Search

In this paper, we study the implications of extending the balanced cost reduction property from queueing problems to general games. As a direct translation of the balanced cost reduction property, the axiom of balanced externalities for solutions of games, requires that the payoff of any player is equal to the total externality she inflicts on the other players with her presence. We show that this axiom and efficiency together characterize the Shapley value for 2-additive games. However, extending this axiom in a straightfoward way to general games is incompatible with efficiency. Keeping as close as possible to the idea behind balanced externalities, we weaken this axiom by requiring that every player's payoff is the same fraction of its total externality inflicted on the other players. This weakening, which we call weak balanced externalities, turns out to be compatible with efficiency. More speci fically, the unique efficient solution that satisfi es this weaker property is the proportional allocation of nonseparable contribution (PANSC) value, which allocates the total worth proportional to the separable costs of the players. We also provide characterizations of the PANSC value using a reduced game consistency axiom.

We aimed to explore the heterogeneity of schema therapy regarding (a) patient characteristics, (b) content, and (c) way of delivering schema therapy. A search was conducted of the electronic databases EMBASE, PsycINFO, Web of Science, MEDLINE, and COCHRANE up to June 15, 2022. Treatment studies were eligible if they (a) used schema therapy as (component of) the intervention examined, and (b) reported an outcome measure quantitatively. A total of 101 studies met the inclusion criteria, including randomized controlled trials (n = 30), non-randomized controlled trials (n = 8), pre-post designs (n = 22), cases series (n = 13), and case reports (n = 28), including 4006 patients. Good feasibility was consistently reported irrespective of format (group versus individual), setting (outpatient, day-treatment, inpatient), intensity of treatment, and the specific therapeutic components included. Schema therapy was applied to various (psychiatric) disorders. All studies presented promising results. Effectiveness of the different models of schema therapy as well as application beyond personality disorders should be examined more rigorously.

SamenvattingPijn in de blaasregio kan een grote impact hebben op de kwaliteit van leven van de patiënt. Wanneer patiënten geen baat hebben bij medicamenteuze of intravesicale behandelingen kan plexusblokkade door de pijnspecialist een oplossing zijn ter acute verlichting van de pijn. Dit case report bespreekt twee casus waarbij blokkade van de plexus hypogastricus superior of het ganglion impar uitkomst heeft geboden. Ondanks het gebrek aan bewijs pleiten het relatief weinig-invasieve karakter van de ingreep en het lage risico op complicaties ervan, vóór het toepassen van plexusblokkades ter verlichting van pijn in de blaasregio.

Introduction: The use of anabolic androgenic steroids (AAS) and other image- and performance-enhancing drugs is a growing public health concern. AAS use is associated with various physical and mental harms, including cardiovascular risks, cognitive deficiencies, and dependence. The aim of this study was to determine whether patterns of AAS use and other variables are associated with the presence of an AAS use disorder (AASUD). Methods: An online survey was completed by 103 male AAS consumers visiting gyms. The association of different patterns of AAS consumption (cycling vs. continuous forms of AAS use), psychoactive substance use, mental health disorders, and sociodemographic variables with moderate-severe AASUD (fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ≥4 criteria) was investigated. The associations between duration of AAS use and the AAS dose with moderate-severe AASUD were investigated using logistic regression analysis with moderate-severe AASUD as the dependent variable. Results: Moderate-severe AASUD was present in 25 (24.3%) of the participants. AAS consumers meeting criteria for moderate-severe AASUD, compared to those that did not, in the last 12 months reported a longer duration of AAS use (in weeks), a higher average AAS dose (mg/week), and a greater number of AAS side effects. Duration of AAS use and the AAS dose were the only independent predictors, with an increase of 3.4% in the probability of moderate-severe AASUD with every week increase of the duration of AAS use in the last year (p < 0.05) and an increase in moderate-severe AASUD of 0.1% with every 10 mg increase in the average AAS dose per week (p < 0.05), respectively. Conclusion: Our findings show that moderate-severe AASUD is relatively frequent among male AAS consumers and is positively associated with the duration and average dose of AAS use in the last 12 months.

Rotating shaft balances (RSBs) are devices that are used to measure rotor blade forces and moments of wind tunnel models during wind tunnel tests. The design of an RSB can be challenging, because it has to comply with many and sometimes contradicting requirements such as high stiffness and high strain gauge bridge outputs. The manufacturing of a conventional RSB consists of different subsequent steps, which can be time consuming, expensive and associated with many risks. Therefore, in this work, the authors investigate if a RSB can be designed by topology optimization and manufactured by 3D printing. A topology optimization method was developed with as design objective the minimization of strain energy with constraints for the volume of the RSB’s midsection, defined stresses at strain gauge locations used for the measurement of axial force and torque and an overhang constraint for additive manufacturing. The optimal preliminary design found by topology optimization was translated into a final printable design with the highest bridge sensitivity for axial force and torque, sufficient output for in-plane forces and moments and an acceptable safety factor on strength for combined loads. After adding extra supports required for printing, the RSB was successfully printed in metal by the laser powder bed fusion process, resulting in a product without external defects. The same topology optimization and manufacturing method can potentially be used for other balance types, leading to a reduction in total lead time and manufacturing costs while increasing the design freedom.

In two dogs, skull defects were closed with a patient-specific implant created by additive manufacturing after excision of tumours of the skull. Both dogs presented with a space-occupying mass in which excisional surgery without the use of implants would have resulted in incomplete closure due to extensive bone defects of the skull. The aim of the present case report is to describe the use of individualized three-dimensional-printed titanium implants for skull reconstruction following oncological surgery. The reconstructive implant-based surgeries performed in these patients were feasible without complications.

The physical examination is one of the most important diagnostic tools for physicians. Traditionally, a physical examination consists of inspection (looking), palpation (feeling), percussion (reflection of sound) and auscultation (listening). Handheld echography devices could become the new fifth element of a physical examination. The use of handheld echocardiography has recently increased because the devices have become smaller, easier to handle and more affordable. Handheld echocardiography is used by many specialists involved in acute cardiovascular care. In this narrative review we give a summary of the diagnostic accuracy and limitations of cardiovascular physical examination combined with handheld echocardiography. In patients with cardiovascular disease, adding handheld echocardiography to physical examination increases the sensitivity for detecting valvular heart disease (71% vs 46%) and left ventricular dysfunction with an ejection fraction

Following allogeneic hematopoietic cell transplantation (allo-HCT), the gastrointestinal (GI) tract is frequently affected by acute graft-versus-host disease (aGVHD), the pathophysiology of which is associated with a dysbiotic microbiome. Since microbial composition varies along the length of the GI tract, the authors hypothesized that microbiome features correlate with the pattern of organ involvement after allo-HCT. We evaluated 266 allo-HCT recipients from whom 1303 stool samples were profiled by 16S ribosomal gene sequencing. Patients were classified according to which organs were affected by aGVHD. In the 20 days prior to disease onset, GVHD patients had lower abundances of members of the class Clostridia, lower counts of butyrate producers, and lower ratios of strict-to-facultative (S/F) anaerobic bacteria compared with allograft recipients who were free of GVHD. GI GVHD patients showed significant reduction in microbial diversity preonset. Patients with lower GI aGVHD had lower S/F anaerobe ratios compared with those with isolated upper GI aGVHD. In the 20 days after disease onset, dysbiosis was observed only in GVHD patients with GI involvement, particularly those with lower-tract disease. Importantly, Clostridial and butyrate-producer abundance as well as S/F anaerobe ratio were predictors of longer overall survival; higher abundance of butyrate producers and higher S/F anaerobe ratio were associated with decreased risk of GVHD-related death. These findings suggest that the intestinal microbiome can serve as a biomarker for outcomes of allo-HCT patients with GVHD.

Background: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. Previous studies on the prevalence of cSVD are mostly based on single geographically defined cohorts in high-income countries. Studies investigating the prevalence of cSVD in low- and middle-income countries (LMICs) are expanding but have not been systematically assessed. Aim: This study aims to systematically review the prevalence of cSVD in LMICs. Results: Articles were searched from the Ovid MEDLINE and EMBASE databases from 1 January 2000 to 31 March 2022, without language restrictions. Title/abstract screening, full-text review, and data extraction were performed by two to seven independent reviewers. The prevalence of cSVD and study sample size were extracted by pre-defined world regions and health status. The Risk of Bias for Non-randomized Studies tool was used. The protocol was registered on PROSPERO (CRD42022311133). A meta-analysis of proportion was performed to assess the prevalence of different magnetic resonance imaging markers of cSVD, and a meta-regression was performed to investigate associations between cSVD prevalence and type of study, age, and male: female ratio. Of 2743 studies identified, 42 studies spanning 12 global regions were included in the systematic review. Most of the identified studies were from China (n = 23). The median prevalence of moderate-to-severe white matter hyperintensities (WMHs) was 20.5%, 40.5%, and 58.4% in the community, stroke, and dementia groups, respectively. The median prevalence of lacunes was 0.8% and 33.5% in the community and stroke groups. The median prevalence of cerebral microbleeds (CMBs) was 10.7% and 22.4% in the community and stroke groups. The median prevalence of moderate-to-severe perivascular spaces was 25.0% in the community. Meta-regression analyses showed that the weighted median age (51.4 ± 0.0 years old; range: 36.3–80.2) was a significant predictor of the prevalence of moderate-to-severe WMH and lacunes, while the type of study was a significant predictor of the prevalence of CMB. The heterogeneity of studies was high (>95%). Male participants were overrepresented. Conclusions: This systematic review and meta-analysis provide data on cSVD prevalence in LMICs and demonstrated the high prevalence of the condition. cSVD research in LMICs is being published at an increasing rate, especially between 2010 and 2022. More data are particularly needed from Sub-Saharan Africa and Central Europe, Eastern Europe, and Central Asia.

Purpose: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

ObjectiveCerebral small vessel diseases (cSVDs) are a major cause of stroke and dementia. We used cutting-edge 7T-MRI techniques in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), to establish which aspects of cerebral small vessel function are affected by this monogenic form of cSVD.MethodsWe recruited 23 CADASIL patients (age 51.1 ± 10.1 years, 52% women) and 13 age- and sex-matched controls (46.1 ± 12.6, 46% women). Small vessel function measures included: basal ganglia and centrum semiovale perforating artery blood flow velocity and pulsatility, vascular reactivity to a visual stimulus in the occipital cortex and reactivity to hypercapnia in the cortex, subcortical gray matter, white matter, and white matter hyperintensities.ResultsCompared with controls, CADASIL patients showed lower blood flow velocity and higher pulsatility index within perforating arteries of the centrum semiovale (mean difference − 0.09 cm/s, p = 0.03 and 0.20, p = 0.009) and basal ganglia (mean difference − 0.98 cm/s, p = 0.003 and 0.17, p = 0.06). Small vessel reactivity to a short visual stimulus was decreased (blood-oxygen-level dependent [BOLD] mean difference −0.21%, p = 0.04) in patients, while reactivity to hypercapnia was preserved in the cortex, subcortical gray matter, and normal appearing white matter. Among patients, reactivity to hypercapnia was decreased in white matter hyperintensities compared to normal appearing white matter (BOLD mean difference −0.29%, p = 0.02).InterpretationMultiple aspects of cerebral small vessel function on 7T-MRI were abnormal in CADASIL patients, indicative of increased arteriolar stiffness and regional abnormalities in reactivity, locally also in relation to white matter injury. These observations provide novel markers of cSVD for mechanistic and intervention studies. ANN NEUROL 2022

Bomarea ovallei (Phil.) Ravenna (2n=2x=18) is an endangered endemic species that inhabits only a small part of the coast of the Atacama region. We describe the structure, gene composition and phylogeny of the complete chloroplast sequence of this elusive species. The chloroplast genome consists of 155,018 bp, with typical quadripartite structures: a large single copy region (LSC) of 84,132 bp, a small single copy region (SSC) of 17,794 bp, and two inverted repeat regions (IRs) contain 26,546 bp. One hundred and thirty-four genes were identified out of which 84 coding genes, 8 rRNA, 38 tRNA and 4 pseudogenes. B. ovallei chloroplast resembles chloroplasts from seven species of the order Liliales in length and structure and is most similar to Bomarea edulis (BP=100). The average nucleotide variability (Pi) of 0.00254 between these two Bomarea species is moderate. Nine loci with increased variability were identified: rps16-trnQ, atpF, trnL, ndhC-trnV, rbcL, psbJ, rpl32-trnL, ndhD and ycf1. These loci could be used as DNA markers for classification and evaluation studies in Bomarea populations.

Purpose: Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes. Experimental Design: We examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography–mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant. Results: At 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02). Conclusions: This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention.

Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1–4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5–8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.

Aim: The evaluation of a health technology determines the clinical and non-clinical value of the technology. Among the non-clinical criteria, evaluation models include the organizational impact (OI) of the technology. The objective of this study is to highlight the types of OIs of 3D printing in a hospital setting. Materials & methods: A panel of 12 experts was assembled based on their knowledge of 3D-printed medical devices and then interviewed individually. Results: A strong consensus was reached for three types of impacts out of the 12 types of OIs associated with medical devices: the need for training, cooperation and communication and the logistics circuit. Conclusion: It seems very relevant to integrate these three types of impacts in future evaluations of 3D printing in healthcare.

Schema group therapy is an effective treatment for personality disorders, but its focus on cognitive techniques may be a limitation for older adults. This article describes the rationale and initial evaluation of a group schema therapy protocol enriched with psychomotor therapy (GST+PMT) for older adults in geriatric mental health care.Within an observational feasibility study, we evaluated the effect of a 26-week GST+PMT program in 19 outpatients aged 60-70 years with a cluster B or C personality disorder on the Young Schema Questionnaire, Schema Mode Inventory and Manchester Short Assessment of Quality of Life. Cohen's d effect-sizes were calculated between baseline (T0), mid-treatment (T1) and end-of-treatment (T2).Medium to large pre-post effect-sizes (T0-T2) were found for all outcome measures. Most improvement of schema modes occurred between T0-T1, and of schemas and quality of life between T1-T2.Group schema therapy enriched with PMT is feasible in later life and its effect might be mediated by targeting schema modes. Future research would be helpful, including larger samples and controlled studies.For older adults suffering from personality disorders B or C verbal schema group therapy enriched with non-verbal PMT may be an effective treatment.

Actinidia seed-borne latent virus (ASbLV, Betaflexiviridae, genus Prunevirus) was detected at high frequency in healthy seedlings grown from lines of imported seed in a New Zealand post-entry quarantine facility. To determine the route and efficiency of transmission of ASbLV in this dioecious crop species, we developed a rapid molecular protocol and identified a reliable progeny plant tissue to determine paternal and maternal transmission rates. The virus was detected at a high incidence (98%) in individual seeds, but cotyledon testing of seedlings from selected crosses confirmed staminate (male) transmission at high frequency (~ 60%), and pistillate (female) transmission at even higher frequency (~ 80%). The use of cotyledons allows non-destructive detection of ASbLV in very young seedlings that enables early screening of kiwifruit plants in nurseries to manage its spread to orchards. The high ASbLV transmission rates, whether from infected pollen or ovules, facilitate bulk testing of seed lots that could quickly detect infected parent plants (fruit bearing female or male pollinator) already in an orchard. The dioecious nature of Actinidia may provide a useful biological tool to further investigate ASbLV movement, transmission biology, and ultimately its impact on infected Actinidia plants.

Fluoxetine is one of the worlds most prescribed antidepressant, and frequently detected in surface waters. Once present in the aquatic environment, fluoxetine has been shown to disrupt the swimming behaviour of fish and invertebrates. However, swimming behaviour is also known to be highly variable according to experimental conditions, potentially concealing relevant effects. Therefore, the aims of this study were two-fold: i) investigate the swimming and feeding behaviour of Gammarus pulex after exposure to the antidepressant fluoxetine (0.2, 2, 20, and 200 mu g/L), and ii) assess to what degree the experimental test duration (short-term and long-term) and test location (laboratory and semi-field conditions) affect gammarid's swimming behaviour. We used automated video tracking and analysis to asses a range of swimming behaviours of G. pulex, including swimming speed, startle responses after light transition, acceleration, curvature and thigmotaxis. We found larger effects on the swimming behaviour of G. pulex due to experimental conditions than due to tested antidepressant concentrations. Gammarids swam faster, more straight and showed a stronger startle response during light transition when kept under semi-field conditions compared to the laboratory. Effects found for different test durations were opposite in the laboratory and semi-field. In the laboratory gammarids swam slower and spent more time at the inner zone of the arena after 2 days compared to 21 days while for the semi-field the reverse was observed. Fluoxetine had only minor impacts on the swimming behaviour of G. pulex, but experimental conditions influenced behavioural outcomes in response to fluoxetine exposure. Overall, our results highlight the im-portance of standardizing and optimizing experimental protocols that assess behaviour to achieve reproducible results in ecotoxicology. This project was funded by TKI (Topconsortium voor Kennis en Innovatie) Deltatechnology, jointly financed by the Dutch government and commercial parties through the Precaution project: PREdicting the Chemical sensitivity of AqUaTIc OrgaNisms. This project was also funded by the Netherlands Organization for Scientific Research (NWO) domain TTW through the EMERCHE project: Effect-directed Monitoring tools to assess Ecological and human health Risks of CHemicals of Emerging concern in the water cycle (File number 15760).

For toxicology testing of (agro)chemicals, different study types are being performed with general and/or reproductive toxicity endpoints (see Organisation for Economic Co-operation and Development guidelines). In most of these rat studies, vaginal cytology is performed on serial samples (collected by lavage) for evaluation of cycle regularity and evidence of mating, and/or on a single sample collected on the day of necropsy for information on the estrous cycle stage and allowing correlation with histopathology. In the latter case, the utility of vaginal cytology can be argued. In this article, estrous cycle stages based on vaginal cytology of samples taken on the day of necropsy and histopathology of ovaries, uterus, and vagina (gold standard for estrous cycle stage assessment) were compared. The agreement was generally low. Disagreement between the two methods could be explained by time differences between lavage and necropsy, by manipulation of vaginal epithelium during lavage which may impact epithelial morphology on histology, and by misinterpretation of vaginal cytology during or shortly after lactation. Based on the results of estrous staging within different study types, we strongly discourage vaginal cytology from samples collected on the day of necropsy since there is no added value, vaginal manipulation can be stressful and may complicate the histologic diagnosis.

n.a.v. William Lane Craig, In Quest of the Historical Adam. A Biblical and Scientific Exploration (Grand Rapids: Eerdmans, 2021) 421 p., $ 38.00 (ISBN 9780802879110).

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a−/−) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a−/− T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a−/− T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a−/− T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

This work deals with the weighted excesses of players in cooperative games which are obtained by summing up all the weighted excesses of all coalitions to which they belong. We first show that lexicographically minimizing the individual weighted excesses of players gives the same minimal weighted excess for every player. Moreover, we show that the associated payoff vector is the corresponding least square value. Second, we show that minimizing the variance of the players' weighted excesses on the preimputation set, again yields the corresponding least square value. Third, we show that these results give rise to lower and upper bounds for the core payoff vectors and, using these bounds, we define the weighted super core as a polyhedron that contains the core. It turns out that the least square values can be seen as a center of this weighted super core, giving a third new characterization of the least square values. Finally, these lower and upper bounds for the core inspire us to introduce a new solution for cooperative TU games that has a strong similarity with the Shapley value.

Background: GHB (gamma-hydroxybutyric acid; sodium oxybate) is a general anaesthetic that is clinically used for the treatment of narcolepsy, cataplexy, alcohol withdrawal and alcohol relapse prevention. In addition, GHB is recreationally used. Most clinical and recreational users regard GHB as an innocent drug devoid of adverse effects, despite its high dependence potential and possible neurotoxic effects. At high doses, GHB may lead to a comatose state. This paper systematically reviews possible cognitive impairments due to clinical and recreational GHB use. Methods: PubMed and PsychINFO were searched for literature data about the acute and residual cognitive deficits following GHB use. This review is conducted using the PRISMA protocol. Results: A total of 43 reports covering human and animal data on GHB-induced cognitive impairments were eligible and reviewed. This systematic review found no indication for cognitive impairments after clinical GHB use. However, it supports the view that moderate GHB use may result in acute short-term cognitive impairments, whereas regular high-dose GHB use and/or multiple GHB-induced comas are probably neurotoxic resulting in long-term residual cognitive impairments. Conclusion: These results emphasize the need for awareness among clinicians and recreational users to minimize negative health consequences of recreational GHB use, particularly when high doses are used and GHB-induced comas occur.

Microclimate science has developed into a global discipline. Microclimate science is increasingly used to understand and mitigate climate and biodiversity shifts. Here, we provide an overview of the current status of microclimate ecology and biogeography, and where this field is heading next. We showcase the recent advances in data acquisition, such as novel field sensors and remote sensing methods. We discuss microclimate modelling, mapping, and data processing, including accessibility of modelling tools, advantages of mechanistic and statistical modelling, and solutions for computational challenges that have pushed the state-of-the-art of the field. We highlight the latest research on interactions between microclimate and organisms, including how microclimate influences individuals, and through them populations, communities, and entire ecosystems and their processes. We also briefly discuss recent research on how organisms shape microclimate from the tropics to the poles. Microclimates are also important in ecosystem management under climate change. We showcase new research in microclimate management with examples from biodiversity conservation, forestry, and urban ecology. We discuss the importance of microrefugia in conservation and how to promote microclimate heterogeneity. We identify major knowledge gaps that need to be filled for further advancing microclimate methods, investigations, and applications. These gaps include spatiotemporal scaling of microclimate data, mismatches between macroclimate and microclimate in predicting responses of organisms to climate change, and the need for more evidence on the outcomes of microclimate management. Biosketch The authors are participants of the Microclimate Ecology and Biogeography conference held in Antwerp, Belgium in 2022. Together they collaboratively wrote this perspective paper that brings together 97 experts and their views on the recent advancements and knowledge gaps in terrestrial microclimate. The paper was coordinated by Julia Kemppinen, Jonas Lembrechts, Koenraad Van Meerbeek, and Pieter De Frenne, and writing different sections was led by Jofre Carnicer, Nathalie Chardon, Paul Kardol, Jonathan Lenoir, Daijun Liu, Ilya Maclean, Jan Pergl, Patrick Saccone, Rebecca Senior, Ting Shen, Sandra Słowińska, Vigdis Vandvik, and Jonathan von Oppen. For more details on authors statistics and how the work was organised, please see Supplementary information Figures S1-3.

Background Ketamine and its enantiomers are widely researched and increasingly used to treat mental disorders, especially treatment-resistant depression. The phenomenology of ketamine-induced experiences and their relation to its psychotherapeutic potential have not yet been systematically investigated. Aims To describe the phenomenology of patient experiences during oral esketamine treatment for treatment-resistant depression (TRD) and to explore the potential therapeutic relevance of these experiences. Methods In-depth interviews were conducted with 17 patients after a 6-week, twice-weekly ‘off label’ generic oral esketamine (0.5–3.0mg/kg) treatment program. Interviews explored participants’ perspectives, expectations, and experiences with oral esketamine treatment. Audio interviews were transcribed and analyzed using an Interpretative Phenomenological Analysis (IPA) framework. Results The effects of ketamine were highly variable, and psychological distress was common in most patients. Key themes included (a) perceptual effects (auditory, visual, proprioceptive), (b) detachment (from body, self, emotions, and the world), (c) stillness and openness, (d) mystical-type effects (transcendence, relativeness, spirituality), and (e) fear and anxiety. Key themes related to post-session reports included (a) feeling hungover and fatigued, and (b) lifting the blanket: neutralizing mood effects. Conclusion Patients reported several esketamine effects with psychotherapeutic potential, such as increased openness, detachment, an interruption of negativity, and mystical-type experiences. These experiences deserve to be explored further to enhance treatment outcomes in patients with TRD. Given the frequency and severity of the perceived distress, we identify a need for additional support in all stages of esketamine treatment.

SamenvattingWij presenteren casuïstiek van drie patiënten met een urosymfyseale fistel (USF), een zeldzame complicatie na behandeling van het prostaatcarcinoom. Een USF ontstaat meestal als gevolg van een chirurgische behandeling van een prostaatcarcinoom in combinatie met aanvullende radiotherapie en/of postoperatieve endoscopische interventies. Recidiverende urineweginfecties, (chronische) pubische of perineale pijn tijdens mobilisatie en/of tekenen van osteomyelitis kunnen duiden op de aanwezigheid van een USF. Diagnostiek vindt plaats op basis van een urethrocystoscopie en een MRI-scan van het bekken. Met deze casus laten wij zien dat bij falen van conservatieve therapie patiënten succesvol behandeld kunnen worden middels een chirurgische resectie van het fistelkanaal, het aanleggen van een urinedeviatie en lokale en systemische behandeling van de osteomyelitis.

Checkpoint inhibitors (CPI) have revolutionized the treatment paradigm for advanced solid tumors; however, there remains an opportunity to improve response rates and outcomes. In preclinical models, 4-1BB costimulation synergizes with CPIs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis by activating cytotoxic T-cell–mediated antitumor immunity. DuoBody-PD-L1×4-1BB (GEN1046) is an investigational, first-in-class bispecific immunotherapy agent designed to act on both pathways by combining simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell–mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity [disease control rate: 65.6% (40/61)], including patients resistant to prior PD-(L)1 immunotherapy.Significance:DuoBody-PD-L1×4-1BB (GEN1046) is a first-in-class bispecific immunotherapy with a manageable safety profile and encouraging preclinical and early clinical activity. With its ability to confer clinical benefit in tumors typically less sensitive to CPIs, GEN1046 may fill a clinical gap in CPI-relapsed or refractory disease or as a combination therapy with CPIs.See related commentary by Li et al., p. 1184.This article is highlighted in the In This Issue feature, p. 1171

Supplementary Figure from Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors

PDF file 135KB, Non-specific negative effect of DMSO on the GVT activity of T-cells

PDF file 96K, Pre-treatment of donor T-cells with a c-Rel antagonist promotes IL-2 secretion in vivo

The costimulatory molecules B7-H3 and B7-H4 are overexpressed in a variety of human tumors and have been hypothesized as possible biomarkers and immunotherapeutic targets. Despite this potential, the predominating uncertainty about their functional implication in tumor–host interaction hampers their evaluation as a target for cancer therapy. By means of a highly physiologic, spontaneous tumor model in mice, we establish a causal link between B7-H3 and host tumor control and found B7-H4 to be redundant. Cancer Immunol Res; 3(8); 849–54. ©2015 AACR.

Supplementary Figure Legend

PDF file 128KB, Treg depletion from c-Rel deficient donor T-cells results in exacerbated GVHD

Supplementary Figure 1. Increased B7-H3 and B7-H4 protein expression in murine prostate tumors. Supplementary Figure 2. Higher abundance of neoplastic epithelium in the absence of B7-H3. Supplementary Figure 3. Comparable levels of serum testosterone and AR expression in TRAMP+/- wt and TRAMP+/- B7-H3-/- mice. Supplementary Figure 4. B7-H3 does not influence tumor cell proliferation in a cell-intrinsic manner. Supplementary Figure 5. Immunosuppressive environment in TRAMP+ tumors in the absence of B7-H3. Supplementary Figure 6. B7-H3 does not affect T-cell proliferation or NK or CD8+ T-cell function directly. Supplementary Figure 7. Percentages of FoxP3+ cells in control (brachial) and tumor-draining (periaortic) lymph nodes are the same in TRAMP+wt and TRAMP+B7-H3-/- mice. Supplementary Figure 8. Percentages of NK1.1+, CD8+, CD4+ and CD11c+ cells among TILs in TRAMP+wt and TRAMP+B7-H3-/- mice. Supplementary Figure 9. B7-H3 is expressed by tumor-infiltrating lymphocytes.

PDF file 92K, Table 1. Characteristics of c-Rel inhibitor compounds; Table 2. Roles of c-Rel in T-cell responses and transplantation immunology

PDF file 128KB, c-Rel-deficient T-cells are polarized towards Th2 responses during GVHD