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Curcumin is a biopharmaceutical classification system (BCS) class IV substance with many potential therapeutic effects. However, like many other BCS IV active pharmaceutical ingredients, complex formulations are needed to guarantee a sufficiently high bioavailability. A not-so-well-known delivery system is a suspoemulsion (SE). SEs are emulsions with a crystalline API in continuous or dispersed phases. This study aimed to produce curcumin-loaded o/w suspoemulsions with the particle in the oil phase for, e.g., encapsulation or triggered release effects. The particles need to be smaller than the emulsion droplet size to attain high encapsulation efficiencies (EE) in the oil phase. Sonofragmentation and bead milling were tested for their ability to produce these nanocrystals in different dispersion media. It was discovered that production in miglyol was the best fit for the needed application of the crystals in SEs. Around 85% (by volume) of the particles produced with bead milling were smaller than the droplet size of about 5 µm. In contrast, only 23% of the sonofragmentated particles were below the diameter of those droplets. This oily suspension was then used to successfully produce hydrogel-based o/w suspoemulsions. In the second part of this study, we investigated different methods for determining encapsulation efficiency, but none of the methods accurately and satisfactorily resolved the encapsulation efficiency. Finally, the suspoemulsions could not be macroscopically distinguished from one another and were physically stable. In summary, we showed that stable hydrogel-based curcumin-loaded o/w suspoemulsions could be produced.

As our societies and natural systems are becoming ever more interconnected, it is critical that sustainable management can adapt to new knowledge from both the ecological and the social domains, and act on it in a timely and effective manner. This need is amplifying in the Anthropocene as we are approaching the limit for humanity's safe operating space, leading to irreversible change to ecosystem function. This urgently requires increased attention and concern regarding the information feedbacks between the silos of science, policy and society. A web of policies is in place to protect the health of people and the planet, but to ensure that they are effective we need frameworks to make sense of real-world complexities and interlinkages between multiple factors. The Drivers-Pressures-State-Impacts-Response (DPSIR) framework was created for this purpose, however, its' implicit focus on 1) analytical and 2) procedural aspects must be made explicit, to enable coordination across silos and studies. Continued creation of new DPSIR derivatives may limit its impact, while more explicit coordination between these two aspects can improve the effectiveness of DPSIR while retaining its flexibility. We thus propose five elements to support sustainable policy development and implementation using DPSIR: 1) iteration; 2) risk, uncertainty and analytical bias; 3) flexible integration; 4) use of quantitative methods, and; 5) clear and standard definitions for DPSIR. We illustrate these elements in four cases: Three highlight missing feedbacks when DPSIR elements are not made explicit and a fourth case – on per-and-polyfluorinated alkyl substances (PFAS) – showing a potential roadmap to successful policy implementation using DPSIR.

Circulating tumour DNA (ctDNA) has been increasingly incorporated into the treatment of cancer patients. ctDNA is generally accepted as a powerful diagnostic tool, whereas the utility of ctDNA to monitor disease activity needs to be fully validated. Central to this challenge is the question of whether changes in longitudinal ctDNA measurements reflect disease activity or merely biological variation. Thus, the aim of this study was to explore the intra‐individual biological variation of ctDNA in lung cancer patients. We identified tumour‐specific mutations using next‐generation sequencing. Day‐to‐day and hour‐to‐hour variations in plasma concentrations of the mutant allele and wild‐type cell‐free DNA (cfDNA) were determined using digital PCR. The levels of the mutant alleles varied by as much as 53% from day to day and 27% from hour to hour. cfDNA varied up to 19% from day to day and up to 56% from hour to hour, as determined using digital PCR. Variations were independent of the concentration. Both mutant allele concentrations and wild‐type cfDNA concentrations showed considerable intra‐individual variation in lung cancer patients with nonprogressive disease. This pronounced biological variation of the circulating DNA should be investigated further to determine whether ctDNA can be used for monitoring cancer activity.

Over the last decades, an expansion of the underground network has been taking place to cope with the increasing amount of moving people and freight. As a consequence, it is of vital importance to guarantee the full functionality of the tunnel network by means of preventive maintenance and the monitoring of the tunnel lining state over time. A new method has been developed for the real-time prediction of the utilization level in tunnel segmental linings based on input monitoring data. The new concept is founded on a framework, which encompasses an offline and an online stage. In the former, the generation of feedforward neural networks is accomplished by employing synthetically produced data. Finite element simulations of the lining structure are conducted to analyze the structural response under multiple loading conditions. The scenarios are generated by assuming ranges of variation of the model input parameters to account for the uncertainty due to the not fully determined in situ conditions. Input and target quantities are identified to better assess the structural utilization of the lining. The latter phase consists in the application of the methodological framework on input monitored data, which allows for a real-time prediction of the physical quantities deployed for the estimation of the lining utilization. The approach is validated on a full-scale test of segmental lining, where the predicted quantities are compared with the actual measurements. Finally, it is investigated the influence of artificial noise added to the training data on the overall prediction performances and the benefits along with the limits of the concept are set out.

Abstract Fisheries worldwide face uncertain futures as climate change manifests in environmental effects of hitherto unseen strengths. Developing climate-ready management strategies traditionally requires a good mechanistic understanding of stock response to climate change in order to build projection models for testing different exploitation levels. Unfortunately, model-based projections of fish stocks are severely limited by large uncertainties in the recruitment process, as the required stock-recruitment relationship is usually not well represented by data. An alternative is to shift focus to improving the decision-making process, as postulated by the decision-making under deep uncertainty (DMDU) framework. Robust Decision Making (RDM), a key DMDU concept, aims at identifying management decisions that are robust to a vast range of uncertain scenarios. Here we employ RDM to investigate the capability of North Sea cod to support a sustainable and economically viable fishery under future climate change. We projected the stock under 40,000 combinations of exploitation levels, emission scenarios and stock-recruitment parameterizations and found that model uncertainties and exploitation have similar importance for model outcomes. Our study revealed that no management strategy exists that is fully robust to the uncertainty in relation to model parameterization and future climate change. We instead propose a risk assessment that accounts for the trade-offs between stock conservation and profitability under deep uncertainty.

Abstract Marine fisheries are increasingly impacted by climate change, affecting species distribution and productivity, and necessitating urgent adaptation efforts. Climate vulnerability assessments (CVA), integrating expert knowledge, are vital for identifying species that could thrive or suffer under changing environmental conditions. This study presents a first CVA for the Western Baltic Sea's fish community, a crucial fishing area for Denmark and Germany. Characterized by a unique mix of marine, brackish, and freshwater species, this coastal ecosystem faces significant changes due to the combined effects of overfishing, eutrophication and climate change. Our CVA involved a qualitative expert scoring of 22 fish species, assessing their sensitivity and exposure to climate change. Our study revealed a dichotomy in climate change vulnerability within the fish community of the Western Baltic Sea because traditional fishing targets cod and herring as well as other species with complex life histories are considered to face increased risks, whereas invasive or better adaptable species might thrive under changing conditions. Our findings hence demonstrate the complex interplay between life-history traits and climate change vulnerability in marine fish communities. Eventually, our study provides critical knowledge for the urgent development of tailored adaptation efforts addressing existing but especially future effects of climate change on fish and fisheries in the Western Baltic Sea, to navigate this endangered fisheries systems into a sustainable future.

Curcumin is a biopharmaceutical classification system (BCS) class IV substance with many potential therapeutic effects. However, like many other BCS IV active pharmaceutical ingredients, complex formulations are needed to guarantee a sufficiently high bioavailability. A not-so-well-known delivery system is a suspoemulsion (SE). SEs are emulsions with a crystalline API in continuous or dispersed phases. This study aimed to produce curcumin-loaded o/w suspoemulsions with the particle in the oil phase for, e.g., encapsulation or triggered release effects. The particles need to be smaller than the emulsion droplet size to attain high encapsulation efficiencies (EE) in the oil phase. Sonofragmentation and bead milling were tested for their ability to produce these nanocrystals in different dispersion media. It was discovered that production in miglyol was the best fit for the needed application of the crystals in SEs. Around 85% (by volume) of the particles produced with bead milling were smaller than the droplet size of about 5 µm. In contrast, only 23% of the sonofragmentated particles were below the diameter of those droplets. This oily suspension was then used to successfully produce hydrogel-based o/w suspoemulsions. In the second part of this study, we investigated different methods for determining encapsulation efficiency, but none of the methods accurately and satisfactorily resolved the encapsulation efficiency. Finally, the suspoemulsions could not be macroscopically distinguished from one another and were physically stable. In summary, we showed that stable hydrogel-based curcumin-loaded o/w suspoemulsions could be produced. [ABSTRACT FROM AUTHOR]

Abstract Background The prevalence of sacroiliac joint pain (SIJP) is estimated to be 10–30% in patients with chronic low back pain. Numerous conservative and surgical treatment modalities for SIJP have been described with limited evidence regarding long-term pain relief. Spinal cord stimulation (SCS) is a well-established technique to treat patients with chronic low back pain. However, the effect on patients with SIJP is not consistent. Therefore, peripheral nerve stimulation (PNS) for chronic SIJP was implemented in experimental trials. Clinical data on PNS for SIJP is still lacking. The authors present a case series and a protocol for a prospective, multicenter study to determine the effect of PNS in patients with chronic intractable SIJP. Method A multicenter, prospective randomized controlled trial was designed. Patients with chronic intractable SIJP will be recruited and randomized in a 4:3 ratio to either the peripheral nerve stimulation group or to the best medical treatment group. A total of 90 patients are planned to be enrolled (52 in the PNS group and 38 in the BMT group). Patients in the intervention group receive a percutaneous implantation of a unilateral or bilateral lead which is externalized for a trial phase for 3–14 days. After trial phase only patients with at least 50% reduction of pain receive an impulse generator for permanent stimulation. Regular visits for participants are planned on day 0, after 3 months (± 30 days), 6 months (± 30 days), and 12 months (± 60 days). The primary outcome measurements is the difference in Numeric Pain Rating Scale (NRS) between baseline and after 6 months. Secondary outcomes is improvement of pain associated disability (ODI) and improvement of health-related quality of life after 6 and 12 months. Discussion We have described the protocol for a prospective, multicenter, randomized trial evaluating the influence of PNS on patients with chronic sacroiliac joint syndrome. We believe that PNS on patients with chronic sacroiliac joint syndrome will show promising results regarding pain relief and quality of life in comparison to BMT after 12 months. The design of this trial promises high evidence in comparison to the data to date. Trial registration ClinicalTrials.gov, NCT05357300. Registered on April 26, 2022.

Background: Vagus nerve stimulation (VNS) at low frequencies (≤30 Hz) has been an established treatment for drug-resistant epilepsy (DRE) for over 25 years. Objective: To examine the initial safety and efficacy performance of an investigational, high-frequency (≥250 Hz) VNS paradigm herein called “Microburst VNS” (μVNS). μVNS consists of short, high-frequency bursts of electrical pulses believed to preferentially modulate certain brain regions. Methods: Thirty-three (33) participants were enrolled into an exploratory feasibility study, 21 with focal-onset seizures and 12 with generalized-onset seizures. Participants were titrated to a personalized target dose of μVNS using an investigational fMRI protocol. Participants were then followed for up to 12 months, with visits every 3 months, and monitored for side-effects at all time points. This study was registered as NCT03446664 on February 27th, 2018. Results: The device was well-tolerated. Reported adverse events were consistent with typical low frequency VNS outcomes and tended to diminish in severity over time, including dysphonia, cough, dyspnea, and implant site pain. After 12 months of μVNS, the mean seizure frequency reduction for all seizures was 61.3% (median reduction: 70.4%; 90% CI of median: 48.9%–83.3%). The 12-month responder rate (≥50% reduction) was 63.3% (90% CI: 46.7%–77.9%) and the super-responder rate (≥80% reduction) was 40% (90% CI: 25.0%–56.6%). Participants with focal-onset seizures appeared to benefit similarly to participants with generalized-onset seizures (mean reduction in seizures at 12 months: 62.6% focal [n = 19], versus 59.0% generalized [n = 11]). Conclusion: Overall, μVNS appears to be safe and potentially a promising therapeutic alternative to traditional VNS. It merits further investigation in randomized controlled trials which will help determine the impact of investigational variables and which patients are most suitable for this novel therapy.

Abstract Background Coronary heart diseases (CHDs) have experienced the largest increase worldwide as a cause of death, accounting for 16% of all deaths. In Saxony-Anhalt, a federal state in Germany, both CHD morbidity and acute myocardial infarction mortality rates are particularly high. Several risk factors associated with CHDs have been studied in Saxony-Anhalt, but sex differences in service use and medication have not been investigated. This study therefore aimed to investigate sex differences in the quality and quantity of cardiological care provided to adults with CHD. Methods This study used health claims data from 2018 to 2020 to analyse the utilisation of healthcare services and adherence to medication-related guideline recommendations in primary and specialist care. The sample included 133,661 individuals with CHD from a major statutory health insurance company (Germany). Results Almost all CHD patients (> 99%) received continuous primary care. Continuous cardiologist utilisation was lower for females than for males, with 15.0% and 22.2%, respectively, and sporadic utilisation showed greater differences, with 33.5% of females and 43.4% of males seeking sporadic cardiologist consultations. Additionally, 43.1% of the identified CHD patients participated in disease management programmes (DMPs). The study also examined the impact of DMP participation and cardiologist care on medication uptake and revealed that sex differences in medication uptake, except for statin use, were mitigated by these factors. Statins were prescribed to 42.9% of the CHD patients eligible for statin prescription in accordance with the QiSA indicator for statin prescription eligibility. However, there were significant sex differences in statin utilisation. Female CHD patients were less likely to use statins (35.2%) than male CHD patients were (50.1%). The difference in statin utilisation persisted after adjustment for DMP participation and cardiologist consultation. Conclusions This study highlights sex differences in the utilisation of cardiological healthcare services for patients with CHD in the Saxony-Anhalt cohort. These findings underscore the continuing need for interventions to reduce sex inequalities in accessing healthcare and providing health care for patients with CHD. Factors at the health care system, patient, and physician levels should be further investigated to eventually improve statin prescription in people with CHD, especially women.

Abstract Importance Contact tracing is the process of identifying people who have recently been in contact with someone diagnosed with an infectious disease. During an outbreak, data collected from contact tracing can inform interventions to reduce the spread of infectious diseases. Understanding factors associated with completion rates of contact tracing surveys can help design improved interview protocols for ongoing and future programs. Objective To identify factors associated with completion rates of COVID-19 contact tracing surveys in New York City (NYC) and evaluate the utility of a predictive model to improve completion rates, we analyze laboratory-confirmed and probable COVID-19 cases and their self-reported contacts in NYC from October 1st 2020 to May 10th 2021. Methods We analyzed 742,807 case investigation calls made during the study period. Using a log-binomial regression model, we examined the impact of age, time of day of phone call, and zip code-level demographic and socioeconomic factors on interview completion rates. We further developed a random forest model to predict the best phone call time and performed a counterfactual analysis to evaluate the change of completion rates if the predicative model were used. Results The percentage of contact tracing surveys that were completed was 79.4%, with substantial variations across ZIP code areas. Using a log-binomial regression model, we found that the age of index case (an individual who has tested positive through PCR or antigen testing and is thus subjected to a case investigation) had a significant effect on the completion of case investigation – compared with young adults (the reference group,24 years old 65 years old) were lower by 12.1% (95%CI: 11.1% – 13.3%), and the completion rate for youth group (age

With the fact that the main operational parameters of the construction process in mechanized tunneling are currently selected based on monitoring data and engineering experience without exploiting the advantages of computer methods, the focus of this work is to develop a simulation-based real-time assistant system to support the selection of operational parameters. The choice of an appropriate set of these parameters (i.e., the face support pressure, the grouting pressure, and the advance speed) during the operation of tunnel boring machines (TBM) is determined by evaluating different tunneling-induced soil-structure interactions such as the surface settlement, the associated risks on existing structures and the tunnel lining behavior. To evaluate soil-structure behavior, an advanced process-oriented numerical simulation model based on the finite cell method is utilized. To enable the real-time prediction capability of the simulation model for a practical application during the advancement of TBMs, surrogate models based on the Proper Orthogonal Decomposition and Radial Basis Functions (POD-RBF) are adopted. The proposed approach is demonstrated through several synthetic numerical examples inspired by the data of real tunnel projects. The developed methods are integrated into a user-friendly application called SMART to serve as a support platform for tunnel engineers at construction sites. Corresponding to each user adjustment of the input parameters, i.e., each TBM driving scenario, approximately two million outputs of soil-structure interactions are quickly predicted and visualized in seconds, which can provide the site engineers with a rough estimation of the impacts of the chosen scenario on structural responses of the tunnel and above ground structures.

Abstract Background Transglutaminase 2 (TGase 2) is a multifunctional protein and has a prominent role in various (patho)physiological processes. In particular, its transamidase activity, which is rather latent under physiological conditions, gains importance in malignant cells. Thus, there is a great need of theranostic probes for targeting tumor-associated TGase 2, and targeted covalent inhibitors appear to be particularly attractive as vector molecules. Such an inhibitor, equipped with a radionuclide suitable for noninvasive imaging, would be supportive for answering the general question on the possibility for functional characterization of tumor-associated TGase 2. For this purpose, the recently developed 18F-labeled N ε-acryloyllysine piperazide [ 18 F]7b, which is a potent and selective irreversible inhibitor of TGase 2, was subject to a detailed radiopharmacological characterization herein. Results An alternative radiosynthesis of [ 18 F]7b is presented, which demands less than 300 µg of the respective trimethylammonio precursor per synthesis and provides [ 18 F]7b in good radiochemical yields (17 ± 7%) and high (radio)chemical purities (≥ 99%). Ex vivo biodistribution studies in healthy mice at 5 and 60 min p.i. revealed no permanent enrichment of 18F-activity in tissues with the exception of the bone tissue. In vivo pretreatment with ketoconazole and in vitro murine liver microsome studies complemented by mass spectrometric analysis demonstrated that bone uptake originates from metabolically released [18F]fluoride. Further metabolic transformations of [ 18 F]7b include mono-hydroxylation and glucuronidation. Based on blood sampling data and liver microsome experiments, pharmacokinetic parameters such as plasma and intrinsic clearance were derived, which substantiated the apparently rapid distribution of [ 18 F]7b in and elimination from the organisms. A TGase 2-mediated uptake of [ 18 F]7b in different tumor cell lines could not be proven. Moreover, evaluation of [ 18 F]7b in melanoma tumor xenograft models based on A375-hS100A4 (TGase 2 +) and MeWo (TGase 2 −) cells by ex vivo biodistribution and PET imaging studies were not indicative for a specific targeting. Conclusion [ 18 F]7b is a valuable radiometric tool to study TGase 2 in vitro under various conditions. However, its suitability for targeting tumor-associated TGase 2 is strongly limited due its unfavorable pharmacokinetic properties as demonstrated in rodents. Consequently, from a radiochemical perspective [ 18 F]7b requires appropriate structural modifications to overcome these limitations.

This paper deals with double-pulse laser-induced breakdown spectroscopy (LIBS) underwater, which is a promising analytical method for elemental analysis in the deep sea up to a water depth of 6000 m. A double-pulse laser with a wavelength of 1064 nm is used, which provides a pulse energy of up to 266 mJ for each laser pulse (in single pulse mode), a pulse width of 5–7 ns and a pulse delay in the range of 0.5 to 20 µs. In the double-pulse LIBS method, the first laser pulse creates a cavity on the material surface, and then the second laser pulse forms the plasma in this cavity. It is expected that the plasma is affected by the cavity’s size and lifetime. For this reason, the influence of focus position, pulse energy and pulse delay on the cavity and plasma formation at shallow water depth has been investigated.

Background Hypertension is the leading risk factor for cardiovascular disease worldwide. Patients with blood pressure (BP) response to dietary sodium reduction are referred to as “salt sensitive.” Salt sensitivity (SS) might be due to differences in sodium storage capacity and the erythrocyte SS examines this capacity of the red blood cells. This study aimed to test the effect of a self‐performed sodium reduced diet on BP in patients with essential hypertension and examine whether erythrocyte SS predicts SS. Methods and Results Seventy‐two patients with hypertension were included and randomized 2:1 to either sodium reduction or a control group for 4 weeks. Blood samples, 24‐hour BP measurement, and 24‐hour urine collection were performed before and after. The intervention group received advice on how to lower sodium intake. Urinary sodium excretion decreased 66 mmol (95% CI, −96 to −37 mmol) in the intervention group compared with the control group. Systolic 24‐hour BP decreased 9 mm Hg after low‐sodium diet compared with the control group (95% CI, −13 to −4 mm Hg). Similarly, the difference in reduction in diastolic BP between the groups was 5 mm Hg (95% CI, −8 to −1 mm Hg). We found no correlation between erythrocyte SS at baseline and decrease in 24‐hour BP, neither systolic nor diastolic (P=0.66 and P = 0.84). Conclusions Self‐performed sodium reduction was feasible and led to decrease in 24‐hour BP of 9/5 mm Hg compared with a control group. The erythrocyte SS did not correlate to the change in BP after lowering sodium intake. Registration URL: https://clinicaltrials.gov; Unique Identifier: NCT05165823.

BackgroundSodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood. ObjectiveThe study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD. MethodsWe conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m2). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82Rubidium positron emission tomography–computed tomography (82Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99mTechnetium-diethylene-triamine-pentaacetate (99mTc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system. ResultsRecruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published. ConclusionsThis paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively. Trial RegistrationEU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50 International Registered Report Identifier (IRRID)DERR1-10.2196/56067

Introduction Upper limb (UL) dysfunctions are highly prevalent in people after breast cancer and have a great impact on performing activities in daily living. To improve care, a more comprehensive understanding of the development and persistence of UL dysfunctions is needed. Therefore, the UPLIFT-BC study will primarily examine the prognostic value of different factors at the body functions and structures, environmental and personal level of the International Classification of Functioning, Disability and Health (ICF) framework at 1-month post-surgery for persisting UL dysfunctions at 6 months after finishing cancer treatment.Methods and analysis A prospective longitudinal cohort study, running from 1-week pre-surgery to 6 months post-local cancer treatment, is performed in a cohort of 250 women diagnosed with primary breast cancer. Different potentially prognostic factors to UL dysfunctions, covering body functions and structures, environmental and personal factors of the ICF, are assessed pre-surgically and at different time points post-surgery. The primary aim is to investigate the prognostic value of these factors at 1-month post-surgery for subjective UL function (ie, QuickDASH) at 6 months post-cancer treatment, that is, 6 months post-radiotherapy or post-surgery (T3), depending on the individuals’ cancer treatment trajectory. In this, factors with relevant prognostic value pre-surgery are considered as well. Similar analyses are performed with an objective measure for UL function (ie, accelerometry) and a composite score of the combination of subjective and objective UL function. Second, in the subgroup of participants who receive radiotherapy, the prognostic value of the same factors is explored at 1-month post-radiotherapy and 6 months post-surgery. A forward stepwise selection strategy is used to obtain these multivariable prognostic models.Ethics and dissemination The study protocol was approved by the Ethics Committee of UZ/KU Leuven (reference number s66248). The results of this study will be published in peer-reviewed journals and will be presented at several research conferences.Trial registration number NCT05297591.

Introduction Lymphoedema is a chronic condition caused by lymphatic insufficiency. It leads to swelling of the limb/midline region and an increased risk of infection. Lymphoedema is often associated with mental and physical problems limiting quality of life. The first choice of treatment is a conservative treatment, consisting of exercises, skin care, lymph drainage and compression. Reconstructive lymphatic surgery is also often performed, that is, lymphovenous anastomoses, lymph node transfer or a combination. However, robust evidence on the effectiveness of reconstructive lymphatic surgery is missing. Therefore, the objective of this trial is to investigate the added value of reconstructive lymphatic surgery to the conservative treatment in patients with lymphoedema.Methods and analysis A multicentre randomised controlled and pragmatic trial was started in March 2022 in three Belgian university hospitals. 90 patients with arm lymphoedema and 90 patients with leg lymphoedema will be included. All patients are randomised between conservative treatment alone (control group) or conservative treatment with reconstructive lymphatic surgery (intervention group). Assessments are performed at baseline and at 1, 3, 6, 12, 18, 24 and 36 months. The primary outcome is lymphoedema-specific quality of life at 18 months. Key secondary outcomes are limb volume and duration of wearing the compression garment at 18 months. The approach of reconstructive lymphatic surgery is based on presurgical investigations including clinical examination, lymphofluoroscopy, lymphoscintigraphy, lymph MRI or CT angiography (if needed). All patients receive conservative treatment during 36 months, which is applied by the patient’s own physical therapist and by the patient self. From months 7 to 12, the hours a day of wearing the compression garment are gradually decreased.Ethics and dissemination The study has been approved by the ethical committees of University Hospitals Leuven, Ghent University Hospital and CHU UCL Namur. Results will be disseminated via peer-reviewed journals and presentations.Trial registration number NCT05064176

Raw observations (carrier-phase and code observations) from the Global Navigation Satellite System (GNSS) can now be accessed from Android mobile phones (Version 7.0 onwards). This paves the way for GNSS data to be utilized for low-cost precise positioning or in ionospheric or tropospheric applications. This paper presents results from data collection campaigns using the CAMALIOT mobile app. In the first campaign, 116.3 billion measurements from 11,828 mobile devices were collected from all continents. Although participation decreased during the second campaign, data are still being collected globally. In this contribution, we demonstrate the potential of volunteered geographic information (VGI) from mobile phones to fill data gaps in geodetic station networks that collect GNSS data, e.g. in Brazil, but also how the data can provide a denser set of observations than current networks in countries across Europe. We also show that mobile phones capable of dual-frequency reception, which is an emerging technology that can provide a richer source of GNSS data, are contributing in a substantial way. Finally, we present the results from a survey of participants to indicate that participation is diverse in terms of backgrounds and geography, where the dominant motivation for participation is to contribute to scientific research.

Abstract Background Understanding community transmission of SARS-CoV-2 variants of concern (VOCs) is critical for disease control in the post pandemic era. The Delta variant (B.1.617.2) emerged in late 2020 and became the dominant VOC globally in the summer of 2021. While the epidemiological features of the Delta variant have been extensively studied, how those characteristics shaped community transmission in urban settings remains poorly understood. Methods Using high-resolution contact tracing data and testing records, we analyze the transmission of SARS-CoV-2 during the Delta wave within New York City (NYC) from May 2021 to October 2021. We reconstruct transmission networks at the individual level and across 177 ZIP code areas, examine network structure and spatial spread patterns, and use statistical analysis to estimate the effects of factors associated with COVID-19 spread. Results We find considerable individual variations in reported contacts and secondary infections, consistent with the pre-Delta period. Compared with earlier waves, Delta-period has more frequent long-range transmission events across ZIP codes. Using socioeconomic, mobility and COVID-19 surveillance data at the ZIP code level, we find that a larger number of cumulative cases in a ZIP code area is associated with reduced within- and cross-ZIP code transmission and the number of visitors to each ZIP code is positively associated with the number of non-household infections identified through contact tracing and testing. Conclusions The Delta variant produced greater long-range spatial transmission across NYC ZIP code areas, likely caused by its increased transmissibility and elevated human mobility during the study period. Our findings highlight the potential role of population immunity in reducing transmission of VOCs. Quantifying variability of immunity is critical for identifying subpopulations susceptible to future VOCs. In addition, non-pharmaceutical interventions limiting human mobility likely reduced SARS-CoV-2 spread over successive pandemic waves and should be encouraged for reducing transmission of future VOCs.

RESUMO A partir da trajetória pessoal e intelectual de Raúl Prebisch - de um jovem neoclássico a serviço da oligarquia argentina a um crítico do desenvolvimento latino-americano - este artigo fornece uma análise detalhada e uma avaliação crítica de sua contribuição final ao capitalismo periférico. Em conclusão, pretende-se afirmar que sua busca por uma abordagem alternativa ao capitalismo latino-americano não conseguiu quebrar as fronteiras da economia política burguesa.

Abstract Objective Topoisomerase I (topo I) is a highly conserved enzyme which is known to reduce torsional stress at double-stranded (ds) DNA. Torsional stress induced by supercoiling of dsDNA requires either very long dsDNA existing in genomic DNA or circulation as presented in plasmid DNA. To enable DNA relaxation, topo I induce a transient single-strand break followed by stress-relieving rotation of the released DNA strand. Our group found by serendipity that the topo I inhibitor irinotecan is able to suppress murine systemic lupus erythematosus (SLE), an autoimmune disease which is characterized by the existence of pathogenic anti-dsDNA antibodies (abs). As a possible mechanism we demonstrated in the absence of immunosuppression an increased binding of anti-dsDNA abs to long genomic or circulated plasmid dsDNA modified with topo I. Results Here we show that this effect requires active site tyrosine of topo I which is known to facilitate DNA relaxation activity. Moreover, topo I enhanced anti-dsDNA abs binding to short linear oligonucleotides down to a size of 42 bp. Since oligonucleotides of such length are devoid of torsional stress and relaxation respectively, our results suggest a new and unknown function for the enzyme topo I.

Abstract Neuronal ceroid lipofuscinosis 6 (CLN6) is a rare and fatal autosomal recessive disease primarily affecting the nervous system in children. It is caused by a pathogenic mutation in the CLN6 gene for which no therapy is available. Employing an untargeted metabolomics approach, we analyzed the metabolic changes in CLN6 subjects to see if this system could potentially yield biomarkers for diagnosis and monitoring disease progression. Neuronal-like cells were derived from human fibroblast lines from CLN6-affected subjects (n = 3) and controls (wild type, n = 3). These were used to assess the potential of a neuronal-like cell-based metabolomics approach to identify CLN6 distinctive and specific biomarkers. The most impacted metabolic profile is associated with sphingolipids, glycerophospholipids metabolism, and calcium signaling. Over 2700 spectral features were screened, and fifteen metabolites were identified that differed significantly between both groups, including the sphingolipids C16 GlcCer, C24 GlcCer, C24:1 GlcCer and glycerophospholipids PG 40:6 and PG 40:7. Of note, these fifteen metabolites were downregulated in the CLN6 disease group. This study is the first to analyze the metabolome of neuronal-like cells with a pathogenic mutation in the CLN6 gene and to provide insights into their metabolomic alterations. This could allow for the development of novel biomarkers for monitoring CLN6 disease.

Cellulose microspheres have a wide range of applications due to their unique properties and versatility. Various preparation methods have been explored to tailor these microspheres for specific applications. Among these methods, the acetate method using cellulose acetate is well known. However, replacement of the acetate group through the butyrate group significantly extends the variety of morphological properties. In the present work, microspheres based on cellulose acetate butyrate are being developed with modified characteristics in terms of particle size, porosity, surface morphology and the inner structure of the microspheres. While the inner structure of cellulose acetate microspheres is predominantly porous, microspheres prepared from cellulose acetate butyrate are mainly filled or contain several smaller microspheres. Carbon materials from cellulose acetate butyrate microspheres exhibit a high specific surface area of 567 m2 g−1, even without further activation. Activation processes can further increase the specific surface area, accompanied by an adaptation of the pore structure. The prepared carbons show promising results in symmetrical supercapacitors with aqueous 6 M KOH electrolytes. Activated carbons derived from cellulose acetate butyrate microspheres demonstrate an energy density of 12 Wh kg−1 at a power density of 0.9 kW kg−1.