Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study.

BACKGROUND: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. METHODS: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. RESULTS: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. CONCLUSIONS: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02610283.

CytoSorb Rescue for COVID-19 Patients With Vasoplegic Shock and Multiple Organ Failure: A Prospective, Open-Label, Randomized Controlled Pilot Study.

OBJECTIVES: To investigate the effect of extracorporeal cytokine reduction by CytoSorb (CytoSorbents, Monmouth Junction, NJ) on COVID-19-associated vasoplegic shock. DESIGN: Prospective, randomized controlled pilot study. SETTING: Eight ICUs at three sites of the tertiary-care university hospital Charité-Universitätsmedizin Berlin. PATIENTS: COVID-19 patients with vasoplegic shock requiring norepinephrine greater than 0.2 µg/kg/min, C-reactive protein greater than 100 mg/L, and indication for hemodialysis. INTERVENTIONS: Randomization of 1:1 to receive CytoSorb for 3-7 days or standard therapy. To account for inadvertent removal of antibiotics, patients in the treatment group received an additional dose at each adsorber change. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time until resolution of vasoplegic shock, estimated by Cox-regression. Secondary endpoints included mortality, interleukin-6 concentrations, and catecholamine requirements. The study was registered in the German Registry of Clinical Trials (DRKS00021447). From November 2020 to March 2021, 50 patients were enrolled. Twenty-three patients were randomized to receive CytoSorb and 26 patients to receive standard of care. One patient randomized to cytokine adsorption was excluded due to withdrawal of informed consent. Resolution of vasoplegic shock was observed in 13 of 23 patients (56.5%) in the CytoSorb and 12 of 26 patients (46.2%) in the control group after a median of 5 days (interquartile range [IQR], 4-5 d) and 4 days (IQR, 3-5 d). The hazard ratio (HR) for the primary endpoint, adjusted for the predefined variables age, gender, extracorporeal membrane oxygenation-therapy, or time from shock onset to study inclusion was HR, 1.23 (95% CI, 0.54-2.79); p = 0.63. The mortality rate was 78% in the CytoSorb and 73% in the control group (unadjusted HR, 1.17 [95% CI, 0.61-2.23]; p = 0.64). The effects on inflammatory markers, catecholamine requirements, and the type and rates of adverse events were similar between the groups. CONCLUSIONS: In severely ill COVID-19 patients, CytoSorb did not improve resolution of vasoplegic shock or predefined secondary endpoints.

Evaluation of severity of delayed graft function in kidney transplant recipients.

BACKGROUND: The most common definition of delayed graft function (DGF) relies on dialysis during the first week post-transplant and does not consider DGF severity. The impact of DGF severity on long-term graft outcome remains controversial. METHODS: We analysed 627 deceased-donor kidney transplant recipients (KTRs) transplanted in 2005-2015 at our centre for DGF severity, associated risk factors and long-term consequences of DGF. RESULTS: We found 349 (55.7%) KTRs with DGF, which were classified into four groups according to DGF duration (0-1, 2-7, 8-14, >14 days) and were compared with KTR with no DGF. A longer duration of DGF was associated with progressive worsening of 10-year death-censored graft survival {no DGF: 88.3% [95% confidence interval (CI) 82.4-94.2]; 0-1 day: 81.3% [95% CI 68.2-94.4], 2-7 days: 61.5% [95% CI 43.1.1-79.9], 8-14 days: 66.6% [95% CI 47.4-85.8], >14 days: 51.2% [95% CI 33-69.4]; P < 0.001}. In kidneys with a Kidney Donor Profile Index (KDPI) ≥85%, all DGF severity groups demonstrated reduced graft survival. However, in the <85% KDPI kidneys, only >14 days DGF duration showed worse outcomes. CONCLUSIONS: DGF had a duration-dependent effect on graft survival, which varied depending on the KDPI. Of note, 0- to 1-day DGF showed comparable results to no DGF in the whole cohort.

Initial Experience With SARS-CoV-2-Neutralizing Monoclonal Antibodies in Kidney or Combined Kidney-Pancreas Transplant Recipients.

Background: Antiviral drugs have shown little impact in patient infected with acute respiratory coronavirus 2 (SARS-CoV-2). Especially for immunocompromised persons positive for SARS-CoV-2, novel treatments are warranted. Recently, the U.S. FDA has granted an emergency use authorization (EUA) to two monoclonal antibodies (mAb) targeting the viral spike protein: bamlanivimab and casivirimab and imdevimab. As per the EUA, all SARS-CoV-2 positive organ transplant recipients can receive mAb treatment. Patients and methods: We queried our center's transplant registry to identify SARS-CoV-2 infected recipients treated with single doses of either Bamlanivimab or casivirimab/imdevimab up to May 31, 2021. We analyzed clinical outcomes, renal function and virus-specific antibodies. The co-primary endpoints were hospitalization due to COVID-19 and SARS-CoV-2 RT-PCR negativity. Results: Thirteen patients at a median interval of 55 (IQR, 26-110) months from transplant were treated: 8 with bamlanivimab and 5 with casivirimab/imdevimab. In all, 4/13 (31%) patients were hospitalized at some time, while 11/13 (85%) achieved PCR negativity. 2/4 hospitalized patients received mAb as rescue treatment. Overall mortality was 23%, with one death attributable to transplant-associated lymphoma. All six patients infected with the B 1.1.7 variant were alive at last contact. Conclusion: mAb treatment appears effective when administered early to SARS-CoV-2-infected transplant recipients.

Resilient yet entirely degradable gelatin-based biogels for soft robots and electronics.

Biodegradable and biocompatible elastic materials for soft robotics, tissue engineering or stretchable electronics with good mechanical properties, tunability, modifiability or healing properties drive technological advance, and yet they are not durable under ambient conditions and do not combine all the attributes in a single platform. We have developed a versatile gelatin-based biogel, which is highly resilient with outstanding elastic characteristics, yet degrades fully when disposed. It self-adheres, is rapidly healable and derived entirely from natural and food-safe constituents. We merge all the favourable attributes in one material that is easy to reproduce and scalable, and has a low-cost production under ambient conditions. This biogel is a step towards durable, life-like soft robotic and electronic systems that are sustainable and closely mimic their natural antetypes.

What happens after graft loss? A large, long-term, single-center observation.

The number of patients returning to dialysis after graft failure increases. Surprisingly, little is known about the clinical and immunological outcomes of this cohort. We retrospectively analyzed 254 patients after kidney allograft loss between 1997 and 2017 and report clinical outcomes such as mortality, relisting, retransplantations, transplant nephrectomies, and immunization status. Of the 254 patients, 49% had died 5 years after graft loss, while 27% were relisted, 14% were on dialysis and not relisted, and only 11% were retransplanted 5 years after graft loss. In the complete observational period, 111/254 (43.7%) patients were relisted. Of these, 72.1% of patients were under 55 years of age at time of graft loss and only 13.5% of patients were ≥65 years. Age at graft loss was associated with relisting in a logistic regression analysis. In the complete observational period, 42 patients (16.5%) were retransplanted. Only 4 of those (9.5%) were ≥65 years at time of graft loss. Nephrectomy had no impact on survival, relisting, or development of dnDSA. Patients after allograft loss have a high overall mortality. Immunization contributes to long waiting times. Only a very limited number of patients are retransplanted especially when ≥65 years at time of graft loss.

Validation of the Living Kidney Donor Profile Index in a European cohort and comparison of long-term outcomes with US results.

BACKGROUND: Recently, a risk index for living donor kidney (LDK) transplantation [living kidney donor profile index (LKDPI)] was proposed to compare LDKs with each other and with deceased donor kidneys (DDKs). Until now, the LKDPI has not been validated externally. METHODS: This long-term retrospective analysis included 1305 consecutive adult kidney transplant recipients who were transplanted 2000-16 in our centre. The Kidney Donor Profile Index (KDPI) was calculated in 889 DDKs and the LKDPI in 416 LDKs. Outcome was followed over a median of 6.5 years. RESULTS: The median LKDPI was 17 and the median KDPI was 69, with a high proportion of donor kidneys with a very high KDPI (40% KDPI ≥ 80). Categorization of LDK into LKDPI quartiles (LKDPI -45-3, 3-17, 17-33, 33-90) revealed a significant difference in death-censored graft survival. Comparing corresponding subgroups of the LKDPI and KDPI (LKDPI/KDPI 0-20 or 20-40) showed comparable graft survival. A multivariate analysis adjusting for relevant recipient factors revealed the KDPI [hazard ratio (HR) 1.21; P < 0.001) and LKDPI (HR 1.15; P = 0.049) as significant independent predictors of graft loss. Time-to-event receiver operating characteristic analyses for graft survival demonstrated lower predictive discrimination of the LKDPI [area under the curve (AUC) 0.55] compared with the KDPI (AUC 0.66). The 10-year graft survival of LDK recipients was inferior in the USA compared with our centre (79% versus 84%). CONCLUSIONS: These results provide external validation of the LKDPI to predict death-censored graft survival and confirm comparability of the LKDPI with the KDPI to discriminate post-transplant outcome.

A prospective study of daclatasvir and sofosbuvir in chronic HCV-infected kidney transplant recipients.

BACKGROUND: Only a few prospective trials exist regarding the use of novel direct-acting antiviral agents (DAAs) in kidney transplant recipients (KTR) with chronic hepatitis C virus (HCV) infection. METHODS: This prospective single-center trial evaluated treatment with daclatasvir (DCV) and sofosbuvir (SOF) over 12 weeks in 16 adult chronic HCV infected KTR and eGFR > 30 ml/min/1.73m2. Primary endpoint was sustained virological response 12 weeks after end of therapy (SVR12). Beside baseline liver biopsy, hepatic function and glucose metabolism were regularly assessed. RESULTS: Four of 16 study patients had previously failed interferon-based HCV treatment. Liver biopsy showed mostly moderate fibrosis score before therapy with DCV/SOF was initiated at a median of 10.3 years after transplantation. In total, 15 of 16 KTR achieved SVR12. One patient showed early viral relapse because of resistance-associated variants (RAVs) in the HCV NS5A region. Rescue treatment with SOF/velpatasvir/voxilaprevir resulted in SVR12. DAAs treatment led to significant improvement of liver metabolism and glucose tolerance accompanied with no therapy-associated major adverse events and excellent tolerability. CONCLUSIONS: Our study demonstrates safety, efficacy and functional benefit of DCV/SOF treatment in KTR with chronic HCV infection. We provide data on rescue strategies for treatment failures due to present RAVs and amelioration of hepatic function and glucose tolerance. TRIAL REGISTRATION: Registry name: European Clinical Trials Register; Trial registry number (Eudra-CT): 2014-004551-32 , Registration date: Aug 28th 2015.

Assessment of the Kidney Donor Profile Index in a European cohort.

Background: Recently, transplant societies have had to change their allocation policies to counter global organ shortages. However, strategies differ significantly and long-term outcomes and cross-regional applicability remain to be evaluated. Methods: Therefore, we retrospectively analysed the Kidney Donor Profile Index (KDPI) of 987 adult kidney transplants at our centre using data from the Organ Procurement and Transplantation Network (OPTN) as a reference. Results: In our cohort, the median KDPI was 66%, with a higher proportion of >85% KDPI kidneys compared with the US cohort (32.3% versus 9.2%). Among elderly patients (≥65 years of age), 62% received >95% KDPI kidneys, which were primarily allocated within the Eurotransplant Senior Program (ESP). After 10 years, the rate of death-censored graft survival was 70.5%. Recipients of >85% KDPI kidneys were significantly older, demonstrating higher mortality, poorer graft survival and lower estimated glomerular filtration rate. Patients receiving ≥99% KDPI kidneys had a satisfactory 5-year death-censored graft survival (72.9%). The 5-year survival rate of patients living with a functioning graft exceeded the matched OPTN data in the whole KDPI range, despite a higher proportion of elderly recipients. Multivariate analysis revealed KDPI as an independent risk factor for graft loss (hazard ratio 1.14/10%, P < 0.001), although C-statistics of 0.62 indicated limited discriminative ability for individuals. Conclusion: The analysis demonstrated KDPI as a potentially useful tool for donor quality assessment in a European cohort. Most importantly, our analysis revealed acceptable outcomes even for very high KDPI kidneys.

Evaluation of adherence and tolerability of prolonged-release tacrolimus (Advagraf™) in kidney transplant patients in Germany: A multicenter, noninterventional study.

This study assessed adherence to prolonged-release tacrolimus (PR-T)-based immunosuppression during routine maintenance of renal transplant recipients in Germany. Patients had received PR-T for ≥1 month at inclusion. Data were collected during four visits (V): baseline (V1), 6 (V2), 12 (V3), and 18 (V4) months. Composite primary endpoint: nonadherence at V4, defined as self-reported nonadherence on the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS© ), investigator-rated nonadherence, and/or V4 tacrolimus trough level outside a predefined range. Secondary endpoints: individual BAASIS items, incidence of rejection, kidney function, and safety. Overall, 153 adult kidney recipients (mean [standard deviation] time post-transplant 5.8 [4.6] years) were included. Nonadherence was high at V4 (67.7% [95% confidence interval 58.9%, 75.6%]). Medication-taking adherence was 86.9% and 91.3% at V1 and V4, respectively; adherence to timing of medication intake was 58.2% and 58.3%, with little evidence of missed doses/drug holidays. Investigators rated adherence "good" in 85.6% of patients (V4). Two (1.3%) patients had acute rejection episodes. Kidney function remained stable (mean creatinine clearance, V1: 62.1 mL/min; V4: 65.3 mL/min). Investigators rated effectiveness of PR-T as "very good"/"good" in 91.5% of patients. Most patients (94.7%) found PR-T dosing more convenient than immediate-release tacrolimus. PR-T was well tolerated with high medication persistence.

Hyperlactatemia, Lactate Kinetics and Prediction of Citrate Accumulation in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Regional Citrate Anticoagulation.

OBJECTIVES: Citrate accumulation is a major complication of regional citrate anticoagulation during continuous renal replacement therapy. We studied the prediction of citrate accumulation during continuous veno-venous hemodialysis with regional citrate anticoagulation by initial lactate concentrations and lactate kinetics. DESIGN: A retrospective follow-up analysis from a cohort of critically ill patients. SETTING: Mixed medical-surgical ICUs at a university hospital. PATIENTS: All adult patients with acute kidney injury and treated with regional citrate anticoagulation-continuous veno-venous hemodialysis during a 3-year period (n = 1,070) were included in this retrospective study and screened for metabolic signs of citrate accumulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The frequency of citrate accumulation during the first 48 hours of therapy was 2.26%. In patients with initial normal lactate (< 2.2 mmol/L), elevated lactate (≥ 2.2 to < 4 mmol/L), or severe hyperlactatemia (≥ 4 mmol/L), the frequency of citrate accumulation was 0.77%, 2.70%, and 6.33%, respectively. Receiver operating characteristics-area under the curve of initial lactate concentration was 0.789 for the prediction of citrate accumulation. Optimal cutoff from receiver operating characteristics (2.39 mmol/L) showed strong negative prediction (99.28%), but weak positive prediction (5.21%). The slope intercept of lactate kinetics over 48 hours was positive and significantly higher in patients with citrate accumulation compared to those without (+0.2 vs -0.006 mmol/L/hr; p < 0.001). In patients with initial severe hyperlactatemia (≥ 4 mmol/L), the median calculated lactate clearance at 6, 12, and 18 hours was 24.0%, 48.1%, and 59.4% in the nonaccumulation group. These clearance rates were significantly higher at each time-point compared to patients with citrate accumulation (-9.8%, -20.5%, and 2.3%, respectively; p < 0.001 for each time-point). The highest receiver operating characteristics-area under the curve for citrate accumulation was observed for 12-hour values of lactate clearance (area under the curve = 0.839; 95% CI, 0.751-0.927) with an optimal cut-off value of 24.3%. CONCLUSIONS: Risk of citrate accumulation during regional citrate anticoagulation in a well-selected cohort of patients is low even in case of initial severe hyperlactatemia. Lactate kinetics rather than initially elevated lactate concentration should be considered in assessing the risk of citrate accumulation.

Immunologic outcome in elderly kidney transplant recipients: is it time for HLA-DR matching?

BACKGROUND: The Eurotransplant Senior Program (ESP) neglects HLA matching for elderly (≥65 years) kidney transplant recipients (KTR). Few data regarding the influence of DR matching on clinical and immunologic outcome in elderly KTR exist. METHODS: This retrospective long-term observational study included 244 elderly out of n = 972 adult KTR between 2004 and 2014. Data analysis included patient and graft survival, biopsy-proven rejections [T-cell-mediated rejections (TCMR) and antibody-mediated rejections] and development of de novo donor-specific HLA antibodies (DSA). Outcome data were assessed over a maximum period of 10 years. RESULTS: Due to the nature of the ESP, elderly KTR showed significantly more HLA mismatches, shorter time on dialysis and shorter cold ischaemia time. Elderly KTR had significantly worse graft and patient survival, and after 7 years, the rate of de novo DSA (33 versus 25%, P = 0.034) and TCMR (39 versus 27%, P < 0.001) was significantly higher compared with younger KTR. Multivariate analysis identified donor age, delayed graft function and HLA-DR mismatches as independent risk factors for TCMR. Within the group of elderly KTR, HLA-DR mismatches were associated with a significantly higher incidence of TCMR and development of de novo DSA. Occurrence of TCMR and de novo DSA in elderly KTR resulted in significantly worse graft survival. CONCLUSIONS: In elderly KTR, HLA-DR mismatches are independent risk factors for TCMR and the development of all classes of de novo DSA, both of which significantly impair graft survival. Introduction of HLA-DR matching in elderly KTR might significantly improve immunologic and overall outcome.

The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy.

BACKGROUND: Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. METHODS: Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. RESULTS: The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. CONCLUSION: The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.

Outcome-Orientated Organ Allocation-A Composite Risk Model for Pancreas Graft Evaluation and Acceptance.

Background: Pancreas transplantation (PTX) remains the most effective treatment to prevent long-term complications and provide consistent euglycemia in patients with endocrine pancreatic insufficiency, mainly in type I diabetic patients. Considering early graft loss (EGL) and the perioperative complication rate, an optimal risk stratification based on donor risk factors is paramount. Methods: In our single-center study, we retrospectively assessed the risk factors for EGL and reduced graft survival in 97 PTXs (82 simultaneous pancreas and kidney [SPK], 11 pancreases transplanted after kidney [PAK] and 4 pancreases transplanted alone [PTA]) between 2010 and 2021. By statistically analyzing the incorporation of different donor risk factors using the Kaplan-Meier method and a log-rank test, we introduced a composite risk model for the evaluation of offered pancreas grafts. Results: The overall EGL rate was 6.5%. In the univariate analysis of donor characteristics, age > 45 years, BMI > 25 kg/m2, lipase > 60 U/L, cerebrovascular accident (CVA) as the cause of death, mechanical cardiopulmonary resuscitation (mCPR), cold ischemia time (CIT) > 600 min and retrieval by another center were identified as potential risk factors; however, they lacked statistical significance. In a multivariate model, age > 45 years (HR 2.05, p = 0.355), BMI > 25 kg/m2 (HR 3.18, p = 0.051), lipase > 60 U/L (HR 2.32, p = 0.148), mCPR (HR 8.62, p < 0.0001) and CIT > 600 min (HR 1.89, p = 0.142) had the greatest impact on pancreas graft survival. We subsumed these factors in a composite risk model. The combination of three risk factors increased the rate of EGL significantly (p = 0.003). Comparing the pancreas graft survival curves for ≥3 risk factors to <3 risk factors in a Kaplan-Meier model revealed significant inferiority in the pancreas graft survival rate (p = 0.029). Conclusions: When evaluating a potential donor organ, grafts with a combination of three or more risk factors should only be accepted after careful consideration to reduce the risk of EGL and to significantly improve outcomes after PTX.

Elucidating the Origins of High Preferential Crystal Orientation in Quasi-2D Perovskite Solar Cells.

Incorporating large organic cations to form 2D and mixed 2D/3D structures significantly increases the stability of perovskite solar cells. However, due to their low electron mobility, aligning the organic sheets to ensure unimpeded charge transport is critical to rival the high performances of pure 3D systems. While additives such as methylammonium chloride (MACl) can enable this preferential orientation, so far, no complete description exists explaining how they influence the nucleation process to grow highly aligned crystals. Here, by investigating the initial stages of the crystallization, as well as partially and fully formed perovskites grown using MACl, the origins underlying this favorable alignment are inferred. This mechanism is studied by employing 3-fluorobenzylammonium in quasi-2D perovskite solar cells. Upon assisting the crystallization with MACl, films with a degree of preferential orientation of 94%, capable of withstanding moisture levels of 97% relative humidity for 10 h without significant changes in the crystal structure are achieved. Finally, by combining macroscopic, microscopic, and spectroscopic studies, the nucleation process leading to highly oriented perovskite films is elucidated. Understanding this mechanism will aid in the rational design of future additives to achieve more defect tolerant and stable perovskite optoelectronics.

An autonomous wearable biosensor powered by a perovskite solar cell.

Wearable sweat sensors can potentially be used to continuously and non-invasively monitor physicochemical biomarkers that contain information related to disease diagnostics and fitness tracking. However, the development of such autonomous sensors faces a number of challenges including achieving steady sweat extraction for continuous and prolonged monitoring, and addressing the high power demands of multifunctional and complex analysis. Here we report an autonomous wearable biosensor that is powered by a perovskite solar cell and can provide continuous and non-invasive metabolic monitoring. The device uses a flexible quasi-two-dimensional perovskite solar cell module that provides ample power under outdoor and indoor illumination conditions (power conversion efficiency exceeding 31% under indoor light illumination). We show that the wearable device can continuously collect multimodal physicochemical data - glucose, pH, sodium ions, sweat rate, and skin temperature - across indoor and outdoor physical activities for over 12 hours.

Effect of the AMP-kinase modulators AICAR, metformin and compound C on insulin secretion of INS-1E rat insulinoma cells under standard cell culture conditions.

BACKGROUND/AIMS: The function of ß-cells is regulated by nutrient uptake and metabolism. The cells' metabolic state can be expressed as concentration ratios of AMP, ADP and ATP. Relative changes in these ratios regulate insulin release. An increase in the intracellular ATP concentration causes closure of K(ATP) channels and cell membrane depolarization, which triggers stimulus-secretion coupling (SSC). In addition to K(ATP) channels, the AMP-dependent protein kinase (AMPK), a major cellular fuel sensor in a variety of cells and tissues, also affects insulin secretion and ß-cell survival. In a previous study we found that the widely used AMPK inhibitor compound C retards proliferation and induces apoptosis in the rat ß-cell line INS-1E. We therefore tested the effects of AMPK activators (AICAR and metformin), and compound C on AMPK phosphorylation, insulin secretion, K(ATP) channel currents, cell membrane potential, intracellular calcium concentration, apoptosis and cell cycle distribution of INS-1E cells under standard cell culture conditions (11 mM glucose). METHODS: Western blotting, ELISA, patch-clamp, calcium imaging and flow cytometry. RESULTS: We found that basal AMPK phosphorylation is enhanced by AICAR (1 mM) and metformin (1 mM) but remained unaffected by compound C (10 µM). Both AICAR and compound C stimulated basal insulin secretion whereas metformin had no effect. Pre-incubation with AICAR (1 mM) caused an inhibition of K(ATP) currents but did not significantly alter the average cell membrane potential (Vm) or the threshold potential of electrical activity. Acute administration of AICAR (300 µM) led to a depolarization of Vm, which was not due to an inhibition of the basal- or glucose-induced chloride conductance, and was not accompanied by elevations of intracellular calcium (Ca(i)). AICAR had no additive blocking effect on K(ATP) currents when applied together with tolbutamide. Compound C applied over 24 hours induced an increase in the percentage of cells positive for caspase activity, whereas AICAR (1 mM) applied for 48 hours was without effect. Medium glucose concentration <3 mM caused cell cycle arrest, caspase activation and an increase of cell granularity. CONCLUSION: We conclude that under standard cell culture conditions the AMPK modulators AICAR and compound C, but not metformin, stimulate insulin secretion by AMPK-independent mechanisms.

Welfare state support during the COVID-19 pandemic: Change and continuity in public attitudes towards social policies in Germany.

Our analysis asks whether the pandemic situation affects welfare state support in Germany. The pandemic has increased the health and income risks calling for welfare state intervention. While increased needs, more deservingness, and higher state responsibility during such a crisis would suggest augmented support generally and among those at risk, this might be a short-term effect and cost considerations could reverse this trend. We study public attitudes towards four key social policy areas based on the German Internet Panel (GIP). We use three waves prior and further three waves since the pandemic had been declared in March 2020. The analysis shows both continuity in the popularity of social policies, in particular health and pensions, and some short-term increase in support for unemployment and family policies. The results after nearly 2 years suggest rather continuation with some thermostatic short-term boosts in support instead of any long-lasting change.

Nuestro análisis investiga si la situación de la pandemia afecta al apoyo del estado de bienestar en Alemania. La pandemia ha aumentado los riesgos para la salud y los ingresos, lo que requiere una mayor intervención del estado de bienestar. Si bien una mayor necesidad, más merecimiento y una mayor responsabilidad del estado durante una crisis de este tipo sugerirían un mayor apoyo en general y entre aquellos en riesgo, esto podría ser un efecto a corto plazo y las consideraciones de costos podrían revertir esta tendencia. Estudiamos las actitudes públicas hacia cuatro áreas clave de política social basadas en el Panel de Internet alemán, utilizando tres encuestas GIP anteriores y tres oleadas posteriores desde que se declaró la pandemia en marzo de 2020. El análisis muestra tanto la continuidad en la popularidad de las políticas sociales, en en particular, salud y pensiones, y algún aumento a corto plazo en el apoyo al desempleo y las políticas familiares. Nuestros resultados después de casi dos años sugieren más bien una continuación con algunos aumentos termostáticos a corto plazo en el soporte en lugar de un cambio duradero.