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Abstract Eccentric upper‐body exercise performed 24 h prior to high‐altitude decompression has previously been shown to aggravate venous gas emboli (VGE) load. Yet, it is unclear whether increasing the muscle mass recruited (i.e., upper vs. whole‐body) during eccentric exercise would exacerbate the decompression strain. Accordingly, this study aimed to investigate whether the total muscle mass recruited during eccentric exercise influences the decompression strain. Eleven male participants were exposed to a simulated altitude of 24,000 ft for 90 min on three separate occasions. Twenty‐four hours before each exposure, participants performed one of the following protocols: (i) eccentric whole‐body exercise (ECCw; squats and arm‐cycling exercise), (ii) eccentric upper‐body exercise (ECCu; arm‐cycling), or (iii) no exercise (control). Delayed onset muscle soreness (DOMS) and isometric strength were evaluated before and after each exercise intervention. VGE load was evaluated at rest and after knee‐ and arm‐flex provocations using the 6‐graded Eftedal–Brubakk scale. Knee extensor (−20 ± 14%, P = 0.001) but not elbow flexor (−12 ± 18%, P = 0.152) isometric strength was reduced 24 h after ECCw. ECCu reduced elbow flexor isometric strength at 24 h post‐exercise (−18 ± 10%, P

Abstract Background Biodiversity loss is particularly pronounced in agroecosystems. Agricultural fields cover about one-third of the European Union and are crucial habitats for many species. At the same time, agricultural fields receive the highest pesticide input in European landscapes. Non-target species, including plants and arthropods, closely related to targeted pests, are directly affected by pesticides. Direct effects on these lower trophic levels cascade through the food web, resulting in indirect effects via the loss of food and habitat for subsequent trophic levels. The overarching goals of the European pesticide legislation require governments to sufficiently consider direct and indirect effects on plants and arthropods when authorising pesticides. This publication provides an overview of a workshop's findings in 2023 on whether the current pesticide risk assessment adequately addresses these requirements. Results Effects due to in-field exposure to pesticides are currently not assessed for plants and inadequately assessed for arthropods, resulting in an impairment of the food web support and biodiversity. Deficiencies lie within the risk assessment, as defined in the terrestrial guidance document from 2002. To overcome this problem, we introduce a two-step assessment method feasible for risk assessors, that is to determine (i) whether a pesticide product might have severe impacts on plants or arthropods and (ii) whether these effects extend to a broad taxonomic spectrum. When each step is fulfilled, it can be concluded that the in-field exposure of the pesticide use under assessment could lead to unacceptable direct effects on non-target species in-field and thus subsequent indirect effects on the food web. While our primary focus is to improve risk assessment methodologies, it is crucial to note that risk mitigation measures, such as conservation headlands, exist in cases where risks from in-field exposure have been identified. Conclusions We advocate that direct and indirect effects caused by in-field exposure to pesticides need to be adequately included in the risk assessment and risk management as soon as possible. To achieve this, we provide recommendations for the authorities including an evaluation method. Implementing this method would address a major deficiency in the current in-field pesticide risk assessment and ensure better protection of biodiversity.

Abstract Background Geriatric rehabilitation aims at increasing physical and social activity and maintaining the functional reserve of older people. However, the continuity of geriatric rehabilitation in the outpatient setting is limited due to a lack of structured aftercare programs. In order to overcome this, a three-month multimodal home-based intervention program (GeRas) was implemented. The aim of this early qualitative process evaluation was to assess GeRas in terms of perceived reach, effectiveness/efficacy, adoption/uptake, implementation, and maintenance/sustainability (Domains within the RE-AIM Framework) from the perspective of patients who received the intervention and healthcare providers who were involved in the delivery of the intervention. Methods In a qualitative process evaluation, 13 healthcare providers and 10 patients were interviewed throughout the beginning of the implementation period of GeRas to capture early experiences using a semi-structured interview guide. The interview guide and qualitative content analysis was guided by the RE-AIM Framework. Results The GeRas program was perceived to be largely well implemented and beneficial by healthcare providers and patients. According to healthcare providers, GeRas showed more advantages compared to usual care. Additionally, outcome expectations were mainly met (Domain 1: Effectiveness). However, the implementation of the intervention delivered via the eHealth system was perceived as challenging (Domain 2: Adoption). Nevertheless, the outpatient physical exercise, the outpatient counselling, and the continuous care after discharge improved perceived well-being regardless of the intervention type (Domain 3: Implementation). To facilitate the continued use of GeRas, technical requirements should be created to increase user-friendliness and to motivate patients to continue the training in the long term (Domain 4: Maintenance). Conclusion Although initial experiences with the implementation and effectiveness of GeRas were positive in general, organisational and technical issues need to be resolved to enhance sustainable and successful implementation of the GeRas program. Trial registration German Clinical Trials Register (DRKS00029559). Registered 5/10/2022.

Improving the accuracy of monitoring cropland CO2 exchange at heterogeneous spatial scales is of great importance for reducing spatial and temporal uncertainty in estimating terrestrial carbon (C) dynamics. In this study, an approach to estimate daily cropland C fluxes is developed and tested by combining time series of field-scale eddy covariance (EC) CO2 flux data and Sentinel-2 satellite-based vegetation indices (VIs) after appropriately accounting for the spatial alignment between the two time series datasets. The study was carried out for an agricultural field (118 ha) in the lowlands of northeastern Germany. The ability of different VIs to estimate daily net ecosystem exchange (NEE) and gross primary productivity (GPP) based on linear regression models was assessed. Most VIs showed high (>0.9) and statistically significant (p) correlations with GPP and NEE, although some VIs deviated from the seasonal pattern of CO2 exchange. By contrast, correlations between ecosystem respiration (Reco) and VIs were weak and not statistically significant, and no attempt was made to estimate Reco from VIs. Linear regression models explained generally more than 80 % and 70 % of the variability in NEE and GPP, respectively, with high variability among the individual VIs. The performance in estimating daily C fluxes varied among VIs depending on the C flux component (NEE or GPP) and observation period. Root mean square error (RMSE) values ranged from 1.35 g C m−2 d−1 using the green normalized difference vegetation index (GNDVI) for NEE to 5 g C m−2 d−1 using the simple ratio (SR) for GPP. This equated to an underestimated net C uptake of only 41 g C m−2 (18 %) and an overestimation of gross C uptake of 854 g C m−2 (73 %). Differences between the measured and estimated C fluxes were mainly explained by the diversion of the C flux and VI signal during winter when C uptake remained low, while VI values indicated an increased C uptake due to relatively high crop leaf area. Overall, the results exhibited similar error margins to mechanistic crop models. Thus, they indicated the suitability and expandability of the proposed approach for monitoring cropland C exchange with satellite-derived VIs.

Abstract The complex architecture and biochemistry of the inner mitochondrial membrane generate ultra-structures with different phospholipid and protein compositions, shapes, characteristics, and functions. The crista junction (CJ) serves as an important barrier separating the cristae (CM) and inner boundary membranes (IBM). Thereby CJ regulates the movement of ions and ensures distinct electrical potentials across the cristae (ΔΨC) and inner boundary (ΔΨIBM) membranes. We have developed a robust and flexible approach to visualize the CJ permeability with super-resolution microscopy as a readout of local mitochondrial membrane potential (ΔΨmito) fluctuations. This method involves analyzing the distribution of TMRM fluorescence intensity in a model that is restricted to the mitochondrial geometry. We show that mitochondrial Ca2+ elevation hyperpolarizes the CM most likely caused by Ca2+ sensitive increase of mitochondrial tricarboxylic acid cycle (TCA) and subsequent oxidative phosphorylation (OXPHOS) activity in the cristae. Dynamic multi-parameter correlation measurements of spatial mitochondrial membrane potential gradients, ATP levels, and mitochondrial morphometrics revealed a CJ-based membrane potential overflow valve mechanism protecting the mitochondrial integrity during excessive cristae hyperpolarization.

Abstract Background Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. Methods In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. Results The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72–98) and 88% (95% CI: 67–96); ≥ CR2 were 81% (95% CI: 61–92) and 68% (95% CI: 47–82) and refractory disease were 32% (95% CI: 11–54) and 20% (95% CI: 6–40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64–87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). Conclusion The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611).

Abstract Streptococcus suis is a bacterial pathogen that causes important economic losses to the swine industry worldwide. Since there are no current commercial vaccines, the use of autogenous vaccines applied to gilts/sows to enhance transfer of passive immunity is an attractive alternative to protect weaned piglets. However, there is no universal standardization in the production of autogenous vaccines and the vaccine formulation may be highly different among licenced manufacturing laboratories. In the present study, an autogenous vaccine that included S. suis serotypes 2, 1/2, 5, 7 and 14 was prepared by a licensed laboratory and administrated to gilts using a three-dose program prior to farrowing. The antibody response in gilts as well as the passive transfer of antibodies to piglets was then evaluated. In divergence with previously published data with an autogenous vaccine produced by a different company, the increased response seen in gilts was sufficient to improve maternal antibody transfer to piglets up to 5 weeks of age. However, piglets would still remain susceptible to S. suis disease which often appears during the second part of the nursery period. Vaccination did not affect the shedding of S. suis (as well as that of the specific S. suis serotypes included in the vaccine) by either gilts or piglets. Although all antibiotic treatments were absent during the trial, the clinical protective effect of the vaccination program with the autogenous vaccine could not be evaluated, since limited S. suis cases were present during the trial, confirming the need for a complete evaluation of the clinical protection that must include laboratory confirmation of the aetiological agent involved in the presence of S. suis-associated clinical signs. Further studies to evaluate the usefulness of gilt/sow vaccination with autogenous vaccines to protect nursery piglets should be done.

Abstract Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Background: Proximal humerus fractures are the third most common fracture type for patients between the ages of 65 and 89 and occur more frequently in women than men. Given the variety of surgical treatments for proximal humerus fractures, the aim of this study was to (1) report United States national volume and incidence estimates for surgical management of proximal humerus fractures to better understand the changing practice over the past decade and (2) to analyze differences in volume and incidence among age groups, sex, and geographic region. Methods: Using IBM Marketscan national database, all patients that underwent open reduction internal fixation (ORIF), hemiarthroplasty, or reverse total shoulder arthroplasty (RTSA) between 2010 and 2019 were identified with Current Procedural Terminology codes. The dataset was further stratified to identify patients treated for proximal humerus fractures. IBM Marketscan provided discharge weights that were used to determine estimated national annual volumes of each procedure in IBM SPSS Statistics software (IBM Corp., Armonk, NY, USA). Volume and incidence were adjusted per 1,000,000 persons and calculated for subgroups according to age group, sex, and geographical region. The United States Census Bureau annual population data was used for all incidence calculations. Results: Over the past decade, the total volume and incidence of surgically treated proximal humerus fractures increased by 13% and 5%, respectively. Although overall incidence decreased, ORIF remained the most common surgical treatment. The greatest decrease in volume and incidence of ORIF occurred in patients ≥75. The incidence of ORIF treatment increased in the South and West while it decreased in the Northeast and Midwest. Total volume and incidence of HA decreased between 2010 and 2019 and this trend remained among all subgroups. Total volume and incidence of RTSA increased by over 300%. The incidence of males and females receiving RTSA increased by 266% and 320%, respectively. Volume and incidence of RTSA increased across all age groups. Volume and incidence of RTSA increased in the Midwest, South, and Western regions while it remained unchanged in the Northeast. Conclusion: Surgical management trends of proximal humerus fractures have changed greatly over the past decade. ORIF remains the most common surgical treatment for proximal humerus fractures. HA has fallen out of favor while RTSA has seen significant increases in usage across sex, age groups, and geographic regions. These trends represent a change in practice for treating proximal humerus fractures by considering all patient and fracture characteristics when opting for surgical management.

Paleoceanographic interpretations of Plio-Pleistocene climate variability over the past 5 million years rely on the evaluation of event timing of proxy changes in sparse records across multiple ocean basins. In turn, orbital-scale chronostratigraphic controls for these records are often built from stratigraphic alignment of benthic foraminiferal stable oxygen isotope (δ18O) records to a preferred dated target stack or composite. This chronostratigraphic age model approach yields age model uncertainties associated with alignment method, target selection, the assumption that the undated record and target experienced synchronous changes in benthic foraminiferal δ18O values, and the assumption that any possible stratigraphic discontinuities within the undated record have been appropriately identified. However, these age model uncertainties and their impact on paleoceanographic interpretations are seldom reported or discussed. Here, we investigate and discuss these uncertainties for conventional manual and automated tuning techniques based on benthic foraminiferal δ18O records and evaluate their impact on sedimentary age models over the past 3.5 Myr using three sedimentary benthic foraminiferal δ18O records as case studies. In one case study, we present a new benthic foraminiferal δ18O record for International Ocean Discovery Program (IODP) Site U1541 (54°13′ S, 125°25′ W), recently recovered from the South Pacific on IODP Expedition 383. The other two case studies examine published benthic foraminiferal δ18O records of Ocean Drilling Program (ODP) Site 1090 and the ODP Site 980/981 composite. Our analysis suggests average age uncertainties of 3 to 5 kyr associated with manually derived versus automated alignment, 1 to 3 kyr associated with automated probabilistic alignment itself, and 2 to 6 kyr associated with the choice of tuning target. Age uncertainties are higher near stratigraphic segment ends and where local benthic foraminiferal δ18O stratigraphy differs from the tuning target. We conclude with recommendations for community best practices for the development and characterization of age uncertainty of sediment core chronostratigraphies based on benthic foraminiferal δ18O records.

Abstract Actinobacillus pleuropneumoniae (APP) is a bacterium frequently associated with porcine pleuropneumonia. The acute form of the disease is highly contagious and often fatal, resulting in significant economic losses for pig farmers. Serotype diversity and antimicrobial resistance (AMR) of APP strains circulating in north Italian farms from 2015 to 2022 were evaluated retrospectively to investigate APP epidemiology in the area. A total of 572 strains isolated from outbreaks occurring in 337 different swine farms were analysed. The majority of isolates belonged to serotypes 9/11 (39.2%) and 2 (28.1%) and serotype diversity increased during the study period, up to nine different serotypes isolated in 2022. The most common resistances were against tetracycline (53% of isolates) and ampicillin (33%), followed by enrofloxacin, florfenicol and trimethoprim/sulfamethoxazole (23% each). Multidrug resistance (MDR) was common, with a third of isolates showing resistance to more than three antimicrobial classes. Resistance to the different classes and MDR varied significantly depending on the serotype. In particular, the widespread serotype 9/11 was strongly associated with florfenicol and enrofloxacin resistance and showed the highest proportion of MDR isolates. Serotype 5, although less common, showed instead a concerning proportion of trimethoprim/sulfamethoxazole resistance. Our results highlight how the typing of circulating serotypes and the analysis of their antimicrobial susceptibility profile are crucial to effectively manage APP infection and improve antimicrobial stewardship.

The U.S. Department of Agriculture (USDA) has performed European pear (Pyrus communis L.) scion breeding for over a century. The breeding program started in the early 1900s by Merton B. Waite in the Washington D.C. area and the program’s main goal was to develop host resistance to the devastating disease fire blight, caused by Erwinia amylovora. Most of the historic European pear cultivars being produced in the U.S. were susceptible to fire blight, prompting a need to breed for resistance. More than six generations of USDA breeders have continued this effort to breed disease-resistant European pears. Along with fire blight resistance, the pear breeding programs sought improved fruit quality, cold hardiness, and resistance to psylla (Cacopsylla pyricola Foërster), a significant insect pest of pear. Herein, we discuss the history of the program through each generation of breeder(s). We also present breeding aims, parental selection, and releases. In total, the program has released ten named pear varieties between 1938 and 2022.

Summary: Chemical synaptic transmission is modulated to accommodate different activity levels, thus enabling homeostatic scaling in pre- and postsynaptic compartments. In nematodes, cholinergic neurons use neuropeptide signaling to modulate synaptic vesicle content. To explore if this mechanism is conserved in vertebrates, we studied the involvement of neuropeptides in cholinergic transmission at the neuromuscular junction of larval zebrafish. Optogenetic stimulation by photoactivated adenylyl cyclase evoked locomotion. We generated mutants lacking the neuropeptide-processing enzyme carboxypeptidase E (cpe), and the most abundant neuropeptide precursor in motor neurons, tachykinin (tac1). Both mutants showed exaggerated locomotion after photostimulation. Recording excitatory postsynaptic currents demonstrated overall larger amplitudes in the wild type. Exaggerated locomotion in the mutants thus reflected upscaling of postsynaptic excitability. Both mutant muscles expressed more nicotinic acetylcholine receptors (nAChRs) on their surface; thus, neuropeptide signaling regulates synaptic transmitter output in zebrafish motor neurons, and muscle cells homeostatically regulate nAChR surface expression, compensating reduced presynaptic input.

A defendant in criminal court should only be convicted if guilt is proven by the prosecution beyond any reasonable doubt. That is the burden of proof. Any doubt emerging should benefit the defendant. In this perspective, evidence from police investigations is challenged by defense lawyers to create sufficient doubt so that the defendant can be acquitted. In the current case study regarding prosecution of the former president at the International Biathlon Union, this article reviews defense lawyers’ attempts to create sufficient doubt regarding corruption to cause acquittal of the defendant. Evidence from police investigation in Austria and Norway ended up in competing narratives of the prosecution and the defense with the metaphor of the courtroom as a theater scene. In a policing and criminology perspective, this research is important as it documents the space of knowledge rivalry between prosecution and defense depending on the extent of convincing power found in the evidence that is resulting from police investigations.

The theory of convenience addresses white-collar and corporate crime. The theory is applied in this article to a case study of Norwegian publishing houses having to pay infringement fees because of competition act violation. Cartel members agreed and coordinated a boycott of a distribution channel. This article reviews the research literature on cartels before presenting the convenience case study. Combatting cartels is a matter of reducing the attractiveness and convenience of joining cartels. Guardianship, oversight, and controls are at the core of reducing deviance convenience. Detection is an element of oversight. However, detection is rare, as this case illustrated by email sent by mistake. Combatting cartels is a matter of control at the top of organizations where typically each chief executive officer (CEO) is involved. Therefore, the corporate compliance officer should never report to the CEO but rather to the chairperson on the board and to the external auditor.

ABSTRACT The limited temporal completeness and taxonomic accuracy of species lists, made available in a traditional manner in scientific publications, has always represented a problem. These lists are invariably limited to a few taxonomic groups and do not represent up-to-date knowledge of all species and classifications. In this context, the Brazilian megadiverse fauna is no exception, and the Catálogo Taxonômico da Fauna do Brasil (CTFB) (http://fauna.jbrj.gov.br/), made public in 2015, represents a database on biodiversity anchored on a list of valid and expertly recognized scientific names of animals in Brazil. The CTFB is updated in near real time by a team of more than 800 specialists. By January 1, 2024, the CTFB compiled 133,691 nominal species, with 125,138 that were considered valid. Most of the valid species were arthropods (82.3%, with more than 102,000 species) and chordates (7.69%, with over 11,000 species). These taxa were followed by a cluster composed of Mollusca (3,567 species), Platyhelminthes (2,292 species), Annelida (1,833 species), and Nematoda (1,447 species). All remaining groups had less than 1,000 species reported in Brazil, with Cnidaria (831 species), Porifera (628 species), Rotifera (606 species), and Bryozoa (520 species) representing those with more than 500 species. Analysis of the CTFB database can facilitate and direct efforts towards the discovery of new species in Brazil, but it is also fundamental in providing the best available list of valid nominal species to users, including those in science, health, conservation efforts, and any initiative involving animals. The importance of the CTFB is evidenced by the elevated number of citations in the scientific literature in diverse areas of biology, law, anthropology, education, forensic science, and veterinary science, among others.

Streptococcus suis causes diseases in pigs and has emerged as a zoonotic agent. When infected, the host develops an exacerbated inflammation that can lead to septic shock and meningitis. Although neutrophils greatly infiltrate the lesions, their dynamics during S. suis infection remain poorly described. Moreover, very few studies reported on the production and role of a key factor in the regulation of neutrophils: the colony-stimulating granulocyte factor (G-CSF). In this study, we characterized the G-CSF-neutrophil axis in the pathogenesis of S. suis induced disease. Using a mouse model of S. suis infection, we first evaluated the recruitment of neutrophils and their activation profile by flow cytometry. We found that infection provokes a massive neutrophil recruitment from the bone marrow to the blood and spleen. In both compartments, neutrophils displayed multiple activation markers. In parallel, we observed high systemic levels of G-CSF, with a peak of production coinciding with that of neutrophil recruitment. We then neutralized the effects of G-CSF and highlighted its role in the release of neutrophils from the bone marrow to the blood. However, it did not affect bacteremia nor the cytokine storm induced by S. suis. In conclusion, systemic G-CSF induces the release of neutrophils from the bone marrow to the blood, but its role in inflammation or bacterial clearance seems to be compensated by unknown factors. A better understanding of the role of neutrophils and inflammatory mediators could lead to better strategies for controlling the infection caused by S. suis.

Background: Antimicrobial resistance is a serious public health threat. Overuse of antibiotics leads to the development and spread of antibiotic resistant pathogens. Antibiotics are also responsible for a high percentage of emergency department visits for adverse drug events. Despite this, ambulatory and urgent care providers often cite patient expectations as a reason for inappropriate antibiotic prescribing practices. We investigated patient and community understanding of antibiotics and antimicrobial resistance to inform how they can be engaged as partners in combating antimicrobial resistance in our southwestern Virginia community. Methods: From July to September 2023, we conducted an online survey of patients and community members within the footprint of a large healthcare system in Southwest Virginia. Electronic medical records were used to randomly select and directly email the survey link to a representative sample of ambulatory patients who met criteria. Respondents were also recruited through the health system’s social media channels and through posters with quick response (QR) codes in outpatient offices. The survey used Likert scales and multiple-choice questions to understand experiences with and perceptions about antibiotics and antimicrobial resistance. We conducted a descriptive analysis of survey responses. Results: In total, 2,021 individuals completed the survey. Nearly 16% of respondents agreed with the statement “antibiotics can kill viruses” and almost 12% more were unsure. Thirty percent of respondents either agreed with or were unsure about the statement “antibiotics work on most coughs and colds”. When asked more directly about antimicrobial resistance, almost a quarter (25%) of respondents agreed with or were unsure about the statement “there is no connection between taking antibiotics and the development of resistant bacteria”. Responding to questions about possible negative effects of antibiotics, over 9% disagreed with the statement “antibiotics can kill the 'good' bacteria that normally live on the skin and in the gut” and another 19% were unsure. Similarly, over 20% disagreed with or were unsure about the statement “bacteria that do not respond to antibiotics could infect me or my family”. Reflecting on their own providers, nearly 83% of respondents trusted their doctor’s or nurse’s advice about antibiotic necessity. Conclusions: There are opportunities for patient and community engagement around antibiotic effectiveness for common viral illnesses and about the negative effects of overuse of antibiotics. Our data suggests most patients trust their providers as it relates to antibiotic prescribing and may be receptive to discussions and strategies that promote antimicrobial stewardship.

Background Tetrahydrobiopterin (BH4) and its oxidized derivative dihydrobiopterin (BH2) were found to be strongly elevated in ME/CFS patients with orthostatic intolerance (ME + OI). Objective However, the molecular mechanism of biopterin biogenesis is poorly understood in ME + OI subjects. Here, we report that the activation of the non-oxidative pentose phosphate pathway (PPP) plays a critical role in the biogenesis of biopterins (BH4 and BH2) in ME + OI subjects. Research Design and Results Microarray-based gene screening followed by real-time PCR-based validation, ELISA assay, and finally enzyme kinetic studies of glucose-6-phosphate dehydrogenase (G6PDH), transaldolase (TALDO1), and transketolase (TK) enzymes revealed that the augmentation of anaerobic PPP is critical in the regulations of biopterins. To further investigate, we devised a novel cell culture strategy to induce non-oxidative PPP by treating human microglial cells with ribose-5-phosphate (R5P) under a hypoxic condition of 85%N 2 /10%CO 2 /5%O 2 followed by the analysis of biopterin metabolism via ELISA, immunoblot, and dual immunocytochemical analyses. Moreover, the siRNA knocking down of the taldo1 gene strongly inhibited the bioavailability of phosphoribosyl pyrophosphate (PRPP), reduced the expressions of purine biosynthetic enzymes, attenuated GTP cyclohydrolase 1 (GTPCH1), and suppressed subsequent production of BH4 and its metabolic conversion to BH2 in R5P-treated and hypoxia-induced C20 human microglia cells. These results confirmed that the activation of non-oxidative PPP is indeed required for the upregulation of both BH4 and BH2 via the purine biosynthetic pathway. To test the functional role of ME + OI plasma-derived biopterins, exogenously added plasma samples of ME + OI plasma with high BH4 upregulated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in human microglial cells indicating that the non-oxidative PPP-induced-biopterins could stimulate inflammatory response in ME + OI patients. Conclusion Taken together, our current research highlights that the induction of non-oxidative PPP regulates the biogenesis of biopterins contributing to ME/CFS pathogenesis.

ABSTRACT Paramycodrosophila Duda, 1924 is a small cosmopolitan genus which encompasses 16 described species. In the Neotropical region there are records of only two species, P. costaricana Duda, 1925 and P. nephelea Wheeler, 1968. In this paper, we describe the first 19 new species from South America – P. itatiaiensis n. sp., P. blauthae n. sp., P. rafaeli n. sp., P. boldrinii n. sp., P. roraimensis n. sp., P. amazonensis n. sp., P. moratoi n. sp., P. mineira n. sp., P. leonensis n. sp., P. marinhoi n. sp., P. viscondedemauaensis n. sp., P. pedraseladensis n. sp., P. vicenziae n. sp., P. pallidifacies n. sp., P. acreensis n. sp., P. mantiqueira n. sp., P. maculosa n. sp., P. melana n. sp., P. puri n. sp. – based on morphological traits. A distribution map and a taxonomic key for male imagoes of the Neotropical species was also produced. By adding 19 new species, we establish the Neotropical region as the biogeographical region with the most known diversity in the world for the genus.

Objective: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating xenobiotic responses as well as physiological metabolism. Dietary AhR ligands activate the AhR signaling axis, whereas AhR activation is negatively regulated by the AhR repressor (AhRR). While AhR-deficient mice are known to be resistant to diet-induced obesity (DIO), the influence of the AhRR on DIO has not been assessed so far. Methods: In this study, we analyzed AhRR−/− mice and mice with a conditional deletion of either AhRR or AhR in myeloid cells under conditions of DIO and after supplementation of dietary AhR ligands. Moreover, macrophage metabolism was assessed using Seahorse Mito Stress Test and ROS assays as well as transcriptomic analysis. Results: We demonstrate that global AhRR deficiency leads to a robust, but not as profound protection from DIO and hepatosteatosis as AhR deficiency. Under conditions of DIO, AhRR−/− mice did not accumulate TCA cycle intermediates in the circulation in contrast to wild-type (WT) mice, indicating protection from metabolic dysfunction. This effect could be mimicked by dietary supplementation of AhR ligands in WT mice. Because of the predominant expression of the AhRR in myeloid cells, AhRR-deficient macrophages were analyzed for changes in metabolism and showed major metabolic alterations regarding oxidative phosphorylation and mitochondrial activity. Unbiased transcriptomic analysis revealed increased expression of genes involved in de novo lipogenesis and mitochondrial biogenesis. Mice with a genetic deficiency of the AhRR in myeloid cells did not show alterations in weight gain after high fat diet (HFD) but demonstrated ameliorated liver damage compared to control mice. Further, deficiency of the AhR in myeloid cells also did not affect weight gain but led to enhanced liver damage and adipose tissue fibrosis compared to controls. Conclusions: AhRR-deficient mice are resistant to diet-induced metabolic syndrome. Although conditional ablation of either the AhR or AhRR in myeloid cells did not recapitulate the phenotype of the global knockout, our findings suggest that enhanced AhR signaling in myeloid cells deficient for AhRR protects from diet-induced liver damage and fibrosis, whereas myeloid cell-specific AhR deficiency is detrimental.

Background:. To effectively counsel patients prior to shoulder arthroplasty, surgeons should understand the overall life trajectory and life expectancy of patients in the context of the patient’s shoulder pathology and medical comorbidities. Such an understanding can influence both operative and nonoperative decision-making and implant choices. This study evaluated 5-year mortality following shoulder arthroplasty in patients ≥65 years old and identified associated risk factors. Methods:. We utilized Centers for Medicare & Medicaid Services Fee-for-Service inpatient and outpatient claims data to investigate the 5-year mortality rate following shoulder arthroplasty procedures performed from 2014 to 2016. The impact of patient demographics, including fracture diagnosis, year fixed effects, and state fixed effects; patient comorbidities; and hospital-level characteristics on 5-year mortality rates were assessed with use of a Cox proportional hazards regression model. A p value of

Abstract Virus-specific T cells (VST) from partially-HLA matched donors have been effective for treatment of refractory viral infections in immunocompromised patients in prior studies with a good safety profile, but rare adverse events have been described. Here we describe a unique and severe adverse event of VST therapy in an infant with severe combined immunodeficiency, who receives, as part of a clinical trial (NCT03475212), third party VSTs for treating cytomegalovirus viremia following bone marrow transplantation. At one-month post-VST infusion, rejection of graft and reversal of chimerism is observed, as is an expansion of T cells exclusively from the VST donor. Single-cell gene expression and T cell receptor profiling demonstrate a narrow repertoire of predominantly activated CD4+ T cells in the recipient at the time of rejection, with the repertoire overlapping more with that of peripheral blood from VST donor than the infused VST product. This case thus demonstrates a rare but serious side effect of VST therapy.

Abstract Streptococcus suis serotype 2 is a major swine pathogen and a zoonotic agent, causing meningitis in both swine and humans, responsible for substantial economic losses to the swine industry worldwide. The pathogenesis of infection and the role of bacterial cell wall components in virulence have not been fully elucidated. Lipoproteins, peptidoglycan, as well as lipoteichoic acids (LTA) have all been proposed to contribute to virulence. In the present study, the role of the LTA in the pathogenesis of the infection was evaluated through the characterisation of a mutant of the S. suis serotype 2 strain P1/7 lacking the LtaS enzyme, which mediates the polymerization of the LTA poly-glycerolphosphate chain. The ltaS mutant was confirmed to completely lack LTA and displayed significant morphological defects. Although the bacterial growth of this mutant was not affected, further results showed that LTA is involved in maintaining S. suis bacterial fitness. However, its role in the pathogenesis of the infection appears limited. Indeed, LTA presence reduces self-agglutination, biofilm formation and even dendritic cell activation, which are important aspects of the pathogenesis of the infection caused by S. suis. In addition, it does not seem to play a critical role in virulence using a systemic mouse model of infection.

The working group ‘Clinical Tissue Regeneration’ of the German Society of Orthopedics and Traumatology (DGOU) issues this paper with updating its guidelines. Literature was analyzed regarding different topics relevant to osteochondral lesions of the talus (OLT) treatment. This process concluded with a statement for each topic reflecting the best scientific evidence available with a grade of recommendation. All group members rated the statements to identify possible gaps between literature and current clinical practice. Fixation of a vital bony fragment should be considered in large fragments. In children with open physis, retrograde drilling seems to work better than in adults, but even there, the revision rate reaches 50%. The literature supports debridement with bone marrow stimulation (BMS) in lesions smaller than 1.0 cm² without bony defect. The additional use of a scaffold can be recommended in lesions larger than 1.0 cm². For other scaffolds besides AMIC®/Chondro-Gide®, there is only limited evidence. Systematic reviews report good to excellent clinical results in 87% of the patients after osteochondral transplantation (OCT), but donor site morbidity is of concern, reaching 16.9%. There is no evidence of any additional benefit from autologous chondrocyte implantation (ACI). Minced cartilage lacks any supporting data. Metallic resurfacing of OLT can only be recommended as a second-line treatment. A medial malleolar osteotomy has a minor effect on the clinical outcome compared to the many other factors influencing the clinical result.

Abstract Background Fall prevention is important for healthy ageing, but the economic impact of fall prevention are scarcely investigated. A recent cost-effectiveness analysis compared a group-delivered Lifestyle-integrated Functional Exercise Program (gLiFE) with an individually-delivered program (LiFE) in community-dwelling people (aged ≥ 70 years) at risk of falling. In addition, the current study aimed to analyze the budget impact of LiFE and gLiFE, compared with standard care in Germany. Methods A Markov model was developed to reflect falls and associated care needs for community-dwelling persons over 5 years. The intervention effects of LiFE and gLiFE were shown to be equivalent in a non-inferiority trial, although the costs differed. Outpatient, inpatient, and intervention costs were assessed from a payer’s perspective. The effect of parameter uncertainty was assessed in sensitivity analyses. Results The budget impact due to intervention costs was €510 million for LiFE and €186 million for gLiFE. Over five years, health care expenditures were €35,008 million for those receiving standard care, €35,416 million for those receiving LiFE, and €35,091 million for persons receiving gLiFE. Thereby, LiFE and gLiFE could prevent 2700 deaths and 648,000 falls over 5 years. Parameter uncertainties in the risk of falling, uptake of an intervention offer, and in the intervention effects had a major influence; thus cost savings for LiFE and gLiFE compared with standard care could be achieved for individuals with a high risk of falling. Conclusions The results revealed that cost savings for LiFE and gLiFE compared with standard care could only be achieved for individuals at high risk of falling, with gLiFE being superior to LiFE. Future research should consider benefits and aspects of fall prevention beyond falls (e.g., physical activity, social aspects, and personal preferences of participants). Trial registration The study was preregistered under underclinicaltrials.gov (identifier: NCT03462654) on 12th March 2018; https://clinicaltrials.gov/ct2/show/NCT03462654 .

Abstract Rewetting drained peatlands is recognized as a leading and effective natural solution to curb greenhouse gas emissions. However, rewetting creates novel ecosystems whose emission behaviors are not adequately captured by currently used emission factors. These emission factors are applied immediately after rewetting, thus do not reflect the temporal dynamics of greenhouse gas emissions during the period wherein there is a transition to a rewetted steady-state. Here, we provide long-term data showing a mismatch between actual emissions and default emission factors and revealing the temporal patterns of annual carbon dioxide and methane fluxes in a rewetted peatland site in northeastern Germany. We show that site-level annual emissions of carbon dioxide and methane approach the IPCC default emission factors and those suggested for the German national inventory report only between 13 to 16 years after rewetting. Over the entire study period, we observed a source-to-sink transition of annual carbon dioxide fluxes with a decreasing trend of −0.36 t CO2-C ha−1 yr−1 and a decrease in annual methane emissions of −23.6 kg CH4 ha−1 yr−1. Our results indicate that emission factors should represent the temporally dynamic nature of peatlands post-rewetting and consider the effect of site characteristics to better estimate associated annual emissions.

Abstract Streptococcus suis is a zoonotic pathogen that causes a major health problem in the pig production industry worldwide. Spain is one of the largest pig producers in the world. This work aimed to investigate the genetic and phenotypic features of invasive S. suis isolates recovered in Spain. A panel of 156 clinical isolates recovered from 13 Autonomous Communities, representing the major pig producers, were analysed. MLST and serotyping analysis revealed that most isolates (61.6%) were assigned to ST1 (26.3%), ST123 (18.6%), ST29 (9.6%), and ST3 (7.1%). Interestingly, 34 new STs were identified, indicating the emergence of novel genetic lineages. Serotypes 9 (27.6%) and 1 (21.8%) prevailed, followed by serotypes 7 (12.8%) and 2 (12.2%). Analysis of 13 virulence-associated genes showed significant associations between ST, serotype, virulence patterns, and clinical features, evidencing particular virulence traits associated with genetic clusters. The pangenome was generated, and the core genome was distributed in 7 Bayesian groups where each group included a variable set of over- and under-represented genes of different categories. The study provides comprehensive data and knowledge to improve the design of new vaccines, antimicrobial treatments, and bacterial typing approaches.

Abstract Background Geriatric rehabilitation aims to maintain the functional reserves of older adults in order to optimize social participation and prevent disability. After discharge from inpatient geriatric rehabilitation, patients are at high risk for decreased physical capacity, increased vulnerability, and limitations in mobility. As a result, ageing in place becomes uncertain for a plethora of patients after discharge from geriatric rehabilitation and effective strategies to prevent physical decline are required. Collaboration between different health-care providers is essential to improve continuity of care after discharge from inpatient geriatric rehabilitation. The aim of this study is to evaluate the effectiveness of a multi-professional home-based intervention program (GeRas) to improve functional capacity and social participation in older persons after discharge from inpatient geriatric rehabilitation. Methods The study is a multicenter, three-arm, randomized controlled trial with a three-month intervention period. Two hundred and seventy community-dwelling older people receiving inpatient geriatric rehabilitation will be randomized with a 1:1:1 ratio to one of the parallel intervention groups (conventional IG or tablet IG) or the control group (CG). The participants of both IGs will receive a home-based physical exercise program supervised by physical therapists, a nutritional recommendation by a physician, and social counseling by social workers of the health insurance company. The collaboration between the health-care providers and management of participants will be realized within a cloud environment based on a telemedicine platform and supported by multi-professional case conferences. The CG will receive usual care, two short handouts on general health-related topics, and facultative lifestyle counseling with general recommendations for a healthy diet and active ageing. The primary outcomes will be the physical capacity measured by the Short Physical Performance Battery and social participation assessed by the modified Reintegration to Normal Living Index, three months after discharge. Discussion The GeRas program is designed to improve the collaboration between health-care providers in the transition from inpatient geriatric rehabilitation to outpatient settings. Compared to usual care, it is expected to improve physical capacity and participation in geriatric patients after discharge from inpatient geriatric rehabilitation. Trial registration German Clinical Trials Register (DRKS00029559). Registered on October 05, 2022.

ABSTRACTBackground: Sudden gains, defined as large and stable improvements of psychopathological symptoms, are a ubiquitous phenomenon in psychotherapy. They have been shown to occur across several clinical contexts and to be associated with better short-term and long-term treatment outcome. However, the approach of sudden gains has been criticized for its tautological character: sudden gains are included in the computation of treatment outcomes, ultimately resulting in a circular conclusion. Furthermore, some authors criticize sudden gains as merely being random fluctuations.Objective: Use of efficient methods to evaluate whether the amount of sudden gains in a given sample lies above chance level.Method: We used permutation tests in a sample of 85 patients with posttraumatic stress disorder (PTSD) treated with trauma-focused cognitive behaviour therapy in routine clinical care. Scores of self-reported PTSD symptom severity were permuted 10.000 times within sessions and between participants to receive a random distribution.Results: Altogether, 18 participants showed a total of 24 sudden gains within the first 20 sessions. The permutation test yielded that the frequency of sudden gains was not beyond chance level. No significant predictors of sudden gains were identified and sudden gains in general were not predictive of treatment outcome. However, subjects with early sudden gains had a significantly lower symptom severity after treatment.Conclusions: Our data suggest that a significant proportion of sudden gains are due to chance. Further research is needed on the differential effects of early and late sudden gains.

ABSTRACTStreptococcus suis is a significant and emerging zoonotic pathogen. ST1 and ST7 strains are the primary agents responsible for S. suis human infections in China, including the Guangxi Zhuang Autonomous Region (GX). To enhance our understanding of S. suis ST1 population characteristics, we conducted an investigation into the phylogenetic structure, genomic features, and virulence levels of 73 S. suis ST1 human strains from GX between 2005 and 2020. The ST1 GX strains were categorized into three lineages in phylogenetic analysis. Sub-lineage 3-1a exhibited a closer phylogenetic relationship with the ST7 epidemic strain SC84. The strains from lineage 3 predominantly harboured 89K-like pathogenicity islands (PAIs) which were categorized into four clades based on sequence alignment. The acquirement of 89K-like PAIs increased the antibiotic resistance and pathogenicity of corresponding transconjugants. We observed significant diversity in virulence levels among the 37 representative ST1 GX strains, that were classified as follows: epidemic (E)/highly virulent (HV) (32.4%, 12/37), virulent plus (V+) (29.7%, 11/37), virulent (V) (18.9%, 7/37), and lowly virulent (LV) (18.9%, 7/37) strains based on survival curves and mortality rates at different time points in C57BL/6 mice following infection. The E/HV strains were characterized by the overproduction of tumour necrosis factor (TNF)-α in serum and promptly established infection at the early phase of infection. Our research offers novel insights into the population structure, evolution, genomic features, and pathogenicity of ST1 strains. Our data also indicates the importance of establishing a scheme for characterizing and subtyping the virulence levels of S. suis strains.

This paper develops a mathematical framework that aims to control the temperature and rotational speed in the activation process of a gas turbine in an optimal way. These controls influence the deformation and the stress in the component due to centripetal loads and transient thermal stress. An optimal control problem is formulated as the minimization of maximal von Mises stress over a given time and over the whole component. To find a solution for this, we need to solve the linear thermoelasticity and the heat equations using the finite element method. The results for the optimal control as functions of the rotation speed and external gas temperature over time are computed by sequential quadratic programming, where gradients are computed using finite differences. The overall outcome reveals a significant reduction of approximately 10%, from [Formula: see text] to [Formula: see text], in von Mises stress by controlling two parameters, along with the temporal separation of physical control phenomena.

Systemic lupus erythematosus (SLE, lupus) is a debilitating, multisystem autoimmune disease that can affect any organ in the body. The disease is characterized by circulating autoantibodies that accumulate in organs and tissues, which triggers an inflammatory response that can cause permanent damage leading to significant morbidity and mortality. Lyn, a member of the Src family of non-receptor protein tyrosine kinases, is highly implicated in SLE as remarkably both mice lacking Lyn or expressing a gain-of-function mutation in Lyn develop spontaneous lupus-like disease due to altered signaling in B lymphocytes and myeloid cells, suggesting its expression or activation state plays a critical role in maintaining tolerance. The past 30 years of research has begun to elucidate the role of Lyn in a duplicitous signaling network of activating and inhibitory immunoreceptors and related targets, including interactions with the interferon regulatory factor family in the toll-like receptor pathway. Gain-of-function mutations in Lyn have now been identified in human cases and like mouse models, cause severe systemic autoinflammation. Studies of Lyn in SLE patients have presented mixed findings, which may reflect the heterogeneity of disease processes in SLE, with impairment or enhancement in Lyn function affecting subsets of SLE patients that may be a means of stratification. In this review, we present an overview of the phosphorylation and protein-binding targets of Lyn in B lymphocytes and myeloid cells, highlighting the structural domains of the protein that are involved in its function, and provide an update on studies of Lyn in SLE patients.

Deferred prosecution agreements and similar arrangements are practiced in many countries when there is suspicion of corporate crime. It is an agreement based on a negotiation that permits the allegedly guilty party not to undergo a criminal trial if they avoid committing further wrongdoing for a specified period of time. This article reviews such agreements in light of two different situations where the corporation is actually guilty and where the corporation is actually not guilty. An innocent company signing such an agreement suffers from miscarriage of justice. A guilty company on the other hand can restore the convenience of committing corporate crime. This article argues that deferred prosecution agreements violate basic principles of justice. The research suggests that serious fraud offices and other public bodies need to be restored to enable complete criminal prosecution when there are suspicions of corporate wrongdoing. This suggestion is based on the assumption that the underlying problem is law enforcement incompetence at investigating and prosecuting corporate crime.

Despite intensive therapies, pediatric patients with relapsed or refractory solid tumors have poor outcomes and need novel treatments. Immune therapies offer an alternative to conventional treatment options but require the identification of differentially expressed antigens to direct antitumor activity to sites of disease. B7-H3 (CD276) is an immune regulatory protein that is expressed in a range of malignancies and has limited expression in normal tissues. B7-H3 is highly expressed in pediatric solid tumors including osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, neuroblastoma, and many rare tumors. In this article we review B7-H3-targeted chimeric antigen receptor (B7-H3-CAR) T cell therapies for pediatric solid tumors, reporting preclinical development strategies and outlining the landscape of active pediatric clinical trials. We identify challenges to the success of CAR T cell therapy for solid tumors including localizing to and penetrating solid tumor sites, evading the hostile tumor microenvironment, supporting T cell expansion and persistence, and avoiding intrinsic tumor resistance. We highlight strategies to overcome these challenges and enhance the effect of B7-H3-CAR T cells, including advanced CAR T cell design and incorporation of combination therapies.

Recurrent and/or refractory (R/R) pediatric acute myeloid leukemia (AML) remains a recalcitrant disease with poor outcomes. Cell therapy with genetically modified immune effector cells holds the promise to improve outcomes for R/R AML since it relies on cytotoxic mechanisms that are distinct from chemotherapeutic agents. While T cells expressing chimeric antigen receptors (CAR T cells) showed significant anti-AML activity in preclinical models, early phase clinical studies have demonstrated limited activity, irrespective of the targeted AML antigen. Lack of efficacy is most likely multifactorial, including: (i) a limited array of AML-specific targets and target antigen heterogeneity; (ii) the aggressive nature of R/R AML and heavy pretreatment of patients; (iii) T-cell product manufacturing, and (iv) limited expansion and persistence of the CAR T cells, which is in part driven by the immunosuppressive AML microenvironment. Here we review the results of early phase clinical studies with AML-specific CAR T cells, and avenues investigators are exploring to improve their effector function.

ABSTRACT Zygothrica is a genus of Drosophilidae (Diptera) whose species utilize flowers and fungi for breeding sites, with records of fungi being used as courtship arena. Due to this habit, its representation in Drosophilidae surveys using banana-baited traps is generally low. However, Zygothrica orbitalis was well represented in a few samples with these traps. In this study, we report for the first time the breeding site of Z. orbitalis in living fruits of Psychotria brachyceras (Rubiaceae), noting that the use of living fruits is rare among Drosophilidae. The fructification of the plant occurs in the area of study from May to August, with previous collection records of the species in the Restinga (sandbank or strand) forest. Additionally, the emergence of some individuals of the invasive species Drosophila suzukii was observed, which highlights the necessity for continuous study of this plant to understand the dynamics between a native and an exotic species. Besides the ecological importance, our results are relevant for understanding the evolution of trophic resource use by the Zygothrica genus.

ABSTRACT Ecological interactions are diverse, variable across space and time and not always well understood. The use of interaction network analysis has become a tool that promotes a deeper understanding on ecological and evolutionary processes. The interaction between insects and fungi is an interesting research model, helping to understand colonization dynamics and species specialization in spatially aggregated and ephemeral resources. Here, we describe the interactions between Drosophilidae species and the fungal basidiocarps in a subtropical forest in Brazil. Flies were collected when were visiting basidiocarps and then the basidiocarps themselves were also collected to obtain the emerging flies whose larvae fed on the fungi. We observed 31 species of drosophilids interacting with basidiocarps of 23 fungi species. An ecological network analysis was performed for the drosophilids breeding on basidiocarps and for those visiting them as adults. We found a specialized breeding network, with stronger interactions involving Hirtodrosophila and Auricularia and Zygothrica bilineata and a Marasmius species. Our results indicate the generalist habit of most Zygothrica species. The visitation network was highly specialized. Despite being well represented in the sampling, most Zygothrica species did not emerge from any fungal species. This study advances the knowledge on patterns of Drosophilid-fungi interactions and provides insights into their drivers.

IntroductionMalignant ascites indicates ovarian cancer progression and predicts poor clinical outcome. Various ascites components induce an immunosuppressive crosstalk between tumor and immune cells, which is poorly understood. In our previous study, imbalanced electrolytes, particularly high sodium content in malignant ascites, have been identified as a main immunosuppressive mechanism that impaired NK and T-cell activity.MethodsIn the present study, we explored the role of high concentrations of ascites proteins and immunoglobulins on antitumoral NK effector functions. To this end, a coculture system consisting of healthy donor NK cells and ovarian cancer cells was used. The anti-EGFR antibody Cetuximab was added to induce antibody-dependent cellular cytotoxicity (ADCC). NK activity was assessed in the presence of different patient ascites samples and immunoglobulins that were isolated from ascites.ResultsOverall high protein concentration in ascites impaired NK cell degranulation, conjugation to tumor cells, and intracellular calcium signaling. Immunoglobulins isolated from ascites samples competitively interfered with NK ADCC and inhibited the conjugation to target cells. Furthermore, downregulation of regulatory surface markers CD16 and DNAM-1 on NK cells was prevented by ascites-derived immunoglobulins during NK cell activation.ConclusionOur data show that high protein concentrations in biological fluids are able to suppress antitumoral activity of NK cells independent from the mechanism mediated by imbalanced electrolytes. The competitive interference between immunoglobulins of ascites and specific therapeutic antibodies could diminish the efficacy of antibody-based therapies and should be considered in antibody-based immunotherapies.

Species living in spatially structured populations require a network of interconnected habitat patches. Due to changes in forest management, this network of habitat patches has been lost for insect species inhabiting open spots within forests. We studied two of the last populations of the Southern White Admiral (Limenitis reducta) in Germany. The aim of our study was to provide information for the conservation of this species. We conducted a capture-mark-recapture study over three consecutive years and we estimated population sizes and demographic parameters using Jolly-Seber and Cormack-Jolly-Seber models. Furthermore, we used different dispersal kernels to study the dispersal of L. reducta. We found that apparent survival rates differed greatly between the sexes. The mean residence times were eight to nine days for males and only two to four days for females. Apparent survival rates of both sexes decreased with increasing wing deterioration. Total population sizes of L. reducta varied between sites and years and ranged between 61 and 123. Daily abundances were generally low, especially that of females. The mean dispersal distance of individual recaptured butterflies increased in years with higher population densities, suggesting density-dependent dispersal. The dispersal data in our study was clearly bimodal, probably reflecting ‘routine movement’ at short distances and ‘displacement movement’ between habitat patches at longer distances. Consequently, the processes generating the dispersal data were better represented by the lognormal mixture model than by the negative exponential and the inverse power function. The mixed kernel predicted that about 9 % of the population disperses over > 1 km but that long-distance dispersal is rare. Our study highlights the urgent need for conservation measures to protect L. reducta in Germany and, based on our data, we recommend to create new habitat patches at distances of 1 to 1.5 km from existing habitats.

Abstract Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring.

Abstract Limited data is available on the effect of vaccination and previous virus exposure on the nature of SARS-CoV-2 transmission and immune-pressure on variants. To understand the impact of pre-existing immunity on SARS-CoV-2 airborne transmission efficiency, we perform a transmission chain experiment using naïve, intranasally or intramuscularly AZD1222 vaccinated, and previously infected hamsters. A clear gradient in transmission efficacy is observed: Transmission in hamsters vaccinated via the intramuscular route was reduced over three airborne chains (approx. 60%) compared to naïve animals, whereas transmission in previously infected hamsters and those vaccinated via the intranasal route was reduced by 80%. We also find that the Delta B.1.617.2 variant outcompeted Omicron B.1.1.529 after dual infection within and between hosts in naïve, vaccinated, and previously infected transmission chains, yet an increase in Omicron B.1.1.529 competitiveness is observed in groups with pre-existing immunity against Delta B.1.617.2. This correlates with an increase in the strength of the humoral response against Delta B.1.617.2, with the strongest response seen in previously infected animals. These data highlight the continuous need to improve vaccination strategies and address the additional evolutionary pressure pre-existing immunity may exert on SARS-CoV-2.

Abstract Background Effects of demographic change, such as declining birth rates and increasing individual life expectancy, require health system adjustments offering age- and needs-based care. In addition, healthcare factors can also influence health services demand. Methods The official German hospital statistics database with odd-numbered years between 1995 and 2011 was analysed. This is a national comprehensive database of all general hospital inpatient services delivered. Official data from hospital statistics were linked at the district level with demographic and socio-economic data as well as population figures from the official regional statistics. Panel data regression, modelling case numbers per hospital, was performed for 13 diagnosis groups that characterised the patient structure. Socio-demographic variables included age, sex, household income, and healthcare factors included bed capacity, personnel and hospital characteristics. Results The median number of annual treatments per hospital increased from 6 015 (5th and 95th percentile [670; 24 812]) in 1995 to 7 817 in 2011 (5th and 95th percentile [301; 33 651]). We developed models characterising the patient structure of health care in Germany, considering both socio-demographic and hospital factors. Demographic factors influenced case numbers across all major diagnosis groups. For example, the age groups 65–74 and 75 + influenced cerebrovascular disease case numbers (p

The impacts of anthropogenic activities are increasing at alarming rates, leading to biodiversity loss and the displacement of native habitats. One of the main contributors to human disturbances is livestock farming, which degrades native habitats through cattle grazing and trampling. To understand these impacts, we investigated the effects of cattle trampling on the structure and diversity of fruit-feeding butterflies in Restinga forests of southern Brazil. We addressed questions regarding the effects of cattle raising on butterfly diversity and composition, identified indicator species, and examined the influence of environmental variables on butterfly richness, dominance, abundance, and species composition. Our dataset comprises the long-term monitoring of fruit-feeding butterflies in Restinga forests from 2014 to 2019, across sites with low, medium, and high levels of disturbance due to cattle trampling. We found that medium and high levels of disturbance increased butterfly richness and abundance, whereas low-level disturbance was associated with lower abundance. Additionally, the species composition of butterflies in medium to highly disturbed sites differed from that in preserved Restinga forests, indicating that any perturbation can markedly alter alpha and beta diversity parameters. These changes simplify the native forest structure, open the canopy, disrupt the understory, and favor butterfly species commonly associated with disturbed forests.

The bitter rot of apple is caused by Colletotrichum spp. and is a serious pre-harvest disease that can manifest in postharvest losses on harvested fruit. In this study, we obtained genome sequences from four different species, C. chrysophilum, C. noveboracense, C. nupharicola, and C. fioriniae, that infect apple and cause diseases on other fruits, vegetables, and flowers. Our genomic data were obtained from isolates/species that have not yet been sequenced and represent geographic-specific regions. Genome sequencing allowed for the construction of phylogenetic trees, which corroborated the overall concordance observed in prior MLST studies. Bioinformatic pipelines were used to discover CAZyme, effector, and secondary metabolic (SM) gene clusters in all nine Colletotrichum isolates. We found redundancy and a high level of similarity across species regarding CAZyme classes and predicted cytoplastic and apoplastic effectors. SM gene clusters displayed the most diversity in type and the most common cluster was one that encodes genes involved in the production of alternapyrone. Our study provides a solid platform to identify targets for functional studies that underpin pathogenicity, virulence, and/or quiescence that can be targeted for the development of new control strategies. With these new genomics resources, exploration via omics-based technologies using these isolates will help ascertain the biological underpinnings of their widespread success and observed geographic dominance in specific areas throughout the country.

When Russia attacked Ukraine, national states as well as multinational bodies such as the European Union imposed economic sanctions against Russia. Companies in sanctioning countries were expected to terminate their business with companies in the sanctioned country. However, the threat of bankruptcy made some companies chose deviance to circumvent and evasion sanctions. The case study in this paper describes an insurance firm’s attempt to terminate an insurance arrangement to avoid allegations of money laundering. The ownership of a seafood company in Norway had been transferred from Russians to a Norwegian. However, it seemed that the Russians were still the real owners since the Norwegian had paid nothing for the ownership. This paper presents the civil trial in the case and discusses convenience propositions for the Norwegian based on convenience theory in the dimensions of motive, opportunity, and willingness for deviance.

Many countries have established national authorities to investigate and prosecute serious and complex white-collar and corporate crime incidents. This article reviews research literature regarding external challenges and barriers for national agencies in Norway (Økokrim), New Zealand (SFO), the United Kingdom (SFO), and the Netherlands (OSF). The policing study in this article is important as it illustrates dilemmas that governments need to address when reviewing their national fraud offices and economic crime authorities. While Økokrim in Norway seems reluctant to prosecute too complex economic crime cases, the SFO in New Zealand attempts prevention of deinstitutionalization, the SFO in the UK might have deterrence effects, while the OSF in the Netherlands is challenged by the private industry of corporate investigators. These are some of the challenges and barriers facing national authorities that are charged with the tasks of investigating and prosecuting white-collar and corporate crime at the national level. The identified challenges and barriers especially related to the convenience theory perspective should enable future research to identify relevant actions.

Streptococcus suis is a bacterial gram-positive pathogen that causes invasive infections in swine and is also a zoonotic disease agent. Traditional molecular typing techniques such as ribotyping, multilocus sequence typing, pulse-field gel electrophoresis, or randomly amplified polymorphic DNA have been used to investigate S. suis population structure, evolution, and genetic relationships and support epidemiological and virulence investigations. However, these traditional typing techniques do not fully reveal the genetically heterogeneous nature of S. suis strains. The high-resolution provided by whole-genome sequencing (WGS), which is now more affordable and more commonly available in research and clinical settings, has unlocked the exploration of S. suis genetics at full resolution, permitting the determination of population structure, genetic diversity, identification of virulent clades, genetic markers, and other bacterial features of interest. This approach will likely become the new gold standard for S. suis strain typing as WGS instruments become more widely available and traditional typing techniques are gradually replaced.

Neonatal Graves disease is the most common cause of hyperthyroidism during the newborn period. Maternal Graves disease increases the risk of intrauterine growth restriction, small for gestational age, and neonatal Graves disease. Intrauterine growth restriction and small for gestational age are associated with hypoglycemia and transient neonatal hyperinsulinism. Neonatal Graves disease with severe persistent hypoglycemia has not been well described. We present the case of a female patient born at 34 weeks and 3 days with a birth weight of 1.6 kg (fifth percentile) to a mother with recent treatment for Graves disease. Prenatal ultrasounds were significant for intrauterine growth restriction and small for gestational age. The mother did not begin hyperthyroidism medical therapy until 23 weeks and 2 days of gestation. After the infant was born, the infant not only had symptoms of hyperthyroidism such as tachycardia and abnormal thyroid values but also had persistent hypoglycemia, which could be due to maternal propranolol usage, prematurity, IUGR, increased metabolism due to neonatal Graves, and transient stress-induced hyperinsulinism. The infant was started on methimazole for hyperthyroidism and propranolol for tachycardia. She was also started on diazoxide for persistent hypoglycemia. By 6 months of age, the hyperthyroidism and hypoglycemia had resolved. This is an interesting case of neonatal Graves disease with severe persistent hypoglycemia which we suspect is due to transient neonatal hyperinsulinism induced by multiple stress responses.