Luc and to look for demographic and clinical characteristics associated with drug adherence. Methods Demographic and clinical data were collected from medical files in a standardised case report form. Blood pressure was measured in the sitting position after 5 min rest, using validated oscillometric devices. Drug adherence was assessed by drug dosage in urine using liquid chromatography coupled with tandem mass spectrometry. Results Our analysis included 53 kidney transplants recipients (75% of men, mean age: 57.2 ± 12.6 years, time since kidney transplantation: 9.5 ± 7.3 years, blood pressure: 130 ± 16/78 ± 11 mmHg on 2.1 ± 1.1 antihypertensive drugs). The proportion of patients showing full drug adherence, partial drug adherence, and total non-adherence to antihypertensive drugs was 79% (N = 42), 15% (N = 8), and 6% (N = 3), respectively. Adherent patients did not differ from less or non- adherers in any of the analysed characteristics. Conclusion The proportion of patients adhering to antihypertensive drug treatment among kidney transplant recipients appears similar to that reported for immunosuppressive drugs in renal transplanted patients (∼70%), but much higher than that observed in patients with drug-resistant hypertension (30–40%). Our results need further confirmation in a large, multicenter, prospective cohort.

BackgroundKidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC.ObjectiveTo report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium.ResultsSeven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 – 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort.ConclusionThe present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo – and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

Short bubble and subsequent surface oxygenation is an innovative oxygenation technique and alternative for membrane oxygenation during hypothermic machine perfusion (HMP). The metabolic effect of the interruption of surface oxygenation for 4 h (mimicking organ transport) during HMP was compared to continuous surface and membrane oxygenation in a pig kidney ex situ preservation model. After 30 min of warm ischemia by vascular clamping, a kidney of a ±40 kg pig was procured and subsequently preserved according to one of the following groups: (1) 22-h HMP + intermittent surface oxygenation (n = 12); (2) 22-h HMP + continuous membrane oxygenation (n = 6); and (3) 22-h HMP + continuous surface oxygenation (n = 7). Brief perfusate O2 uploading before kidney perfusion was either obtained by direct bubble (groups 1, 3) or by membrane (group 2) oxygenation. Bubble oxygenation during minimum 15 min was as efficient as membrane oxygenation in achieving supraphysiological perfusate pO2 levels before kidney perfusion. Metabolic tissue analysis (i.e., lactate, succinate, ATP, NADH, and FMN) during and at the end of the preservation period demonstrated similar mitochondrial protection between all study groups. Short bubble and subsequent intermittent surface oxygenation of the perfusate of an HMP-kidney might be an effective and cheap preservation strategy to protect mitochondria, eliminating the need/costs of a membrane oxygenator and oxygen source during transport.

The use of high-risk renal grafts for transplantation requires the optimization of pretransplant assessment and preservation reconditioning strategies to decrease the organ discard rate and to improve short- and long-term clinical outcomes. Active oxygenation is increasingly recognized to play a central role in dynamic preservation strategies, independent of preservation temperature, to recondition mitochondria and to restore the cellular energy profile. The oxygen-related decrease in mitochondrial succinate accumulation ameliorates the harmful effects of ischemia-reperfusion injury. The differences between normothermic and hypothermic machine perfusion with regard to organ assessment, preservation, and reconditioning, as well as the logistic and economic implications, are factors to take into consideration for implementation at a local level. Therefore, these different techniques should be considered complementary to the perfusion strategy selected depending on functional intention and resource availability. This review provides an overview of the current clinical evidence of normothermic and oxygenated hypothermic machine perfusion, either as a continuous or end-ischemic preservation strategy, and future perspectives.

Rationale & Objective: Neutralizing monoclonal antibody treatments have shown promising preliminary results in kidney transplant recipients infected with severe acute respiratory syndrome coronavirus 2. However, their efficacy in kidney transplant recipients infected with the Omicron variant has not been reported yet. Study Design: Single-center retrospective study. Setting & Participants: We included all consecutive kidney transplant recipients treated with monoclonal antibodies for severe acute respiratory syndrome coronavirus 2 infections (positive polymerase chain reaction on nasopharyngeal swab) between June 10, 2021, and January 14, 2022. Forty-seven kidney transplant recipients were included. All patients had symptoms evolving for ≤7 days and no oxygen therapy need at monoclonal antibody infusion. Results: Symptoms at diagnosis were mainly cough (n = 25; 53%) and fever (n = 15; 32%). Eighty-three percent of the cohort (n = 39) had been vaccinated with at least 2 doses before infection, of whom 30 (77%) had demonstrated a vaccine-induced humoral response. They were treated with either casirivimab-imdevimab (n = 16; 34%) or sotrovimab (n = 31; 66%) a median of 2 days (range, 0-6 days) after the onset of symptoms. Except for 1 mild allergic reaction during casirivimab-imdevimab infusion, no side effects were reported. The median viral loads at admission (day 0) and 7 days after monoclonal antibody infusion were 2,110,027 copies/mL (range, 1,000-153,798,962 copies/mL) and 1,000 copies/mL (range, 0-10,000,000 copies/mL), respectively. Genotypes were available for 22 kidney transplant recipients (47%). Omicron, Delta, and Gamma variants were identified in 13 (59%), 8 (36%), and 1 (5%) patients, respectively. In kidney transplant recipients infected with the Omicron variant, the median viral loads at day 0 and day 7 were 752,789 copies/mL (range, 4,000-12,859,300 copies/mL) and 1,353 copies/mL (range, 0-1,211,163 copies/mL), respectively. 2 kidney transplant recipients required hospitalization immediately after sotrovimab perfusion for oxygen therapy that was weaned in 3 days, allowing patients’ discharge. None were admitted to the intensive care unit or died. Limitations: Small sample size, no control group. Conclusions: Neutralizing monoclonal antibody therapy is associated with positive outcomes in kidney transplant recipients with mild coronavirus disease 2019, including those infected with the Omicron variant.

Transparent exopolymer particles (TEP) and Coomassie stainable particles (CSP), two prominent classes of gel-like particles in the ocean primarily produced by phytoplankton, play crucial roles in ecological and biogeochemical processes, influencing microbial nutrition, growth, and particle aggregation. The distribution of these particles is intricately linked to the spatiotemporal dynamics of phytoplankton. Mesoscale cyclonic eddies (CEs) are known to stimulate phytoplankton growth and influence particle transport, but their effects on TEP and CSP remain to be determined. In the Eastern Tropical North Atlantic (ETNA), we examined three CEs: one off the Mauritanian coast during summer (Mau), one offshore during winter (Sal), and another near Brava island during winter. Mau and Brava CEs were in their intensification/maturity phase, while the Sal CE was in its decay phase. Both TEP and CSP concentrations correlated with primary productivity, but TEP increased with chlorophyll-a concentration, whereas elevated CSP coincided also with the highest abundance of pico-nanophytoplankton (<20 µm), mainly Synechococcus. Both gels exhibited a positive correlation with bacterial biomass production, indicating their consumption by heterotrophic bacteria. TEP total area in the epipelagic waters of all CEs (Mau, Brava, and Sal) was elevated compared to surrounding waters, with on average 4, 2.5, and 1.6-fold higher values, respectively. However, no significant difference in TEP size distribution was observed within any CEs and their surroundings. Similarly, CSP total area increased in the epipelagic waters of Mau and Brava CEs, with on average 5 and 2.4-fold higher values, respectively, compared to surrounding waters. CSP particles were notably larger in these two eddies, while the Sal CE showed no significant difference from surrounding waters in CSP abundance and size. Overall, TEP and CSP exhibited distinct responses to CEs, with increased concentrations during their intensification/maturation stage and remineralization dominating during their decaying stage. [ABSTRACT FROM AUTHOR]

Summary: Plant–pollinator interactions evolved early in the angiosperm radiation. Ongoing environmental changes are however leading to pollinator declines that may cause pollen limitation to plants and change the evolutionary pressures shaping plant mating systems.We used resurrection ecology methodology to contrast ancestors and contemporary descendants in four natural populations of the field pansy (Viola arvensis) in the Paris region (France), a depauperate pollinator environment. We combine population genetics analysis, phenotypic measurements and behavioural tests on a common garden experiment.Population genetics analysis reveals 27% increase in realized selfing rates in the field during this period. We documented trait evolution towards smaller and less conspicuous corollas, reduced nectar production and reduced attractiveness to bumblebees, with these trait shifts convergent across the four studied populations.We demonstrate the rapid evolution of a selfing syndrome in the four studied plant populations, associated with a weakening of the interactions with pollinators over the last three decades. This study demonstrates that plant mating systems can evolve rapidly in natural populations in the face of ongoing environmental changes. The rapid evolution towards a selfing syndrome may in turn further accelerate pollinator declines, in an eco‐evolutionary feedback loop with broader implications to natural ecosystems. See also the Commentary on this article by Kelly, 242: 331–332. [ABSTRACT FROM AUTHOR]

Kidney transplant recipients (KTRs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have an increased risk of mortality compared with the general population and hemodialysis patients. As these patients are immunosuppressed, it might seem obvious to attribute this excess mortality to the impaired immunity induced by immunosuppression. In line with this reasoning is the low immune response, both cellular and humoral, that KTRs mount in response to the anti–SARS-CoV-2 vaccine; however, acute respiratory distress syndrome associated with coronavirus disease 2019 is triggered by a state of inflammation and cytokine release syndrome that lead to pulmonary damage and increased mortality. In that context, immunosuppressive treatment dampening the immune response could, in theory, be potentially beneficial. This review aims at analyzing the current knowledge on the impact of immunosuppressive treatment on mortality in SARS-CoV-2–infected KTRs, the optimal management of immunosuppression in the coronavirus disease 2019 era, and the vaccine response and management in immunosuppressed KTRs.

Sino-orbital aspergillosis is a rare and severe infection mostly seen in immunocompromised individuals in which diagnosis may be challenging with potentially life-threatening consequences. Infection usually starts in the paranasal sinuses with secondary spreading to the adjacent orbits. Here, we report the case of a kidney transplant recipient who presented with proven invasive sino-orbital aspergillosis resulting in irreversible loss of vision despite surgical management and antifungal therapy. We review the literature with a focus on clinical presentation, diagnostic tools, and recommended treatment in the context of kidney transplantation.

Rationale & Objective: The world is facing a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although kidney transplant recipients are at increased risk for viral infections, the impact of their chronic immunosuppressed status on the risk for acquiring coronavirus disease 2019 (COVID-19) and disease severity is unknown. Study Design: All cases of COVID-19 infection in our cohort of kidney transplant recipients were prospectively monitored. Clinical features, management, and outcomes were recorded. A standard strategy of immunosuppression minimization was applied: discontinue the antimetabolite drug and reduce trough levels of calcineurin or mammalian target of rapamycin inhibitors. Unless contraindicated, hydroxychloroquine was administered only to hospitalized patients. Setting & Participants: 22 COVID-19 infections were diagnosed in our cohort of 1,200 kidney transplant recipients. Results: Most common initial symptoms included fever, cough, or dyspnea. 18 (82%) patients required hospitalization. Of those patients, 3 had everolimus-based immunosuppression. Computed tomography of the chest at admission (performed in 15 patients) showed mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1) involvement. Immunosuppression reduction was initiated in all patients. Hydroxychloroquine was administered to 15 patients. 11 patients required supplemental oxygen; 2 of them were admitted to an intensive care unit (ICU) with mechanical ventilation. After a median of 10 days, 13 kidney transplant recipients were discharged, 2 were hospitalized in non-ICU units, 1 was in the ICU, and 2 patients had died. Limitations: Small sample size and short follow-up. Conclusions: The clinical presentation of COVID-19 infection was similar to that reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with 11% mortality among kidney transplant recipients hospitalized with COVID-19 infection.