The sex-specific factor SOA controls dosage compensation in Anopheles mosquitoes.

The Anopheles mosquito is one of thousands of species in which sex differences play a central part in their biology, as only females need a blood meal to produce eggs. Sex differentiation is regulated by sex chromosomes, but their presence creates a dosage imbalance between males (XY) and females (XX). Dosage compensation (DC) can re-equilibrate the expression of sex chromosomal genes. However, because DC mechanisms have only been fully characterized in a few model organisms, key questions about its evolutionary diversity and functional necessity remain unresolved1. Here we report the discovery of a previously uncharacterized gene (sex chromosome activation (SOA)) as a master regulator of DC in the malaria mosquito Anopheles gambiae. Sex-specific alternative splicing prevents functional SOA protein expression in females. The male isoform encodes a DNA-binding protein that binds the promoters of active X chromosomal genes. Expressing male SOA is sufficient to induce DC in female cells. Male mosquitoes lacking SOA or female mosquitoes ectopically expressing the male isoform exhibit X chromosome misregulation, which is compatible with viability but causes developmental delay. Thus, our molecular analyses of a DC master regulator in a non-model organism elucidates the evolutionary steps that lead to the establishment of a chromosome-specific fine-tuning mechanism.

Exploring in-plane interactions beside an adsorbed molecule with lateral force microscopy.

Atomic force microscopy with a CO-functionalized tip can be used to directly image the internal structure of a planar molecule and to characterize chemical bonds. However, hydrogen atoms usually cannot be directly observed due to their small size. At the same time, these atoms are highly important, since they can direct on-surface chemical reactions. Measuring in-plane interactions at the sides of PTCDA (3,4,9,10-perylenetetracarboxylic dianhydride) molecules with lateral force microscopy allowed us to directly identify hydrogen atoms via their repulsive signature, which we confirmed with a model incorporating radially symmetric atomic interactions. Additional features were observed in the force data and could not be explained by H-bonding of the CO tip with the PTCDA sides. Instead, they are caused by electrostatic interaction of the large dipole of the metal apex, which we verified with density functional theory. This calculation allowed us to estimate the strength of the dipole at the metal tip apex. To further confirm that this dipole generally affects measurements on weakly polarized systems, we investigated the archetypical surface adsorbate of a single CO molecule. We determined the radially symmetric atomic interaction to be valid over a large solid angle of 5.4 sr, corresponding to 82°. We therefore find that in both the PTCDA and CO systems, the underlying interaction preventing direct observations of H-bonding and causing a collapse of the radially symmetric model is the dipole at the metal apex, which plays a significant role when approaching closer than standard imaging heights.

Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS: In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS: A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS: Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.).

A neural network model for the evolution of learning in changing environments.

Learning from past experience is an important adaptation and theoretical models may help to understand its evolution. Many of the existing models study simple phenotypes and do not consider the mechanisms underlying learning while the more complex neural network models often make biologically unrealistic assumptions and rarely consider evolutionary questions. Here, we present a novel way of modelling learning using small neural networks and a simple, biology-inspired learning algorithm. Learning affects only part of the network, and it is governed by the difference between expectations and reality. We use this model to study the evolution of learning under various environmental conditions and different scenarios for the trade-off between exploration (learning) and exploitation (foraging). Efficient learning readily evolves in our individual-based simulations. However, in line with previous studies, the evolution of learning is less likely in relatively constant environments, where genetic adaptation alone can lead to efficient foraging, or in short-lived organisms that cannot afford to spend much of their lifetime on exploration. Once learning does evolve, the characteristics of the learning strategy (i.e. the duration of the learning period and the learning rate) and the average performance after learning are surprisingly little affected by the frequency and/or magnitude of environmental change. In contrast, an organism's lifespan and the distribution of resources in the environment have a clear effect on the evolved learning strategy: a shorter lifespan or a broader resource distribution lead to fewer learning episodes and larger learning rates. Interestingly, a longer learning period does not always lead to better performance, indicating that the evolved neural networks differ in the effectiveness of learning. Overall, however, we show that a biologically inspired, yet relatively simple, learning mechanism can evolve to lead to an efficient adaptation in a changing environment.

Women and Men are the Barometers of Relationships: Testing the Predictive Power of Women's and Men's Relationship Satisfaction.

There is a longstanding belief in relationship science and popular opinion that women are the barometers in mixed-gender relationships such that their perceptions about the partnership carry more weight than men's in predicting future relationship satisfaction, but this idea has yet to be rigorously tested. We analyze data from two studies to test within-person links between men's and women's relationship satisfaction on their own and their partner's next-day and next-year satisfaction. Study 1 combined nine daily diary datasets from Canada and the United States with 901 mixed-gender couples who provided 29,541 daily reports of relationship satisfaction. Study 2 analyzed five annual waves of data from the German Family Panel (pairfam) that surveyed 3,405 mixed-gender couples who provided 21,115 relationship satisfaction reports. Latent curve models with structured residuals (LCM-SR) revealed that in both studies, men's and women's relationship satisfaction significantly predicted their own and their partner's relationship satisfaction, with no gender differences in the magnitude of these effects. Results underscore the interdependence of romantic partners' satisfaction and indicate that both men and women jointly shape romantic relationship satisfaction.

[68Ga]Ga-FAPI-46 PET/CT for penile cancer - a feasibility study.

PURPOSE: Penile cancer is a rare entity and has a good prognosis in localized stage. Delayed surgical treatment of lymphatic disease is associated with poor overall survival but conventional imaging cannot detect occult lymph node metastasis sufficiently. Imaging cancer related fibroblasts has shown promising results as non-invasive staging tool in various tumor entities but has not yet been evaluated in penile cancer. METHODS: In this single-center pilot study, patients planned for surgical treatment for penile cancer underwent preoperatively [68Ga]Ga-FAPI-46 PET/CT. Post-operative histopathology was compared to [68Ga]Ga-FAPI-46 PET/CT results. RESULTS: From January 2022 to June 2022, a total number 11 patients with histopathologically proven penile cancer underwent surgery and received [68Ga]Ga-FAPI-46 PET/CT prior therapy. 8 primary tumor sites and 4 lymph node regions were analyzed. FAPI uptake was increased on primary tumor site (SUVmax 16.2 (9.1 - 25.8)). Histopathological proven lymph node regions showed highly increased FAPI uptakes (SUVmax 17.9 (16.4 - 23.5) on [68Ga]Ga-FAPI-46 PET/CT. CONCLUSION: In this first pilot cohort, there were no false-positive FAPI uptake which might allow the detection of occult lymph node metastasis by [68Ga]Ga-FAPI-46 PET/CT and might consequently lead to omitting lymph node regions during surgery that had no increased FAPI uptake pre-operatively.

Dismal prognosis of Pneumocystis jirovecii pneumonia in patients with multiple myeloma.

Patients with multiple myeloma (MM) are at high risk for infections, including opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP). We conducted a retrospective analysis of patients with MM developing PJP over a 6-year period between January 2016 and December 2021 at the University Hospital of Würzburg by screening cases of microbiologically documented PJP. A total of 201 positive results for P. jirovecii in respiratory specimens were retrospectively retrieved through our microbiology database. Of these cases, 13 patients with MM fulfilled the definition of probable PJP according to EORTC fungal disease definitions. We observed two peaks in PJP incidence, one after stem cell transplantation during first-line treatment (n = 5) and the other in heavily pretreated patients with six or more prior lines of therapy (n = 6). There was high morbidity with nine (69%) patients admitted to the ICU, seven of whom (78%) required mechanical ventilation, and high mortality (62%, n = 8). Notably, only two of the 13 patients (15%) had received PJP prophylaxis. The main reason for discontinuation of prophylaxis with trimethoprim-sulfamethoxazole was grade IV neutropenia. The observed morbidity and mortality of PJP in MM patients are significant and even higher than reported for patients with other hematologic malignancies. According to most current guidelines, the use of prophylaxis would have been clearly recommended in no more than three (23%) of the 13 patients. This illustrates the need to critically reconsider the indications for PJP prophylaxis, which remain incompletely defined.

Augmentation of keratinized tissue using autogenous soft-tissue grafts and collagen-based soft-tissue substitutes at teeth and dental implants: Histological findings in a pilot pre-clinical study.

AIM: To histomorphometrically assess three treatment modalities for gaining keratinized tissue (KT) at teeth and at dental implants. MATERIALS AND METHODS: In five dogs, the distal roots of the mandibular second, third and fourth premolars were extracted. Dental implants were placed at the distal root areas 2 months later. After another 2 months, KT augmentation was performed at both distal (implants) and at mesial root (teeth) areas in the presence (wKT groups) or absence (w/oKT groups) of a KT band at the mucosal/gingival level. Three treatment modalities were applied randomly: apically positioned flap only (APF), free gingival grafts (FGGs) and xenogeneic collagen matrices (XCMs). A combination of the above produced six groups. Two months later, tissue sections were harvested and analysed histomorphometrically. RESULTS: The median KT height and length were greatest at implants with FGG in both wKT (3.7 and 5.1 mm, respectively) and w/oKT groups (3.7 and 4.6 mm), and at teeth with FGG in wKT groups (3.7 and 6.1 mm) and with APF in the w/oKT groups (3.9 and 4.4 mm). The XCM and APF produced more favourable results at teeth than at implants. CONCLUSIONS: FGG was advantageous in gaining KT, especially at implants.

Enhancing guided bone regeneration with cross-linked collagen-conjugated xenogeneic bone blocks and membrane fixation: A preclinical in vivo study.

OBJECTIVE: To determine whether combining cross-linked (CL) collagen-integrated xenogeneic bone blocks stabilized with the fixation of resorbable collagen membranes (CM) can enhance guided bone regeneration (GBR) in the overaugmented calvarial defect model. MATERIALS AND METHODS: Four circular defects with a diameter of 8 mm were prepared in the calvarium of 13 rabbits. Defects were randomly assigned to receive one of the following treatments: (i) non-cross-linked (NCL) porcine-derived collagen-embedded bone block covered by a CM without fixation (NCL + unfix group); (ii) NCL bone block covered by CM with fixation using bone-tack (NCL + fix group); (iii) cross-linked (CL) porcine-derived collagen-embedded bone block covered by CM without fixation (CL + unfix group); and (iv) CL bone block covered by CM with fixation using bone-tack fixation (CL + fix group). The efficacy of GBR was assessed through histological and molecular analyses after 2 and 8 weeks. RESULTS: At 2 weeks, there were no significant differences in histologically measured areas of newly formed bone among the groups. At 8 weeks, however, the CL + fix group exhibited a larger area of new bone (5.08 ± 1.09 mm2, mean ± standard deviation) compared to the NCL + unfix (1.62 ± 0.42 mm2; p < .0083), NCL + fix (3.97 ± 1.39 mm2) and CL + unfix (2.55 ± 1.04 mm2) groups. Additionally, the expression levels of tumour necrosis factor-alpha, fibroblast growth factor-2, vascular endothelial growth factor, osteocalcin and calcitonin receptor were significantly higher in the CL + fix group compared to the other three groups (p < .0083). CONCLUSION: Cross-linked bone blocks stabilized with collagen membrane fixation can significantly enhance GBR.

Correction procedure for a tomographic optical setup employing imaging fiber bundles and intensified cameras.

For reliable tomographic measurements the underlying 2D images from different viewing angles must be matched in terms of signal detection characteristics. Non-linearity effects introduced by intensified cameras and spatial intensity variations induced from inhomogeneous transmission of the optical setup can lead, if not corrected, to a biased tomographic reconstruction result. This paper presents a complete correction procedure consisting of a combination of a non-linearity and flatfield correction for a tomographic optical setup employing imaging fiber bundles and four intensified cameras. Influencing parameters on the camera non-linearity are investigated and discussed. The correction procedure is applied to 3D temperature measurements by two-color pyrometry and compared to results without correction. The present paper may serve as a guideline for an appropriate correction procedure for any type of measurement involving optical tomography and intensified cameras.

Scavenger-induced scattering of wild boar carcasses over large distances and its implications for disease management.

Vertebrate scavengers provide essential ecosystem services such as accelerating carrion decomposition by consuming carcasses, exposing tissues to microbial and invertebrate decomposers, and recycling nutrients back into the ecosystem. Some scavengers do not consume carcasses on site but rather scatter their remains in the surroundings, which might have important implications for nutrient transport, forensic investigations and the spread of diseases such as African Swine Fever. However, only a few studies have investigated and measured the scatter distances. Using wild boar (Sus scrofa) carcasses and limbs, we monitored scavenging behavior and measured scatter distances of mammals. We placed 20 carcasses (up to 25 kg) and 21 separate limbs equipped with very high frequency (VHF) transmitters and monitored scavenger activity using camera traps in a mountainous region in southeast Germany. Except for one carcass, all other carcasses and limbs were scattered. We measured 72 scatter distances (of 89 scattering events; mean = 232 m, maximum = 1250 m), of which 75% were dispersed up to 407 m. Scavengers moved scattered pieces into denser vegetation compared to the half-open vegetation at provisioning sites. Red foxes (Vulpes vulpes) were the most common scavenger species, contributing to 72 scattering events (58 measured scatter distances). Our results provide evidence of scatter distances farther than previously assumed and have far-reaching implications for disease management or forensic investigations, as the broader surroundings of carcasses must be included in search efforts to remove infectious material or relevant body parts for forensic analysis.

Immediate loading of definitive restorations in partially edentulous patients requiring an implant-supported prosthesis: A scoping review.

STATEMENT OF PROBLEM: Interest is growing in immediately loading definitive implant-supported prostheses. However, it appears that implant protocols are evolving faster than their scientific validation. PURPOSE: The purpose of this scoping review was to identify the current trends, feasibility, and clinical outcomes of a specific clinical loading scenario (type A), where a single definitive implant-retained restoration is delivered within 3 days. The focus question was "In partially edentulous patients requiring an implant-retained prosthesis (population), is immediate loading with a definitive restoration (concept) a viable treatment option (context)?" MATERIAL AND METHODS: An electronic search was conducted in the PubMed, CENTRAL, Scopus, Embase, and Web of Science databases. Two authors independently reviewed the studies, screened titles and abstracts, and performed full-text analysis. Cross-reference checks within the bibliography of included studies, relevant reviews, and guideline were conducted. Bibliometric information and study details were extracted. RESULTS: The search identified 2568 titles after removing duplicates. Four studies involving 91 participant and 100 implant-retained restorations were included in this scoping review. The selected articles were a randomized controlled trial (RCT), a prospective clinical study, and the remaining 2 were case series. The follow-up periods investigated ranged from 6 to 26 months. All studies evaluated marginal bone loss as a primary outcome, and only 1 implant failure was reported. Patient-reported outcome measures were favorable, and no major biological or technical complications were reported in any study. CONCLUSIONS: Immediate loading with a definitive restoration within 3 days appears to be a suitable approach in specific clinical situations.

A consumer cross-over trial suggests that there are significant seasonal changes of the tensile properties (wet) of human hair.

OBJECTIVES: Through the cooperation with an industrial partner, we gained a set of data for the tensile properties (wet) of human hair. The hair samples originated from a cross-over study with two groups of individuals, using for a topical application sequentially two products (A and B). Each phase of the study lasted 6 months. The phases of the study by chance covered first largely the winter and then the summer period. Initially, tensile variables were chosen, which not only reflect the mechanical properties of hair (modulus, break strain, and break stress) but which are also considered to have a good connection to practice-relevant hair properties. The initial analysis of the data showed that changes were observed for the variables due to the treatment phases. However, these were either small or difficult to interpret. METHODS: Against this background and using two-factor analysis of variance, we investigated the hypothesis that the tensile properties of hair (wet) may show significant seasonal changes. For this, we chose those two independent variables, which reflect the properties of the intermediate filaments (modulus) and the matrix (break strain) in the composite structure of the hair cortex. RESULTS: The results support the 'seasonal' hypothesis and clearly show that the variables show significant changes from Winter to Summer (modulus: 10% increase; break strain: 3% decrease). The seasonal effect was thus a major reason, why the first stage of the analysis of the data was inconclusive. CONCLUSIONS: The tensile properties of the main morphological components of the cortex show distinct seasonal changes. Towards the summer, the hair becomes stiffer and more brittle. Furthermore, the results suggest that seasonal effects may need to be taken into account when conducting studies on lengths of hair grown during different seasons.

OBJECTIFS: Grâce à la coopération avec un partenaire industriel, nous avons obtenu un ensemble de données sur les propriétés de traction des cheveux (humides) humains. Les échantillons de cheveux provenaient d'une étude croisée avec deux groupes de personnes, utilisant pour une application topique deux produits (A et B) de manière séquentielle. Chaque phase de l'étude a duré 6 mois. Les phases de l'étude ont principalement couvert l'hiver, puis l'été. Initialement les variables de traction ont été choisies reflètent non seulement les propriétés mécaniques des cheveux (modulus, extension de rupture et stress de rupture), mais sont également considérées comme ayant un lien étroit avec les propriétés pertinentes des cheveux. L'analyse initiale des données a montré que des changements ont été observés pour les variables en raison des phases de traitement. Cependant, ils étaient faibles ou difficiles à interpréter. MÉTHODES: Dans ce contexte et à l'aide d'une analyse de variance à deux facteurs, nous avons étudié l'hypothèse selon laquelle les propriétés de traction des cheveux (humides) pourraient montrer des changements saisonniers significatifs. Pour cela, nous avons choisi ces deux variables indépendantes, qui reflètent les propriétés des filaments intermédiaires (modulus) et de la matrice (extension de rupture) dans la structure composite du cortex capillaire. RÉSULTATS: Les résultats appuient l'hypothèse « saisonnière ¼ et indiquent clairement que les variables montrent des évolutions significatives de l'hiver à l'été (modulus : augmentation de 10 % ; extension de rupture : diminution de 3 %). L'effet saisonnier était donc une raison majeure pour laquelle la première étape de l'analyse des données n'a pas été concluante. CONCLUSIONS: Les propriétés de traction des principaux composants morphologiques du cortex montrent des changements saisonniers distincts. Vers l'été, les cheveux deviennent plus raides et plus cassants. En outre, les résultats indiquent que les effets saisonniers devrait être pris en compte lors de la réalisation d'études sur les longueurs des cheveux ayant poussé à différentes saisons.

Use of optical see-through head-mounted devices in dentistry - a scoping review.

AIM: The aim of this scoping review was to identify the scientific evidence related to the utilization of Optical See- Through Head-Mounted Display (OST-HMD) in dentistry, and to determine future research needs. METHODS: The research question was formulated using the "Population" (P), "Concept" (Cpt), and "Context" (Cxt) framework for scoping reviews. Existing literature was designated as P, OST-HMD as Cpt, and Dentistry as Cxt. An electronic search was conducted in PubMed, Embase, Web of Science, and CENTRAL. Two authors independently screened titles and abstracts and performed the full-text analysis. RESULTS: The search identified 286 titles after removing duplicates. Nine studies, involving 138 participants and 1760 performed tests were included in this scoping review. Seven of the articles were preclinical studies, one was a survey, and one was a clinical trial. The included manuscripts covered various dental fields: three studies in orthodontics, two in oral surgery, two in conservative dentistry, one in general dentistry, and the remaining one in prosthodontics. Five articles focused on educational purposes. Two brands of OST-HMD were used: in eight studies HoloLens Microsoft was used, while Google Glass was utilized in one article. CONCLUSIONS: The overall number of included studies was low; therefore, the available data from this review cannot yet support an evidence-based recommendation for the clinical use of OST-HMDs. However, the existing preclinical data indicate a significant capacity for clinical and educational implementation. Further adoption of these devices will facilitate more reliable and objective quality and performance assessments, as well as more direct comparisons with conventional workflows. More clinical studies must be conducted to substantiate the potential benefits and reliability for patients and clinicians.

The Joint Evolution of Animal Movement and Competition Strategies.

AbstractCompetition typically takes place in a spatial context, but eco-evolutionary models rarely address the joint evolution of movement and competition strategies. Here we investigate a spatially explicit forager-kleptoparasite model where consumers can either forage on a heterogeneous resource landscape or steal resource items from conspecifics (kleptoparasitism). We consider three scenarios: (1) foragers without kleptoparasites, (2) consumers specializing as foragers or as kleptoparasites, and (3) consumers that can switch between foraging and kleptoparasitism depending on local conditions. We model movement strategies as individual-specific combinations of preferences for environmental cues, similar to step-selection coefficients. Using mechanistic, individual-based simulations, we study the joint evolution of movement and competition strategies, and we investigate the implications for the distribution of consumers over this landscape. Movement and competition strategies evolve rapidly and consistently across scenarios, with marked differences among scenarios, leading to differences in resource exploitation patterns. In scenario 1, foragers evolve considerable individual variation in movement strategies, while in scenario 2, movement strategies show a swift divergence between foragers and kleptoparasites. In scenario 3, where individuals' competition strategies are conditional on local cues, movement strategies facilitate kleptoparasitism, and individual consistency in competition strategy also emerges. Even in the absence of kleptoparasitism (scenario 1), the distribution of consumers deviates considerably from predictions of ideal free distribution models because of the intrinsic difficulty of moving effectively on a depleted resource landscape with few reliable cues. Our study emphasizes the advantages of a mechanistic approach when studying competition in a spatial context and suggests how evolutionary modeling can be integrated with current work in animal movement ecology.

Assortative Mating in an Ecological Context: Effects of Mate Choice Errors and Relative Species Abundance on the Frequency and Asymmetry of Hybridization.

AbstractThe frequency and asymmetry of mixed-species mating set the initial stage for the ecological and evolutionary implications of hybridization. How such patterns of mixed-species mating, in turn, are influenced by the combination of mate choice errors and relative species abundance remains largely unknown. We develop a mathematical model that generates predictions for how relative species abundances and mate choice errors affect hybridization patterns. When mate choice errors are small (<5%), the highest frequency of hybridization occurs when one of the hybridizing species is at low abundance, but when mate choice errors are high (>5%), the highest hybridization frequency occurs when species occur in equal proportions. Furthermore, females of the less abundant species are overrepresented in mixed-species matings. We compare our theoretical predictions with empirical data on naturally hybridizing Ficedula flycatchers and find that hybridization is highest when the two species occur in equal abundance, implying rather high mate choice errors. We discuss ecological and evolutionary implications of our findings and encourage future work on hybrid zone dynamics that take demographic aspects, such as relative species abundance, into account.

Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis. METHODS: We conducted a 12-week, randomized, double-blind, phase 2 trial of nemolizumab (at a dose of 0.5 mg per kilogram of body weight) administered subcutaneously at baseline, week 4, and week 8, as compared with placebo, in patients with moderate-to-severe prurigo nodularis and severe pruritus. Moderate-to-severe prurigo nodularis was defined as 20 or more nodules, and severe pruritus was defined as a mean score of at least 7 for the worst daily intensity of pruritus on the numerical rating scale (scores range from 0 [no itch] to 10 [worst itch imaginable]). The primary outcome was the percent change from baseline in the mean peak score for pruritus on the numerical rating scale at week 4. Secondary outcomes included additional measures of itching and disease severity. Safety assessments were performed through week 18. RESULTS: A total of 70 patients were randomly assigned in a 1:1 ratio to receive nemolizumab (34 patients) or placebo (36). The initial pruritus score on the numerical rating scale was 8.4 in each group. At week 4, the peak pruritus score on the numerical rating scale was reduced from baseline by 4.5 points (change, -53.0%) in the nemolizumab group, as compared with a reduction of 1.7 points (change, -20.2%) in the placebo group (difference, -32.8 percentage points; 95% confidence interval, -46.8 to -18.8; P<0.001). Results for secondary outcomes were in the same direction as for the primary outcome. Nemolizumab was associated with gastrointestinal symptoms (abdominal pain and diarrhea) and musculoskeletal symptoms. CONCLUSIONS: Nemolizumab resulted in a greater reduction in pruritus and severity of skin lesions than placebo in patients with prurigo nodularis but was associated with adverse events. Larger and longer trials are needed to determine the durability and safety of nemolizumab for the treatment of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT03181503.).

Classical Surrogates for Quantum Learning Models.

The advent of noisy intermediate-scale quantum computers has put the search for possible applications to the forefront of quantum information science. One area where hopes for an advantage through near-term quantum computers are high is quantum machine learning, where variational quantum learning models based on parametrized quantum circuits are discussed. In this work, we introduce the concept of a classical surrogate, a classical model which can be efficiently obtained from a trained quantum learning model and reproduces its input-output relations. As inference can be performed classically, the existence of a classical surrogate greatly enhances the applicability of a quantum learning strategy. However, the classical surrogate also challenges possible advantages of quantum schemes. As it is possible to directly optimize the Ansatz of the classical surrogate, they create a natural benchmark the quantum model has to outperform. We show that large classes of well-analyzed reuploading models have a classical surrogate. We conducted numerical experiments and found that these quantum models show no advantage in performance or trainability in the problems we analyze. This leaves only generalization capability as a possible point of quantum advantage and emphasizes the dire need for a better understanding of inductive biases of quantum learning models.

Dynamic Friction Unraveled by Observing an Unexpected Intermediate State in Controlled Molecular Manipulation.

The pervasive phenomenon of friction has been studied at the nanoscale via a controlled manipulation of single atoms and molecules with a metallic tip, which enabled a precise determination of the static friction force necessary to initiate motion. However, little is known about the atomic dynamics during manipulation. Here, we reveal the complete manipulation process of a CO molecule on a Cu(110) surface at low temperatures using a combination of noncontact atomic force microscopy and density functional theory simulations. We found that an intermediate state, inaccessible for the far-tip position, is enabled in the reaction pathway for the close-tip position, which is crucial to understanding the manipulation process, including dynamic friction. Our results show how friction forces can be controlled and optimized, facilitating new fundamental insights for tribology.

Venous waveform analysis detects acute right ventricular failure in a rat respiratory arrest model.

BACKGROUND: Peripheral intravenous analysis (PIVA) has been shown to be more sensitive than central venous pressure (CVP) for detecting hemorrhage and volume overload. We hypothesized that PIVA is superior to CVP for detecting right ventricular (RV) failure in a rat model of respiratory arrest. METHODS: Eight Wistar rats were studied in accordance with the ARRIVE guidelines. CVP, mean arterial pressure (MAP), and PIVA were recorded. Respiratory arrest was achieved with IV Rocuronium. PIVA utilizes Fourier transform to quantify the amplitude of the peripheral venous waveform, expressed as the "f1 amplitude". RV diameter was measured with transthoracic echocardiography. RESULTS: RV diameter increased from 0.34 to 0.54 cm during arrest, p = 0.001, and returned to 0.33 cm post arrest, p = 0.97. There was an increase in f1 amplitude from 0.07 to 0.38 mmHg, p = 0.01 and returned to 0.08 mmHg, p = 1.0. MAP decreased from 119 to 67 mmHg, p = 0.004 and returned to 136 mmHg, p = 0.50. There was no significant increase in CVP from 9.3 mmHg at baseline to 10.5 mmHg during respiratory arrest, p = 0.91, and recovery to 8.6 mmHg, p = 0.81. CONCLUSIONS: This study highlights the utility of PIVA to detect RV failure in small-caliber vessels, comparable to peripheral veins in the human pediatric population. IMPACT: Right ventricular failure remains a diagnostic challenge, particularly in pediatric patients with small vessel sizes limiting invasive intravascular monitor use. Intravenous analysis has shown promise in detecting hypovolemia and volume overload. Intravenous analysis successfully detects right ventricular failure in a rat respiratory arrest model. Intravenous analysis showed utility despite utilizing small peripheral venous access and therefore may be applicable to a pediatric population. Intravenous analysis may be helpful in differentiating various types of shock.