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Butynediol is an important intermediate in the chemical industry and is produced from acetylene and aqueous formaldehyde. Mixtures of formaldehyde + water + butynediol are complex reacting multicomponent systems in which oligomerization reactions of formaldehyde with both water and butynediol occur. The chemical equilibria of the reactions of formaldehyde with butynediol were studied recently by quantitative NMR spectroscopy (Berje et al., DOI: 10.1002/AIC.15788). The present work complements this by a kinetic study of these reactions. Aqueous formaldehyde solutions were diluted with aqueous butynediol solutions, and the kinetic response was monitored by 1H NMR spectroscopy. Most of the experiments were carried out in NMR sample tubes; additional experiments were carried out with a micromixer NMR probe to extend the studied range to kinetics with time constants well below 1 min. The new reaction kinetic data cover temperatures between 293.15 and 328.15 K and pH values between 3 and 6. A reaction kinetic model was developed based on the equilibrium model from the previous study, and the reaction kinetic constants were determined from the new data. Furthermore, new reaction kinetic data for the system formaldehyde + water were measured, which extend the available data on that system to faster kinetics. These new data confirm the mole fraction-based reaction kinetic model of Hahnenstein et al. (DOI: 10.1021/ie00041a003).

The COVID-19 pandemic has affected everyone's life and how people spend their time. In this surrounding of changes, leisure activities and leisure-related travel gain special attention. Little is known about how affected people behave over time under the circumstances of a pandemic. This paper analyzes the impact of the COVID-19 pandemic on leisure activities and leisure-related travel patterns in Germany. The evaluation is based on the unique data set of the German Mobility Panel (MOP), a panel survey where individuals participate for one week in three consecutive years. The analyses show that the different stages of the pandemic drove changes in how people behave in their free time. During the first fall of the COVID-19 pandemic, significant decreases in travel demand are identified across all sociodemographic groups. With the relaxation of preventive measures during the summer of 2021, the previous plunge of leisure activities between 2019 and 2020 slowly returned in the direction of the initial state of 2019. Furthermore, it can be seen that the impact of sociodemographic characteristics such as gender, economic status or occupation status varies between the years and different leisure travel indicators.

Real-world data showing the long-term effectiveness of long-acting injectable cabotegravir and rilpivirine are scarce. We assessed the effectiveness of cabotegravir and rilpivirine in all individuals who switched to cabotegravir and rilpivirine in the Netherlands.

Podocytes possess immune system components allowing for a variety of innate responses to endogenous and exogenous stimuli. Recently, several groups have linked inappropriate innate immune signaling to podocyte injury, particularly chronic, sustained injury; however, the immune capabilities of podocytes have not been fully elucidated. Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from damaged cells, including podocytes, and can elicit an inflammatory response and recruit immune cells to areas of injury. This is performed through binding to pattern recognition receptors. Believed largely to be protective and responsive to injury or infection, recent evidence suggests signaling through DAMP pathways can aggravate and promote chronic diseases already associated with inflammation. The purpose of this narrative review was to highlight current knowledge with respect to specific podocyte DAMPs and pattern recognition receptors and to provide insight into ongoing work and possible future research avenues to advance our understanding of podocyte immune mechanisms.

Glioblastoma (GBM) is a lethal brain tumor without effective treatment options. This study aimed to characterize longitudinal tumor changes in order to find potentially actionable targets to prevent GBM relapse. We extracted RNA and proteins from fresh frozen tumor samples from patient-matched IDHwtWHO grade 4 primary (pGBM) and recurrent (rGBM) tumors for transcriptomics and proteomics analysis. A tissue microarray containing paired tumor samples was processed for spatial transcriptomics analysis. Differentially expressed genes and proteins between pGBM and rGBM were involved in synapse development and myelination. By categorizing patients into short (STTR) and long (LTTR) time-to-lapse, we identified genes/proteins whose expression levels positively or negatively correlated with TTR. In rGBM, expressions of Fcγ receptors (FCGRs) and complement system genes were negatively correlated with TTR, whereas expression of genes involved in DNA methylation was positively correlated with TTR. Spatial transcriptomics of the tumor cells showed enrichment of oligodendrocytes in rGBM. Besides, we observed changes in the myeloid compartment such as a switch from quiescent to activated microglia and an enrichment in B and T cells in rGBM with STTR. Our results uncover a role for activated microglia/macrophages in GBM recurrence and suggest that interfering with these cells may hinder GBM relapse.

This study examined the relationship between change in symptom severity and personal recovery in patients with severe mental illness (SMI). Forty-nine outpatients at Mentrum/Arkin, Amsterdam, the Netherlands, were assessed at baseline and 3 years later, using the Brief Psychiatric Rating Scale and the Mental Health Recovery Measure. Correlation coefficients and linear regression analyses were used. Further, the impact of severity of symptoms at baseline on change in personal recovery was evaluated. Results show that change in symptom severity explained 31.8% of the variance of change in personal recovery. Change in depression/anxiety explained 27.3% of the variance of change in personal recovery. Higher affective symptom severity at baseline significantly predicted positive change in personal recovery. In conclusion, besides change in symptom severity, other potential determinants of personal recovery should be addressed in treatment of patients with SMI, for example, self-esteem and social functioning. Treatment of depression/anxiety symptoms may increase personal recovery.

Extracellular vesicles, small membrane-bound packages secreted by virtually all cells of the body, have become a focus of interest in nephrology over the recent years. After the first characterization of their proteomic and transcriptomic content, scientific attention shifted toward their potential as biomarkers for kidney diseases both as diagnostic and monitoring tools. More recently, researchers have begun exploring whether extracellular vesicles mediate intercellular signaling inside the nephron and between the kidney and other organs throughout the body. Nevertheless, the field of extracellular vesicle research has struggled to translate major findings to the clinical context due to numerous methods to separate extracellular vesicles, yielding fractions of different sizes and varying purity, unclear terminology, and, hence, limitations concerning reproducibility. The International Society of Extracellular Vesicles, therefore, has striven to reduce these barriers by an ongoing initiative to increase rigor and standardization of extracellular vesicle research. The “Minimal Information for Studies of Extracellular Vesicles” guideline is the result of this initiative and, in its now third iteration, provides the most concise suggestions for investigating extracellular vesicles to date. This mini review illustrates the advances made in extracellular vesicle research in nephrology so far using informative examples, outlines the advances made by the former Minimal Information for Studies of Extracellular Vesicles guidelines, and shows what potential using the latest iteration holds.

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The first commercial dual-chamber leadless pacemaker (LLPM) was introduced recently. The system combines two separate implants situated in the right atrium and the right ventricle of the heart. Implant synchronization is accomplished with conductive intracardiac communication (CIC) using the myocardium and blood as transmission channel. Successful implant synchronization of this dual-chamber LLPM has been demonstrated. However, the continuously active synchronization transceivers, consuming about 800 nA, cause a 25-45$\mathbf{\%}$ reduction in the projected device longevity. This work proposes an alternative strategy for power-optimized LLPM synchronization, which is based on synchronous duty-cycling of the transceivers and direct-digital CIC (DD-CIC). In line with this strategy, a novel low-power DD-CIC receiver for short-packet communication based on Manchester-encoded data and with fast startup time is presented. The circuit was fabricated in 180 nm CMOS technology and analyzed with respect to sensitivity, current consumption and startup time under highly duty-cycled operation. The receiver achieves a sensitivity of 81.6$\mathbf{\pm}$7.4 $\mu$V at a data rate of 100 kb/s, with an active current consumption of 39.1$\mathbf{\pm}$0.6 $\mu$A and a startup time below 250 $\mathbf{\mu}$s. Operating the receiver as specified by the proposed LLPM synchronization strategy reduces the current consumption to a measured average value of 73 nA. In conclusion, this work suggests synchronous duty-cycling for CIC-based implant synchronization as a promising concept to severely reduce the current consumption of contemporary dual-chamber LLPMs. Consequently, device longevity may be increased significantly, potentially reducing the frequency of costly and complication-prone re-interventions.

In Deutschland trat 2018 der § 132g SGB V in Kraft, wodurch stationäre Pflegeeinrichtungen und besondere Wohnformen der Eingliederungshilfe Leistungen der gesundheitlichen Versorgungsplanung (GVP) zu Lasten der gesetzlichen Krankenversicherung abrechnen können. Ziel dieser Arbeit war zu evaluieren, in welcher Anzahl die zu übermittelnden Leistungsnachweise vorliegen, sowie zu prüfen, welche Informationen sie über den Beratungsprozess enthalten und inwiefern diese für Forschungszwecke nutzbar sind.

Now extinct, the aurochs (Bos primigenius) was a keystone species in prehistoric Eurasian and North African ecosystems, and the progenitor of cattle (Bos taurus), domesticates that have provided people with food and labour for millennia1. Here we analysed 38 ancient genomes and found 4 distinct population ancestries in the aurochs—European, Southwest Asian, North Asian and South Asian—each of which has dynamic trajectories that have responded to changes in climate and human influence. Similarly to Homo heidelbergensis, aurochsen first entered Europe around 650 thousand years ago2, but early populations left only trace ancestry, with both North Asian and European B. primigeniusgenomes coalescing during the most recent glaciation. North Asian and European populations then appear separated until mixing after the climate amelioration of the early Holocene. European aurochsen endured the more severe bottleneck during the Last Glacial Maximum, retreating to southern refugia before recolonizing from Iberia. Domestication involved the capture of a small number of individuals from the Southwest Asian aurochs population, followed by early and pervasive male-mediated admixture involving each ancestral strain of aurochs after domestic stocks dispersed beyond their cradle of origin.

Poly(oxymethylene) dimethyl ethers of chain length 3–5 ( ▪ ) are discussed as synthetic diesel fuels due to their potential to significantly reduce soot emissions while presenting physicochemical properties similar to conventional diesel fuels. A recently developed process to produce ▪ directly from methanol and aqueous formaldehyde is a promising way to avoid expensive intermediates such as trioxane, methylal, or dimethyl ether. The process consists of a reactor, a distillation sequence, and a membrane unit. The first distillation column is particularly challenging due to the reactive character of the separation, the high number of components present, and the limited solubility of formaldehyde. Up to now, the feasibility of this separation has yet to be demonstrated. This work presents closed-loop experiments in a demonstration plant erected at the Campus Straubing of the Technical University of Munich with closing recycle. In the distillation step, ▪ with very small impurities of around 800 ppm of formaldehyde was obtained. The experimental results were compared with simulations based on a reactive equilibrium stage model. The simulations of the temperature and composition profiles for the majority of the components are in line with the experiments. Although the membrane separation exhibited weaker water selectivity than in previous tests, it was sufficient to overcome distillation boundaries. Additionally, this study assesses the potential for solid precipitation, explores trade-offs in product quality, and discusses overall mass balances of the process, demonstrating the overall feasibility of the process.

Background: The CRC-PIPAC-II study prospectively assessed bidirectional therapy (BT) consisting of first-line palliative systemic therapy and electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC-OX) in patients with unresectable colorectal peritoneal metastases (CPM). This study describes the exploration of patient-reported outcomes (PROs). Methods: In this phase II trial, 20 patients with isolated CPM were treated with up to three cycles of BT, each cycle consisting of two to three courses of systemic therapy, followed by ePIPAC-OX (92 mg/m2). Patients were asked to complete the EuroQoL EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CR29 questionnaires at baseline, during the first cycle of BT, and one and four weeks after each consecutive BT cycle. PRO scores were calculated and compared between baseline and each subsequent time point using linear-mixed modeling (LMM). PROs were categorized into symptom scales and function scales. Symptom scales ranged from 0 to 100, with 100 representing the maximum symptom load. Function scales ranged from 0 to 100, with 100 representing optimal functioning. Results: Twenty patients underwent a total of 52 cycles of bidirectional therapy. Most PROs (29 of 37, 78%) were not significantly affected during trial treatment. In total, only eight PROs (22%) were significantly affected during trial treatment: Six PROs (index value, global health status, emotional functioning, C30, appetite, and insomnia) showed transient improvement at different time points. Two PROs transiently deteriorated: pain initially improved during the first BT cycle [− 16, p< 0.001] yet worsened temporarily one week after the first two BT cycles (+ 20, p< 0.001; + 17, p= 0.004; respectively). Abdominal pain worsened temporarily one week after the first BT cycle (+ 16, p= 0.004), before improving again four weeks after treatment ended (− 10, p= 0.004). All significant effects on Pros were clinically significant and all deteriorations in PROs were of temporary nature. Discussion: Patients undergoing BT for unresectable CPM had significant, but reversible alterations in several PROs. Most affected PROs concerned improvements and only two PROs showed deteriorations. Both deteriorated PROs returned to baseline after trial treatment and were of a temporary nature. These outcomes help to design future studies on the role of ePIPAC in the palliative setting.

Dual-chamber leadless pacemakers (LLPMs) consist of two implants, one in the right atrium and one in the right ventricle. Inter-device communication, required for atrioventricular (AV) synchrony, however, reduces the projected longevity of commercial dual-chamber LLPMs by 35–45%. This work analyzes the power-saving potential and the resulting impact on AV-synchrony for a novel LLPM synchronization protocol. Relevant parameters of the proposed window scheduling algorithm were optimized with system-level simulations investigating the resulting trade-off between transceiver current consumption and AV-synchrony. The parameter set included the algorithm’s setpoint for the target number of windows per cardiac cycle and the number of averaging cycles used in the window update calculation. The sensing inputs for the LLPM model were derived from human electrocardiogram recordings in the MIT-BIH Arrhythmia Database. Transceiver current consumption was estimated by combining the simulation results on the required communication resources with electrical measurements of a receiver microchip developed for LLPM synchronization in previous work. The performance ratio given by AV-synchrony divided by current consumption was maximized for a target of one window per cardiac cycle and three averaging cycles. Median transceiver current of both LLPMs combined was 166 nA (interquartile range: 152–183 nA) and median AV-synchrony was 92.5%. This corresponded to median reduction of 18.3% and 3.2% in current consumption and AV-synchrony, respectively, compared to a non-rate-responsive implementation of the same protocol, which prioritized maximum AV-synchrony. In conclusion, adopting a rate-responsive communication protocol may significantly increase device longevity of dual-chamber LLPMs without compromising AV-synchrony, potentially reducing the frequency of device replacements.

ABSTRACTBackgroundDolutegravir (DTG) is an antiviral agent used for the treatment of HIV, however, there is uncertainty over the influence of genetic variation on DTG exposure, and whether it has clinical implications for the efficacy or toxicity in different populations. This systematic review aims to create an overview of the impact of pharmacogenomics (PGx) on DTG exposure, efficacy, and toxicity.MethodsPublications up to 14 November 2023 were searched and articles were selected on the following criteria: original research articles providing data on people with HIV, data on PGx and either PK or PD or both PD and PGx.Results711 records were identified, and after screening 10 articles were included. Commonly analyzed genes across the articles were UGT1A1, ABCB1, ABCG2, and NR1I2. The most reported variant associated with PD variability was in SLC22A2, with carriers at higher risk of neuropsychiatric adverse events.ConclusionsThis review concludes that while PGx testing may help explain some variability in DTG pharmacokinetics when combined with therapeutic drug monitoring (TDM), current evidence is insufficient to support its routine clinical use. The role of PGx research for DTG remains relevant, especially in specific patient populations where interindividual PK variations are still unexplained.

Undesired coupling to the surrounding environment destroys long-range correlations in quantum processors and hinders coherent evolution in the nominally available computational space. This noise is an outstanding challenge when leveraging the computation power of near-term quantum processors1. It has been shown that benchmarking random circuit sampling with cross-entropy benchmarking can provide an estimate of the effective size of the Hilbert space coherently available2–8. Nevertheless, quantum algorithms’ outputs can be trivialized by noise, making them susceptible to classical computation spoofing. Here, by implementing an algorithm for random circuit sampling, we demonstrate experimentally that two phase transitions are observable with cross-entropy benchmarking, which we explain theoretically with a statistical model. The first is a dynamical transition as a function of the number of cycles and is the continuation of the anti-concentration point in the noiseless case. The second is a quantum phase transition controlled by the error per cycle; to identify it analytically and experimentally, we create a weak-link model, which allows us to vary the strength of the noise versus coherent evolution. Furthermore, by presenting a random circuit sampling experiment in the weak-noise phase with 67 qubits at 32 cycles, we demonstrate that the computational cost of our experiment is beyond the capabilities of existing classical supercomputers. Our experimental and theoretical work establishes the existence of transitions to a stable, computationally complex phase that is reachable with current quantum processors.

Anastomotic leakage is a severe postoperative complication in colorectal surgery and compromised bowel perfusion is considered a major contributing factor. Conventional methods to assess bowel perfusion have a low predictive value for anastomotic leakage. We therefore aimed to evaluate the efficacy of real-time assessment with near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) in the prevention of anastomotic leakage.

Alkanolamine-based chemical absorption carbon capture may present a promising pathway to achieving much-needed CO2emissions reductions, although high energy requirements pose a key challenge. A potential solution could be to replace water, the traditional alkanolamine cosolvent, with an organic (nonaqueous) alternative. To this end, this work presents the final step in parametrizing the s-SAFT-γ Mie predictive group-contribution equation of state (EoS) for alkanolamine/CO2/organic cosolvent systems. s-SAFT-γ Mie is extended to CO2/glyme and CO2/ethylene glycol mixtures and finally to alkanolamine/CO2/organic cosolvent systems. Using only a single parameter set, s-SAFT-γ Mie provides qualitatively meaningful predictions for a wide range of systems. This highlights the broad generalizability afforded by the group-contribution approach. While this generalizability comes at the cost of quantitative accuracy for individual systems, s-SAFT-γ Mie’s robust predictive capabilities and wide applicability render it suitable for potential use within an alkanolamine solvent/organic cosolvent screening tool.

We characterized population pharmacokinetics in 42 African children receiving once-daily 25 mg (14 to <20 kg) or 50 mg (>20 kg) dolutegravir. Coadministration with emtricitabine and tenofovir alafenamide reduced dolutegravir bioavailability by 19.6% (95% confidence interval: 8.13%–30.8%) compared with zidovudine or abacavir with lamivudine. Nevertheless, concentrations remained above efficacy targets, confirming current dosing recommendations.

Currently, real-world data on doravirine are scarce. In a national prospective cohort, we assessed the effectiveness and tolerability of switching to doravirine-based antiretroviral therapy (ART) in people with HIV.

•T-bet acts as a tumor suppressor by enhancing interferon signaling and suppressing proliferation of malignant B cells.•T-bet expression in CLL cells is positively correlated with longer overall survival in patients with CLL.

A comprehensive research agenda is needed to identify gaps and actionable steps to prioritize infant and early life mental health care globally.