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Abstract Background Gastrointestinal bleeding (GIB) is a clinical challenge in kidney failure. INSPIRE group assessed if machine learning could determine a hemodialysis (HD) patient’s 180-day GIB hospitalization risk. Methods An eXtreme Gradient Boosting (XGBoost) and logistic regression model were developed using an HD dataset in United States (2017–2020). Patient data was randomly split (50% training, 30% validation, and 20% testing). HD treatments ≤ 180 days before GIB hospitalization were classified as positive observations; others were negative. Models considered 1,303 exposures/covariates. Performance was measured using unseen testing data. Results Incidence of 180-day GIB hospitalization was 1.18% in HD population (n = 451,579), and 1.12% in testing dataset (n = 38,853). XGBoost showed area under the receiver operating curve (AUROC) = 0.74 (95% confidence interval (CI) 0.72, 0.76) versus logistic regression showed AUROC = 0.68 (95% CI 0.66, 0.71). Sensitivity and specificity were 65.3% (60.9, 69.7) and 68.0% (67.6, 68.5) for XGBoost versus 68.9% (64.7, 73.0) and 57.0% (56.5, 57.5) for logistic regression, respectively. Associations in exposures were consistent for many factors. Both models showed GIB hospitalization risk was associated with older age, disturbances in anemia/iron indices, recent all-cause hospitalizations, and bone mineral metabolism markers. XGBoost showed high importance on outcome prediction for serum 25 hydroxy (25OH) vitamin D levels, while logistic regression showed high importance for parathyroid hormone (PTH) levels. Conclusions Machine learning can be considered for early detection of GIB event risk in HD. XGBoost outperforms logistic regression, yet both appear suitable. External and prospective validation of these models is needed. Association between bone mineral metabolism markers and GIB events was unexpected and warrants investigation. Trial registration This retrospective analysis of real-world data was not a prospective clinical trial and registration is not applicable. Graphical Abstract

Abstract Background Hemodialyzers should efficiently eliminate small and middle molecular uremic toxins and possess exceptional hemocompatibility to improve well-being of patients with end-stage kidney disease. However, performance and hemocompatibility get compromised during treatment due to adsorption of plasma proteins to the dialyzer membrane. Increased membrane hydrophilicity reduces protein adsorption to the membrane and was implemented in the novel FX CorAL dialyzer. The present randomized controlled trial compares performance and hemocompatibility profiles of the FX CorAL dialyzer to other commonly used dialyzers applied in hemodiafiltration treatments. Methods This prospective, open, controlled, multicentric, interventional, crossover study randomized stable patients on post-dilution online hemodiafiltration (HDF) to FX CorAL 600, FX CorDiax 600 (both Fresenius Medical Care) and xevonta Hi 15 (B. Braun) each for 4 weeks. Primary outcome was β2-microglobulin removal rate (β2-m RR). Non-inferiority and superiority of FX CorAL versus comparators were tested. Secondary endpoints were RR and/or clearance of small and middle molecules, and intra- and interdialytic profiles of hemocompatibility markers, with regards to complement activation, cell activation/inflammation, platelet activation and oxidative stress. Further endpoints were patient reported outcomes (PROs) and clinical safety. Results 82 patients were included and 76 analyzed as intention-to-treat (ITT) population. FX CorAL showed the highest β2-m RR (76.28%), followed by FX CorDiax (75.69%) and xevonta (74.48%). Non-inferiority to both comparators and superiority to xevonta were statistically significant. Secondary endpoints related to middle molecules corroborated these results; performance for small molecules was comparable between dialyzers. Regarding intradialytic hemocompatibility, FX CorAL showed lower complement, white blood cell, and platelet activation. There were no differences in interdialytic hemocompatibility, PROs, or clinical safety. Conclusions The novel FX CorAL with increased membrane hydrophilicity showed strong performance and a favorable hemocompatibility profile as compared to other commonly used dialyzers in clinical practice. Further long-term investigations should examine whether the benefits of FX CorAL will translate into improved cardiovascular and mortality endpoints. Trial registration eMPORA III registration on 19/01/2021 at ClinicalTrials.gov (NCT04714281).

IntroductionNeurofibromatosis 1 (NF1) is a chronic neurocutaneous disease known to profoundly affect quality of life (QoL). We have performed an analysis of disease severity, mental and physical QoL and compare the different subclasses among patients with neurofibromatosis 1 (NF1).Patients and methodsWe conducted a prospective analysis of 89 NF1 patients between January 2016 and March 2018. Data sourced from local records including demographic information, employment status, education level, and marital status. All patients completed 36-Item Short Form Health Survey (SF-36) and additionally the numerical pain rating scale (NPS). Patients were stratified based on severity of NF1, visibility and disease severity.ResultsAmong 89 patients, severity was classified as grade 4 was identified in 42 (47.2%), moderate in 17 (19.1%), mild in 23 (25.8%) and minimal in 7 (7.9%) cases. According to visibility scale, severe grade 3 was found in 28 (31.5%), moderate grade 2 in 26 (29.2%) and mild grade in 35 (39.3%) cases. SF-36 data, except for pain, showed significantly lower values, if compared to the standard German population (P < 0.001, physical component summary P = 0.045). Sex, marital status and education level did not significantly influence results. Employment was significantly associated with better mental and physical status (P = 0.028 and P = 0.01 respectively) and age >40 was linked to lower physical (P = 0.027) but not mental component scores (P = 0.362). The numerical pain rating scale indicated pain levels of 7–10 in 9 cases (10,1%), 5–6 in 10 patients (11.2%), 1–4 in 26 patients (29.2%) and no pain in 44 cases (49.4%). Physical component scores significantly differed across different NPS grades (P < 0.001) but not in mental component scores (P = 0.06). Finally, no significant differences were found in mental component scores across severity or visibility grades.ConclusionSeverity and visibility grades of patients with NF1 may not necessarily result in poor mental health. Symptomatic treatment should be considered even for severely disabled patients as they may have comparable QoL to less severely affected patients with NF1. Employment was linked to better quality of life outcomes in our findings.

BackgroundThe use of online information and communication is globally increasing in the healthcare sector. In addition to known benefits in other medical fields, possible specific potentials of eHealth lie in the monitoring of oncological patients undergoing outpatient therapy. Specifically, the treatment with immune checkpoint inhibitors (ICI) requires intensive monitoring due to various possible negative side effects. The present study explores cancer patients’ perspectives on eHealth and demonstrates how eHealth applications, from the patients’ point of view, can contribute to further improving outpatient immunotherapy.Methods and findingsOur multicenter study was executed at the university hospitals in Bonn and Aachen. A structured questionnaire was distributed to patients receiving outpatient immunotherapy. Contents addressed were (1) the patients’ attitude towards eHealth applications, (2) the use of modern information and communications technologies (ICT) in (2a) everyday life and (2b) health-related information search including eHealth literacy, (3) the use of internet-enabled devices as well as (4) socio-demographic data. 164 patients were included in the study, of whom 39.0% were female and 61.0% male and the average age was 62.8 years. Overall, there was a high distribution of internet-enabled devices for everyday use and a great interest in integrating eHealth applications into outpatient immunotherapy. The assessment of eHealth potentials significantly depended on age. The younger participants demonstrated a broader use of modern ICT and a higher affinity for its use in outpatient immunotherapy. In some aspects, level of education and gender were also relevant factors influencing the patients’ view on eHealth.ConclusionThis study demonstrates the potential for further integration of eHealth applications into outpatient immunotherapy from the patients’ perspective. It indicates a dependency on age and educational level for the further integration of eHealth into patient care in oncology. Due to particular patient needs regarding age, level of education, gender and other subgroups, specific education and training as well as target-group specific digital health interventions are necessary to fully utilize the potentials of eHealth for outpatient immunotherapy. Future studies are required to specifically address target-group specific usability of eHealth applications and eHealth literacy, as well as to address information security and data protection.

**Background:** Understanding how population density affected the transmission of COVID-19 is vitally important, since crowded cities were the epicenters for the disease. Since human contact was the main cause of the spread, population-weighted densities have been shown to be a better measure than conventional densities, since the variation in density across subareas matters more than the density in the total area. **Objectives:** This study investigates the impact of population-weighted density and other demographics on the rate of COVID-19 spread in the United States. **Methods:** The study considers population-weighted density and many other demographics. The population-weighted density index is the weighted average of density across the tracts, where tracts are weighted by population. Multivariate analysis has been used to determine the elasticity of the spread. **Results:** Using U.S. county-level data, we calculated the elasticity of COVID-19 spread with respect to population-weighted density to be 0.085 after controlling for other factors. In addition to the density, the proportion of people over 65 years of age, the number of total healthcare workers, and average temperature in each county positively contributed to the case numbers, while education level and income per capita had a negative effect. **Discussion:** For the spread, understanding the population characteristics and dynamics is as important as understanding the infectious disease itself. This will help policy makers to utilize and reallocate the resources more effectively. If the spread is successfully contained early, there will be less stress placed upon the healthcare system, resulting in better healthcare access for those who are sick. **Conclusions:** Our analysis suggests that population-weighted density can be a useful tool to control and manage outbreaks, especially within the early stage of the spread. We presented the early dynamics of the spread and recommended a policy measure on how to transfer healthcare workers from low-spread-risk areas to high-spread-risk areas to utilize resources better.

Abstract Prosthetic implants, particularly hip endoprostheses, often lead to stress shielding because of a mismatch in compliance between the bone and the implant material, adversely affecting the implant’s longevity and effectiveness. Therefore, this work aimed to demonstrate a computationally efficient method for density-based topology optimization of homogenized lattice structures in a patient-specific hip endoprosthesis. Thus, the root mean square error (RMSE) of the stress deviations between the physiological femur model and the optimized total hip arthroplasty (THA) model compared to an unoptimized-THA model could be reduced by 81 % and 66 % in Gruen zone (GZ) 6 and 7. However, the method relies on homogenized finite element (FE) models that only use a simplified representation of the microstructural geometry of the bone and implant. The topology-optimized hip endoprosthesis with graded lattice structures was synthesized using algorithmic design and analyzed in a virtual implanted state using micro-finite element (micro-FE) analysis to validate the optimization method. Homogenized FE and micro-FE models were compared based on averaged von Mises stresses in multiple regions of interest. A strong correlation (CCC > 0.97) was observed, indicating that optimizing homogenized lattice structures yields reliable outcomes. The graded implant was additively manufactured to ensure the topology-optimized result’s feasibility.

The expression levels of TCRs on the surface of human T cells define the avidity of TCR-HLA/peptide interactions. In this study, we have explored which components of the TCR-CD3 complex are involved in determining the surface expression levels of TCRs in primary human T cells. The results show that there is a surplus of endogenous TCR α/β chains that can be mobilised by providing T cells with additional CD3γ,δ,ε,ζ chains, which leads to a 5-fold increase in TCR α/β surface expression. The analysis of individual CD3 chains revealed that provision of additional ζ chain alone was sufficient to achieve a 3-fold increase in endogenous TCR expression. Similarly, CD3ζ also limits the expression levels of exogenous TCRs transduced into primary human T cells. Interestingly, transduction with TCR plus CD3ζ not only increased surface expression of the introduced TCR, but it also reduced mispairing with endogenous TCR chains, resulting in improved antigen-specific function. TCR reconstitution experiments in HEK293T cells that do not express endogenous TCR or CD3 showed that TCRα/β and all four CD3 chains were required for optimal surface expression, while in the absence of CD3ζ the TCR expression was reduced by 50%. Together, the data show that CD3ζ is a key regulator of TCR expression levels in human T cells, and that gene transfer of exogenous TCR plus CD3ζ improved TCR surface expression, reduced TCR mispairing and increased antigen-specific function.

Objective The usage of digital information and communication technologies in European healthcare is growing. Unlike numerous technological possibilities, the present use of these technologies and perspectives towards them in relation to otolaryngology care have so far been of less interest. This study evaluates the utilisation of and attitudes towards digital information and communication technologies in cross-sectoral otolaryngology care among German patients. Methods A structured interview-based study was conducted at the outpatient facility of a tertiary hospital in Germany. It focused on chief complaints, current use of digital technologies, estimated benefits of increased digital technology use in otolaryngology care, and sociodemographic data. The detailed statistical analysis employed Chi-squared tests and multivariate logistic regression. Results A total of 208 otolaryngology patients completed the interview. Digital communication technologies exhibited a high penetration rate (91.8%) and were regularly used in daily life (78.7%) and for health reasons (73.3%). Younger age ( p ≤ 0.003) and higher education levels ( p ≤ 0.008) were significantly correlated with the increased digital communication technology use. The overall potential of eHealth technologies was rated significantly higher by younger patients ( p ≤ 0.001). The patients’ chief complaints showed no significant influence on the current and potential use of these technologies for cross-sectoral otolaryngology care. Conclusion Regardless of their chief complaints, German otolaryngology patients regularly use digital information and communication technologies for health reasons and express interest in their further use for cross-sectoral care. To enhance digital patient communication in otolaryngology, attention should be given to treatment quality, usability, data security and availability and financial remuneration for service providers.

Abstract Innovative methods for evaluating virus risk and spread, independent of test-seeking behavior, are needed to improve routine public health surveillance, outbreak response, and pandemic preparedness. Throughout the COVID-19 pandemic, environmental surveillance strategies, including wastewater and air sampling, have been used alongside widespread individual-based SARS-CoV-2 testing programs to provide population-level data. These environmental surveillance strategies have predominantly relied on pathogen-specific detection methods to monitor viruses through space and time. However, this provides a limited picture of the virome present in an environmental sample, leaving us blind to most circulating viruses. In this study, we explore whether pathogen-agnostic deep sequencing can expand the utility of air sampling to detect many human viruses. We show that sequence-independent single-primer amplification sequencing of nucleic acids from air samples can detect common and unexpected human respiratory and enteric viruses, including influenza virus type A and C, respiratory syncytial virus, human coronaviruses, rhinovirus, SARS-CoV-2, rotavirus, mamastrovirus, and astrovirus.

The ninhydrin reaction is commonly used for the detection of amino acids. However, in the literature, different conditions with respect to the buffer system, its pH and concentration, type of organic solvent, incubation time, and temperature, as well as the concentrations of the reagents, are described. To identify the most suitable conditions, colour development with reagents of varying compositions and different reaction temperatures and times were investigated using asparagine as a model amino acid. Asparagine was selected since it is one of the most abundant free amino acids in many types of samples. The optimal reaction mixture consisted of 0.8 mol L−1 potassium acetate, 1.6 mol L−1 acetic acid, 20 mg mL−1 ninhydrin and 0.8 mg mL−1 hydrindantin in DMSO/acetate buffer 40/60 (v/v) (final concentrations). The best reaction condition was heating the samples in 1.5 mL reaction tubes to 90 °C for 45 min. Afterwards, the samples were diluted with 2-propanol/water 50/50 (v/v) and the absorbance was measured at 570 nm. The proteinogenic amino acids showed a similar response except for cysteine and proline. The method was highly sensitive and showed excellent linearity as well as intra-day and inter-day reproducibility.

Abstract Reports on autonomic responses to transcutaneous auricular vagus nerve stimulation (taVNS) and osteopathic manipulative techniques have been equivocal, partly due to inconsistent interpretation of heart rate variability (HRV). We developed a mechanistic framework for the interpretation of HRV based on a model of sinus node automaticity that considers autonomic effects on Phase 3 repolarization and Phase 4 depolarization of the sinoatrial action potential. The model was applied to HRV parameters calculated from ECG recordings (healthy adult humans, both genders) before (30 min), during (15 min), and after (30 min) a time control intervention (rest, n = 23), taVNS (10 Hz, 300 μs, 1–2 mA, cymba concha, left ear, n = 12), or occipitoatlantal decompression (OA‐D, n = 14). The experimental protocol was repeated on 3 consecutive days. The model simulation revealed that low frequency (LF) HRV best predicts sympathetic tone when calculated from heart rate time series, while high frequency (HF) HRV best predicts parasympathetic tone when calculated from heart period time series. Applying our model to the HRV responses to taVNS and OA‐D, revealed that taVNS increases cardiac parasympathetic tone, while OA‐D elicits a mild decrease in cardiac sympathetic tone.

Wireless sensor networks (WSNs) are attracting increasing research interest due to their ability to monitor large areas independently. Their reliability is a crucial issue, as it is influenced by hardware, data, and energy-related factors such as loading conditions, signal attenuation, and battery lifetime. Proper selection of sensor node positions is essential to maximise system reliability during the development of products equipped with WSNs. For this purpose, this paper presents an approach to estimate WSN system reliability during the development phase based on the analysis of measurements, using strain measurements in finite element (FE) models as an example. The approach involves dividing the part under consideration into regions with similar strains using a region growing algorithm (RGA). The WSN configuration is then analysed for reliability based on data paths and measurement redundancy resulting from the sensor positions in the identified measuring regions. This methodology was tested on an exemplary WSN configuration at an aircraft wing box under bending load and found to effectively estimate the hardware perspective on system reliability. Therefore, the methodology and algorithm show potential for optimising sensor node positions to achieve better reliability results.

Multiple sclerosis is an autoinflammatory condition that results in damage to myelinated neurons in affected patients. While disease-modifying treatments have been successful in slowing the progression of relapsing–remitting disease, most patients still progress to secondary progressive disease that is largely unresponsive to disease-modifying treatments. Similarly, there is currently no effective treatment for patients with primary progressive MS. Innate and adaptive immune cells in the CNS play a critical role in initiating an autoimmune attack and in maintaining the chronic inflammation that drives disease progression. In this review, we will focus on recent insights into the role of T cells with regulatory function in suppressing the progression of MS, and, more importantly, in promoting the remyelination and repair of MS lesions in the CNS. We will discuss the exciting potential to genetically reprogram regulatory T cells to achieve immune suppression and enhance repair locally at sites of tissue damage, while retaining a fully competent immune system outside the CNS. In the future, reprogramed regulatory T cells with defined specificity and function may provide life medicines that can persist in patients and achieve lasting disease suppression after one cycle of treatment.

While efficient removal of uremic toxins and accumulated water is pivotal for the well-being of dialysis patients, protein adsorption to the dialyzer membrane reduces the performance of a dialyzer. Hydrophilic membrane modification with polyvinylpyrrolidone (PVP) has been shown to reduce protein adsorption and to stabilize membrane permeability. In this study we compared middle molecule clearance and filtration performance of nine polysulfone-, polyethersulfone-, and cellulose-based dialyzers over time. Protein adsorption was simulated in recirculation experiments, while β2-microglobulin clearance as well as transmembrane pressure (TMP) and filtrate flow were determined over time. The results of this study showed that β2-microglobulin clearance (−7.2 mL/min/m2) and filtrate flow (−54.4 mL/min) decreased strongly during the first 30 min and slowly afterwards (−0.7 mL/min/m2 and −6.8 mL/min, respectively, for the next 30 min); the TMP increase (+37.2 mmHg and +8.6 mmHg, respectively) showed comparable kinetics. Across all tested dialyzers, the dialyzer with a hydrophilic modified membrane (FX CorAL) had the highest β2-microglobulin clearance after protein fouling and the most stable filtration characteristics. In conclusion, hydrophilic membrane modification with PVP stabilizes the removal capacity of middle molecules and filtration performance over time. Such dialyzers may have benefits during hemodiafiltration treatments which aim to achieve high exchange volumes.

In 2020, the Fayetteville Police Department (FPD), located in a small urban community in Arkansas, began efforts to develop alternative responses to crisis-related calls for service. The main motivation for this effort was the influx of calls related to crises involving substance use, mental health, and homelessness both before and during COVID-19, although the George Floyd protests during that summer also played a meaningful role. FPD collaborated with the University of Arkansas School of Social Work (UA) to develop an MSW internship within the department with the intent of ultimately creating a co-response program. It is crucial to determine a baseline of staff attitudes when developing a new program or implementing organizational change to assess any subsequent shifts over time. As such, this paper presents baseline data from a survey assessing attitudes among sworn and civilian staff at FPD toward incorporating a social worker into the department. Data from semi-structured interviews provide a deeper understanding of these attitudes along with insight into lessons learned during the implementation of the internship and the eventual Crisis Intervention Response Team (CIRT). Survey results indicated that overall, FPD staff were supportive but somewhat hesitant about the programmatic change, particularly regarding safety concerns when bringing unarmed civilians into the field. Themes from the interviews showed that although there was certainly doubt among FPD staff initially, the intentionally collaborative efforts made by FPD administrators and UA faculty to support organizational acceptance of the program produced early successes. By highlighting crucial aspects of the implementation process and the lessons learned along the way, the results from this study can guide future replication efforts in similarly situated localities.

Abstract Background Vascular calcification is a major contributor to the high cardiac burden among hemodialysis patients. A novel in vitro T50-test, which determines calcification propensity of human serum, may identify patients at high risk for cardiovascular (CV) disease and mortality. We evaluated whether T50 predicts mortality and hospitalizations among an unselected cohort of hemodialysis patients. Methods This prospective clinical study included 776 incident and prevalent hemodialysis patients from 8 dialysis centers in Spain. T50 and fetuin-A were determined at Calciscon AG, all other clinical data were retrieved from the European Clinical Database. After their baseline T50 measurement, patients were followed for two years for the occurrence of all-cause mortality, CV-related mortality, all-cause and CV-related hospitalizations. Outcome assessment was performed with proportional subdistribution hazards regression modelling. Results Patients who died during follow-up had a significantly lower T50 at baseline as compared to those who survived (269.6 vs. 287.7 min, p = 0.001). A cross-validated model (mean c statistic: 0.5767) identified T50 as a linear predictor of all-cause-mortality (subdistribution hazard ratio (per min): 0.9957, 95% CI [0.9933;0.9981]). T50 remained significant after inclusion of known predictors. There was no evidence for prediction of CV-related outcomes, but for all-cause hospitalizations (mean c statistic: 0.5284). Conclusion T50 was identified as an independent predictor of all-cause mortality among an unselected cohort of hemodialysis patients. However, the additional predictive value of T50 added to known mortality predictors was limited. Future studies are needed to assess the predictive value of T50 for CV-related events in unselected hemodialysis patients.

The importance of establishing effective literacy/reading skills at an early age, preschool to early elementary, is well known and accepted among educators. For students whose heritage language is not English, the influential factors of cultural relevance and parent/family involvement for the acquisition of these fundamental skills are underscored. OneCommunity (OC) Reads is a literacy program focused on enhancing Latino children's reading proficiency in a culturally sensitive manner utilizing the funds of knowledge of parents/families and community. Using a community-based, participatory evaluation/research paradigm, the impact of OC Reads was examined using both quantitative and qualitative data. Findings indicated parents/families were affected positively, resulting in increased empowerment and involvement in the schools and the community. Themes derived from the qualitative data included (a) broad empowerment, (b) increased mutual understanding and respect, (c) shared responsibility, and (d) academic and reading improvement. Strengths were noted in the areas of culturally sensitive and helpful processes, and additional activities and enhancements. OC Reads' success in enhancing literacy/reading proficiency with its nontraditional approach of empowering parents and building on the cultural realities of the students gives further credence to the literature regarding the success of such approaches.

Objective: To evaluate high-frequency (10-kHz) spinal cord stimulation (SCS) treatment in refractory painful diabetic neuropathy. Patients and Methods: A prospective, multicenter randomized controlled trial was conducted between Aug 28, 2017 and March 16, 2021, comparing conventional medical management (CMM) with 10-kHz SCS+CMM. The participants had hemoglobin A1c level of less than or equal to 10% and pain greater than or equal to 5 of 10 cm on visual analog scale, with painful diabetic neuropathy symptoms 12 months or more refractory to gabapentinoids and at least 1 other analgesic class. Assessments included measures of pain, neurologic function, and health-related quality of life (HRQoL) over 12 months with optional crossover at 6 months. Results: The participants were randomized 1:1 to CMM (n=103) or 10-kHz SCS+CMM (n=113). At 6 months, 77 of 95 (81%) CMM group participants opted for crossover, whereas none of the 10-kHz SCS group participants did so. At 12 months, the mean pain relief from baseline among participants implanted with 10-kHz SCS was 74.3% (95% CI, 70.1-78.5), and 121 of 142 (85%) participants were treatment responders (≥50% pain relief). Treatment with 10-kHz SCS improved HRQoL, including a mean improvement in the EuroQol 5-dimensional questionnaire index score of 0.136 (95% CI, 0.104-0.169). The participants also reported significantly less pain interference with sleep, mood, and daily activities. At 12 months, 131 of 142 (92%) participants were “satisfied” or “very satisfied” with the 10-kHz SCS treatment. Conclusion: The 10-kHz SCS treatment resulted in substantial pain relief and improvement in overall HRQoL 2.5- to 4.5-fold higher than the minimal clinically important difference. The outcomes were durable over 12 months and support 10-kHz SCS treatment in patients with refractory painful diabetic neuropathy. Trial registration: clincaltrials.gov Identifier: NCT03228420

Air surveillance offers a potential means of monitoring airborne pathogens without the need for individual sampling. Here, the authors perform continuous air sampling in 15 community settings in the US for 29 weeks and demonstrate its feasibility for routine detection of SARS-CoV-2 and other respiratory pathogens.

T cell receptor (TCR) gene modified T cells are a promising form of adoptive cellular therapy against human malignancies and viral infections. Since the first human clinical trial was carried out in 2006, several strategies have been developed to improve the efficacy and safety of TCR engineered T cells by enhancing the surface expression of the introduced therapeutic TCRs whilst reducing the mis-pairing with endogenous TCR chains. In this study, we explored how modifications of framework residues in the TCR variable domains affect TCR expression and function. We used bioinformatic and protein structural analyses to identify candidate amino acid residues in the framework of the variable β domain predicted to drive high TCR surface expression. Changes of these residues in poorly expressed TCRs resulted in improved surface expression and boosted target cell specific killing by engineered T cells expressing the modified TCRs. Overall, these results indicate that small changes in the framework of the TCR variable domains can result in improved expression and functionality, while at the same time reducing the risk of toxicity associated with TCR mis-pairing.

Abstract Background The vascular access preservation and the maintenance of a complication-free fistula remains an Achilles’ heel of hemodialysis in chronic kidney patients due to its substantial contribution to the morbidity and mortality. Systematic studies in the area of examining cannulation practices, achieving complication-free cannulation, and strategies to improve fistula survival are needed. For this reason, we consider it essential to create and investigate new methodologies for approaching fistula in patients on regular HD. The Multiple Single Cannulation Technique (MuST) is based on the association between the rope-ladder (RL) using the arteriovenous vessel through progressive rotation, and the buttonhole (BH) since there are three specific cannulation sites for each cannulation day during the week. The MuST is simple to implement and seems to be a very promising technique in terms of patient safety. Previous studies already showed an arteriovenous fistula survival similar to RL but significantly higher than BH. Methods This MuST study is a multicenter, prospective, non-blind, parallel-group, randomized controlled trial with the intervention group submitted to MuST and a control group undergoing the rope-ladder, up to 100 subjects for each group. Patients will be randomized 1:1 to one of two cannulation technique (CT), and the follow-up period of this study will be 12 months. Primary outcome is to evaluate the arteriovenous fistula survival rate at 12 months determined by the percentage of fistulas in use from the beginning of the study to the date of the first clinical intervention by angioplasty or vascular surgery, to maintain or restore patency (unassisted patency). Secondary outcome is to evaluate arteriovenous fistula survival rate at 12 month determined by the percentage of fistulas in use from the study start to the date of access abandonment due to dysfunction, patient abandonment, or death, treatment change modality or study end. We will also evaluate the assisted primary patency and include the following secondary outcomes associated with the cannulation technique: Infection, Hematoma, Aneurysm development, and pain. Discussion The study will investigate whether fistula survival can be improved when using cannulation by MuST compared to the RL. MuST study will provide important information on fistula survival when cannulated by MuST but also information related to its use in fistulas previously cannulated by other CTs. Trial registration ClinicalTrials.gov identifier NCT05081648 registered on 18 October 2021.

Summary: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is little evidence to guide systemic therapeutic options. We performed genomic profiling of a cohort of tumors through the analysis of whole genomes, transcriptomes, as well as flow cytometry and immunohistochemistry in order to gain a deeper understanding of their molecular biology. We find neutral evolution after early tumor activation with a lack of secondary driver events. We show that these tumors have epithelial derivation, possibly from the macula densa, a specialized paracrine cell of the renal juxtaglomerular apparatus. They subsequently develop into immune excluded tumors. We provide transcriptomic and protein expression evidence of a highly specific tumor marker, PAPPA2. These translational findings have implications for the diagnosis and treatment for this rare tumor subtype.

This study proposed using enamel surface texture and thickness for the objective detection and monitoring of erosive tooth wear (ETW), comparing them to the standard subjective Basic Erosive Wear Evaluation (BEWE). Thirty-two subjects (n = 597 teeth) were enrolled in this longitudinal observational clinical study. Enamel thickness (by cross-polarization optical coherence tomography, CP-OCT) and 3D dental microwear parameters, i.e., area-scale fractal complexity (Asfc), anisotropy (Str), and roughness (Sa) (by white-light scanning confocal profilometry), were obtained from buccal surfaces. Buccal, occlusal, and lingual surfaces were scored for BEWE and the maximum score per tooth (BEWEMax) was determined at baseline and 12 months (M12). Data outcome relationships were evaluated (alpha = 0.05). Enamel thickness decreased (p < 0.001), BEWE scores, Sa, and Str increased (p < 0.001), while Asfc did not change at M12. Baseline BEWEBuccal correlated strongly with BEWEMax (r = 0.86, p < 0.001) and moderately with BEWELingual (r = 0.42, p < 0.001), but not with enamel thickness (r = 0.03, p = 0.43). Change (Δ) in surface texture outcomes correlated poorly but significantly with ΔBEWEBuccal (r = −0.15–0.16, p < 0.001) and did not correlate with Δenamel thickness (r = 0.02–0.09, p > 0.06). Teeth with BEWE progression revealed a greater increase in ΔSa and ΔStr. These findings suggest that enamel surface roughness can potentially determine ETW severity, and CP-OCT may be relevant for clinically monitoring enamel thickness.

Sebastian Zschätzsch,1 Manuela Stauss-Grabo,2 Adelheid Gauly,2 Jennifer Braun2 1Center for Kidney and Blood Pressure Diseases, Georg-Haas-Dialysis Center, Giessen, Germany; 2Fresenius Medical Care, Global Medical Office, Bad Homburg, GermanyCorrespondence: Adelheid GaulyFresenius Medical Care Deutschland GmbH, Global Medical Office, Else-Kröner-Strasse 3, Bad Homburg, 61352, GermanyTel +49 6172 6092260Email adelheid.gauly@fmc-ag.comPurpose: Volume management in hemodialysis (HD) requires the ability to assess volume status objectively and determine treatment strategies that achieve euvolemia without compromising hemodynamic stability. The aim of this study was to compare dialysis with and without blood volume-controlled ultrafiltration (UF) in combination with body composition monitoring, and to evaluate indicators for adequate dialysis (Kt/V), ultrafiltration volume, fluid status, and the occurrence of intradialytic morbid events (IME).Patients and Methods: Patients undergoing hemodialysis or on-line hemodiafiltration with support of a blood volume monitor (BVM) – a feedback control device integrated into the 5008 and 6008 HD systems – were enrolled. Patients received treatment for four weeks using the 6008 CAREsystem and the BVM (6008+). Data on dialysis dose (Kt/V), UF volume and predialysis fluid status were documented. This data was also documented retrospectively for four weeks with (5008+) and without (5008−) the use of the BVM with the 5008 system. Comparisons were analyzed using linear mixed models.Results: Twenty-four patients were enrolled. Kt/V was unaffected by blood volume-controlled UF (5008− vs 5008+: p=0.230) and was equally achieved with both HD systems (5008+ vs 6008+: p=0.922). The UF volume and fluid status achieved were comparable, independent of the use of UF control with BVM (5008− vs 5008+; UF volume: p=0.166; fluid overload: p=0.390) or the HD system (5008+ vs 6008+: UF volume: p=0.003; fluid overload: p=0.838), except for UF volume being higher in the 6008+ phase. IMEs occurred in less than 3% of treatments, with no difference between study phases.Conclusion: This study demonstrates that a clinical approach to kidney replacement therapy that tracks volume status and manages intradialytic fluid removal by blood volume-controlled UF delivers adequate dialysis without compromising fluid removal. It maintains volume status and ensures low incidence of IMEs.Keywords: fluid status, blood volume monitoring, body composition monitoring, dialysis dose, intradialytic morbid events

Shared metabolic pathways could allow simultaneous manipulation of T cells, viruses and tumours. Here the authors show targeting cholesterol esterification restrains hepatitis B in vitro, whilst bolstering exhausted antigen-specific T cell responses from human liver and hepatocellular carcinoma.

Abstract Background SARS-CoV-2 (COVID-19) is a novel coronavirus associated with high mortality rates. The use of Continuous Positive Airway Pressure (CPAP) has been recognised as a management option for severe COVID-19 (NHS, Specialty guides for patient management during the coronavirus pandemic Guidance for the role and use of non-invasive respiratory support in adult patients with coronavirus (confirmed or suspected), https://www.nice.org.uk/guidance/ng159 ). We offered ward-based CPAP to COVID-19, dialysis patients not suitable for escalation to ICU. The aim of the study was to evaluate the use of CPAP for COVID-19 dialysis patients compared to non-dialysis COVID-19 patients outside of the intensive care setting. We further aimed to investigate factors associated with improved outcomes. Methods Data was collected from a single centre (Royal Preston Hospital, UK), from March to June 2020. Treatment outcomes were compared for dialysis and non-dialysis dependent patients who received CPAP with limitations on their escalation and resuscitation status. Kaplan-Meier survival curves and Cox regression models were used to compare outcomes. The primary study outcome was 30 day mortality. Confounders including length of admission, systemic anticoagulation and ultrafiltration volumes on dialysis were also analysed. Results Over the study period, 40 dialysis patients tested positive for COVID-19, with 30 requiring hospital admission. 93% (n = 28) required supplementary oxygen and 12% (n = 9) required CPAP on the ward. These patients were compared to a serial selection of 14 non-dialysis patients treated with CPAP during the same period. Results showed a significant difference in 30 day survival rates between the two groups: 88.9% in the dialysis group vs. 21.4% in the non-dialysis group. Statistical modelling showed that anticoagulation was also an important factor and correlated with better outcomes. Conclusion This is to the best of our knowledge, the largest series of COVID-19 dialysis patients treated with CPAP in a ward-based setting. In general, dialysis dependent patients have multiple co-morbidities including cardiovascular disease and diabetes mellitus making them vulnerable to COVID-19 and not always suitable for treatment in ICU. We showed a significantly lower 30 day mortality rate with the use of CPAP in the dialysis group (11.1%) compared to the non-dialysis group (78.6%). Despite a small sample size, we believe this study provides impetus for further work clarifying the role of CPAP in treating COVID-19 dialysis dependent patients.

Abstract Vagus nerve stimulation (VNS) facilitates weight loss in animals and patients treated with VNS for depression or epilepsy. Likewise, chronic transcutaneous auricular VNS (taVNS) reduces weight gain and improves glucose tolerance in Zucker diabetic fatty rats. If these metabolic effects of taVNS observed in rats translate to humans is unknown. Therefore, the hypothesis of this study was that acute application of taVNS affects glucotropic and orexigenic hormones which could potentially facilitate weight loss and improve glucose tolerance if taVNS were applied chronically. In two single‐blinded randomized cross‐over protocols, blood glucose levels, plasma concentrations of insulin, C‐peptide, glucagon, leptin, and ghrelin, together with heart rate variability and baroreceptor‐heart rate reflex sensitivity were determined before and after taVNS (left ear, 10 Hz, 300 µs, 2.0–2.5 mA, 30 min) or sham‐taVNS (electrode attached to ear with the stimulator turned off). In a first protocol, subjects (n = 16) were fasted throughout the protocol and in a second protocol, subjects (n = 10) received a high‐calorie beverage (220 kCal) after the first blood sample, just before initiation of taVNS or sham‐taVNS. No significant effects of taVNS on heart rate variability and baroreceptor‐heart rate reflex sensitivity and only minor effects on glucotropic hormones were observed. However, in the second protocol taVNS significantly lowered postprandial plasma ghrelin levels (taVNS: −115.5 ± 28.3 pg/ml vs. sham‐taVNS: −51.2 ± 30.6 pg/ml, p

Increasing TCR cell surface expression can potentiate T cell responses to low-concentrations of antigen. Here the authors identify aminoacids in human TCR variable domains that impact its surface expression, and demonstrate how editing these residues can improve T cell activation and effector function without altering antigen specificity.

Abstract Inflammatory processes are crucial in atherosclerosis and atherothrombosis. This study aimed to identify a cytokine-pattern that is associated with plaque-vulnerability or symptomatic state in comprehensively investigated patients with symptomatic (sCS) and asymptomatic carotid stenosis (aCS). Twenty-two patients with sCS and twenty-four patients with aCS undergoing carotid endarterectomy (CEA) were considered. A cytokine-panel was measured in plasma-specimens prior to surgery and at a 90 day follow-up. Doppler-ultrasound detecting microembolic signals (MES) in the ipsilateral middle cerebral artery was performed. Carotid plaques were analysed regarding histopathological criteria of plaque-vulnerability and presence of chemokine receptor CXCR4. Correction for multiple comparisons and logistic regression analysis adjusting for vascular risk factors, grade of stenosis, antithrombotic and statin pretreatment were applied. In sCS-patients higher plasma-levels of Fractalkine (CX3CL1), IFN-α2, IL-1β, IL-2, IL-3, IL-7 were found compared to aCS-patients. CXCR4-expression on inflammatory cells was more evident in sCS- compared to aCS-plaques and was associated with vulnerability-criteria. In contrast, plasma-cytokine-levels were not related to CXCR4-expression or other vulnerability-criteria or MES. However, in both groups distinct inter-cytokine correlation patterns, which persisted at follow-up and were more pronounced in the sCS-group could be detected. In conclusion, we identified a distinct cytokine/chemokine-network in sCS-patients with elevated and closely correlated mediators of diverse functions.

The thymus is essential for T cell maturation and selection, and thymic defects result in severe immune problems. Here the authors identify a thymus cell population that is expandable in vitro, and can repopulate natural thymic matrix to generate tissue that supports mature T cell development in vitro and in vivo.

Recent clinical trials are evaluating induced pluripotent stem cells (iPSCs) as a cellular therapy in the field of regenerative medicine. The widespread clinical utility of iPSCs is expected to be realized using allogeneic cells that have undergone thorough safety evaluations, including assessment of their immunogenicity. IPSC-derived neural crest stem cells (NCSCs) have significant potential in regenerative medicine; however, their application in cellular therapy has not been widely studied to date, and no reports on their potential immunogenicity have been published so far. In this study, we have assessed the expression of immune-related antigens in iPSC-NCSCs, including human leukocyte antigen (HLA) class I and II and co-stimulatory molecules. To investigate functional immunogenicity, we used iPSC-NCSCs as stimulator cells in a one-way mixed lymphocyte reaction. In these experiments, iPSC-NCSCs did not stimulate detectable proliferation of CD3+ and CD3+CD8+ T cells or induce cytokine production. We show that this was not a result of any immunosuppressive features of iPSC-NCSCs, but rather more consistent with their non-immunogenic molecular phenotype. These results are encouraging for the potential future use of iPSC-NCSCs as a cellular therapy.

Despite the significant medical and technical improvements in the field of dialytic renal replacement modalities, morbidity and mortality are excessively high among patients with end-stage kidney disease, and most interventional studies yielded disappointing results. Hemodiafiltration, a dialysis method that was implemented in clinics many years ago and that combines the two main principles of hemodialysis and hemofiltration—diffusion and convection—has had a positive impact on mortality rates, especially when delivered in a high-volume mode as a surrogate for a high convective dose. The achievement of high substitution volumes during dialysis treatments does not only depend on patient characteristics but also on the dialyzer (membrane) and the adequately equipped hemodiafiltration machine. The present review article summarizes the technical aspects of online hemodiafiltration and discusses present and ongoing clinical studies with regards to hard clinical and patient-reported outcomes.

Telemedicine and digitalised healthcare have recently seen exponential growth, led, in part, by increasing efforts to improve patient flexibility and autonomy, as well as drivers from financial austerity and concerns over climate change. Nephrology is no exception, and daily innovations are underway to provide digitalised alternatives to current models of healthcare provision. Wearable technology already exists commercially, and advances in nanotechnology and miniaturisation mean interest is also garnering clinically. Here, we outline the current existing wearable technology pertaining to the diagnosis and monitoring of patients with a spectrum of kidney disease, give an overview of wearable dialysis technology, and explore wearables that do not yet exist but would be of great interest. Finally, we discuss challenges and potential pitfalls with utilising wearable technology and the factors associated with successful implementation.

Background: Specific microRNAs (miRs) have been implicated in the pathophysiology of atherosclerosis and may represent interesting diagnostic and therapeutic targets in carotid stenosis. We hypothesized that the levels of specific circulating miRs are altered in patients with symptomatic carotid stenosis (sCS) in comparison to those in patients with asymptomatic carotid stenosis (aCS) planned to undergo carotid endarterectomy (CEA). We also studied whether miR levels are associated with plaque vulnerability and stability over time after CEA.Methods: Circulating levels of vascular-enriched miR-92a, miR-126, miR-143, miR-145, miR-155, miR-210, miR-221, miR-222, and miR-342-3p were determined in 21 patients with sCS and 23 patients with aCS before CEA and at a 90-day follow-up. Transcranial Doppler ultrasound for detection of microembolic signals (MES) in the ipsilateral middle cerebral artery was performed prior to CEA. Carotid plaques were histologically analyzed.Results: Mean levels of miRs were not considerably different between groups and were only marginally higher in sCS than aCS concerning miR-92a, miR-210, miR-145, and miR-143 with the best evidence concerning miR-92a. After adjustment for vascular risk factors and statin pre-treatment, the effect sizes remained essentially unchanged. At follow-up, however, these modest differences remained uncorroborated. There were no relevant associations between miR-levels and MES or histological plaque vulnerability features.Conclusions: This study does not provide evidence for strong associations between specific circulating miRs and symptomatic state in a collective of comprehensively characterized patients with carotid stenosis. Further work is needed to elucidate the role of circulating miRs as targets in advanced carotid atherosclerosis.

This study expands the literature of online human diversity courses in social work by comparing the effectiveness of these courses to face-to-face instruction. To measure effectiveness, pre- and posttests were completed by 117 students. The instrument used measured awareness of and ability to recognize cultural diversity and oppression and the level of belief that our society is just. The findings suggest that online and face-to-face students showed an increase in their awareness of diversity and oppression issues with little to no significant difference between the two groups. Although not statistically significant, the online students' belief in a just world decreased, whereas their face-to-face counterparts showed an increase, which was an unexpected finding. Implications for online social work classes are discussed.