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Abstract Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.

Abstract Background Around 10% of fractures lead to complications. With increasing fracture incidences in recent years, this poses a serious burden on the healthcare system, with increasing costs for treatment. In the present study, we aimed to identify potential ‘new’ blood markers to predict the development of post-surgical complications in trauma patients following a fracture. Methods A total of 292 trauma patients with a complete three-month follow-up were included in this cohort study. Blood samples were obtained from 244 of these patients. Two complication groups were distinguished based on the Clavien-Dindo (CD) classification: CD grade I and CD grade III groups were compared to the controls (CD 0). The Mann-Whitney U test was used to compare the complication groups to the control group. Results Analysis of the patients’ data revealed that risk factors are dependent on sex. Both, males and females who developed a CD III complication showed elevated blood levels of B7-1 (p = 0.015 and p = 0.018, respectively) and PlGF-1 (p = 0.009 and p = 0.031, respectively), with B7-1 demonstrating greater sensitivity (B7-1: 0.706 (male) and 0.692 (female), PlGF-1: 0.647 (male) and 0.615 (female)). Further analysis of the questionnaires and medical data revealed the importance of additional risk factors. For males (CD 0: 133; CD I: 12; CD III: 18 patients) alcohol consumption was significantly increased for CD I and CD III compared to control with p = 0.009 and p = 0.007, respectively. For females (CD 0: 107; CD I: 10; CD III: 12 patients) a significantly increased average BMI [kg/m2] from 25.5 to 29.7 with CD III was observed, as well as an elevation from one to three comorbidities (p = 0.003). Conclusions These two potential new blood markers hold promise for predicting complication development in trauma patients. Nevertheless, further studies are necessary to evaluate the diagnostic utility of B7-1 and PlGF-1 in predicting complications in trauma patients and consider sex differences before their possible use as routine clinical screening tools.

Peat soils store a large part of the global soil carbon stock, which can potentially be lost when they are drained and taken into cultivation, resulting in CO2 emission and land subsidence. Groundwater level (GWL) management has been proposed to mitigate peat oxidation, but may lead to increased emissions of nitrous oxide (N2O) and methane (CH4).The aim of this experiment was to study trade-offs between greenhouse gas emissions from peat soils as a function of GWL. We incubated 1 m deep, 24 cm diameter undisturbed bare soil cores, after removal of the grass layer, from three contrasting Dutch grassland peat sites for 370 days at 16 °C. The cores were subjected to drying-wetting cycles, with the GWL varying between near the soil surface to 160 cm below the surface. We measured gas fluxes of CO2, N2O and CH4 from the soil surface, extracted pore water for DOC and mineral nitrogen analysis, and measured soil hydraulic and shrinkage characteristics.Emissions of CO2 increased after lowering the GWL, but showed different GWL-response curves during rewetting of the soil. On average, highest CO2 emissions of 1.5 g C·m−2 day−1 were found at a GWL of 80 cm below the surface. However, the 0 cm GWL was the only treatment with significantly lower CO2 emissions than other GWLs. Cumulative CO2 emissions differed significantly between sampling sites. Emissions of N2O showed a different response, peaking at GWL heights above −20 cm, particularly after a recent GWL rise. Though not significantly different, the highest N2O emissions were measured at the 0 cm GWL treatment. We confirmed this pattern for N2O in un-replicated soil cores with grass sward, although emission values were lower in these cores due to the root uptake of mineral nitrogen. CH4 emissions or −uptake remained low under any GWL. We conclude that raising the GWL is a successful strategy to reduce CO2 emissions from peat oxidation. However, raising the GWL close to the soil surface could lead to N2O emissions that negate any gains in terms of global warming potential. Our results suggest that raising the GWL in peat grasslands to −20 cm creates such a risk. A constant GWL at the surface (0 cm) would be preferential for mitigating both CO2 and N2O emissions, although such conditions don’t allow for agricultural grass production (mowing or grazing).

Early and reliable detection of infection is vital for successful treatment. Serum markers such as C-reactive protein (CRP) and procalcitonin (PCT) are known to increase with a time lag. Azurocidin 1 (AZU1) has emerged as a promising marker for septic patients, but its diagnostic value in orthopedic and trauma patients remains unexplored. Between July 2020 and August 2023, all patients necessitating inpatient treatment for periprosthetic joint infection (PJI), peri-implant infection (II), soft tissue infection, chronic osteomyelitis, septic arthrodesis, bone non-union with and without infection were enrolled. Patients undergoing elective total joint arthroplasty (TJA) served as the control group. Blood samples were collected and analyzed for CRP, white blood cell count (WBC), PCT, and AZU1. Based on the inclusion and exclusion criteria 222 patients were included in the study (trauma = 38, soft tissue infection = 75, TJA = 33, PJI/II = 39, others = 37). While sensitivity and specificity were comparably high for AZU1 (0.734/0.833), CRP and PCT had higher specificity (0.542/1 and 0.431/1, respectively), and WBC a slightly higher sensitivity (0.814/0.455) for septic conditions. Taken together, the area under the curve (AUC) showed the highest accuracy for AZU1 (0.790), followed by CRP (0.776), WBC (0.641), and PCT (0.656). The Youden-Index was 0.57 for AZU1, 0.54 for CRP, 0.27 for WBC, and 0.43 for PCT. Elevated AZU1 levels effectively distinguished patients with a healthy condition from those suffering from infection. However, there is evidence suggesting that trauma may influence the release of AZU1. Additional research is needed to validate the diagnostic value of this new biomarker and further explore its potential clinical applications.

Persistent infections caused by Strongyloides stercoralis are probably underestimated in the elderly Italian population. This nematode is unique among helminths: it can last asymptomatically in the host for decades and may present with a broad range of clinical pictures upon reactivation. Misdiagnosis often occurs even when the clinical picture is suggestive. If undetected, this parasitosis can lead to serious consequences when hyperinfection occurs. Herein, we report two peculiar clinical cases of complicated strongyloidiasis with multiple skin lesions. The aim of our report is to lead clinicians to familiarize themselves with skin patterns and clinical features that can suggest a possible underlying strongyloidiasis.

Purpose Hypertension should be confirmed with the use of home BP measurement (HBPM) or 24h ambulatory BP measurement (ABPM). The aim of our study was to compare measurements obtained by OBPM, HBPM and ABPM in individuals with elevated OBPM participating in the population-based Swiss Longitudinal Cohort Study (SWICOS). Material and Methods Participants with OBPM ≥140/90 mmHg assessed their BP using HBPM and ABPM. The cut-off for hypertension was ≥135/85 mmHg for HBPM, ≥130/80 mmHg for ABPM. White-coat hypertension (WCH) was defined as normal HPBM and ABPM in participants not taking antihypertensive drugs. Uncontrolled hypertension was defined as hypertension in HBPM or ABPM despite antihypertensive treatment. Results Of 72 hypertensive subjects with office BP ≥140/90 mmHg and valid measurements of HBPM and ABPM, 39 were males (aged 62.8 ± 11.8y), 33 were females (aged 57.4 ± 14.2y). Hypertension was confirmed with HBPM and ABPM in 17 participants (24%), with ABPM only in 24 further participants (33%), and with HBPM only in 2 further participants (3%). Participants who had hypertension according to ABPM but not HBPM were younger (59 ± 11 y versus 67 ± 16 y; p

Abstract N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus + low infusion (15 mg + 0.6 mg/min), and high bolus + high infusion (25 mg + 1 mg/min). Study sessions lasted for 5 h and were separated by at least 1 week. Participant’s lifetime use of psychedelics was ≤20 times. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics of DMT, and plasma levels of brain-derived neurotropic factor (BDNF) and oxytocin. Low (15 mg) and high (25 mg) DMT bolus doses rapidly induced very intense psychedelic effects that peaked within 2 min. DMT infusions (0.6 or 1 mg/min) without a bolus induced slowly increasing and dose-dependent psychedelic effects that reached plateaus after 30 min. Both bolus doses produced more negative subjective effects and anxiety than infusions. After stopping the infusion, all drug effects rapidly decreased and completely subsided within 15 min, consistent with a short early plasma elimination half-life (t1/2α) of 5.0–5.8 min, followed by longer late elimination (t1/2β = 14–16 min) after 15–20 min. Subjective effects of DMT were stable from 30 to 90 min, despite further increasing plasma concentrations, thus indicating acute tolerance to continuous DMT administration. Intravenous DMT, particularly when administered as an infusion, is a promising tool for the controlled induction of a psychedelic state that can be tailored to the specific needs of patients and therapeutic sessions. Trial registration: ClinicalTrials.gov identifier: NCT04353024

AIMS: There is a lack of national and international publicly available long-term survival outcome data from individual healthcare providers in medical oncology. In this study, the overall survival at a medium-sized medical oncology service at Olten Cantonal Hospital was evaluated and compared as a local benchmark report with national data from the Swiss Cancer Registries. Furthermore, adherence to treatment guidelines was investigated as an additional quality indicator. METHODS: The 1- and 5-year overall survival of all patients with breast cancer, testicular cancer, colon cancer, non-small-cell lung cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma in Switzerland from 2008 to 2017 with at least one outpatient visit at the in-house medical oncology service at Olten Cantonal Hospital was analysed and compared with the specific overall population-based outcome data provided by the National Agency for Cancer Registration (NACR), which were set as a national benchmark. Until 2020, no data from the Canton of Solothurn, to which Olten belongs, were reported to the NACR. Further, adherence to internationally recognized clinical guidelines for stage-specific treatment was assessed. RESULTS: Until September 8, 2020, data on 842 patients with a median follow-up period of 70 months were collected and analysed. The 1- and 5-year overall survival for colon and non-small cell cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma and the 5-year overall survival for testicular cancer in the Olten cohort did not significantly differ from the NACR data. The 1-year overall survival for testicular cancer was not comparable statistically. The 5-year overall survival for breast cancer (unadjusted for stage) was significantly higher in the NACR collective (84.5%) than in the Olten collective (79.7%) but not for the individual breast cancer stages. The Olten collective included approximately 2.5 times as many patients with stage 4 breast cancer (17.5%) as the NACR collective (6.9%). Approximately 92.4% of the patients in the curative setting and 85.8% of the patients in the palliative setting received first-line treatment according to guidelines. CONCLUSIONS: The statistically comparable local 1- and 5-year overall survival of the analysed malignancies, with adjustment for stage for the 5-year overall survival for breast cancer, is in line with the national benchmark. Adherence to treatment guidelines is high.

Schizophrenia is a serious cognitive disorder characterized by disruptions in neurotransmission, a process requiring the coordination of multiple kinase-mediated signaling events. Evidence suggests that the observed deficits in schizophrenia may be due to imbalances in kinase activity that propagate through an intracellular signaling network. Specifically, 3′-5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways are coupled to the activation of neurotransmitter receptors and modulate cellular functions through the activation of protein kinase A (PKA), an enzyme whose function is altered in the frontal cortex in schizophrenia. In this study, we measured the activity of PKA in human postmortem anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) tissue from schizophrenia and age- and sex-matched control subjects. No significant differences in PKA activity were observed in male and female individuals in either brain region; however, correlation analyses indicated that PKA activity in the ACC may be influenced by tissue pH in all subjects and by age and tissue pH in females. Our data provide novel insights into the function of PKA in the ACC and DLPFC in schizophrenia.

Abstract To help reduce the spread of the SARS-CoV-2 virus during the COVID-19 pandemic, ICU visits were banned or restricted. Therefore, family-centered care as usually practiced was not feasible Video calls were recommended to meet relatives’ needs. The aim of this study was to investigate the effect of video calls on symptoms of post-traumatic stress disorder (PTSD) in relatives of ICU patients. This single-center study was performed during the first wave (15.03.2020‒30.04.2020; visits banned) and the second wave (01.10.20‒08.02.21: visits restricted) of the COVID-19 pandemic. The Impact of Event Scale-Revised (IES-R) was used to assess PTSD symptoms and an adapted version of the Family Satisfaction in the Intensive Care Unit 24-Item-Revised questionnaire (aFS-ICU 24R) to assess family satisfaction 3 months after ICU stay. The primary outcome was the difference in IES-R score at 3 months between the video call group (VCG) and the standard care group (SCG, no video calls). In addition, inductive content analysis of relatives’ comments regarding their satisfaction with decision-making and ICU care was performed. Fifty-two relatives (VCG: n = 26, SCG: n = 26) were included in this study. No significant difference in IES-R scores was observed between the VCG and the SCG (49.52 ± 13.41 vs. 47.46 ± 10.43, p = 0.54). During the ICU stay (mean 12 days, range 5.25‒18.75 days), the members of the VCG made a median of 3 (IQR 1‒10.75) video calls. No difference between the groups was found for conventional telephone calls during the same period (VCG: 9 calls, IQR 3.75‒18.1; SCG: 5 calls, IQR 3‒9; p = 0.12). The aFS-ICU 24R scores were high for both groups: 38 (IQR 37‒40) in the VCG and 40 (IQR 37‒40: p = 0.24) in the SCG. Video calls appeared largely ineffective in reducing PTSD symptoms or improving satisfaction among relatives affected by banning/restriction of ICU visits during the COVID-19 pandemic. Further investigations are needed to acquire more data on the factors involved in PTSD symptoms experienced by relatives of ICU patients during the COVID-19 pandemic.

Abstract Aims Synchronized diaphragmatic stimulation (SDS) modulates intrathoracic and intra‐abdominal pressures with favourable effects on cardiac function for patients with a reduced left ventricular ejection fraction (LVEF) and heart failure (HFrEF). VisONE‐HF is a first‐in‐patient, observational study assessing the feasibility and 1 year effects of a novel, minimally invasive SDS device. Methods and results The SDS system comprises a pulse generator and two laparoscopically delivered, bipolar, active‐fixation leads on the inferior diaphragmatic surface. Fifteen symptomatic men with HFrEF and ischaemic heart disease receiving guideline‐recommended therapy were enrolled (age 60 [56, 67] years, New York Heart Association class II [53%] /III [47%], LVEF 27 [23, 33] %, QRSd 117 [100, 125] ms, & N terminal pro brain natriuretic peptide [NT‐proBNP] 1779 [911, 2,072] pg/mL). Implant success was 100%. Patients were evaluated at 3, 6, and 12 months for device‐related or lead‐related complications, quality of life (SF‐36 QOL), 6 min hall walk distance (6MHWd), and by echocardiography. No implant procedure or SDS‐related adverse event occurred, and patients were unaware of diaphragmatic stimulation. By 12 months, left ventricular end‐systolic volume decreased (136 [123, 170] mL to 98 [89, 106] mL; P = 0.05), 6MHWd increased (315 [300, 330] m to 340 [315, 368] m; P = 0.004), and SF‐36 QOL improved (physical scale 0 [0, 0] to 25 [0, 50], P = 0.006; emotional scale 0 [0, 33] to 33 [33, 67], P = 0.001). Although neither reached statistical significance, LVEF decreased (28 [23, 40]% vs. 34 [29, 38]%; P = ns) and NT‐proBNP was lower (1784 [920, 2540] pg/mL vs. 1492 [879, 2028] pg/mL; P = ns). Conclusions These data demonstrate the feasibility of laparoscopic implantation and delivery of SDS without raising safety concerns. These encouraging findings should be investigated further in adequately powered randomized trials.

Abstract Synchronized diaphragmatic stimulation (SDS) is a novel extra‐cardiac device‐based therapy for symptomatic heart failure with reduced ejection fraction. SDS provides imperceptible chronic stimulation of the diaphragm through a laparoscopically implanted system consisting of an implantable pulse generator and two sensing/stimulating leads affixed to the inferior surface of the diaphragm delivering imperceptible R‐wave gaited pulses that alter intrathoracic pressure improving ventricular filling and cardiac output. We describe, in a man with a history of myocardial infarctions resulting in heart failure and persistent New York Heart Association Class III symptoms despite standard therapies, the successful implantation of SDS resulting in improved quality of life, N‐terminal pro brain natriuretic peptide, cardiac function, and exercise tolerance through 12 months of follow‐up. Randomized trials are now required to validate these findings.

Biochemical methane potential (BMP) test is a common technique for determining the methane generation potential (Lo) of substrates at an anaerobic condition. In this study, Lo of seven components of municipal solid waste, namely cooked food waste (CFW), fruit waste (FW), vegetable waste (VW), uncooked food waste (UCFW), paper waste (PW), garden waste (GW), and textile waste (TW) were assessed in a mesophilic condition for 37 days. Beside that, theoretical Lo was predicted based on the organic composition of substrates, the elemental compositions and chemical oxygen demand (COD) of substrates. In addition to that, the biodegradability index (BDI) was calculated to determine the ratio of experimental BMP to theoretical BMP. The findings from the experimental BMP showed that CFW had a greater methane generation potential, which was 328.39 mlCH4/gVS, than TW with 174.02 mlCH4/gVS of methane generation potential. Among all seven substrates, UCFW had the highest BDI, while the lowest organic fraction identified in the current study wasTW. Theoretical prediction for all substrates reveals the overestimation of methane production compared to the experimental method, with a percentage error in the range of 0.08 %–327.02 %. The theoretical BMP method based on COD composition had correction factors ranging from 0.96 to 2.55, while the theoretical BMP method based on elemental composition had correction factors ranging from 0.50 to 4.27. Two models which were the First-order kinetic model (FOKM) and the ModifiedGompertz model (MGM) were utilised in the current study to evaluate the kinetic behaviours of the measured substrates. The results revealed that the MGM fitted the predicted methane generation potential with the highest R2 value (0.96–0.98) and lowest RMSE (8.71–17.20). Therefore, the baseline data can be used to establish potential solutions in municipal solid waste management systems in Malaysia, as well as to provide guidance to waste-to-energy (WTE) parties.

Gas-fired condensing boilers are widely used in domestic heating. However, emission of nitrogen oxides (NOx) remains a concern due to their adverse environmental effects. Employing lean premixed surface-stabilized combustion, ultra-low NOx generation is achievable.We studied NOx formation in realistic, axi-symmetric condensing boiler setups featuring lean combustion of methane stabilized by a porous cylindrical burner using a dedicated numerical model. To accurately represent the physical conditions, our model comprises most notably laminar combustion using a GRI-3.0 kinetic mechanism, a volumetric heat transfer coefficient for heat exchange inside the porous solid, conjugate heat transfer at the gas-solid interface and radiative heat exchange between burner surface and combustion chamber wall. A comprehensive assessment included validation of individual model aspects against literature data, a mesh study and validation with experimental measurements from a full-scale condensing boiler setup. Our findings suggest that the effective diffusion due to dispersive flow in porous media is critical for accurately capturing the reaction zone, thus preventing overprediction of flame temperature and NO concentration.The dependencies of NOx generation and heat release parameters on varying parametric and geometric configurations of the setup were assessed in a comprehensive numerical parameter study. We found that NO emission increases in a near-linear way with firing rate, while radiation efficiency decreases. At constant input power, NO emission rises with increasing equivalence ratio alongside radiation efficiency and peak flame temperature. By optimizing inflow uniformity, peak temperatures can be reduced by 9%, leading to significantly lower NOx generation without affecting the heat flow rate.

Abstract Sustained forms of atrial fibrillation (AF) may be associated with a higher risk of adverse outcomes, but few if any long-term studies took into account changes of AF type and co-morbidities over time. We prospectively followed 3843 AF patients and collected information on AF type and co-morbidities during yearly follow-ups. The primary outcome was a composite of stroke or systemic embolism (SE). Secondary outcomes included myocardial infarction, hospitalization for congestive heart failure (CHF), bleeding and all-cause mortality. Multivariable adjusted Cox proportional hazards models with time-varying covariates were used to compare hazard ratios (HR) according to AF type. At baseline 1895 (49%), 1046 (27%) and 902 (24%) patients had paroxysmal, persistent and permanent AF and 3234 (84%) were anticoagulated. After a median (IQR) follow-up of 3.0 (1.9; 4.2) years, the incidence of stroke/SE was 1.0 per 100 patient-years. The incidence of myocardial infarction, CHF, bleeding and all-cause mortality was 0.7, 3.0, 2.9 and 2.7 per 100 patient-years, respectively. The multivariable adjusted (a) HRs (95% confidence interval) for stroke/SE were 1.13 (0.69; 1.85) and 1.27 (0.83; 1.95) for time-updated persistent and permanent AF, respectively. The corresponding aHRs were 1.23 (0.89, 1.69) and 1.45 (1.12; 1.87) for all-cause mortality, 1.34 (1.00; 1.80) and 1.30 (1.01; 1.67) for CHF, 0.91 (0.48; 1.72) and 0.95 (0.56; 1.59) for myocardial infarction, and 0.89 (0.70; 1.14) and 1.00 (0.81; 1.24) for bleeding. In this large prospective cohort of AF patients, time-updated AF type was not associated with incident stroke/SE.

Abstract Background Noise exposure leads to a reduction in cognitive abilities in diverse settings, however, only limited data exist examining the effects of environmental ICU noise on the cognitive performance of ICU professionals. A frequently occurring and demanding retention task in ICUs are ward rounds, which are considered key for the provision of medical care. Here, we investigate the influence of noise on information retention in a simulated ward round. Methods ICU professionals were exposed to a recorded, ICU ward round, simulated partly with and partly without environmental ICU noise. Ward rounds were followed by specific questions about previously provided information. Results 56 ICU professionals (aged 26–59 years) were included. A logistic mixed model showed a reduction of 27% (P

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin–9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Background: The fingers’ tactile sensibility is essential in surgery, especially in microsurgery. Therefore, surgeons seeking to improve their performance often prefer certain glove brands and wearing habits. There is the need of objectively testing these glove wearing conditions and determine the effect of surgical experience with regard to tactile sensibility by comparing surgeons with non-surgeons. Methods: This cross-sectional single-center pilot-study was conducted between June and August 2021. Two groups of 27 surgeons and 27 non-surgeons underwent two-point-discrimination (2PD) and Semmes-Weinstein monofilament testing (SWMT) of both index fingers with bare hands and with wearing six different brands of surgical gloves. Different wearing conditions, such as single-gloving, double-gloving, well-fitted, under- and oversized gloves, were evaluated within and between the groups. Results: Most glove types decreased tactile sensibility (2PD and SWMT) of surgeons and non-surgeons. Interestingly, the thinnest gloves showed similar 2PD values to bare hands in both groups. Double-gloving negatively impacted SWMT, without influencing 2PD. Undersized gloves showed better 2PD and SWMT than well-fitted gloves, while oversized gloves showed no tactile drawbacks. With bare hands and certain glove conditions, the surgeons' 2PD and SWMT was significantly better than the non-surgeons’, indicating a positive effect of surgical experience on tactile sensibility. Conclusion: Our study demonstrated the positive impact of surgical experience on tactile sensibility, as demonstrated by the surgeons. The sensibility of the gloved hand varies on the surgical glove type, but favors thinner gloves, single gloving (rather than double gloving) and undersized or well-fitted gloves.

Purpose Poor adherence to drug therapy and inadequate drug regimens are two frequent factors responsible for the poor blood pressure (BP) control observed in patients with apparent resistant hypertension. We evaluated the efficacy of an antihypertensive management strategy combining a standardised therapy with three long acting drugs and electronic monitoring of drug adherence in patients with apparent resistant hypertension. Materials and Methods In this multicentric observational study, adult patients with residual hypertension on 24 h ambulatory BP monitoring (ABMP) despite the use of three or more antihypertensive drugs could be included. Olmesartan/amlodipine (40/10 mg, single pill fixed-dose combination) and chlorthalidone (25 mg) were prescribed for 3 months in two separated electronic pills boxes (EPB). The primary outcome was 24 h ambulatory systolic BP (SBP) control at 3 months, defined as mean SBP

Abstract Aims We aimed to assess the long‐term effect of a strategy of comprehensive vasodilation versus usual care on health‐related quality of life (HRQL) among patients with acute heart failure (AHF). Methods and results Health‐related quality of life was prospectively assessed by the generic 3‐levelled EQ‐5D and the disease‐specific Kansas City Cardiomyopathy Questionnaire (KCCQ) among adult AHF patients enrolled in an international, multicentre, randomised, open‐label blinded‐end‐point trial of a strategy that emphasized early intensive and sustained vasodilation using maximally tolerated doses of established oral and transdermal vasodilators according to systolic blood pressure. Changes in EQ‐5D and KCCQ from admission to 180 day follow‐up were individually compared between the intensive vasodilatation and the usual care group. Among 666 patients eligible for 180 day follow‐up, 284 (43%, median age 79 years, 35% women) and 198 (30%, median age 77 years, 35% women) had completed the EQ‐5D and KCCQ at baseline and follow‐up, respectively. There was a significant improvement in HRQL as quantified by both, EQ‐5D and KCCQ, from hospitalization to 180 day follow‐up, with no significant differences in the change of HRQL between both treatment strategies. For instance, 39 (26%) versus 33 (25%) patients had an improvement by at least one level in at least two categories in the EQ‐5D. Median increase in KCCQ overall summary score (KCCQ‐OSS) was 17.6 (IQR 2.0–42.6) in the intervention group versus 18.5 (IQR 3.9–39.3) in the usual care group (P

Abstract Background During the COVID-19 pandemic, suspension of visits by next of kin to patients in intensive care units (ICU), to prevent spread of the SARS-CoV-2 virus, has been a common practice. This could impede established family-centered care and may affect the mental health of the next of kin. The aim of this study was to explore symptoms of post-traumatic stress syndrome (PTSD) in the next of kin of ICU patients. Methods In this prospective observational single-center study, next of kin of ICU patients were interviewed by telephone, using the Impact of Event Scale-Revised (IES-R), to assess symptoms of acute stress disorder during the ICU stay and PTSD symptoms at 3 months after the ICU stay. The primary outcome was the prevalence of severe PTSD symptoms (IES-R score ≥ 33) at 3 months. The secondary outcomes comprised the IES-R scores during the ICU stay, at 3 months, and the prevalence of severe symptoms of acute stress disorder during ICU stay. An inductive content analysis was performed of the next of kin’s comments regarding satisfaction with patient care and the information they were given. Results Of the 411 ICU patients admitted during the study period, 62 patients were included together with their next of kin. An IES-R score > 33 was observed in 90.3% (56/62) of next of kin during the ICU stay and in 69.4% (43/62) 3 months later. The median IES-R score was 49 (IQR 40–61) during the ICU stay and 41 (IQR 30–55) at 3 months. The inductive content analysis showed that communication/information (55%), support (40%), distressing emotions (32%), and suspension of ICU visits (24%) were mentioned as relevant aspects by the next of kin. Conclusions During the suspension of ICU visits in the COVID-19 pandemic, high prevalence and severity of both symptoms of acute stress disorder during the ICU stay and PTSD symptoms 3 months later were observed in the next of kin of ICU patients.

Summary: Age-related diseases are major concern in developed countries. To avoid disabilities that accompany increased lifespan, pharmaceutical approaches are considered. Therefore, appropriate animal models are required for a better understanding of aging processes and potential in vivo assays to evaluate the impact of molecules that may delay the occurrence of age-related diseases. Few mouse models exhibiting pathological aging exist, but currently, none of them reproducibly mimics human diseases like osteoporosis, cognitive dysfunctions or sarcopenia that can be seen in some, but not all, elders. Here, we describe the premature aging phenotypes of Dicer-deficient mature animals, which exhibit an overall deterioration of many organs and tissues (skin, heart, and adipose tissue) ultimately leading to a significant reduction of their lifespan. Molecular characterization of transcriptional responses focused on the adipose tissue suggested that both canonical and non-canonical functions of DICER are involved in this process and highlight potential actionable pathways to revert it.

The main question proposed in this research is whether different types of organizational approaches could help in shortening the response time needed to analyze advanced design solutions in accordance with the changed circumstances. Approaches that we are considering have been adapted from rapidly changing disciplines—such as the IT industry, and software engineering. This paradigm allows for architectural programming to obtain different positions in the timeline of project planning and realization. We proposed a novel methodology of architectural design and project management as an instrument inspired by the Agile Manifesto and some of its instantiations, most notably by the Scrum framework. This research shows that application of the proposed framework significantly shortens the design process and facilitates the involvement of a larger number of authors within the same project team. This study focused on the specific case of architectural competitions. However, the results showed that the same framework could be applied in a broader design context, details of which have been left for future considerations.

Abstract In this paper we sought to develop and assess the reproducibility of an updated 6-point grading system for lumbar foraminal stenosis based on the widely used Lee classification that more accurately describes lumbar foraminal stenosis as seen on high-resolution MRI. Grade A indicates absence of foraminal stenosis. Grades B, C, D and E indicate presence of foraminal stenosis with contact of the nerve root with surrounding anatomical structures (on one, two, three or four sides for B, C, D and E respectively) yet without morphological change of the nerve root. To each grade, a number code indicating the location of contact between the nerve root and surrounding anatomical structure(s) is appended. 1, 2, 3 and 4 indicate contact of the nerve root at superior, posterior, inferior and anterior position of the borders of the lumbar foramen. Grade F indicates presence of foraminal stenosis with morphological change of the nerve root. Three readers graded the lumbar foramina of 101 consecutive patients using high-resolution T2w (and T1w) MR images with a spatial resolution of beyond 0.5 mm3. Interreader agreement was excellent (Cohen’s Kappa = 0.866–1). Importantly, 30.6%/31.6%/32.2% (reader 1/reader 2/ reader 3) of foramina were assigned grades that did not appear in the original Lee grading system (grades B and D). The readers found no foramen that could not be described accurately with the updated grading system. Thus, an updated 6-point grading system for lumbar foraminal stenosis is reproducible and comprehensively describes lumbar foraminal stenosis as seen on high-resolution MRI.

BackgroundMicrovascular obstruction (MVO) and Late Gadolinium Enhancement (LGE) assessed in cardiac magnetic resonance (CMR) are associated with adverse outcome in patients with ST-elevation myocardial infarction (STEMI). Our aim was to analyze the diagnostic performance of segmental strain for the detection of MVO and LGE.MethodsPatients with anterior STEMI, who underwent additional CMR were enrolled in this sub-study of the CARE-AMI trial. Using CMR feature tracking (FT) segmental circumferential peak strain (SCS) was measured and the diagnostic performance of SCS to discriminate MVO and LGE was assessed in a derivation and validation cohort.ResultsForty-eight STEMI patients (62 ± 12 years old), 39 (81%) males, who underwent CMR (i.e., mean 3.0 ± 1.5 days) after primary percutaneous coronary intervention (PCI) were included. All patients presented with LGE and in 40 (83%) patients, MVO was additionally present. Segments in all patients were visually classified and 146 (19%) segments showed MVO (i.e., LGE+/MVO+), 308 (40%) segments showed LGE and no MVO (i.e., LGE+/MVO–), and 314 (41%) segments showed no LGE (i.e., LGE–). Diagnostic performance of SCS for detecting MVO segments (i.e., LGE+/MVO+ vs. LGE+/MVO–, and LGE–) showed an AUC = 0.764 and SCS cut-off value was –11.2%, resulting in a sensitivity of 78% and a specificity of 67% with a positive predictive value (PPV) of 30% and a negative predictive value (NPV) of 94% when tested in the validation group. For LGE segments (i.e., LGE+/MVO+ and LGE+/MVO– vs. LGE–) AUC = 0.848 and SCS with a cut-off value of –13.8% yielded to a sensitivity of 76%, specificity of 74%, PPV of 81%, and NPV of 70%.ConclusionSegmental strain in STEMI patients was associated with good diagnostic performance for detection of MVO+ segments and very good diagnostic performance of LGE+ segments. Segmental strain may be useful as a potential contrast-free surrogate marker to improve early risk stratification in patients after primary PCI.

Abstract Immune checkpoint therapy, where CD8 tumor infiltrating T lymphocytes (TIL) are reactivated, is a promising anti‐cancer treatment approach, yet with low response rates. The extracellular matrix, in particular tenascin‐C, may generate barriers for TIL. To investigate this possibility, we used a MMTV‐NeuNT and syngeneic mammary gland grafting model derived thereof with engineered tenascin‐C levels and observed accumulation of CD8 TIL in tenascin‐C‐rich stroma. Inhibition studies revealed that tenascin‐C induced CXCL12 through TLR4. By binding CXCL12, tenascin‐C retained CD8 TIL in the stroma. Blockade of CXCR4, the receptor of CXCL12, enhanced macrophage and CD8 TIL infiltration and reduced tumor growth and subsequent metastasis. Retention of CD8 TIL by tenascin‐C/CXCL12 was also observed in human breast cancer by tissue staining. Moreover, whereas high CD8 TIL numbers correlated with longer metastasis‐free survival, this was not the case when also tenascin‐C and CXCL12 levels were high. Altogether, these results may be useful for improving tumor immunity as diagnostic tool and to formulate a future “TIL‐matrix‐release‐and‐reactivate” strategy.

Pancreatic cancer is known for its tumor microenvironment (TME), which is rich in stromal and immune cells supporting cancer growth and therapy resistance. In particular, tumor-associated macrophages (TAMs) are known for their angiogenesis- and metastasis-promoting properties, which lead to the failure of conventional therapies for pancreatic cancer. Hence, treatment options targeting TAMs are needed. The C-C chemokine receptor type 4 (CCR4) is critical for immune cell recruitment into the TME, and in this paper we explore the effects of its genetic or immunotherapeutic blockade in pancreatic-cancer-bearing mice. Murine PDA6606 pancreatic cancer cells and murine peritoneal macrophages were used for in vitro migration assays. In vivo, a syngeneic, orthotropic pancreatic cancer model was established. Tumor growth and survival were monitored under prophylactic and therapeutic application of a CCR4 antagonist (AF-399/420/18025) in wildtype (CCR4wt) and CCR4-knockout (CCR4−/−) mice. Immune infiltration was monitored in tumor tissue sections and via flow cytometry of lysed tumors. PDA6606 cells induced less migration in CCR4−/− than in CCR4wt macrophages in vitro. Pancreatic TAM infiltration was higher, and survival was reduced in CCR4wt mice compared to CCR4−/− mice. Antagonizing CCR4 in wildtype mice revealed similar results as in CCR4−/− mice without antagonization. Prophylactic CCR4 antagonist application in wildtype mice was more efficient than therapeutic antagonization. CCR4 seems to be critically involved in TAM generation and tumor progression in pancreatic cancer. CCR4 blockade may help prolong the relapse-free period after curative surgery in pancreatic cancer and improve prognosis.

This study seeks to explore the critical success factors of education for sustainable development. As the world has realized a move towards sustainability is inevitable, sustainable development (SD) was adopted and headed by the United Nations. To embed the concept of sustainable development in the minds of young people who will be the future generations and to create the best practice and attitude towards environment, education for sustainable development (ESD) was introduced as an approach of teaching and learning in schools. Malaysia has implemented (ESD) and became a member of the Foundation of Environmental Education (FEE) and a member of the Worldwide Fund for Nature (WWF) which is running the eco school program nationally. However, as the uptake of the ecoschool status and environmental excellence of ‘Green Flag’ is very low, this gives the hint of the need for these schools to be aware of the success factors which can lead to effective implementation of education for sustainable development. Hence, an exploratory study based on the grounded theory approach was conducted. The data was attained from interviews with eco leaders of awarded eco-schools and with a “program officer” of the eco-school program in WWF Malaysia. The findings suggest for a model that consists of 33 critical success factors of implementing (ESD), fulfilled through four main elements of 1) the eco- committee, 2) the teacher (eco leader), 3) the students and 4) the school management. This model can be used as guidelines for those seeking to effectively implement education for sustainable development in eco-schools. The findings also emphasize on the importance of cooperation and collaboration between the school community, the public and private agencies, and non-government agencies to fulfill the sustainable development goals.

The permanent shut down of Fessenheim nuclear power plant in June 2020 had been preceded by the signature of a policy document, the Projet d’avenir du territoire de Fessenheim (PAT), which aims at ensuring its industrial reconversion. Drafted by the French administration’s services and local authorities, it introduces three spatial scales framing the post-nuclear transition. Mobilizing the case of Fessenheim, this paper offers to strengthen our knowledge of the politics of scales’ concrete practices within energy transitions by questioning (1) the impact of these three scales on the post-nuclear transition and (2) the sociopolitical dynamics leading to their production. By moderating the dominant constructivist approach to scales, sometimes criticized for its teleological nature, we focus on actors’ “scalecrafts”, understood as the messy craftwork, techniques, competences and difficulties underpinning all scalar assemblage. To do so, this paper is built on a corpus of regional newspaper’s articles and 46 semi-directive interviews with actors involved in the PAT’s production. Results show that these scales, which are effectively constraining the extend of the post-nuclear transition, relies on three dynamics: discursive strategies tending to naturalize and essentialize scales through the economization of the debates as well as legal interpretations; the politicization of the transition around the conflicting issue of tax losses’ compensation; and lobbying efforts by local authorities. We conclude by identifying seven entangled factors participating in the scales’ production. These results lead us to question the process of territorial denuclearization.

Abstract The maximum temperature (Tmax) and subsequent exhumation reflect the relations between advective and conductive heat transport, which in turn depend on the tectonic evolution. To unravel these relations in an orogen, precise Tmax data need to be combined with relative time information for the displacements of adjacent units. We present new Tmax data based on Raman spectroscopy of carbonaceous material (RSCM) and zircon fission track (FT) data, which are combined with previous data and then discussed jointly. We follow this approach in the Central Alps at the western edge of the Lepontine dome. Our analysis indicates two main tectono-metamorphic domains in this area: domain A comprises the Lower Helvetic units involving the Aar Massif; domain B is situated south of the Helvetic main thrust, in the footwall of the Simplon line. In domain A, thrusted Helvetic units were overprinted mainly by reverse faulting in the Aar Massif. The thermal evolution is related to the inversion of the former Doldenhorn basin. Tectonic transport during inversion brought into contact units with substantially different Tmax. Temperature gradients were then reduced by conductive heat transfer, but thermal overprinting during cooling involved subsequent vertical movements as well. Zircon FT data yield apparent ages between 12 and 18 Ma in the external part, but 8–9 Ma in the internal part of the Aar Massif. The youngest ages are taken as the cooling at a given temperature, whereas the other data are discussed as being only partially resetted along a temperature path in the partial annealing zone of the zircon FT. When combined with age data for Tmax and apatite FT data from the literature, the youngest group exhibits exhumation rates between 0.5 and 1.2 km/Ma in the time range between 20 Ma and today. In all of domain B, Tmax was significantly higher than in domain A. In domain B the estimated rates of exhumation are 0.8–1.0 km/Ma for the post-20 Ma time interval. Despite of different temperature evolution, the exhumation rates are similar in both domains. The study shows the necessity to combine detailed tectonic data to interpret the T–t evolution of such an area.

Abdominal gunshot trauma is the third leading cause of death and is responsible for more than 90% of deaths among people ages 15 to 24 years old. It can cause multi-system organ damage, shock, and infection. We present a case of a through-and-through abdominal bullet wound where laparotomy exploration has found nothing as damage inside the abdomen.

Little is known about the antimicrobial resistance (AMR) status of uropathogens in Western Africa. We performed a retrospective evaluation of urine cultures collected from the rural Margret Marquart Catholic Hospital, Kpando, Ghana during the time period from October 2019–December 2021. Urine samples from 348 patients (median age 40 years, 52.6% male) were examined. Of these, 125 (35.9%) showed either fungal or bacterial growth, including Escherichia coli in 48 (38.4%), Candida species (spp.) in 29 (23.2%), Klebsiella spp. in 27 (21.6%), Proteus spp. in 12 (9.6%), Citrobacter spp. in 10 (8.0%), Salmonella spp. in 4 (3.2%), Staphylococcus spp. in 3 (2.4%), and Pseudomonas spp. in 2 (1.6%) cases. Two bacterial spp. were detected in 7 samples (5.6%). Antibiotic susceptibility testing showed resistance to a mean 8.6 out of 11 tested antibiotics per patient. Significant predictors (p < 0.05) of bacterial growth were age (OR 1.03), female sex (OR 3.84), and the number of pus cells (OR 1.05) and epithelial cells (OR 1.07) in urine microscopy. We observed an alarmingly high AMR rate among the uropathogens detected, even to reserve antibiotics. A similar resistance profile can be expected in West African patients living in high-income countries. These observations warrant the implementation of restrictive antibiotic protocols, together with the expansion of urine culture testing capacities, improvement of documentation and reporting of AMR rates, and continued research and development of new antibiotic therapies in order to stem the progression of AMR in this West African region.