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Abstract Thin film interference is integral to modern photonics, e.g., allowing for precise design of high performance optical filters, photovoltaics and light-emitting devices. However, interference inevitably leads to a generally undesired change of spectral characteristics with angle. Here, we introduce a strategy to overcome this fundamental limit in optics by utilizing and tuning the exciton-polariton modes arising in ultra-strongly coupled microcavities. We demonstrate optical filters with narrow pass bands that shift by less than their half width (

Increased hazards threatening the United Nations Educational, Scientific and Cultural Organization (UNESCO)-designated sites and endangering cultural heritage and community well-being require attention and action. Considering the pivotal role of UNESCO sites in conservation and development, this study assessed their levels of disaster preparedness. The absence of studies assessing disaster awareness, risk perception, and preparedness among UNESCO site actors, as well as the pivotal place of preparedness within the Disaster Risk Management (DRM) cycle justifies this research. Applying the tenets of the Person-Relative-to-Event framework, we hypothesized that a strong positive correlation exists between perceived risks, resources, and disaster preparedness. To collect pertinent data, we employed an embedded mixed-method design and conducted an online questionnaire survey yielding 141 responses from 59 countries. From the results of relevant analyses, wildfires, floods, and droughts are top hazards occurring frequently in UNESCO sites, with significant concerns about pollution and habitat loss during future events. Smartphones emerged as the most available crucial DRM resource, with higher availability of DRM resources correlating positively and significantly with sites’ preparedness. Our findings contribute valuable insights to address missing links for disaster-ready and resilient UNESCO sites, promoting their preservation for future generations.

Heritage plays a critical role in sustainability. The absence of studies examining core competencies among UNESCO actors for disaster risk management (DRM) and preparedness in heritage sites prompted this survey. Respondents from 59 countries revealed a high rating of all listed competencies with significant discrepancies concerning relationship-building requiring attention. Additionally, substantial variations in competencies were linked to factors such as age, job positions, and previous experiences with disaster damages. Holistic DRM proficiency is the primary predictor of disaster preparedness within heritage sites. Thus, enhancing preparedness through experiential learning and coordinated knowledge-sharing mechanisms will preserve our collective heritage for sustainable futures.

Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal Clostridium sporogenes possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with C. sporogenes (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of Il22 gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3+ regulatory T cells (Tregs). In DSS-induced colitis, conventional mice suffered severe inflammation accompanied by loss of colonic crypts. These symptoms were absent in CS mice. In conventional, but not CS mice, bulk RNAseq analysis of the colon revealed an increase in inflammatory and Th17-related gene signatures. C. sporogenes-derived IPA reduced IL-17A protein expression by suppressing mTOR activity and by altering ribosome-related pathways in Th17 cells. Additionally, BCFAs and SCFAs generated by C. sporogenes enhanced the activity of Tregs and increased the production of IL-22, which led to protection from colitis. Collectively, we identified C. sporogenes as a therapeutically relevant probiotic bacterium that might be employed in patients with inflammatory bowel disease (IBD).

Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997–12/31/2006 who did not receive curative treatments. Cases were those who developed metastasis within 10 years from diagnosis. Controls were selected using density sampling. Ninety-eight candidate genes were selected from functional categories of cell cycle control, metastasis/tumour suppressors, cell signalling, cell adhesion/motility/invasion, angiogenesis, and immune function, and 41 from pluripotency genes. Cancer DNA from diagnostic biopsy blocks were extracted and analysed. Associations of methylation status were assessed using CpG site level and principal components-based analysis in conditional logistic regressions. In 215 cases and 404 controls, 27 candidate genes were found to be statistically significant in at least one of the two analytical approaches. The agreement between the methods was 25.9% (7 candidate genes, including 2 pluripotency markers). The DNA methylation status of several candidate genes was significantly associated with risk of metastasis in untreated localized PCa patients. These findings may inform future risk prediction models for PCa metastasis beyond clinical characteristics.

Abstract Background Rollover crashes continue to be a substantial public health issue in North America. Previous research has shown that the cervical spine is the most injured spine segment in rollovers, but much of the past research has focused on risk factors rather than the actual cervical spine injuries. We sought to examine how different types of cervical spine injuries (vertebral and/or cord injury) vary with different occupant-related factors in rollovers and to compare these with non-rollovers. Methods We obtained crash and injury information from the National Automotive Sampling System–Crashworthiness Data System (NASS-CDS) for 2005–2015 and Crash Investigation Sampling System (CISS) for 2017–2022. Based on weighted data, we calculated relative risks to assess how occupant sex, seat belt use, ejection status, and fatal outcome relate to the rate of different cervical spine injuries in rollovers and non-rollovers. Results In NASS-CDS occupants with cervical spine injuries (N = 111,040 weighted cases), about 91.5% experienced at least one vertebral injury whereas only 11.3% experienced a spinal cord injury (most of which had a concomitant vertebral fracture). All types of cervical spine injuries we examined were 3.4–5.2 times more likely to occur in rollovers compared to non-rollovers. These relative risks were similar for both sexes, belted and unbelted, non-ejected, and non-fatal occupants. The number of weighted CISS occupants with cervical spine injuries (N = 42,003) was smaller than in the NASS analysis, but cervical spine injuries remained 6.25 to 6.36 times more likely in rollovers compared to non-rollovers despite a more modern vehicle fleet. Conclusions These findings underscore the continued need for rollover-specific safety countermeasures, especially those focused on cervical spine injury prevention, and elucidate the frequency, severity and other characteristics of the specific vertebral and spinal cord injuries being sustained in rollovers. Our findings suggest that countermeasures focused on preventing cervical vertebral fractures will also effectively prevent most cervical spinal cord injuries.

Objective In the digital age, patients turn to online sources for lumbar spine fusion information, necessitating a careful study of large language models (LLMs) like chat generative pre-trained transformer (ChatGPT) for patient education. Methods Our study aims to assess the response quality of Open AI (artificial intelligence)’s ChatGPT 3.5 and Google’s Bard to patient questions on lumbar spine fusion surgery. We identified 10 critical questions from 158 frequently asked ones via Google search, which were then presented to both chatbots. Five blinded spine surgeons rated the responses on a 4-point scale from ‘unsatisfactory’ to ‘excellent.’ The clarity and professionalism of the answers were also evaluated using a 5-point Likert scale. Results In our evaluation of 10 questions across ChatGPT 3.5 and Bard, 97% of responses were rated as excellent or satisfactory. Specifically, ChatGPT had 62% excellent and 32% minimally clarifying responses, with only 6% needing moderate or substantial clarification. Bard’s responses were 66% excellent and 24% minimally clarifying, with 10% requiring more clarification. No significant difference was found in the overall rating distribution between the 2 models. Both struggled with 3 specific questions regarding surgical risks, success rates, and selection of surgical approaches (Q3, Q4, and Q5). Interrater reliability was low for both models (ChatGPT: k = 0.041, p = 0.622; Bard: k = -0.040, p = 0.601). While both scored well on understanding and empathy, Bard received marginally lower ratings in empathy and professionalism. Conclusion ChatGPT3.5 and Bard effectively answered lumbar spine fusion FAQs, but further training and research are needed to solidify LLMs’ role in medical education and healthcare communication.

The development of a knowledge-based decision support system for the evaluation and planning of location and urban development concepts was implemented. In order to achieve this goal, cross-domain ontologies were developed for interdisciplinary databases, which are then mapped in semantic networks. The exponential growth in computing power in the hardware sector alone can no longer solve this problem, but at the same time enables the application of new methods for storing and evaluating data. Essentially, it is no longer just about the digital recording of object properties in conventional databases, but also about the digital representation of their significance for specific questions and the linking of meanings across the boundaries of specialist domains. This information is stored in a multimedia knowledge base, together with the methods and rules for its use and the evaluations and decisions based on it. The motivation for this project is the rapidly growing amount of data, which extends across ever new specialist domains and can no longer be sufficiently integrated into the decision-making of experts using conventional methods of knowledge acquisition. After determining this data, it was linked to a georeferencing. Within the framework of the project, documents were analyzed with the help of AI and examined for semantic text corpora. This data was georeferenced. Various algorithms were used to accomplish this task, including TF-IDF, TextRank and Word2Vec.

Remote video imagery using shoreline edge detection is widely used in coastal monitoring in order to acquire measurements of nearshore and swash features. Some of these systems are constrained by their long setup time, positioning requirements and considerable hardware costs. As such, there is a need for an autonomous low-cost system (~EUR 500), such as Timex cameras, that can be rapidly deployed in the field, while still producing the outcomes required for coastal monitoring. This research presents an assessment of the effect of the sampling strategy (time-lapse intervals) on the precision of shoreline detection for two low-cost cameras located in a remote coastal area in western Ireland, overlooking a dissipative beach–dune system. The analysis shows that RMSD in the detected shoreline is similar to other studies for sampling intervals ranging between 1 s and 30 s (i.e., RMSDmean for Camera 1 = 1.4 m and Camera 2 = 0.9 m), and an increase in the sampling interval from 1 s to 30 s had no significant adverse effect on the precision of shoreline detection. The research shows that depending on the intended use of the detected shorelines, the current standard of 1 s image sampling interval when using Timex cameras can be increased up to 30 s without any significant loss of accuracy. This positively impacts battery life and memory storage, making the systems more autonomous; for example, the battery life increased from ~10 days to ~100 days when the sampling interval was increased from 1 to 5 s.

Abstract The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported worldwide. Glucocorticoids have attracted worldwide attention for their potential efficacy in the treatment of COVID-19. Various glucocorticoids with different dosages and treatment durations have been studied in patients with different severities, with a suitable dosage and treatment duration not yet defined. This study aimed to investigate whether in-hospital survival differs between critically ill patients treated with low-dose glucocorticoids, high-dose glucocorticoids or no glucocorticoids. All critically ill patients admitted to the intensive care unit of the Charité Hospital—Universitätsmedizin Berlin between February 2020 and December 2021 with COVID-19 pneumonia receiving supplemental oxygen were eligible to participate in this multicenter real-world data study. Patients were retrospectively assigned to one of three groups: the high corticosteroid dose (HighC) group (receiving 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), the low corticosteroid dose (LowC) group (receiving less than 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), or the no corticosteroid (NoC) group. Overall survival and risk effects were compared among groups within the total observation period, as well as at 35 days after the onset of COVID-19 symptoms. Adjusted multivariable Cox proportional hazard regression analysis was performed to compare the risk of death between the treatment groups. Out of 1561 critically ill COVID-19 patients, 1014 were included in the baseline analysis. In the survival study, 1009 patients were assigned to the NoC (n = 346), HighC (n = 552), or LowC group (n = 111). The baseline characteristics were balanced between groups, except for age, BMI, APACHE II score, SOFA and SAPS II. While the 35-day survival did not show any differences, a landmark analysis of the patients surviving beyond 35 days revealed differences between groups. The restricted mean survival time was 112 days in the LowC group [95% CI: 97 – 128], 133 days in the HighC group [95% CI: 124 – 141] and 144 days in the NoC group [95% CI: 121 – 167]. The multivariable-adjusted Cox proportional hazard analysis indicated that, regardless of age, sex, health status or invasive oxygenation, a low-dose treatment increased the hazard of death of critically ill COVID-19 patients by a factor of 2.09 ([95% CI: 0.99, 4.4], p = 0.05) and a high-dose corticosteroid treatment increased the risk by a factor of 1.07 ([95% CI: 0.53, 2.15], p = 0.85) compared to no treatment with glucocorticoids. The analysis reveals that corticosteroid treatment does not influence the survival of critically ill COVID-19 patients in the intensive care unit within 35 days. Our evaluations further suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness.

Abstract Ezetimibe undergoes glucuronidation that results in the active metabolite ezetimibe phenoxy‐glucuronide (ezetimibe‐glucuronide). This phase‐II metabolite was shown to interact with the clinically relevant hepatic transporter organic anion transporting polypeptide (OATP) 1B1. In recent years, coproporphyrin I (CPI) was established as a Tier 1 biomarker for OATP1B‐mediated interactions among other endogenous substrates like CPIII. To evaluate whether levels of the biomarker are affected by ezetimibe treatment, we assessed the impact of ezetimibe and ezetimibe‐glucuronide on OATP1B1‐mediated transport of CPs in vitro. Then, we quantified CP levels in serum samples of healthy volunteers treated with a single oral dose of ezetimibe (20 mg) alone or in combination with rifampin (600 mg). Results from our in vitro experiments showed a significant reduction in cellular CPI accumulation in the presence of ezetimibe‐glucuronide with an IC50 of 1.97 μM [95% CI: 1.04 to 3.96], while CPIII accumulation was impacted by 10 μM and above. In the in vivo study, we observed peak CP concentrations 1.33 h after dosing, which is closest to the tmax of the ezetimibe metabolite. Co‐administration of ezetimibe with rifampin resulted in even higher serum CP levels. The AUC0–24h of CPI and CPIII increased two‐ and threefold, respectively, after concomitant dosing compared to ezetimibe alone. Moreover, we quantified CP levels in cumulative urine from both study phases where the renally excreted amount (Ae) of CPI and CPIII increased after ezetimibe and rifampin co‐administration compared to ezetimibe alone. In conclusion, our findings indicate that rifampin co‐administration results in additional inhibition of OATP1B1 in vivo.

Among the various molecular CO2 reduction catalysts, the [Ni(cyclam)]2+ (Ni-{N4}) complex with its earth-abundant metal center and macrocyclic ligand proved to be efficient for the selective electrochemical conversion of CO2 to CO. In the present study we now connected the two Ni-cyclam units by using para- and meta-xylene as organic linkers attached to the amines of the macrocycle to form the p-{Ni2} and m-{Ni2} complexes, respectively, and test them as catalysts for the electrochemical CO2 reduction reactions. Notably, the p-{Ni2} complex demonstrates a higher faraday efficiency in the electrochemical reduction of CO2 to CO compared to the m-{Ni2} complex. This finding highlights the significant role played by the M-M distance in influencing this catalytic process.

Climate change induced precipitation changes can impact wastewater influent volumes and, in turn, the design and operation of wastewater treatment plants (WWTPs). As influent volumes approach or exceeds the design capacity of the WWTP, the likelihood of poor treatment or untreated discharges that result in environmental damage, increases. To date, there has been a lack of research analysing the impact changes in precipitation may have on influent volumes of WWTPs with combined sewerage systems. This study leverages data driven models of observed precipitation and influent volumes for 14 Irish WWTPs with combined sewerage systems, to project monthly wastewater influent volumes in 2041 – 2060 using Ireland’s most up-to-date high resolution multi-model RCM projections under RCPs 4.5 and 8.5. With changing monthly average daily precipitation, influent volumes for all the WWTPs demonstrated maximum decreases during summer months for both RCP 4.5 and RCP 8.5. Winter months showed increasing trends in influent volumes, particularly under RCP 8.5. The results indicate that with projected increase in high and very high precipitation days in Ireland (under CMIP5), the return periods for influent volumes that exceed the hydraulic capacity of 5 of the WWTPs will reduce. This work also presents a framework by which newer high-resolution downscaled climate models can be used to developed updated impact analysis of changing rainfall patterns on wastewater. It likely that wastewater treatment infrastructure will need to adapt to more intense precipitation to minimise the occurrence of combined sewer overflows.

Abstract Drowsiness while driving negatively impacts road safety, especially in truck drivers. The present study investigated the feasibility and alerting effects of a daylight-supplementing in-truck lighting system (DS) providing short-wavelength enriched light before, during, and after driving. In a within-participants design, eight truck drivers drove a fully-loaded truck under wintry Scandinavian conditions (low daylight levels) with a DS or placebo system for five days. Subjective and objective measures of alertness were recorded several times daily, and evening melatonin levels were recorded three times per study condition. DS significantly increased daytime light exposure without causing negative side effects while driving. In addition, no negative carry-over effects were observed on evening melatonin and sleepiness levels or on nighttime sleep quality. Moreover, objective alertness (i.e., psychomotor vigilance) before and after driving was significantly improved by bright light exposure. This effect was accompanied by improved subjective alertness in the morning. This field study demonstrated that DS was able to increase daytime light exposure in low-daylight conditions and to improve alertness in truck drivers before and after driving (e.g., during driving rest periods). Further studies are warranted to investigate the effects of daylight-supplementing in-cabin lighting on driving performance and road safety measures.

Aims: Periprosthetic joint infection (PJI) demonstrates the most feared complication after total joint replacement (TJR). The current work analyzes the demographic, comorbidity, and complication profiles of all patients who had in-hospital treatment due to PJI. Furthermore, it aims to evaluate the in-hospital mortality of patients with PJI and analyze possible risk factors in terms of secondary diagnosis, diagnostic procedures, and complications. Methods: In a retrospective, cross-sectional study design, we gathered all patients with PJI (International Classification of Diseases (ICD)-10 code: T84.5) and resulting in-hospital treatment in Germany between 1 January 2019 and 31 December 2022. Data were provided by the Institute for the Hospital Remuneration System in Germany. Demographic data, in-hospital deaths, need for intensive care therapy, secondary diagnosis, complications, and use of diagnostic instruments were assessed. Odds ratios (ORs) with 95% confidence intervals (CIs) for in-hospital mortality were calculated. Results: A total of 52,286 patients were included, of whom 1,804 (3.5%) died. Hypertension, diabetes mellitus, and obesity, the most frequent comorbidities, were not associated with higher in-hospital mortality. Cardiac diseases as atrial fibrillation, cardiac pacemaker, or three-vessel coronary heart disease showed the highest risk for in-hospital mortality. Postoperative anaemia occurred in two-thirds of patients and showed an increased in-hospital mortality (OR 1.72; p < 0.001). Severe complications, such as organ failure, systemic inflammatory response syndrome (SIRS), or septic shock syndrome showed by far the highest association with in-hospital mortality (OR 39.20; 95% CI 33.07 to 46.46; p < 0.001). Conclusion: These findings highlight the menace coming from PJI. It can culminate in multi-organ failure, SIRS, or septic shock syndrome, along with very high rates of in-hospital mortality, thereby highlighting the vulnerability of these patients. Particular attention should be paid to patients with cardiac comorbidities such as atrial fibrillation or three-vessel coronary heart disease. Risk factors should be optimized preoperatively, anticoagulant therapy stopped and restarted on time, and sufficient patient blood management should be emphasized. Cite this article: Bone Jt Open 2024;5(4):367–373.

Purpose Diabetes mellitus, a frequent comorbid condition in cancer patients, has been shown to increase risk of all-site cancer mortality. This relationship has not been systematically studied in bladder cancer patients. This systematic review and meta-analysis aimed to identify, evaluate, and synthesize available evidence on the relationship between history of diabetes and outcomes in bladder cancer patients. Materials and Methods Systematic searches interrogated OVID MEDLINE, Embase, Web of Science, Google Scholar, and Cochrane Library to identify scholarly reports relating diabetes to all-cause mortality, bladder cancer-specific mortality, recurrence, and progression in bladder cancer patients. After critical review, meta-analysis was used to quantitively synthesize qualifying data and assess potential influence of publication bias, clinical heterogeneity, and residual confounding. Results We synthesized data on over 226,472 patients treated with curative intent uniquely represented in 28 studies that met quality metrics. Having diabetes was positively associated with each outcome. Hazard ratio estimates were indistinguishable for mortality from any cause, 1.22 (95% confidence interval [CI], 1.12–1.33) and bladder cancer-specific mortality, 1.28 (95% CI 1.17–1.41) and notably stronger in patients with muscle-invasive and high-risk non–muscle-invasive bladder cancer, 1.32 (95% CI, 1.15–1.50) and 1.48 (95% CI, 1.06–2.06). Neither publication bias, systematic error, nor confounding by factors such as smoking or obesity is likely to explain the observed associations. Conclusions Bladder cancer patients with diabetes experience elevated mortality that is not explained by diabetes-related comorbidities or complications. Future research should explore type, severity, and duration of diabetes in relation to unfavorable bladder cancer outcomes.

There is a wide variety of drought indices, yet a consensus on suitable indices and temporal scales for monitoring streamflow drought remains elusive across diverse hydrological settings. Considering the growing interest in spatially distributed indices for ungauged areas, this study addresses the following questions: (i) What temporal scales of precipitation-based indices are most suitable to assess streamflow drought in catchments with different hydrological regimes? (ii) Do soil moisture indices outperform meteorological indices as proxies for streamflow drought? (iii) Are snow indices more effective than meteorological indices for assessing streamflow drought in snow-influenced catchments? To answer these questions, we examined 100 near-natural catchments in Chile with four hydrological regimes, using the standardised precipitation index (SPI), standardised precipitation evapotranspiration index (SPEI), empirical standardised soil moisture index (ESSMI), and standardised snow water equivalent index (SWEI), aggregated across various temporal scales. Cross-correlation and event coincidence analysis were applied between these indices and the standardised streamflow index at a temporal scale of 1 month (SSI-1), as representative of streamflow drought events. Our results underscore that there is not a single drought index and temporal scale best suited to characterise all streamflow droughts in Chile, and their suitability largely depends on catchment memory. Specifically, in snowmelt-driven catchments characterised by a slow streamflow response to precipitation, the SPI at accumulation periods of 12–24 months serves as the best proxy for characterising streamflow droughts, with median correlation and coincidence rates of approximately 0.70–0.75 and 0.58–0.75, respectively. In contrast, the SPI at a 3-month accumulation period is the best proxy over faster-response rainfall-driven catchments, with median coincidence rates of around 0.55. Despite soil moisture and snowpack being key variables that modulate the propagation of meteorological deficits into hydrological ones, meteorological indices are better proxies for streamflow drought. Finally, to exclude the influence of non-drought periods, we recommend using the event coincidence analysis, a method that helps assessing the suitability of meteorological, soil moisture, and/or snow drought indices as proxies for streamflow drought events.

Abstract Malaria ranks high among prevalent and ravaging infectious diseases in sub-Saharan Africa (SSA). The negative impacts, disease burden, and risk are higher among children and pregnant women as part of the most vulnerable groups to malaria in Nigeria. However, the burden of malaria is not even in space and time. This study explores the spatial variability of malaria prevalence among children under five years (U5) in medium-sized rapidly growing city of Akure, Nigeria using model-based geostatistical modeling (MBG) technique to predict U5 malaria burden at a 100 × 100 m grid, while the parameter estimation was done using Monte Carlo maximum likelihood method. The non-spatial logistic regression model shows that U5 malaria prevalence is significantly influenced by the usage of insecticide-treated nets—ITNs, window protection, and water source. Furthermore, the MBG model shows predicted U5 malaria prevalence in Akure is greater than 35% at certain locations while we were able to ascertain places with U5 prevalence > 10% (i.e. hotspots) using exceedance probability modelling which is a vital tool for policy development. The map provides place-based evidence on the spatial variation of U5 malaria in Akure, and direction on where intensified interventions are crucial for the reduction of U5 malaria burden and improvement of urban health in Akure, Nigeria.

We thank Hockenhull et al [...]

BackgroundPyogenic vertebral osteomyelitis (VO) represents a clinical challenge and is linked to substantial morbidity and mortality. This study aimed to examine mortality as well as potential risk factors contributing to in-hospital mortality among patients with VO.MethodsThis retrospective analysis involved patients receiving treatment for VO at University Regensburg in Germany from January 1, 2000, to December 3, 2020. It included in-hospital mortality rate, comorbidities and pathogens. Patients were identified using ICD-10 diagnosis codes: M46.2, M46.3, M46.4, and M46.5. Kaplan–Meier probability plots and odds ratios (OR) for mortality were calculated.ResultsOut of the total cohort of 155 patients with VO, 53 patients (34.1%) died during a mean follow-up time of 87.8 ± 70.8 months. The overall mortality was 17.2% at one year, 19.9% at two years and 28.3% at five years. Patients with congestive heart failure (p = 0.005), renal disease (p

Abstract In recent years, the identification of endogenous substrates as biomarkers became an uprising topic. Particularly coproporphyrins (CPs), byproducts of heme biosynthesis, are intensely investigated as biomarkers for predicting interactions with the organic anion transporting polypeptide (OATP) 1B transporters. In the context of drug–drug interactions, several preclinical and clinical studies assessed the effect of the OATP1B‐index inhibitor rifampin on CPI levels. However, rifampin is not only a “perpetrator” drug of transporters but is also known for its interaction with the nuclear receptor pregnane X receptor (PXR) leading to the efficient induction of PXR‐target genes. These include hemoproteins like cytochrome P450 enzymes but also the δ‐aminolevulinate synthase 1, which is the rate‐limiting enzyme in heme biosynthesis. In this study, we showed that quantification of CPs in clinical serum samples was possible after long‐term storage at −20°C. We quantified CPI, CPIII, and heme levels in clinical serum samples (at selected timepoints) that originated from a trial investigating the interaction potential of repeated rifampin administration in 12 healthy participants. In samples collected at the assumed time to maximum concentration of rifampin, higher CP levels were observed compared to baseline. Increased levels persisted even 14 h after discontinuation of rifampin. No impact on heme serum levels was observed. We found a correlation between CP isomers at baseline and at 14 h after rifampin intake. In summary, we show that multiple doses of rifampin affect CP levels. However, besides inhibition of hepatic OATP function there is evidence for an interaction with CP levels beyond the transporter level.

Background: While MRI is the primary diagnostic tool for the diagnosis of spondylodiscitis, the role of [18F]-fluorodeoxyglucose ([18F]FDG) PET/CT is gaining prominence. This study aimed to determine the frequency of [18F]FDG PET/CT usage and its impact on the in-hospital mortality rate in patients with spondylodiscitis, particularly in the geriatric population. Methods: We conducted a Germany-wide cross-sectional study from 2019 to 2021 using an open-access, Germany-wide database, analyzing cases with ICD-10 codes M46.2-, M46.3-, and M46.4- (‘Osteomyelitis of vertebrae’, ‘Infection of intervertebral disc (pyogenic)’, and ‘Discitis unspecified’). Diagnostic modalities were compared for their association with in-hospital mortality, with a focus on [18F]FDG PET/CT. Results: In total, 29,362 hospital admissions from 2019 to 2021 were analyzed. Of these, 60.1% were male and 39.9% were female, and 71.8% of the patients were aged 65 years and above. The overall in-hospital mortality rate was 6.5% for the entire cohort and 8.2% for the geriatric subgroup (p < 0.001). Contrast-enhanced (ce) MRI (48.1%) and native CT (39.4%) of the spine were the most frequently conducted diagnostic modalities. [18F]FDG PET/CT was performed in 2.7% of cases. CeCT was associated with increased in-hospital mortality (OR = 2.03, 95% CI: 1.90–2.17, p < 0.001). Cases with documented [18F]FDG PET/CT showed a lower frequency of in-hospital deaths (OR = 0.58, 95% CI: 0.18–0.50; p = 0.002). This finding was more pronounced in patients aged 65 and above (OR = 0.42, 95% CI: 0.27–0.65, p = 0.001). Conclusions: Despite its infrequent use, [18F]FDG PET/CT was associated with a lower in-hospital mortality rate in patients with spondylodiscitis, particularly in the geriatric cohort. This study is limited by only considering data on hospitalized patients and relying on the assumption of error-free coding. Further research is needed to optimize diagnostic approaches for spondylodiscitis.

The objective of this study is to systematically investigate not only the influence of different additive types—beyond the much-considered case of aluminum-silicate-based additives—but also to carry out an additional comparison between primary and secondary emission mitigation measures during small-scale wood-chip combustion. Hence, combustion trials are realized within a 33-kW combustion plant. Pine wood chips additivated with 1.0 wt%a.r. of four additives have shown promising emission reduction effects in the past; namely kaolin (i.e., aluminum-silicate-based), anorthite (i.e., aluminum-silicate- and calcium-based), aluminum hydroxide (i.e., aluminum-based), and titanium dioxide (i.e., titanium-based). In addition to the primary mitigation measure (i.e., (fuel) additivation), an electrostatic precipitator (ESP) as a common secondary mitigation measure for total particulate matter (TPM) reduction is used for comparison. In addition to standard analyses (e.g., gravimetric determination of TPM emissions), an extended methodology (e.g., characterization of the elemental composition and ultrafine particle fraction of TPM emissions) is applied. The results show that the additivation of wood chips with kaolin and anorthite can lead to an operation of the combustion plant in compliance with the German legal TPM limit values by undercutting the absolute emission level achievable by the ESP. Additionally, kaolin and anorthite achieve significant reductions in carbon monoxide (CO) emissions, while kaolin simultaneously, and similarly to ESP, also leads to a shift in the particle size number distribution of PM emissions towards coarser particles. All additives show a significant reduction of potassium (K) emissions by the formation of high-temperature stable K compounds in the resulting ashes.

Background: Late-stage pressure sore (PS) patients are particularly susceptible to osteomyelitis (OM), as bony prominences commonly constitute the focal point of the ulcer. There are lack of data regarding the associated factors and the clinical relevance of this diagnosis in the context of PS treatment. Methods: This retrospective analysis investigated the clinical characteristics, blood markers indicative of infection in PS patients, and development of histologically evident OM. A total of 125 patient were included from 2014 to 2019. The patient records were especially scanned for histological diagnosis of OM. Results: OM was detected in 39% (37/96) of the samples taken during the index procedure. OM prevalence increased to 56% (43/77) at the second and 70% (41/59) at the third debridement. Therefore, the diagnosis of OM was acquired during treatment in 35 cases. Patients diagnosed with initial OM presented significantly higher blood markers, indicative of infection upon admission. Only patients with consistent OM (three positive biopsies) showed higher flap revision rates. Conclusion: This study found no compelling evidence linking OM to worse clinical outcomes in PS patients. In the absence of elevated inflammatory markers, reducing bone biopsy frequency and adopting a less aggressive bone debridement approach may help prevent OM in PS patients.

Abstract Background We used a genome‐wide discovery approach to identify methylation markers associated with metastasis in men with localized prostate cancer (PCa), as better identification of those at high risk of metastasis can inform treatment decision‐making. Methods We identified men with localized PCa at Kaiser Permanente California (January 1, 1997–December 31, 2006) who did not receive curative treatment and followed them for 10 years to determine metastasis status. Cases were chart review‐confirmed metastasis, and controls were matched using density sampling. We extracted DNA from the cancerous areas in the archived diagnostic tissue blocks. We used Illumina's Infinium MethylationEPIC BeadChip for methylation interrogation. We used conditional logistic regression and Bonferroni's correction to identify methylation markers associated with metastasis. In a separate validation cohort (2007), we evaluated the added predictive utility of the methylation score beyond clinical risk score. Results Among 215 cases and 404 controls, 31 CpG sites were significantly associated with metastasis status. Adding the methylation score to the clinical risk score did not meaningfully improve the c‐statistic (0.80–0.81) in the validation cohort, though the score itself was statistically significant (p

Communities residing in UNESCO-designated sites, characterised by outstanding universal values, face heightened vulnerability during disasters, necessitating innovative Disaster Risk Reduction (DRR) strategies. The critical role of well-equipped UNESCO site actors in DRR necessary for achieving the goals of broader international frameworks such as Agenda 2030 and the Sendai Framework for Disaster Risk Reduction (SFDRR) warrants this needs assessment study. This study uses a descriptive survey design to assess the competency gaps of UNESCO site actors, including managers and staff, for effective utilisation of DRR innovations (DRRI). Employing the Borich Needs Assessment Model and Ranked Discrepancy Model, an online questionnaire garnered 141 responses from 59 countries. Descriptive statistics, significance tests (at p

Abstract Background Hospitalized older adults spend as much as 95% of their time in bed, which can result in adverse events and delay recovery while increasing costs. Observational studies have shown that general mobility interventions (e.g., ambulation) can mitigate adverse events and improve patients’ functional status. Mobility technicians (MTs) may address the need for patients to engage in mobility interventions without overburdening nurses. There is no data, however, on the effect of MT-assisted ambulation on adverse events or functional status, or on the cost tradeoffs if a MT were employed. The AMBULATE study aims to determine whether MT-assisted ambulation improves mobility status and decreases adverse events for older medical inpatients. It will also include analyses to identify the patients that benefit most from MT-assisted mobility and assess the cost-effectiveness of employing a MT. Methods The AMBULATE study is a multicenter, single-blind, parallel control design, individual-level randomized trial. It will include patients admitted to a medical service in five hospitals in two regions of the USA. Patients over age 65 with mild functional deficits will be randomized using a block randomization scheme. Those in the intervention group will ambulate with the MT up to three times daily, guided by the Johns Hopkins Mobility Goal Calculator. The intervention will conclude at hospital discharge, or after 10 days if the hospitalization is prolonged. The primary outcome is the Short Physical Performance Battery score at discharge. Secondary outcomes are discharge disposition, length of stay, hospital-acquired complications (falls, venous thromboembolism, pressure ulcers, and hospital-acquired pneumonia), and post-hospital functional status. Discussion While functional decline in the hospital is multifactorial, ambulation is a modifiable factor for many patients. The AMBULATE study will be the largest randomized controlled trial to test the clinical effects of dedicating a single care team member to facilitating mobility for older hospitalized patients. It will also provide a useful estimation of cost implications to help hospital administrators assess the feasibility and utility of employing MTs. Trial registration Registered in the United States National Library of Medicine clinicaltrials.gov (# NCT05725928). February 13, 2023.

Abstract Attention is essential to the work. This study investigated the effects of two different light pulses on a simple attention task. In addition, the effects of subsequent exposure to constant but different illuminance levels on the continuation of the simple attention task and a subsequent complex attention task were examined. A total of 56 subjects were assigned in random order to two white light interventions that were repeated five times during the morning. Each light intervention consisted of a brief light pulse followed by constant light exposure and differed in temporal dimming dynamics and corneal illuminance. Subjective and psychometric parameters were recorded several times during light exposure. Heart rate variability (HRV) was derived from continuous electrocardiograms. Subjects showed improved reaction speed in the simple attention task, accompanied by higher HRV under a brighter light pulse without habituation by repetition. This difference in simple attention performance disappeared when light exposure remained the same after the light pulse. In addition, higher reaction speed and HRV were observed in the complex attention task under constant bright light exposure. Intermittent bright light seems promising to acutely improve attentional performance in office workplaces. Future research is needed to investigate daytime light effects on other work-related cognitive functions.

Abstract Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene affecting the Sec39 domain are associated with a predominant hepatic phenotype named infantile liver failure syndrome type 2 (ILFS2). Individuals are at risk of developing life‐threatening acute liver failure episodes, most likely triggered by febrile infections. Pregnancy, delivery, and the postpartum period are well known triggers of decompensation in different inherited metabolic diseases and therefore entail a potential risk also for individuals with ILFS2. We studied pregnancy, birth, and postpartum period in a woman with ILFS2 (homozygous for the NBAS variant c.2708 T > G, p.(Leu903Arg)). During two pregnancies there were no complications associated with the underlying genetic condition. Two healthy boys were born by cesarean section. To reduce the risk of fever and febrile infections, we avoided prolonged labor, epidural analgesia, and breastfeeding. Maternal body temperature and liver function were closely monitored. In case of elevated body temperature, antipyretic treatment (acetaminophen, metamizole) was given without delay. Alanine and aspartate aminotransferases as well as liver function remained normal throughout the observation period. Hence, pregnancy and childbirth are feasible in women with ILFS2 under careful monitoring.

International development organisations have improved billions of human lives in the Global South. However, in both their projects and advice to governments, most of these organisations neglect animal welfare. This blindspot matters. Poor welfare standards risk the organisation’s reputation, particularly with donors; they reduce livestock lifespans and productivity, harming recipients; and they cause animals unnecessary pain and suffering. Here, we set out animal welfare guidelines for international development organisations. They were developed through extensive stakeholder engagement with organisations, donors, and recipients, especially in Africa. To comprehensively cover animal welfare, the guidelines encompass governance structure within the organisation, staff training, standard operating procedures, water, food, housing, social isolation, enrichment, drainage and waste disposal, disease, invasive procedures, transport, slaughter, breeds, record-keeping, and monitoring and evaluation of success. We urge international development organisations to adopt and institutionalise these guidelines, so they promote good animal welfare.

The luminal surface of the intestinal epithelium is protected by a vital mucus layer, which is essential for lubrication, hydration, and fostering symbiotic bacterial relationships. Replicating and studying this complex mucus structure in vitro presents considerable challenges. To address this, we developed a hydrogel-integrated millifluidic tissue chamber capable of applying precise apical shear stress to intestinal models cultured on flat or 3D structured hydrogel scaffolds with adjustable stiffness. The chamber is designed to accommodate nine hydrogel scaffolds, 3D-printed as flat disks with a storage modulus matching the physiological range of intestinal tissue stiffness (~3.7 kPa) from bioactive decellularized and methacrylated small intestinal submucosa (dSIS-MA). Computational fluid dynamics simulations were conducted to confirm a laminar flow profile for both flat and 3D villi-comprising scaffolds in the physiologically relevant regime. The system was initially validated with HT29-MTX seeded hydrogel scaffolds, demonstrating accelerated differentiation, increased mucus production, and enhanced 3D organization under shear stress. These characteristic intestinal tissue features are essential for advanced in vitro models as they critically contribute to a functional barrier. Subsequently, the chamber was challenged with human intestinal stem cells (ISCs) from the terminal ileum. Our findings indicate that biomimicking hydrogel scaffolds, in combination with physiological shear stress, promote multi-lineage differentiation, as evidenced by a gene and protein expression analysis of basic markers and the 3D structural organization of ISCs in the absence of chemical differentiation triggers. The quantitative analysis of the alkaline phosphatase (ALP) activity and secreted mucus demonstrates the functional differentiation of the cells into enterocyte and goblet cell lineages. The millifluidic system, which has been developed and optimized for performance and cost efficiency, enables the creation and modulation of advanced intestinal models under biomimicking conditions, including tunable matrix stiffness and varying fluid shear stresses. Moreover, the readily accessible and scalable mucus-producing cellular tissue models permit comprehensive mucus analysis and the investigation of pathogen interactions and penetration, thereby offering the potential to advance our understanding of intestinal mucus in health and disease.

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. Quad whole exome analysis revealed two likely splicing-affecting disease-causing mutations in the PIGN gene: a synonymous mutation c.2619G>A, p.(Leu873=) in the last nucleotide of exon 29 and a 30 bp-deletion c.996_1023+2del (NM_176787.5) protruding into intron 12, with both mutations in trans configuration in the affected patients. Exon skipping resulting from these two variants was confirmed via RNA sequencing. Our molecular and clinical findings identified compound heterozygosity for two novel splice-affecting variants as the underlying pathomechanism for the development of FS in two patients.

We live in an urban planet. As the world continues to urbanize, urban development that support the health and wellbeing of city dwellers is far more important than ever before to achieve sustainable development targets. This study explores the complex relationship among urban planning, city growth, and health as critical drivers of sustainable development in the rapidly growing nodal city of Akure, Nigeria. The study provides a four-decade spatio-temporal model of urban Land Use Land Cover (LULC) changes in Akure between the years 1984 and 2023 from acquired Landsat satellite imageries. The result shows more than 20% net change increase in developed LULC classes between the study years. A strong positive correlation exists between the years covered in the analyses and urban development (r = 0.93, p = 0.002), and a strong negative relationship with the forest land use (r = −0.94, p = 0.002) with potential debilitating impacts on residents’ health, green infrastructures and the city’s sustainability in the future. Furthermore, results of key informant interviews (KIIs) of officials of the Ministry of Physical Planning and Urban Development (MPPUD) in Akure, Ondo State, unveil various views on the “place of health” in urban planning practices in Akure. A lack of synergy between urban planners and public health practitioners in the city and limiting scope of functions of urban planning on the impact of health in Akure were observed. Thus, we recommend the integration of a sustainable urban planning approach as a guide to manage the city.

D-2-hydroxyglutarate (D-2-HG) accumulates in primary acute myeloid leukemia (AML) patients with mutated isocitrate dehydrogenase (IDH) and other malignancies. D-2-HG suppresses antitumor T cell immunity but little is known about potential effects on non-malignant myeloid cells. Here we show that D-2-HG impairs human but not murine dendritic cell (DC) differentiation, resulting in a tolerogenic phenotype with low major histocompatibility (MHC) class II expression. In line, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, D-2-HG reprogrammed metabolism towards increased lactate production in DCs and AML besides its expected impact on DNA demethylation. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported MHC class II expression. Our results indicate an unexpected link between the immunosuppressive metabolites 2-HG and lactic acid and suggest a potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML.

Introduction: Generative AI is revolutionizing patient education in healthcare, particularly through chatbots that offer personalized, clear medical information. Reliability and accuracy are vital in AI-driven patient education. Research question: How effective are Large Language Models (LLM), such as ChatGPT and Google Bard, in delivering accurate and understandable patient education on lumbar disc herniation? Material and methods: Ten Frequently Asked Questions about lumbar disc herniation were selected from 133 questions and were submitted to three LLMs. Six experienced spine surgeons rated the responses on a scale from “excellent” to “unsatisfactory,” and evaluated the answers for exhaustiveness, clarity, empathy, and length. Statistical analysis involved Fleiss Kappa, Chi-square, and Friedman tests. Results: Out of the responses, 27.2% were excellent, 43.9% satisfactory with minimal clarification, 18.3% satisfactory with moderate clarification, and 10.6% unsatisfactory. There were no significant differences in overall ratings among the LLMs (p = 0.90); however, inter-rater reliability was not achieved, and large differences among raters were detected in the distribution of answer frequencies. Overall, ratings varied among the 10 answers (p = 0.043). The average ratings for exhaustiveness, clarity, empathy, and length were above 3.5/5. Discussion and conclusion: LLMs show potential in patient education for lumbar spine surgery, with generally positive feedback from evaluators. The new EU AI Act, enforcing strict regulation on AI systems, highlights the need for rigorous oversight in medical contexts. In the current study, the variability in evaluations and occasional inaccuracies underline the need for continuous improvement. Future research should involve more advanced models to enhance patient-physician communication.

ABSTRACTIn this study, we generated a novel library approach for high throughput de novo identification of humanized single-domain antibodies following camelid immunization. To achieve this, VHH-derived complementarity-determining regions-3 (CDR3s) obtained from an immunized llama (Lama glama) were grafted onto humanized VHH backbones comprising moderately sequence-diversified CDR1 and CDR2 regions similar to natural immunized and naïve antibody repertoires. Importantly, these CDRs were tailored toward favorable in silico developability properties, by considering human-likeness as well as excluding potential sequence liabilities and predicted immunogenic motifs. Target-specific humanized single-domain antibodies (sdAbs) were readily obtained by yeast surface display. We demonstrate that, by exploiting this approach, high affinity sdAbs with an optimized in silico developability profile can be generated. These sdAbs display favorable biophysical, biochemical, and functional attributes and do not require any further sequence optimization. This approach is generally applicable to any antigen upon camelid immunization and has the potential to significantly accelerate candidate selection and reduce risks and attrition rates in sdAb development.

ABSTRACTHere, we generated bispecific antibody (bsAb) derivatives that mimic the function of interleukin (IL)-18 based on single domain antibodies (sdAbs) specific to IL-18 Rα and IL-18 Rβ. For this, camelids were immunized, followed by yeast surface display (YSD)-enabled discovery of VHHs targeting the individual receptor subunits. Upon reformatting into a strictly monovalent (1 + 1) bispecific sdAb architecture, several bsAbs triggered dose-dependent IL-18 R downstream signaling on IL-18 reporter cells, as well as IFN-γ release by peripheral blood mononuclear cells in the presence of low-dose IL-12. However, compared with IL-18, potencies and efficacies were considerably attenuated. By engineering paratope valencies and the spatial orientation of individual paratopes within the overall design architecture, we were able to generate IL-18 mimetics displaying significantly augmented functionalities, resulting in bispecific cytokine mimetics that were more potent than IL-18 in triggering proinflammatory cytokine release. Furthermore, generated IL-18 mimetics were unaffected from inhibition by IL-18 binding protein decoy receptor. Essentially, we demonstrate that this strategy enables the generation of IL-18 mimetics with tailor-made cytokine functionalities.

Tumor necrosis factor (TNF) receptor 1 (TNFR1), TNFR2 and fibroblast growth factor-inducible 14 (Fn14) belong to the TNF receptor superfamily (TNFRSF). From a structural point of view, TNFR1 is a prototypic death domain (DD)-containing receptor. In contrast to other prominent death receptors, such as CD95/Fas and the two TRAIL death receptors DR4 and DR5, however, liganded TNFR1 does not instruct the formation of a plasma membrane-associated death inducing signaling complex converting procaspase-8 into highly active mature heterotetrameric caspase-8 molecules. Instead, liganded TNFR1 recruits the DD-containing cytoplasmic signaling proteins TRADD and RIPK1 and empowers these proteins to trigger cell death signaling by cytosolic complexes after their release from the TNFR1 signaling complex. The activity and quality (apoptosis versus necroptosis) of TNF-induced cell death signaling is controlled by caspase-8, the caspase-8 regulatory FLIP proteins, TRAF2, RIPK1 and the RIPK1-ubiquitinating E3 ligases cIAP1 and cIAP2. TNFR2 and Fn14 efficiently recruit TRAF2 along with the TRAF2 binding partners cIAP1 and cIAP2 and can thereby limit the availability of these molecules for other TRAF2/cIAP1/2-utilizing proteins including TNFR1. Accordingly, at the cellular level engagement of TNFR2 or Fn14 inhibits TNFR1-induced RIPK1-mediated effects reaching from activation of the classical NFκB pathway to induction of apoptosis and necroptosis. In this review, we summarize the effects of TNFR2- and Fn14-mediated depletion of TRAF2 and the cIAP1/2 on TNFR1 signaling at the molecular level and discuss the consequences this has in vivo.

Abstract The aim of this cross-sectional study was to present the nationwide rates of hospitalized patients with vertebral fractures over one decade and to comprehensively analyze the treatment characteristics and direct costs incurred in 2019. Therefore, the trends in the incidence rate were quantified based on annual ICD-10 diagnosis codes from all German medical facilities between 2009 and 2019, provided by the Federal Statistical Office (Destatis). The ICD-10 Codes “S12.0-2; S22.0-; S32.0-, and S32.1-2” were evaluated. The relative change from 2009 through 2019 was determined. Using data from the Institute for Hospital Remuneration Systems (InEK) for 2019 the secondary diagnoses, OPS-codes, intensive care unit (ICU) treatment, in-hospital mortality, the proportion of G-DRGs and cumulative costs were evaluated. The documented number of vertebral fractures increased by 45.6% between 2009 and 2019 to an incidence of 150.7 per 100,000 inhabitants. The lumbar spine was most commonly affected with an incidence of 70.5/100,000 inhabitants in 2019 (46.8% of all vertebral fractures). The highest increases were seen in the numbers of subaxial cervical fractures (+ 121.2%) and sacral fractures (+ 306.6%). Of all vertebral fractures in 2019, 63.7% were diagnosed in women and 69.0% in patients aged 70 years or older. Osteoporosis was documented in 17.9% of cases as a concomitant diagnosis. In 10.1% of all cases, an ICU treatment was documented. The in-hospital mortality was 2.0% in 2019. I68D was the most frequently used G-DRG code, accounting for 33.3% of cases. The total direct costs for inpatient treatment in 2019 amounted to €589,205,715. The evaluation of 955,091 vertebral fractures showed a sharp increase in the nation-wide incidence rate. The presented age and sex distribution, the comorbidity profile and the in-hospital mortality rate indicate the importance of comprehensive geriatric assessment and emphasize the need for spinal care centers to be established.

The prevalence of anxiety has increased dramatically due to COVID-19, so effective preventive interventions are welcome. The main objective of our study was to compare the acute relaxation response (RR) induced by Tibetan singing bowl (TSB) sound-based treatment against progressive muscle relaxation (PMR) and a control waiting list group (CWL) in a single treatment session in an adult nonclinical anxious population. In this cross-sectional randomized control trial, 50 participants selected based on high state anxiety were randomly assigned to one of the experimental groups. Pre/post self-reported anxiety, electroencephalographic activity (EEG), and heart rate variability (HRV) were recorded at baseline (T1), minute 15 (T2), minute 30 (T3), and minute 45 (T4). The TSB group showed significant reductions in alpha power (from T2 to T4) and increased HRV (from T3 to T4) compared with the PMR and CWL groups. Moreover, TSB and PMR both showed significant reductions in self-reported anxiety compared with CWL, with this effect being more evident in the TSB group. We concluded that a single session of TSB treatment was able to induce a more evident psychological/physiological relaxation response compared with PMR and CWL. TSB could be a relevant acute intervention in stressful situations or crisis intervention and while waiting for conventional interventions.

ABSTRACTAnalysis of prehistoric lithic artefacts helps to answer a wide array of questions concerning archaeological contexts and prehistoric human behaviour. During three projects, we studied the origin of the raw materials of 32 inventories from the Late Glacial and Early Holocene in northwest and southern Germany. The basal petrographic analysis was conducted by the geologist and petro-archaeologist Jehanne Affolter. In addition, data of more than 60 published assemblages from Switzerland as well as western and southern Germany were recorded. The origin of lithic raw materials from most of these inventories was determined using the microfacial method. GIS-based maps of the raw material sources from the aforementioned regions are compiled and raw material catchment areas of the Stone Age sites are mapped. The area calculations of the raw material catchments revealed a diachronic alternation of larger and smaller areas, which above all suggest culturally determined cycles in the range of mobility and communication networks.

The article presents a comparison of results from a simulation of the energy production by a photovoltaic installation with a tracking system and a stationary PV farm in the PVSyst program. The analyzed 1 MW PV installations were located in the Kuyavian-Pomeranian Voivodeship in Poland. Energy production results obtained from the installation with a tracking system were compared with a stationary farm with panels placed at an angle of 20° and an azimuth 0°. The paper also presents the types of tracking systems and discusses the advantages of this solution and its risks compared to traditional panel mounting. The results obtained in the study indicated that the use of a tracking system increased the annual energy production compared to a stationary farm.

In this work we present a novel symmetric bispecific antibody format based on engraftments of cattle-derived knob paratopes onto peripheral loops of the IgG1 Fc region. For this, knob architectures obtained from bovine ultralong CDR-H3 antibodies were inserted into the AB loop or EF loop of the CH3 domain, enabling the introduction of an artificial binding specificity into an IgG molecule. We demonstrate that inserted knob domains largely retain their binding affinities, resulting into bispecific antibody derivatives versatile for effector cell redirection. Essentially, generated bispecifics demonstrated adequate biophysical properties and were not compromised in their Fc mediated functionalities such as FcRn or FcγRIIIa binding.

Introduction: In this study, we demonstrate the feasibility of yeast surface display (YSD) and nextgeneration sequencing (NGS) in combination with artificial intelligence and machine learning methods (AI/ML) for the identification of de novo humanized single domain antibodies (sdAbs) with favorable early developability profiles.Methods: The display library was derived from a novel approach, in which VHH-based CDR3 regions obtained from a llama (Lama glama), immunized against NKp46, were grafted onto a humanized VHH backbone library that was diversified in CDR1 and CDR2. Following NGS analysis of sequence pools from two rounds of fluorescence-activated cell sorting we focused on four sequence clusters based on NGS frequency and enrichment analysis as well as in silico developability assessment. For each cluster, long short-term memory (LSTM) based deep generative models were trained and used for the in silico sampling of new sequences. Sequences were subjected to sequence- and structure-based in silico developability assessment to select a set of less than 10 sequences per cluster for production.Results: As demonstrated by binding kinetics and early developability assessment, this procedure represents a general strategy for the rapid and efficient design of potent and automatically humanized sdAb hits from screening selections with favorable early developability profiles.

Passive psychoeducation is an easily accessible and cost-effective self-guided intervention that does not use elements of active psychotherapies or require homework. The present study aimed to investigate the acceptability and efficacy of a 7-week app-based passive psychoeducation stress management program to promote adaptive emotion regulation and coping skills in university students (i.e., 80% psychology students). Participants were tested via Lime-Survey® at pre- and post-test with the Depression Anxiety Stress Scale-21 (DASS-21), the Response Styles Questionnaire (RSQ), and the Emotion Regulation Questionnaire (ERQ). A stratified permutation block randomization by age, gender, and the DASS-21 stress subscale was performed. Each week, the psychoeducation group (n = 123) received different psychoeducation modules. At the end of each module, participants answered questions about their satisfaction with each module and adherence to psychoeducation. The control group (n = 130) received no intervention. The psychoeducation program led to a significant improvement in the adaptive emotion regulation strategy: “reappraisal” (p = 0.004) and a significant reduction in the dysfunctional coping style: “symptom-related rumination” (p = 0.01) but not to a significant reduction in depression, anxiety, and stress scores compared to the control group. Thus, the present study might demonstrate a preventive effect of an app-based passive psychoeducation program in students with low clinically relevant psychopathological symptoms.

We conducted a comparative study involving 39 female patients with lipedema and group-matched controls at a ratio of 1:5. The primary survey tool was the German Health Update (GEDA 2019/2020-EHIS) questionnaire, which was developed by the Robert Koch Institute (RKI), Germany. The secondary survey tool was the German Pain Questionnaire. The prevalence of hypertension (p = 0.041) and high blood lipids (p = 0.024) was lower in the lipedema group compared to the control group. General health and well-being indicators demonstrated lower overall health ratings (p < 0.001) and higher physiotherapy use in patients with lipedema (p = 0.016). Mental health assessment revealed higher depression prevalence and severity (p = 0.001), together with a lower number of close contacts (p = 0.032). Furthermore, patients with lipedema experienced higher levels of pain (p < 0.001) and more significant pain-related disability in daily activities (p < 0.001) than controls. Correlation analysis among patients with lipedema showed a positive correlation between pain severity and depressive symptoms (ρ = 0.612, p < 0.001) and a moderate positive correlation with impaired health-related quality of life (ρ = 0.418, p = 0.010). In summary, our findings highlight significant differences in health and well-being between patients with lipedema and matched controls, especially in overall, metabolic, and mental health, as well as pain perception. The findings emphasize the need for a validated lipedema-specific questionnaire and a multidisciplinary treatment approach with a combination of physical therapies, lifestyle adjustments, and psychological strategies.

Seeds of “sweet lupins” have been playing an increasing role in the food industry. Lupin proteins may be used for producing a variety of foods, including pasta, bread, cookies, dairy products, and coffee substitutes. In a small percentage of the population, lupin consumption may elicit allergic reactions, either due to primary sensitization to lupin or due to cross-allergy with other legumes. Thus, lupin has to be declared on commercial food products according to EU food regulations. In this study, we investigated the influence of roasting seeds of the L. angustifolius cultivar “Boregine” on the detectability of lupin by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), ELISAs, LC-MS/MS, and real-time PCR. Seeds were roasted by fluidized bed roasting, and samples were drawn at seed surface temperatures ranging from 98 °C to 242 °C. With increasing roasting temperature, the extractability of proteins and DNA decreased. In addition, roasting resulted in lower detectability of lupin proteins by ELISAs and LC-MS/MS and lower detectability of DNA by real-time PCR. Our results suggest reduced allergenicity of roasted lupin seeds used for the production of “lupin coffee”; however, this has to be confirmed in in vivo studies.

Abstract For SARS-CoV-2, R0 calculations in the range of 2–3 dominate the literature, but much higher estimates have also been published. Because capacity for RT-PCR testing increased greatly in the early phase of the Covid-19 pandemic, R0 determinations based on these incidence values are subject to strong bias. We propose to use Covid-19-induced excess mortality to determine R0 regardless of RT-PCR testing capacity. We used data from the Robert Koch Institute (RKI) on the incidence of Covid cases, Covid-related deaths, number of RT-PCR tests performed, and excess mortality calculated from data from the Federal Statistical Office in Germany. We determined R0 using exponential growth estimates with a serial interval of 4.7 days. We used only datasets that were not yet under the influence of policy measures (e.g., lockdowns or school closures). The uncorrected R0 value for the spread of SARS-CoV-2 based on RT-PCR incidence data was 2.56 (95% CI 2.52–2.60) for Covid-19 cases and 2.03 (95% CI 1.96–2.10) for Covid-19-related deaths. However, because the number of RT-PCR tests increased by a growth factor of 1.381 during the same period, these R0 values must be corrected accordingly (R0corrected = R0uncorrected/1.381), yielding 1.86 for Covid-19 cases and 1.47 for Covid-19 deaths. The R0 value based on excess deaths was calculated to be 1.34 (95% CI 1.32–1.37). A sine-function-based adjustment for seasonal effects of 40% corresponds to a maximum value of R0January = 1.68 and a minimum value of R0July = 1.01. Our calculations show an R0 that is much lower than previously thought. This relatively low range of R0 fits very well with the observed seasonal pattern of infection across Europe in 2020 and 2021, including the emergence of more contagious escape variants such as delta or omicron. In general, our study shows that excess mortality can be used as a reliable surrogate to determine the R0 in pandemic situations.

The role of DNA methylation in predisposing to pediatric acute lymphoblastic leukemia remains unknown. Here, the authors utilize a discordant twin model to investigate how DNA methylation variation contributes to disease risk in genetically identical subjects.