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When mammalian spermatozoa are released in the female reproductive tract, they are incapable of fertilizing the oocyte. They need a prolonged exposure to the alkaline medium of the female genital tract before their flagellum gets hyperactivated and the acrosome reaction can take place, allowing the sperm to interact with the oocyte. Ionic fluxes across the sperm membrane are involved in two essential aspects of capacitation: the increase in intracellular pH and the membrane hyperpolarization. In particular, it has been shown that the SLO3 potassium channel and the sNHE sodium-proton exchanger, two sperm-specific transmembrane proteins, are necessary for the capacitation process to occur. As the SLO3 channel is activated by an increase in intracellular pH and sNHE is activated by hyperpolarization, they act together as a positive feedback system. Mathematical modeling provides a unique tool to capture the essence of a molecular mechanism and can be used to derive insight from the existing data. We have therefore developed a theoretical model formalizing the positive feedback loop between SLO3 and sHNE in mouse epididymal sperm to see if this non-linear interaction can provide the core mechanism explaining the existence of uncapacited and capacitated states. We show that the proposed model can fully explain the switch between the uncapacitated and capacited states and also predicts the existence of a bistable behaviour. Furthermore, our model indicates that SLO3 inhibition, above a certain threshold, can be effective to completely abolish capacitation.

Alzheimer’s disease is characterized by a marked dysregulation of intracellular Ca2+ homeostasis. In particular, toxic β-amyloids (Aβ) perturb the activities of numerous Ca2+ transporters or channels. Because of the tight coupling between Ca2+ dynamics and the membrane electrical activity, such perturbations are also expected to affect neuronal excitability. We used mathematical modeling to systematically investigate the effects of changing the activities of the various targets of Aβ peptides reported in the literature on calcium dynamics and neuronal excitability. We found that the evolution of Ca2+ concentration just below the plasma membrane is regulated by the exchanges with the extracellular medium, and is practically independent from the Ca2+ exchanges with the endoplasmic reticulum. Thus, disruptions of Ca2+ homeostasis interfering with signaling do not affect the electrical properties of the neurons at the single cell level. In contrast, the model predicts that by affecting the activities of L-type Ca2+ channels or Ca2+-activated K+ channels, Aβ peptides promote neuronal hyperexcitability. On the contrary, they induce hypo-excitability when acting on the plasma membrane Ca2+ ATPases. Finally, the presence of pores of amyloids in the plasma membrane can induce hypo- or hyperexcitability, depending on the conditions. These modeling conclusions should help with analyzing experimental observations in which Aβ peptides interfere at several levels with Ca2+ signaling and neuronal activity.

The cerebellar pathologies in peroxisomal diseases underscore that these organelles are required for the normal development and maintenance of the cerebellum, but the mechanisms have not been resolved.Here we investigated the origins of the early-onset coordination impairment in a mouse model with neural selective deficiency of multifunctional protein-2, the central enzyme of peroxisomal β-oxidation. At the age of 4 weeks, Nestin-Mfp2−/− mice showed impaired motor learning on the accelerating rotarod and underperformed on the balance beam test. The gross morphology of the cerebellum and Purkinje cell arborization were normal. However, electrophysiology revealed a reduced Purkinje cell firing rate, a decreased excitability and an increased membrane capacitance. The distribution of climbing and parallel fiber synapses on Purkinje cells was immature and was accompanied by an increased spine length. Despite normal myelination, Purkinje cell axon degeneration was evident from the occurrence of axonal swellings containing accumulated organelles. In conclusion, the electrical activity, axonal integrity and wiring of Purkinje cells are exquisitely dependent on intact peroxisomal β-oxidation in neural cells.

Glycine receptors (GlyRs) containing the α2 subunit are highly expressed in the developing brain, where they regulate neuronal migration and maturation, promote spontaneous network activity and subsequent development of synaptic connections. Mutations in GLRA2 are associated with autism spectrum disorder, but the underlying pathophysiology is not described yet. Here, using Glra2-knockout mice, we found a GlyR-dependent effect on neonatal spontaneous activity of dorsal striatum medium spiny neurons (MSNs) and maturation of the incoming glutamatergic innervation. Our data demonstrate that functional GlyRs are highly expressed in MSNs of one-week-old mice, but they do not generate endogenous chloride-mediated tonic or phasic current. Despite of that, knocking out the Glra2 severely affects the shape of action potentials and impairs spontaneous activity and the frequency of miniature AMPA receptor-mediated currents in MSNs. This reduction in spontaneous activity and glutamatergic signaling can attribute to the observed changes in neonatal behavioral phenotypes as seen in ultrasonic vocalizations and righting reflex. In adult Glra2-knockout animals, the glutamatergic synapses in MSNs remain functionally underdeveloped. The number of glutamatergic synapses and release probability at presynaptic site remain unaffected, but the amount of postsynaptic AMPA receptors is decreased. This deficit is a consequence of impaired development of the neuronal circuitry since acute inhibition of GlyRs by strychnine in adult MSNs does not affect the properties of glutamatergic synapses. Altogether, these results demonstrate that GlyR-mediated signaling supports neonatal spontaneous MSN activity and, in consequence, promotes the functional maturation of glutamatergic synapses on MSNs. The described mechanism might shed light on the pathophysiological mechanisms in GLRA2-linked autism spectrum disorder cases.

Medium spiny neurons (MSNs) of the dorsal striatum represent the first relay of cortico–striato–thalamic loop, responsible for the initiation of voluntary movements and motor learning. GABAergic transmission exerts the main inhibitory control of MSNs. However, MSNs also express chloride-permeable glycine receptors (GlyRs) although their subunit composition and functional significance in the striatum is unknown. Here, we studied the function of GlyRs in MSNs of young adult mice. We show that MSNs express functional GlyRs, with α2 being the main agonist binding subunit. These receptors are extrasynaptic and depolarizing at resting state. The pharmacological inhibition of GlyRs, as well as inactivation of the GlyR α2 subunit gene hyperpolarize the membrane potential of MSNs and increase their action potential firing offset. Mice lacking GlyR α2 showed impaired motor memory consolidation without any changes in the initial motor performance. Taken together, these results demonstrate that tonically active GlyRs regulate the firing properties of MSNs and may thus affect the function of basal ganglia.

SUMMARY Friedreich’s ataxia (FRDA) is a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy. FRDA is due to expanded GAA repeats within the first intron of the gene encoding frataxin, a conserved mitochondrial protein involved in iron-sulphur cluster biosynthesis. This mutation leads to partial gene silencing and substantial reduction of the frataxin level. To overcome limitations of current cellular models of FRDA, we derived induced pluripotent stem cells (iPSCs) from two FRDA patients and successfully differentiated them into neurons and cardiomyocytes, two affected cell types in FRDA. All FRDA iPSC lines displayed expanded GAA alleles prone to high instability and decreased levels of frataxin, but no biochemical phenotype was observed. Interestingly, both FRDA iPSC-derived neurons and cardiomyocytes exhibited signs of impaired mitochondrial function, with decreased mitochondrial membrane potential and progressive mitochondrial degeneration, respectively. Our data show for the first time that FRDA iPSCs and their neuronal and cardiac derivatives represent promising models for the study of mitochondrial damage and GAA expansion instability in FRDA.

In the present study, we aimed to determine the time-course of neurochemical changes occurring following metabolic impairments produced by 3-nitropropionic (3NP) acid in a rat model of Huntington's disease. We found that the occurrence of striatal lesions was accompanied by (1) strong transcriptional alterations within the degenerative lateral striatum, (2) receptor upregulations within the preserved medial striatum, and (3) transcriptional increases within the unaltered cerebral cortex. These phenomena were preceded by transcriptional modifications in striatal subareas prone to degeneration even before the lesion was visible but not in the overlying cortex, known to be spared in this model. Of great interest, the density of A2A receptor binding sites, located on striato-pallidal neurons, was (1) downregulated at the time of worsening of symptoms and (2) strongly upregulated within the spared medial striatum after the lesion occurrence. This study therefore highlights the differential neurochemical responses produced by 3NP depending on the fate of the metabolically inhibited area and strongly suggests the involvement of A2A receptors in the development of striatal pathology under metabolic compromise.

Understanding the electrical biophysical properties of the cell membrane can be difficult for neuroscience students as it relies solely on lectures of theoretical models without practical hands on experiments. To address this issue, we developed an open-source lipid bilayer amplifier, the OpenPicoAmp, which is appropriate for use in introductory courses in biophysics or neurosciences at the undergraduate level, dealing with the electrical properties of the cell membrane. The amplifier is designed using the common lithographic printed circuit board fabrication process and off-the-shelf electronic components. In addition, we propose a specific design for experimental chambers allowing the insertion of a commercially available polytetrafluoroethylene film. We provide a complete documentation allowing to build the amplifier and the experimental chamber. The students hand-out giving step-by step instructions to perform a recording is also included. Our experimental setup can be used in basic experiments in which students monitor the bilayer formation by capacitance measurement and record unitary currents produced by ionic channels like gramicidin A dimers. Used in combination with a low-cost data acquisition board this system provides a complete solution for hands-on lessons, therefore improving the effectiveness in teaching basic neurosciences or biophysics.

The striatum is the major input structure of basal ganglia and is involved in adaptive control of behaviour through the selection of relevant informations. Dopaminergic neurons that innervate striatum die in Parkinson disease, leading to inefficient adaptive behaviour. Neuronal activity of striatal medium spiny neurons (MSN) is modulated by dopamine receptors. Although dopamine signalling had received substantial attention, consequences of dopamine depletion on MSN intrinsic excitability remain unclear. Here we show, by performing perforated patch clamp recordings on brain slices, that dopamine depletion leads to an increase in MSN intrinsic excitability through the decrease of an inactivating A-type potassium current, I(A). Despite the large decrease in their excitatory synaptic inputs determined by the decreased dendritic spines density and the increase in minimal current to evoke the first EPSP, this increase in intrinsic excitability resulted in an enhanced responsiveness to their remaining synapses, allowing them to fire similarly or more efficiently following input stimulation than in control condition. Therefore, this increase in intrinsic excitability through the regulation of I(A) represents a form of homeostatic plasticity allowing neurons to compensate for perturbations in synaptic transmission and to promote stability in firing. The present observations show that this homeostatic ability to maintain firing rates within functional range also occurs in pathological conditions, allowing stabilizing neural computation within affected neuronal networks.

Abstract Background Finding effective and curative treatment for mesothelioma remains challenging. While the introduction of immunotherapy combinations using ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have offered hope for some patients, a large proportion of mesothelioma cases, particularly the epithelial subtype, have minimal benefit from this. Methods Our study was inspired by the results of the AdvanTG-105 phase I clinical trial, which showed partial response with anti-TIGIT/PD-1 treatment in two epithelioid mesothelioma patients. Here, we conducted a comprehensive in vivo experiment involving eight animal treatment groups administered with either PBS (control group), cisplatin/pemetrexed, anti-PD-1, anti-PD-1 + anti-CTLA-4, anti-TIGIT, anti-PD-1 + anti-TIGIT, anti-PD-1 + anti-CTLA-4 + anti-TIGIT, and cisplatin/pemetrexed + anti-PD-1 + anti-TIGIT. Results Our results indicate that animals receiving anti-PD-1 + TIGIT exhibited a superior anti-tumour response, with 90% of the treatment group exhibiting an objective response, compared to 60%, 20% and 40% for the standard-of-care anti-PD-1 + CTLA-4, single-agent anti-PD-1 and cisplatin/pemetrexed treatment groups, respectively. Animals receiving anti-PD-1 + TIGIT displayed a significantly reduced average tumour size, with improved weight and survival rates, and fewer adverse effects than those receiving anti-PD-1 + CTLA-4 treatment. Anti-PD-1 + TIGIT-treated animals achieved complete tumour regression, with heightened effector CD8 + T cell and NK cell activity, remaining tumour-free for over 300 days without immune-related adverse events. After initial tumour elimination, anti-PD-1 + TIGIT-treated animals showed no tumour regrowth in the rechallenge experiment. Conclusion These findings provide rationale for the development of an anti-PD-1 + TIGIT combination immunotherapy trial for mesothelioma patients. Graphical Abstract Top) The comparison of standard-of-care treatment and anti-TIGIT novel combination treatment in the mesothelioma animal models, with an example of response treated with tislelizumab and ociperlimab in a pleural mesothelioma patient in the AdvanTIG-105 study. The number of animals/patients treated and the number of treatment responders are presented. Bottom) Schematic illustration of anti-tumour immune response at the cellular level induced by anti-PD-1/TIGIT checkpoint blockade for efficient cancer immunotherapy.

Abstract Natural killer (NK) cells recognize and may kill malignant cells via their cell surface receptors. Killer cell immunoglobulin-like receptor (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 1,638 genetic polymorphisms in 21 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Eleven polymorphisms regulating or located in CD226, CD244, FCGR3A, KLRD1, NCR3, and PVRIG were associated with the risks for relapse and GVHD. These associations could not be confirmed in the replication cohort. Blood donor NK cells carrying alleles showing genetic protection for relapse had a higher in vitro NK cell killing activity than non-carriers whereas those with alleles genetically protective for GVHD had lower cytotoxicity, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in the tested non-KIR NK cell receptors on the outcome of HSCT.

Background: We aim to ascertain prognostic factors in the current management of anal cancer within this study. Methods: We reviewed the management and outcomes of anal cancer cases over a seven-year period, inclusive (2016–2023). The primary objectives were to assess the demographic characteristics, clinical presentation, and outcomes of all anal cancer patients within our institution. Kaplan–Meier survival analysis was used to estimate survival differences between cohorts, with statistical significance determined using log-rank testing. Cox proportional hazards regression was utilised to identify prognostic factors. Cox regression hazard ratios were reported along with confidence intervals and p-values. Results: The median follow-up time for the study was 29.8 months. Seventy-five patients with anal cancer were included in this study, with 88% (66/75) being squamous cell carcinoma (SCC) and the majority having regional disease (82.7% (62/75)). The median age at diagnosis was 63.4 years (36–94). There was a female preponderance (57.3% (43/75)). In total, 84% (63/75) underwent definitive chemoradiation (dCRT), with 7/63 (11.1%) requiring a salvage abdomino-perineal resection (APR) for residual or recurrent disease. Adverse prognostic indicators include those with T4 disease hazard ratio = 3.81, (95% CI 1.13–12.83, * p = 0.04), poorly differentiated tumour disease HR = 3.37, (95% CI 1.13–10.02, * p = 0.04), having N2 nodal status HR = 5.03, (95% CI 1.11–22.8, * p = 0.04), and having metastatic disease at diagnosis HR = 5.8, (95% CI 1.28–26.42, * p = 0.02). Conclusion: Presenting characteristics including stage, nodal, and differentiation status remain key prognostic indicators in those diagnosed with anal malignancy.

El conflicto sucesorio que se originó en el reinado de Pedro I (1350) siguió, a grandes rasgos, los usos de la guerra plenomedieval. No obstante, conforme se fue recrudeciendo el conflicto, su desarrollo se extendió hasta convertirse en un escenario más de la Guerra de los Cien Años. El desarrollo de la disputa se centró, principalmente, en el control de las plazas, principalmente por asedios o golpes de mano. Bien es verdad que algunos hechos de armas, como fueron los cercos de Toledo de 1355 y 1368-9 que estudiamos en este trabajo, tuvieron una transcendencia fundamental, tanto por el lugar en disputa como por el propio desarrollo de las acciones militares ante una plaza de gran envergadura. Finalmente, la batalla decisiva entre Pedro I y Enrique II en las inmediaciones de Montiel, en cuyo desenlace murió el rey Pedro (1369), tuvo su origen precisamente en un movimiento táctico de los petristas para intentar levantar el citado cerco de la ciudad de Toledo.

IntroductionHumans are able to regulate the intensity with which they exert cognitive control in interference tasks in terms of factors such as the control level required on the previous trial, and the overall frequency of conflict. However, recent research has shown that the ability to follow explicit cues predicting the required level of control is more limited than previously assumed. Specifically, participants in color Stroop tasks did only take advantage of pre-cues informing them about the congruency of the following trial when the cue was presented in the interval between successive trials, but not when the information was conveyed by the preceding trial.MethodHere we explore the boundary conditions of these sequential cueing effects by using a Stroop task in which the proportion of high-conflict trials was increased, to improve practice with the rules, or decreased, to make the task less demanding.ResultsThe results showed no effect of trial-by-trial cueing, neither increasing nor decreasing the proportion of high-conflict trials. Furthermore, the cueing effect was not observed either when the cue was conveyed by neutral trials, thus reducing the conflation between the conflict present on a trial and the conflict that this trial predicts.DiscussionAs a whole, the results illustrate how difficult it is to adjust control parameters on the fly on the basis of sequential cues, even if they are explicit.

Abstract A collective tribute to a colleague, friend, and mentor from those that have known him through his journey of the meanderings of the arterial pulse in health and disease; a journey that extended beyond borders and confines, with far-reaching personal and global impact. The Editorial Board of the Artery Research Journal and the Executive Committee of the Artery Society extend their due respects to Prof. Michael O’Rourke.

Abstract Purpose Determine whether combining magnetic resonance imaging (MRI) observations and clinical tests could substantially improve sensitivity for diagnosis of long head of the biceps tendon (LHBT) pathology. Methods The authors retrospectively assessed a consecutive series of 140 patients who underwent arthroscopic rotator cuff repair for isolated supraspinatus tears. The presence of LHBT pathology was assessed preoperatively on MRI using three criteria and four clinical tests specific to shoulder injuries. Binary outcomes of MRI observations and four clinical tests were combined to identify combinations resulting in the best sensitivity using intra‐operative arthroscopic findings as reference. Results The study cohort comprised 100 shoulders (58 men and 42 women) aged 56.6 ± 9.4 years (range, 30–76) at index surgery. A total of 29 combinations were tested to obtain the best diagnostic algorithm for LHBT pathologies. Only four combinations reached a sensitivity ≥0.75, but had a specificity

This multicenter, open-label, phase 1b study (ACE-LY-106) assessed the safety and efficacy of acalabrutinib, bendamustine, and rituximab (ABR) in treatment-naive (TN) and relapsed or refractory (R/R) mantle cell lymphoma (MCL). Patients received acalabrutinib from cycle 1 until disease progression or treatment discontinuation, bendamustine on days 1 and 2 of each cycle for up to 6 cycles, and rituximab on day 1 of each cycle for 6 cycles, continuing every other cycle from cycle 8 for 12 additional doses (TN cohort). Eighteen patients enrolled in the TN and 20 in the R/R cohort. Median duration of exposure to acalabrutinib was 34.0 and 14.6 months in the TN and R/R cohorts, respectively. No new safety risks were identified, and most adverse events (AEs) were grades 1 or 2. Thirteen patients from the TN cohort (72.2%) and 17 patients from the R/R cohort (85.0%) reported grade 3–4 AEs, most commonly neutropenia (TN: 38.9%, R/R: 50.0%). AEs leading to death were pneumonitis (n=1, TN cohort), COVID-19, and cerebrospinal meningitis (n=1 each, R/R cohort). Overall response was 94.4% and 85.0% in the TN and R/R cohorts, respectively; complete response rates were 77.8% and 70.0%, respectively. After a median follow-up of 47.6 months, median progression-free survival (PFS) and overall survival (OS) were not reached in the TN cohort. After a median follow-up of 20.4 months, median PFS was 28.6 months and OS was not reached in the R/R cohort. Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL. ClinicalTrials.gov identifier: NCT02717624

Single-cell transcriptomics has emerged as the preferred tool to define cell identity through the analysis of gene expression signatures. However, there are limited studies that have comprehensively compared the performance of different scRNAseq systems in complex tissues. Here, we present a systematic comparison of two well-established high throughput 3′-scRNAseq platforms: 10× Chromium and BD Rhapsody, using tumours that present high cell diversity. Our experimental design includes both fresh and artificially damaged samples from the same tumours, which also provides a comparable dataset to examine their performance under challenging conditions. The performance metrics used in this study consist of gene sensitivity, mitochondrial content, reproducibility, clustering capabilities, cell type representation and ambient RNA contamination. These analyses showed that BD Rhapsody and 10× Chromium have similar gene sensitivity, while BD Rhapsody has the highest mitochondrial content. Interestingly, we found cell type detection biases between platforms, including a lower proportion of endothelial and myofibroblast cells in BD Rhapsody and lower gene sensitivity in granulocytes for 10× Chromium. Moreover, the source of the ambient noise was different between plate-based and droplet-based platforms. In conclusion, our reported platform differential performance should be considered for the selection of the scRNAseq method during the study experimental designs.

Summary: The Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a ground-breaking immunotherapeutic approach in cancer treatment. To overcome the complexity and high manufacturing cost associated with current ex vivo CAR T cell therapy products, alternative strategies to produce CAR T cells directly in the body have been developed in recent years. These strategies involve the direct infusion of CAR genes via engineered nanocarriers or viral vectors to generate CAR T cells in situ. This review offers a comprehensive overview of recent advancements in the development of T cell-targeted CAR generation in situ. Additionally, it identifies the challenges associated with in vivo CAR T method and potential strategies to overcome these issues.

El Macizo de Peña Ubiña es uno de los enclaves montañosos de mayor elevación y con valores naturales más destacados de las Montañas Cantábricas, lo que ha sido un aspecto clave para su declaración como Parque Natural y Reserva de la Biosfera. Entre los procesos y formas de relieve identificados en dicho macizo se encuentran morfologías de génesis glaciar, periglaciar y nival, gravitacional, fluviotorrencial, lacustre, kárstica, mixta y de origen antropogénico. La variedad de geoformas mencionada y la diversidad litológica de Peña Ubiña, definida por el predominio de calizas y en menor medida, dolomías, cuarcitas, areniscas cuarcíticas, areniscas y pizarras, que abarcan todos los periodos geológicos del Paleozoico a excepción del Pérmico, generan una rica geodiversidad merecedora de protección específica, estudio y divulgación. La identificación del patrimonio geomorfológico es clave para una correcta planificación y gestión de este espacio natural protegido, así como su revalorización como recurso científico y didáctico. A partir de una metodología empleada en trabajos precedentes y adaptada a las características del área de estudio, en este trabajo se han identificado diecisiete geomorfositios que representan los valores citados, y cuyo conocimiento puede contribuir a la adecuada gestión de esta área singular en el contexto de las Montañas Cantábricas.

Background Doxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI‐002) that can be easily self‐administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract. Methods and Results HBI‐002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI‐002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI‐002 had a 6.3‐fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase‐1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI‐002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI‐002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function. Conclusions These findings strongly support using HBI‐002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.

Background: Considering the long head of biceps (LHB) management, important cultural differences exist among the surgeons around the world, especially when repairing small isolated distal supraspinatus tears under arthroscopy. In the perspective of an international survey to analyze our practice regarding biceps management in small rotator cuff tears, the aim is to collect all the possible LHB abnormalities according to literature review, before considering that the LHB could be normal or pathologic. Indications: The SFA (Société Francophone d’Arthroscopie) behind its research biceps group summarized these abnormalities in a description analysis called the “biceps box” concept, which was validated with a strong inter-rater reliability. The aim is to present the description analysis using a common language with short video records for each abnormality described to reproduce “intraoperatively” the different possible scenarios the surgeon has to encounter during arthroscopic evaluation. Technique Description: The description of the “biceps box” concept classifies lesions of the LHB, with so-called intrinsic lesions, for which the LHB should be considered pathological: partial rupture or delamination, fissuring, lateral or medial instability or subluxation, hypertrophy with an hourglass figure; and so-called extrinsic lesions, for which the LHB should be considered healthy: damage to the pulley without bicipital instability, exposure of the articular portion of the biceps by rupture of the supraspinatus tendon, inflammation of the superficial surface of the tendon, presence of type 1 or 2 superior labral anterior to posterior (SLAP) lesions, or a chondral print. Results: We present the 10 possible scenarios with video records according to our description analysis. Discussion/Conclusion: The LHB could be considered as a pain generator in certain situations which are still not completely clear. The indication of biceps tenotomy or tenodesis depends on the interpretation of the surgeon of these abnormalities as a pathologic or a normal condition. The next step is to use these videos in an international survey to assess cultural differences regarding the management and eventually find a consensus regarding treatment options for each abnormality. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Hospital length of stay (LOS) in the USA has been increasing since the start of the COVID-19 pandemic, with numerous negative outcomes, including decreased quality of care, worsened patient satisfaction and negative financial impacts on hospitals. While many proposed factors contributing to prolonged LOS are challenging to modify, poor coordination of care and communication among clinical teams can be improved.Geographical cohorting of provider teams, patients and other clinical staff is proposed as a solution to prolonged LOS and readmissions. However, many studies on geographical cohorting alone have shown no significant impact on LOS or readmissions. Other potential benefits of geographical cohorting include improved quality of care, learning experience, communication, teamwork and efficiency.This paper presents a retrospective study at Duke University Hospital (DUH) on the General Medicine service, deploying a bundled intervention of geographical cohorting of patients and their care teams, twice daily multidisciplinary rounds and incremental case management support. The quality improvement study found that patients in the intervention arm had 16%–17% shorter LOS than those in the control arms, and there was a reduction in 30-day hospital readmissions compared with the concurrent control arm. Moreover, there was some evidence of improved accuracy of estimated discharge dates in the intervention arm.Based on these findings, the health system at DUH recognised the value of geographical cohorting and implemented additional geographically based medicine units with multidisciplinary rounds. Future studies will confirm the sustained impact of these care transformations on hospital throughput and patient outcomes, aiming to reduce LOS and enhance the quality of care provided to patients.

Abstract Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas‐entrapping material containing CO in a pre‐clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

Abstract Documentary climate data describe evidence of past climate arising from predominantly written historical documents such as diaries, chronicles, newspapers, or logbooks. Over the past decades, historians and climatologists have generated numerous document-based time series of local and regional climates. However, a global dataset of documentary climate time series has never been compiled, and documentary data are rarely used in large-scale climate reconstructions. Here, we present the first global multi-variable collection of documentary climate records. The dataset DOCU-CLIM comprises 621 time series (both published and hitherto unpublished) providing information on historical variations in temperature, precipitation, and wind regime. The series are evaluated by formulating proxy forward models (i.e., predicting the documentary observations from climate fields) in an overlapping period. Results show strong correlations, particularly for the temperature-sensitive series. Correlations are somewhat lower for precipitation-sensitive series. Overall, we ascribe considerable potential to documentary records as climate data, especially in regions and seasons not well represented by early instrumental data and palaeoclimate proxies.

Abstract Individuals with hostile expectations (HEX) anticipate harm from seemingly neutral or ambiguous stimuli. However, it is unclear how HEX are acquired, and whether specific components of HEX learning can predict antisocial thought, conduct, and personality. In an online sample of healthy young individuals (n = 256, 69% women), we administered a virtual shooting task and applied computational modelling of behaviour to investigate HEX learning and its constellation of correlates. HEX acquisition was best explained by a hierarchical reinforcement learning mechanism. Crucially, we found that individuals with relatively higher self-reported aggressiveness and psychopathy developed stronger and less accurate hostile beliefs as well as larger prediction errors. Moreover, aggressive and psychopathic traits were associated with more temporally stable hostility representations. Our study thus shows that aggressiveness and psychopathy are linked with the acquisition of robust yet imprecise hostile beliefs through reinforcement learning.

Introduction: Goblet cell carcinoid (GCC) is a rare and poorly understood appendiceal neoplasm, exhibiting mixed histological and aggressive clinical features. Current guidelines recommend right hemicolectomy in all cases, although there is conflicting evidence that appendicectomy alone may be sufficient. This review aims to identify the optimal surgical management for appendiceal GCC. Methods: A systematic review was performed by searching MEDLINE, Embase, Scopus and the Cochrane Register of Controlled Trials. Randomised controlled trials, cohort studies or large case series (>5 patients) reporting clinical outcomes for patients undergoing surgical management of GCC of the appendix were included. Outcomes extracted included participant and tumour characteristics, type of surgery and survival data. Results: A total of 1341 studies were retrieved. After duplicate removal, 796 titles were screened for relevance prior to abstract and full text review. A total of six studies were included for analysis, comprising 3177 patients—1629 females and 1548 males. The median age ranged from 51 to 72 years. A total of 2329 patients underwent right hemicolectomy, while 824 were treated with appendicectomy only. Overall, the included studies report increased survival in patients undergoing right hemicolectomy compared to appendicectomy alone. A meta-analysis was not possible due to insufficient data reported in the published literature to date. Conclusions: There is no consensus regarding the optimal surgical management of appendiceal GCC, as outcomes-based data comparing surgical interventions are lacking. It is possible that some patients with favourable features are overtreated. The absence of robust evidence to support a more conservative approach means that right hemicolectomy remains the standard of care for all patients, in keeping with current international guidelines. The rarity of this condition and limited data in the published studies remain barriers to evidence-based best clinical practice.

Immune dysfunction in patients with MM affects both the innate and adaptive immune system. Molecules involved in the immune response pathways are essential to determine the ability of cancer cells to escape from the immune system surveillance. However, few data are available concerning the role of immune checkpoint molecules in predicting the myeloma control and immunological scape as mechanism of disease progression. We retrospectively analyzed the clinical impact of the CD200 genotype (rs1131199 and rs2272022) in 291 patients with newly diagnosed MM. Patients with a CD200 rs1131199 GG genotype showed a median overall survival (OS) significantly lower than those with CC+CG genotype (67.8 months versus 94.4 months respectively; p: 0.022) maintaining significance in the multivariate analysis. This effect was specially detected in patients not receiving an autologous stem cell transplant (auto-SCT) (p < 0.001). In these patients the rs1131199 GG genotype negatively influenced in the mortality not related with the progression of MM (p: 0.02) mainly due to infections events.

En este artículo presentamos el estudio de los artefactos de base cobre hallados en las excavaciones del vertedero excavado en la fortaleza de La Estrella de Montiel (Ciudad Real), ubicado en la zona oriental de la puerta de Hierro del castillo, con una estratigrafía vinculada a los últimos momentos de ocupación de la fortaleza en la Baja Edad Media. Nos centramos, en concreto, en el conjunto de piezas relacionadas con la indumentaria, los jaeces y el adorno, dada la excepcionalidad del hallazgo en contexto arqueológico que permite contribuir al conocimiento de la cultura material metálica medieval de la Península Ibérica.

The transition from academic training to professional life is not an easy task. In recent years, various learning enhancement methodologies have emerged to reduce this gap, which focuses on both soft and technical skills. Specifically, Competition-Based Learning (CBL) seeks to improve learning and motivation through the competitive component, which has detractors and defenders. In this framework, the present work proposes a national competition, CIC2022, within the field of control engineering that uses a testbed with an Unmanned Aerial Vehicle (UAV) for helping to link theory and practice. The main objective is to analyze the results of CBL on learning. In addition to explaining the characteristics of the competition and the academic results obtained, a survey answered by participants provides conclusions on the effectiveness of the methodology and other issues related to the contest. Greater motivation and teamwork promoted the active learning of students and improved the autonomous acquisition of technical skills.

Abstract. Aims: We aim to develop a Spanish version of the Guilt and Shame Proneness Scale (GASP) and evaluate its psychometric properties with a Spanish sample. Method: A Spanish version of the GASP was developed by Spanish and English speakers using translation and back-translation. The translated GASP was administered to a sample of 277 Spanish college students (239 females). The validity and reliability of the scale were tested using standard statistical methods. Results: The translated version of the GASP scale was found to have outstanding domain coherence and language clarity. The tested scales showed adequate reliability (>.55), which can be considered evidence supporting its reliability, given that the GASP is a scenario-based measure with only four items in each subscale. Confirmatory factor analysis confirmed the four-factor solution. In addition, a nomological network is provided using the Spanish version of the HEXACO questionnaire. Conclusions: This study presents the first validation of the GASP questionnaire among the general Spanish population. Furthermore, the GASP instrument was found to have satisfactory psychometric properties, resulting in a new tool for researching the moral and social aspects of human experience.

Abstract. After the publication of the Big Five Inventory-2 (BFI-2) and its short versions, many validations in other languages have been published. Three studies (total N = 1,673) were conducted to validate a Spanish version of the BFI-2, BFI-2-S and BFI-2-XS). Study 1 first tested the structural validity at both the domain and facet levels of 60 BFI-2 item translations and tested measurement invariance across gender. Study 2 established the temporal stability of the BFI-2 using two data collection waves. Study 3 evaluated in a new sample the generalizability of the measurement properties of the Spanish BFI-2 obtained in Study 1 and the measurement properties of its abbreviated versions. The findings of these studies show that the Spanish BFI-2 is a valid and reliable measure of personality with psychometric properties corresponding to the original in English. The preliminary results of the short forms' measurement properties are promising and should encourage further replication.