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Predicting symptom progression in first-episode psychosis (FEP) is crucial for tailoring treatment and improving outcomes. Temporal lobe function, indicated by neurophysiological biomarkers like N100, predicts symptom progression and correlates with untreated psychosis. Our recent report showed that source-localized magnetoencephalography (MEG) M100 responses to tones in an oddball paradigm predicted recovery in FEP positive symptoms. This study expands these results with a simpler single-tone paradigm, with both MEG and EEG, and measuring associations across symptom dimensions. We recorded MEG (M100) and EEG (N100) in 29 FEP individuals and assessed symptom severity at baseline and after ∼ 7 months using the Positive and Negative Syndrome Scale (PANSS). Sequential regression analyses predicted symptom change (ΔPANSS) from Duration of untreated Active Psychosis (DAP) and baseline M100, controlling for baseline symptoms. Identical regressions were conducted in a subsample measuring N100 with EEG (n = 24). Smaller baseline M100 predicted worse symptom recovery at follow-up, independent of baseline symptom severity. Longer DAP showed a similar predictive effect, but this relationship was accounted for by M100. Regressions revealed M100 predictions were mostly related to general psychopathology. Identical results were found for N100 measured with EEG. Temporal lobe dysfunction in FEP, especially poor auditory sensory processing, indicates a worse recovery trajectory in general psychopathology. Longer untreated psychosis worsens temporal lobe function, predicting poorer progression. N100 measured with EEG and a single-tone task could be a cost-effective tool for informing clinicians about overall symptom progression, guiding treatment resource allocation and interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Infrequent stimulus deviations from repetitive sequences elicit mismatch negativity (MMN) even passively, making MMN practical for clinical applications. Auditory MMN is typically elicited by a change in one (or more) physical stimulus parameters (eg, pitch, duration). This lower-order simple MMN (sMMN) is impaired in long-term schizophrenia. However, sMMN contains activity from release from stimulus adaptation, clouding its face validity as purely deviance-related. More importantly, it is unreliably reduced in samples of first-episode psychosis, limiting its utility as a biomarker. Complex pattern-deviant MMN (cMMN) tasks, which elicit early and late responses, are based on higher-order abstractions and better isolate deviance detection. Their abstract nature may increase the sensitivity to processing deficits in early psychosis. However, both the early and late cMMNs are small, limiting separation between healthy and psychotic samples. In 29 healthy individuals, we tested a new dual-rule cMMN paradigm to assess additivity of deviance. Sounds alternated lateralization between left and right, and low and high pitches, creating a left-low, right-high alternating pattern. Deviants were a repeated left-low, violating lateralization and pitch patterns. Early and late cMMNs on the dual-rule task were significantly larger than those on the one-rule extra tone cMMN task ( P  < .05). Further, the dual-rule early cMMN was not significantly smaller than pitch or duration sMMNs ( P  > .48, .28, respectively). These results demonstrate additivity for cMMN pattern-violating rules. This increase in cMMN amplitude should increase group difference effect size, making it a prime candidate for a biomarker of disease presence at first psychotic episode, and perhaps even prior to the emergence of psychosis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mismatch negativity (MMN) to pitch (pMMN) and to duration (dMMN) deviant stimuli is significantly more attenuated in long-term psychotic illness compared to first-episode psychosis (FEP). It was recently shown that source-modeling of magnetically recorded MMN increases the detection of left auditory cortex MMN deficits in FEP, and that computational circuit modeling of electrically recorded MMN also reveals left-hemisphere auditory cortex abnormalities. Computational modeling using dynamic causal modeling (DCM) can also be used to infer synaptic activity from EEG-based scalp recordings. We measured pMMN and dMMN with EEG from 26 FEP and 26 matched healthy controls (HCs) and used a DCM conductance-based neural mass model including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, N-methyl-D-Aspartate (NMDA), and Gamma-aminobutyric acid receptors to identify any changes in effective connectivity and receptor rate constants in FEP. We modeled MMN sources in bilateral A1, superior temporal gyrus, and inferior frontal gyrus (IFG). No model parameters distinguished groups for pMMN. For dMMN, reduced NMDA receptor activity in right IFG in FEP was detected. This finding is in line with literature of prefrontal NMDA receptor hypofunction in chronic schizophrenia and suggests impaired NMDA-induced synaptic plasticity may be present at psychosis onset where scalp dMMN is only moderately reduced. To the best of our knowledge, this is the first report of impaired NMDA receptor activity in FEP found through computational modeling of dMMN and shows the potential of DCM to non-invasively reveal synaptic-level abnormalities that underly subtle functional auditory processing deficits in early psychosis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The N1 auditory evoked potential amplitude depends heavily on the inter-stimulus interval (ISI). Typically, shorter ISIs result in reduced N1 amplitudes, suggesting a decreased neural response with high stimulus presentation rates. However, an exception known as N1 facilitation occurs with very brief ISIs (∼150-500 ms), where the N1 amplitude increases. This study aimed to further characterize N1 facilitation using an experimental paradigm with a continuous distribution of ISIs (0.25 to 8 s) to identify the specific ISI where N1 facilitation occurs. We also examined the role of ISI history in N1 facilitation and explored correlations between N1 facilitation, overall N1 amplitude and ISI-sensitivity, and results of cognitive tasks. Twenty-nine participants passively listened to a random sequence of auditory clicks at varying intensities (65, 75, or 85 dB) and ISI ranges (0.25-0.5 s, 0.5-1 s, 1-2 s, 2-4 s, 4-8 s) while EEG was recorded. Up to 1800 sweeps were collected in the critical ISI range (0.25 to 0.5 s) where N1 facilitation is expected. Results support N1 facilitation occurring at ISIs under 400 ms (p = 0.03), where N1 amplitudes returned to values seen at longer ISIs (∼1.7 s). Notably, this effect was observed when the ISI two clicks before was shorter than 1.5 s (p = 0.001), but not otherwise (p = 0.37). These findings clarify the temporal dynamics of N1 facilitation and challenge the notion of a rigid, context-independent latent inhibition process explaining this phenomenon., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We study the structure and dynamics of the interface separating a passive fluid from a microtubule-based active fluid. Turbulent-like active flows power giant interfacial fluctuations, which exhibit pronounced asymmetry between regions of positive and negative curvature. Experiments, numerical simulations, and theoretical arguments reveal how the interface breaks up the spatial symmetry of the fundamental bend instability to generate local vortical flows that lead to asymmetric interface fluctuations. The magnitude of interface deformations increases with activity: In the high activity limit, the interface self-folds invaginating passive droplets and generating a foam-like phase, where active fluid is perforated with passive droplets. These results demonstrate how active stresses control the structure, dynamics, and break-up of soft, deformable, and reconfigurable liquid-liquid interfaces., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Executive control over low-level information processing is impaired proximal to psychosis onset with evidence of recovery over the first year of illness. However, previous studies demonstrating diminished perceptual modulation via attention are complicated by simultaneously impaired perceptual responses. The present study examined the early auditory gamma-band response (EAGBR), a marker of early cortical processing that appears preserved in first-episode psychosis (FEP), and its modulation by attention in a longitudinal FEP sample., Methods: Magnetoencephalography was recorded from 25 FEP and 32 healthy controls (HC) during active and passive listening conditions in an auditory oddball task at baseline and follow-up (4-12 months) sessions. EAGBR inter-trial phase coherence (ITPC) and evoked power were measured from responses to standard tones. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS)., Results: There was no group difference in EAGBR power or ITPC. While EAGBR ITPC increased with attention in HC, this modulation was impaired among FEP. Diminished EAGBR modulation in FEP persisted at longitudinal follow-up. However, among FEP, recovery of EAGBR modulation was associated with reduced PANSS negative scores., Conclusion: FEP exhibit impaired executive control over the flow of information at the earliest stages of sensory processing within auditory cortex. In contrast to previous work, this deficit was observed despite an intact measure of sensory processing, mitigating potential confounds. Recovery of sensory gain modulation over time was associated with reductions in negative symptoms, highlighting a source of potential resiliency against some of the most debilitating and treatment refractory symptoms in early psychosis.

Anomalous Mismatch Negativity (MMN) in psychosis could be a consequence of disturbed neural oscillatory activity at sensory/perceptual stages of stimulus processing. This study investigated effective connectivity within and between the auditory regions during auditory odd-ball deviance tasks. The analyses were performed on two magnetoencephalography (MEG) datasets: one on duration MMN in a cohort with various diagnoses within the psychosis spectrum and neurotypical controls, and one on duration and pitch MMN in first-episode psychosis patients and matched neurotypical controls. We applied spectral Granger causality to MEG source-reconstructed signals to compute effective connectivity within and between the left and right auditory regions. Both experiments showed that duration-deviance detection was associated with early increases of effective connectivity in the beta band followed by increases in the alpha and theta bands, with the connectivity strength linked to the laterality of the MMN amplitude. Compared to controls, people with psychosis had overall smaller effective connectivity, particularly from left to right auditory regions, in the pathway where bilateral information converges toward lateralized processing, often rightward. Blunted MMN in psychosis might reflect a deficit in inter-hemispheric communication between auditory regions, highlighting a "dysconnection" already at preattentive stages of stimulus processing as a model system of widespread pathophysiology., Competing Interests: Declaration of competing interest AB has received lecture fees from Otsuka, Janssen, and Lundbeck, as well as consultant fees from Biogen. GP has received lecture fees from Lundbeck. All other authors report no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To evaluate the diagnostic accuracy of [ 68 Ga]Ga-PSMA-11 PET/CT (PET-PSMA) in local and loco-regional nodal staging compared with histopathological results in intermediate- and high-risk prostate cancer patients treated with radical prostatectomy (RP) and pelvic lymph node dissection (PLND)., Materials Y Methods: A total of 122 intermediate- and high-risk prostate cancer (PCa) patients staged with PET-PSMA and treated with RP (36/122) and RP plus PLND (86/122) from December 2018 to December 2023 were included. Visual and semiquantitative analysis findings using the SUVmax of the molecular imaging were correlated with histopathological results., Results: The primary tumor was visible by PET-PSMA in 96.7% of the patients. A positive correlation was found between PSA levels and SUVmax (Spearman's r: 0.303, p < 0.001). PET-PSMA detected nodal involvement in 25/89 patients (28.08%). The sensitivity, specificity, and diagnostic accuracy of PET-PSMA for detecting nodal involvement were 75%, 82.2%, and 80.9%, respectively. Patients with PSA levels >20 ng/mL, Gleason score ≥7b, ISUP grade >2, and extracapsular extension showed significantly higher SUVmax values. No differences were observed in SUVmax between risk groups or in other histopathological variables., Conclusions: PET-PSMA is an effective tool for the initial staging of intermediate- and high-risk PCa. SUVmax values were significantly higher in patients with unfavorable clinical features., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Active liquid crystals exert nonequilibrium stresses on their surroundings through constant consumption of energy, giving rise to dynamical steady states not present in equilibrium. The paradigmatic example of an active liquid crystal is a suspension of microtubule bundles powered by kinesin motor proteins, which exhibits self-sustained spatiotemporal chaotic flows. This system has been modelled using continuum theories that couple the microtubule orientation to active flows. Recently the focus has shifted to the interfacial properties of mixtures of active liquid crystals and passive fluids. Active/passive interfaces have been shown to support propagating capillary waves in the absence of inertia and offer a promising route for relating experimental parameters to those of the continuum theory. In this paper we report the derivation of a minimal model that captures the linear dynamics of the interface between an active liquid crystal and a passive fluid. We show that the dynamics of the interface, although powered by active flows throughout the bulk, is qualitatively captured by equations that couple non-reciprocally interface height and nematic director at the interface. This minimal model reproduces the dynamical structure factor evaluated from numerical simulations and the qualitative form of the wave dispersion relation seen in experiments.

Background: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months., Methods: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response., Results: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models., Conclusions: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: EC has received honoraria from Novartis, Chiesi, Lundbeck, MedScape; his salary has been partially funded by Río Hortega grant Acción Estratégica en Salud 2017–2020, Instituto de Salud Carlos III (CM20/00217). He is a junior editor for Cephalalgia. GE received travel grants and honoraria from Eli-Lilly, Novartis, Lusofarmaco, New Penta and Ecupharma. CNC has received honoraria for advisories, educational or commercial symposia from: Abbvie-Allergan, Kern Pharma, Chiesi, Lilly, Lundbeck, Novartis and Teva Pharmaceuticals And has participated as subinvestigator in Clinical Trials for: Abbvie-Allergan, Amgen, Biohaven, Lilly, Lundbeck, Pfizer and Teva Pharmaceuticals. JAM has received honoraria as consultant and/or speaker for Lilly, Novartis, Teva. FS-C received honoraria from Novartis, Lilly, TEVA, Abbvie. AM has received honoraria from Teva, Lilly, Roche, UCB, Bial, Chiesi, Allergan, Esai, Zambon, Kern Pharma, Pfizer, Biogen Idec, Novartis, TEVA, Merck, Janssen, Neuraxpharm, Genzyme, Sanofi, Bayer, Almirall and/or Celgene. JS received honoraria from Allergan, Lilly, Teva, Novartis. IBB received honoraria for presentations from Novartis, Lilly, Teva, Lundbeck and Abbvie. MW-P received honoraria from Pfizer, Allergan-Abbvie, TEVA, Polpharma. MW-P is member of Editorial Board: The Journal of Headache and Pain. LP received honoraria from Pfizer, Lilly, Abbvie, TEVA, Novartis. AL-R received honoraria for Abbvie, Lilly, Novartis and Teva. IL received honoraria from Novartis, Abbvie, Teva, Eisai, Tecnifar and Bial. LD received honoraria as a speaker for Allergan, Lilly, Teva and Lundbeck. MRA-E, received honoraria from ABBVIE, Lilly, and Novartis. AM has no COI to declare. The University Clinic Hamburg got an unrestricted scientific grant from Novartis (2019-2023). IPM has received honoraria from Allergan Teva, Novartis, Lundbeck and Eli Lilly for lecturing or participating in advisory boards; is principal investigator for phase IV trials sponsored by Novartis, Lundbeck and Teva. CS has received personal fees for lectures/ advisory boards: Novartis, Abbvie and TEVA. PI received honoraria from TEVA, Novartis, Lilly, Abbvie, Lundbeck, Exeltis. ALR received honoraria from TEVA. ABG-V has received speaker honoraria and/or clinical advisor from Novartis, Lilly, TEVA, Exeltis, Chiesi, Abbvie, Pfizer and Lundbeck. RR has received travel grants and/or honoraria for lectures or advisory boards from Allergan/AbbVie, Hormosan, Lilly, Lundbeck, Novartis, Pfizer and Teva. SS reports consultant, speaker or advisory board fees from Abbott, Allergan/Abbvie, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, Medscape, Medtronic, Novartis, Pfizer, Starmed, Teva and Uriach. EC-G received honoraria from TEVA. DGA has received personal compensation for consulting/advising from the WHO. Non-profit board membership in the Spanish Society of Neurology, and the European Union of Medical Specialist section of Neurology. Research funding from the Regional Health Administration (Gerencia Regional de Salud SACYL) in Castilla y Leon, Spain and Carlos III institute, Madrid, Spain. Speaker/travel grants/ clinical trials from Teva, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis and Biohaven. JP has received honoraria from Abbvie, Lilly, Lundbeck, Novartis and Teva. RG-G received honoraria from Allergan/ Abbvie, Lilly, Lundbeck, Novartis, Pfizer, Tecnifar, Teva. MH-V has received honoraria for participating on advisory boards and for collaborations as consultant, scientific communications, speaker, research support as well as funding for travel and congress-attending expenses for Abbie-Allergan, Novartis, Lundbeck, Lilly, Almirall, Chiesi, Esai, Exeltis, Kern Pharma, Menarini, TEVA and Zambon. His research group has received research grants from Abbie-Allergan and has received funding for clinical trials from Lilly, Novartis, TEVA. JVR received honoraria from Novartis, Abbvie, Lilly, TEVA, Lundbeck. SS-L received honoraria from Allergan, Almirall, Amgen, Chiesi, Eisai, Exeltis, Lilly, Lündbeck, Novartis, Pfizer y Teva. MG-S has received honoraria and been involved in research, education and advisory boards with Teva, Lily, Novartis and Abbvie. CT received personal fees for participating in advisory or for speaking at scientific events from AbbVie, Allergan, Biohaven, Dompé, Eli Lilly, Lundbeck, Novartis and Teva. CT has received research funding from the European Commission, the Italian Ministry of Health and Migraine Research Foundation. JDdT has received honoraria as consultant and/or speaker for Lilly, Novartis, Teva. SDI has received honoraria for advisories, educational or commercial symposia from: Abbvie-Allergan, Fundació Universitat-Empresa, Ipsen Pharma, Kern Pharma, Lilly, Lundbeck, MSD-Organon, Novartis and Teva Pharmaceuticals And has participated as PI in Clinical Trials for: Abbvie-Allergan, Alder, Amgen, Biohaven, Ipsen Pharma, Lilly, Lundbeck, Pfizer and Teva Pharmaceuticals. CGO participated in clinical trials from Novartis, St Jude Medical, Lilly, Lundbeck; TEVA, Biohaven, Pfizer. CGO received honoraria as consultant for Novartis, Lilly, Allergan-abbvie, Lundbeck, TEVA, Pfizer. CGO received honoraria as speaker for Allergan-Abbvie, TEVA, Novartis,Lilly, Chiesi, MSD, Almirall. PB reports personal compensation for consulting, serving on a scientific advisory board, speaking, research support, collaborated for clinical trials or other activities with Abbvie, Alder, Allergan, Amgen, Angelini, Assosalute, Bayer, Biohaven, ElectroCore, Eli-Lilly, Fondazione Ricerca e Salute, GSK, Lundbeck, Lusofarmaco, 1MED, MSD, New Penta, Noema Pharma, Novartis, Pfizer, Stx-Med, Teva, Visufarma, Zambon and serves as President with Italian Association of Headache Sufferers. PP-R has received, in the last 3 years, honoraria as a consultant and speaker for: AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. Her research group has received research grants from AbbVie, Novartis and Teva; as well as, Instituto Salud Carlos III, EraNet Neuron, European Regional Development Fund (001-P-001682) under the framework of the FEDER Operative Programme for Catalunya 2014-2020 - RIS3CAT; has received funding for clinical trials from AbbVie, Amgen, Biohaven, Eli Lilly, Novartis, Teva. She is the Honorary Secretary of the International Headache Society. She is in the editorial board of Revista de Neurologia. She is an associate editor for Cephalalgia, Headache, Neurologia, The Journal of Headache and Pain and Frontiers of Neurology. She is a member of the Clinical Trials Guidelines Committee of the International Headache Society. She has edited the Guidelines for the Diagnosis and Treatment of Headache of the Spanish Neurological Society. She is the founder of www.midolordecabeza.org. PP-R does not own stocks from any pharmaceutical company. VJG, MMV, GV, JR-M, NFF, AJS, RO, GG, YG-O, GC, AL-B, FVJ, JR-V and VO reports no disclosures. RO reports personal fees from Eli Lilly, Novartis, Teva, and Pfizer, and non-financial support from Novartis, Teva, and Allergan/AbbVie. CT has received honoraria for lectures from TEVA, Lundbeck and for advisory boards from TEVA. He has received travel support from TEVA and Lundbeck. SS received honoraria from TEVA. AH declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. HB received honoraria from Novartis, Teva and Lundbeck. NPRP received honoraria from ABBVIE, Lilly and Novartis. CF received honoraria from Novartis and Abbvie. AAL received honoraria for Abbvie, Lilly, Novartis and Teva. EMS received a grant from the Portuguese Headache Society, supported by Teva. MTF has received honoraria from Allergan-AbbVie, Novartis, Chiesi and Teva. AA has received honoraria from Allergan-AbbVie, Novartis, Chiesi. PT received grants and honoria from Novartis, Teva, Eli-Lilly and Allergan. CA received travel grants from FB-Health, Lusofarmaco, Almirall, Eli-Lilly Novartis and Teva. RDI received speaker honoraria from Eli-Lilly, TEVA and Lundbeck. GS received personal fees as speaker or advisory board from Eli Lilly, Novartis, Teva, Lundbeck, Pfizer. SB has received honoraria from Teva. SC has received honoraria from Teva, Lilly, Roche, UCB, Bial, Chiesi, Allergan, Esai, Zambon, Kern Pharma, Pfizer, Biogen Idec, Novartis, TEVA, Merck, Janssen, Neuraxpharm, Genzyme, Sanofi, Bayer, Almirall and/or Celgene. EP reports personal fees from Novartis, Teva and Lilly. ALGP Research funding from the Regional Health Administration (Gerencia Regional de Salud SACYL) in Castilla y Leon, Spain. Speaker/travel grants/ clinical trials from Teva, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Biohaven. AS has received honoraria for advisory boards and lectures from Allergan/AbbVie, Hormosan, Lilly, Lundbeck, Novartis, Sanofi, Teva. AGM has received speaker honoraria from TEVA. SQ has received speaker honoraria from Novartis, Lilly and Exeltis. MSR has received consulting fees and honoraria for lectures/presentations from Eli Lily, Lundbeck, Novartis, Teva and Pfizer. Intellectual as Secretary of the European Headache Federation, Review Editor on the Editorial Board of Headache and Neurogenic Pain (specialty section of Frontiers in Neurology). Margarita Sanchez-del-Rio serves as a member of the Board of Directors in the European Headache Federation. ET has received personal fees for lectures/ advisory boards: Novartis, Eli Lilly, Abbvie, TEVA, Roche, Lundbeck, Pfizer, Biogen. Consultant for and owner of stocks and IP in Man & Science. Stocks and IP in Nordic Brain Tech and Keimon Medical. Non-personal research grants from EU, Norwegian Research Council, Dam foundation, KlinBeForsk. Commissioned research (non-personal): Lundbeck, Pfizer. BVP received honoraria from ABBVIE. AOD received honoraria from ABBVIE, Lilly, Teva, Novartis. MR received honoraria from Lilly, Novartis. BC received grants and honoria from Eli-Lilly, Novartis, Teva; SC received travel grants, honoraria for advisory boards, speaker panels or clinical investigation studies from Novartis, Teva, Lilly, Allergan, Abvie, Ibsa, Amgen, Angelini and Lundbeck; FF has received fees for participation on advisory boards, speaker honoraria or consulting activities from Angelini, Cristalfarma, Ecupharma, IBSA, Lundbeck, Novartis, PIAM, Teva; FdO received travel grant, honoraria as a speaker or for partecipating in advisory boards from Novartis, Teva, Neopharmed Gentili, Qbgroup srl, K link srl and Eli-Lilly; MA received grants from Novartis and Lilly; RR received honoraria for speaker panels from Teva, Lilly, Novartis, Allergan, Lundbeck; MZ received travel grants and honoraria from Novartis; MA received travel grants and honoraria from Novartis, Teva, Eli-Lilly and Lundbeck; CF received grants and honoraria from Novartis, Eli Lilly, TEVA, AIM group; AR received travel grants and honoraria from Teva and Eli-Lilly; SZ, RLP, MJRC, VGQ, HCO, SA, IKZ, DGA, IFL, BFP, SB, PRA, AC, AEU, AGG, IM, JPS, VC, AFR, YVE, MT, AS, AC, FZ and MA has no disclosures to declare., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Predicting treatment response would facilitate individualized medical treatment in first-episode psychosis (FEP). We examined relationships between auditory-evoked M100 and longitudinal change in positive symptoms in FEP. M100 was measured from source-resolved magnetoencephalography and symptoms were assessed at initial contact and six months later. M100 at baseline significantly predicted symptom change. Larger M100 at baseline predicted symptom improvement, as did shorter untreated psychosis. Shorter untreated psychosis also correlated with larger M100, and M100 mediated the effect of untreated psychosis on treatment response. Thus, M100 may provide a proximal and objective index of untreated psychosis and a viable route to individualized medicine., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: The tumor suppressor protein p53, a transcription factor playing a key role in cancer prevention, interacts with DNA as its primary means of determining cell fate in the event of DNA damage. When it becomes mutated, it opens damaged cells to the possibility of reproducing unchecked, which can lead to formation of cancerous tumors. Despite its critical role, therapies at the molecular level to restore p53 native function remain elusive, due to its complex nature. Nevertheless, considerable information has been amassed, and new means of investigating the problem have become available., Objectives: We consider structural, biophysical, and bioinformatic insights and their implications for the role of direct and indirect readout and how they contribute to binding site recognition, particularly those of low consensus. We then pivot to consider advances in computational approaches to drug discovery., Materials and Methods: We have conducted a review of recent literature pertinent to the p53 protein., Results: Considerable literature corroborates the idea that p53 is a complex allosteric protein that discriminates its binding sites not only via consensus sequence through direct H-bond contacts, but also a complex combination of factors involving the flexibility of the binding site. New computational methods have emerged capable of capturing such information, which can then be utilized as input to machine learning algorithms towards the goal of more intelligent and efficient de novo allosteric drug design., Conclusions: Recent improvements in machine learning coupled with graph theory and sector analysis hold promise for advances to more intelligently design allosteric effectors that may be able to restore native p53-DNA binding activity to mutant proteins., Clinical Relevance: The ideas brought to light by this review constitute a significant advance that can be applied to ongoing biophysical studies of drugs for p53, paving the way for the continued development of new methodologies for allosteric drugs. Our discoveries hold promise to provide molecular therapeutics which restore p53 native activity, thereby offering new insights for cancer therapies., Graphical Abstract: Structural representation of the p53 DBD (PDBID 1TUP). DNA consensus sequence is shown in gray, and the protein is shown in blue. Red beads indicate hotspot residue mutations, green beads represent DNA interacting residues, and yellow beads represent both., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade. We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-β. Increases in IFNγ concentrations in the tissue culture supernatants were detected upon in-culture activation with the anti-CD137 and anti-PD-1 mAb combinations or concanavalin A as a positive control. No other cytokine from a wide array was informative of stimulation with these mAbs. Interestingly, increases in Ki67 and other activation markers were substantiated in lymphocytes from cell suspensions gathered at the end of 72 h cultures. In mice bearing bilateral tumors in which one was excised prior to in vivo anti-CD137 + anti-PD-1 treatment to perform the fragment culture evaluation, no association was found between IFNγ production from the fragments and the in vivo therapeutic outcome in the non-resected contralateral tumors. The experimental system permitted freezing and thawing of the fragments with similar functional outcomes. Using a series of patient-derived tumor fragments from excised solid malignancies, we showed IFNγ production in a fraction of the studied cases, that was conserved in frozen/thawed fragments. The small tumor fragment culture technique seems suitable to preclinically explore immunotherapy combinations., Competing Interests: I. E.-S., I. R., C. H.-M., E. F.-P., A. A., S. S.-G., E. B., G. G., P. M.-G., E. C., J. A. M., S. C, F. D.-C., C. A. and A. T. declare no conflicts of interest. M. F. S. reports grants from Bristol Myers Squibb and Roche during the conduct of the study, as well as grants and personal fees from Roche and Bristol Myers Squibb, and personal fees from Numab outside the submitted work. I. M. reports grants and personal fees from Genmab during the conduct of the study, as well as grants and personal fees from Bristol Myers Squibb, Roche, AstraZeneca, and Pharmamar and personal fees from F-Star, Numab, Pieris, Boehringer Ingelheim, Gossamer, Alligator, Hotspot, Biolinerx, Bioncotech, Dompe, Highlight Therapeutics, Bright Peaks and Boston Therapeutics outside the submitted work., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Cyclam, known for its potent chelation properties, is explored for diverse applications through selective N -functionalization, offering versatile ligands for catalysis, medical research, and materials science. The challenges arising from N -alkylation, which could decrease the coordination properties, are addressed by introducing a robust C -functionalization method. The facile two-step synthesis proposed here involves the click chemistry-based C -functionalization of a hydroxyethyl cyclam derivative using Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Boc-protecting groups prevent undesired copper coordination, resulting in compounds with a wide range of functionalities. The optimized synthesis conditions enable C -functional cyclams to be obtained easily and advantageously, with high application potential in the previously cited fields. The methodology has been extended to trehalose-based Siamese twin amphiphiles, enabling efficient gene delivery applications.

Background: Gamma-band activity has been the focus of considerable research in schizophrenia. Discrepancies exist regarding the integrity of the early auditory gamma-band response (EAGBR), a stimulus-evoked oscillation, and its relationship to symptoms in early disease. Variability in task design may play a role. This study examined sensitivity of the EAGBR to stimulus intensity and its relation to symptoms and functional impairments in the first-episode schizophrenia spectrum (FESz)., Method: Magnetoencephalography was recorded from 35 FESz and 40 matched healthy controls (HC) during presentation of 3 tone intensities (75 dB, 80 dB, 85 dB). MRIs were collected to localize auditory cortex activity. Wavelet-transformed single trial epochs and trial averages were used to assess EAGBR intertrial phase coherence (ITPC) and evoked power, respectively. Symptoms were assessed using the Positive and Negative Syndrome Scale., Results: Groups did not differ in overall EAGBR power or ITPC. While HC exhibited EAGBR enhancement to increasing intensity, FESz exhibited reduced power to the 80 dB tone and, relative to HC, increased power to the 75 dB tone. Larger power and ITPC were correlated with more severe negative, thought disorganization, and resistance symptoms. Stronger ITPC was associated with impaired social functioning., Discussion: EAGBR showed no overall deficit at disease onset. Rather, FESz exhibited a differential response across tone intensity relative to HC, emphasizing the importance of stimulus characteristics in EAGBR studies. Associations between larger EAGBR and more severe symptoms suggest aberrant synchronization driving overinclusive perceptual binding that may relate to deficits in executive inhibition of initial sensory activity., Competing Interests: Declaration of competing interest None of the authors reported any biomedical financial interests or potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A novel family of precision-engineered gene vectors with well-defined structures built on trehalose and trehalose-based macrocycles (cyclotrehalans) comprising linear or cyclic polyamine heads have been synthesized through procedures that exploit click chemistry reactions. The strategy was conceived to enable systematic structural variations and, at the same time, ensuring that enantiomerically pure vectors are obtained. Notably, changes in the molecular architecture translated into topological differences at the nanoscale upon co-assembly with plasmid DNA, especially regarding the presence of regions with short- or long-range internal order as observed by TEM. In vitro and in vivo experiments further evidenced a significant impact on cell and organ transfection selectivity. Altogether, the results highlight the potential of trehalose-polyamine/pDNA nanocomplex monoformulations to achieve targeting transfection without the need for any additional cell- or organ-sorting component.

Mismatch negativity (MMN) is an auditory event-related response reflecting the pre-attentive detection of novel stimuli and is a biomarker of cortical dysfunction in schizophrenia (SZ). MMN to pitch (pMMN) and to duration (dMMN) deviant stimuli are impaired in chronic SZ, but it is less clear if MMN is reduced in first-episode SZ, with inconsistent findings in scalp-level EEG studies. Here, we investigated the neural generators of pMMN and dMMN with MEG recordings in 26 first-episode schizophrenia spectrum (FE sz ) and 26 matched healthy controls (C). We projected MEG inverse solutions into precise functionally meaningful auditory cortex areas. MEG-derived MMN sources were in bilateral primary auditory cortex (A1) and belt areas. In A1, pMMN FE sz reduction showed a trend towards statistical significance (F (1,50)  = 3.31; p = .07), and dMMN was reduced in FE sz (F (1,50)  = 4.11; p = .04). Hypothesis-driven comparisons at each hemisphere revealed dMMN reduction in FE sz occurred in the left (t (56)  = 2.23; p = .03; d = .61) but not right (t (56)  = 1.02; p = .31; d = .28) hemisphere, with a moderate effect size. The added precision of MEG source solution with high-resolution MRI and parcellation of A1 may be requisite to detect the emerging pathophysiology and indicates a critical role for left hemisphere pathology at psychosis onset. However, the moderate effect size in left A1, albeit larger than reported in scalp MMN meta-analyses, casts doubt on the clinical utility of MMN for differential diagnosis, as a majority of patients will overlap with the healthy individual's distribution., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Introduction: The COVID-19 pandemic entailed confinement and elimination of face-to-face university classes in Spain. The Francisco de Vitoria University in Madrid (UFV by its Spanish acronym) implemented risk management systems to enable on-campus university activity to avoid a negative impact on students, teachers, and faculties., Methods: A tracking/registry system was implemented to collect data, identify COVID-19-related cases, implement containment measures, and do follow-up in the UFV community (administration/services personnel [ASP], teaching/research personnel [TRP], and students), from September 2020 to April 2022. In addition, a prevention plan was implemented on campus to avoid COVID-19 spreading. Satisfaction with these measures was assessed through an online questionnaire., Results: A total of 7,165 suspected COVID-19 cases (84.7% students, 7.7% ASP, 6.5% TRP) were tracked (62.5% female cases, mean age (±SD) 24.8 years (±9.2 years)), and 45% of them confirmed (82% symptomatic/16% asymptomatic), being the student group that with the highest percentage (38.3% total tracked cases). The source of infection was identified in 50.6% of the confirmed cases (90.2% located off-campus). Nineteen COVID-19 outbreaks were registered (inside-10/outside-9). COVID-19 incidence rates were similar or lower than those reported in the Community of Madrid, except in the last wave, corresponding to Omicron variant. The degree of satisfaction (scale 1-6) with the implemented measures was high (scores 4.48-5.44)., Conclusion: During the COVID-19 pandemic, UFV control measures, periodic monitoring, and the effectiveness of the tracking system have contributed to maintaining classroom teaching, guaranteeing health and safety. UFV has adapted to a new reality as an example of good practice for future pandemics or emergency situations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Monge, Gallego-Gil, Neria, Canellas, Caballero, Díaz de Bustamante and Samper.)

Demixing binary liquids is a ubiquitous transition explained using a well-established thermodynamic formalism that requires the equality of intensive thermodynamics parameters across phase boundaries. Demixing transitions also occur when binary fluid mixtures are driven away from equilibrium, but predicting and designing such out-of-equilibrium transitions remains a challenge. Here we study the liquid-liquid phase separation of attractive DNA nanostars driven away from equilibrium using a microtubule-based active fluid. We find that activity lowers the critical temperature and narrows the range of coexistence concentrations, but only in the presence of mechanical bonds between the liquid droplets and reconfiguring active fluid. Similar behaviours are observed in numerical simulations, suggesting that the activity suppression of the critical point is a generic feature of active liquid-liquid phase separation. Our work describes a versatile platform for building soft active materials with feedback control and providing an insight into self-organization in cell biology., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

We use numerical simulations and linear stability analysis to study the dynamics of an active liquid crystal film on a substrate in the regime where the passive system would be isotropic. Extensile activity builds up local orientational order and destabilizes the quiescent isotropic state above a critical activity, eventually resulting in spatiotemporal chaotic dynamics akin to the one observed ubiquitously in the nematic state. Here we show that tuning substrate friction yields a variety of emergent structures at intermediate activity, including lattices of flow vortices with associated regular arrangements of topological defects and a new state where flow vortices trap pairs of +1/2 defect that chase each other's tail. These chiral units spontaneously pick the sense of rotation and organize in a hexagonal lattice, surrounded by a diffuse flow of opposite rotation to maintain zero net vorticity. The length scale of these emergent structures is set by the screening length of the flow, controlled by the shear viscosity η and the substrate friction Γ , and can be captured by simple mode selection of the vortical flows. We demonstrate that the emergence of coherent structures can be interpreted as a phase separation of vorticity, where friction plays a role akin to that of birth/death processes in breaking conservation of the phase separating species and selecting a characteristic scale for the patterns. Our work shows that friction provides an experimentally accessible tuning parameter for designing controlled active flows.

Introduction: Simulation in medicine has developed a lot in the last few decades. There is a broad range of simulators available, above all for training in surgical procedures. Endourology can benefit much from simulation because the minimally-invasive procedures of endourology frequently have long learning curves, which can be reduced by training with simulators., Materials and Methods: A low-fidelity simulator was designed for practicing endourology techniques that use cystoscopy. The process of validation involved 5 experts and 19 non-experts. Experts comprised medical professionals working in a department of urology who had performed at least 100 flexible cystoscopy procedures. Non-experts were residents in internal medicine without experience in any type of endoscopy. Information about face and content validity was collected by means of Likert scales from 1 to 5. To evaluate construct validity, we measured the time to complete two tasks, for which the procedure was evaluated by means of the OSATS global evaluation scale., Results: New simulator was successfully built according to its design. For all evaluated aspects of construct validity, there was a significant difference (p<0.05) between the group of experts and the group of non-experts. Content validity was scored 4.66 (standard deviation ±0.56) by the experts and 4.41 (±0.71) by the non-experts. In the face validity questionnaire, the average score was 4.14 (±0.94), the question receiving the highest score: 4.6 (±0.84) concerned immersion in the procedure., Conclusion: The simulator presented is valid both for training up new urologists in endourology technique and for experts seeking to perfect their skills., (Copyright © 2023. Published by Elsevier España, S.L.U.)

It is not known how Auditory-Evoked Responses (AERs) comprising Middle Latency Responses (MLRs) and Long Latency Responses (LLRs) are modulated by stimulus intensity and inter-stimulus interval (ISI) in an unpredictable auditory context. Further, intensity and ISI effects on MLR and LLR have never been assessed simultaneously in the same humans. To address this important question, thirty participants passively listened to a random sequence of auditory clicks of three possible intensities (65, 75, and 85 dB) at five possible ISI ranges (0.25 to 0.5 s, 0.5 to 1 s, 1 to 2 s, 2 to 4 s, 4 to 8 s) over four to seven one-hour sessions while EEG was recorded. P0, Na, Pa, Nb, and Pb MLR peaks and N1 and P2 LLR peaks were measured. MLRs P0 (p = .005), Pa (p = .021), and Pb (p = <.001) were modulated by intensity, while only MLR Pb (p = <.001) was modulated by ISI. LLR N1 and P2 were modulated by both intensity and ISI (all p values < .001). Intensity and ISI interacted at Pb, N1, and P2 (all p values < .001), with greater intensity effects at longer ISIs and greater ISI effects at louder intensities. Together, these results provide a comprehensive picture of intensity and ISI effects on AER across the entire thalamocortical auditory pathway, while controlling for stimulus predictability. Moreover, they highlight P0 as the earliest MLR response sensitive to stimulus intensity and Pb (~50 ms) as the earliest cortical response coding for ISIs above 250 ms and showing an interdependence between intensity and ISI effects., (© 2022 Society for Psychophysiological Research.)

We use a continuum model to examine the effect of activity on a phase-separating mixture of an extensile active nematic and a passive fluid. We highlight the distinct role of (i) previously considered interfacial active stresses and (ii) bulk active stresses that couple to liquid crystalline degrees of freedom. Interfacial active stresses can arrest phase separation, as previously demonstrated. Bulk extensile active stresses can additionally strongly suppress phase separation by sustained self-stirring of the fluid, substantially reducing the size of the coexistence region in the temperature-concentration plane relative to that of the passive system. The phase-separated state is a dynamical emulsion of continuously splitting and merging droplets, as suggested by recent experiments. Using scaling analysis and simulations, we identify various regimes for the dependence of droplet size on activity. These results can provide a criterion for identifying the mechanisms responsible for arresting phase separation in experiments.

Small-bowel atresias are among the most common causes of intestinal obstruction in newborns, and they often require urgent surgical treatment. Imaging techniques play a very important role in their diagnosis, which is often suspected on prenatal obstetric ultrasound and confirmed on postnatal plain-film X-rays. Abdominal ultrasound's lack of ionizing radiation, wide availability, low cost, and high resolution is making this technique increasingly important in confirming atresias and in detecting possible complications in newborns. This review analyzes a series of cases seen at our center. It summarizes the different types of small-bowel atresias, focusing on the clinical presentation, imaging findings on different modalities, presence of associated disease, management, clinical course, and outcomes., (Copyright © 2021 SERAM. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: The SARS-CoV-2 pandemic has given rise to a major change in healthcare and brought teleconsultation to the forefront. In neurology, headaches are the most frequent reason for visits., Aim: To assess the impact of the COVID-19 pandemic on the structure of headache units in Andalusia and the adaptations made to healthcare that are potentially useful innovations that can continue to be developed when the pandemic is over., Materials and Methods: Cross-sectional observational study using an online survey of neurologists responsible for headache units and specialised consultations in Andalusia., Results: During the state of alarm, all respondents used teleconsultation. The vast majority (92.8%) maintained some face-to-face activity, mostly for invasive techniques and new patients, using individual protection measures and as a way to avoid crowds. Half of them (50%) maintained botulinum toxin administrations at the scheduled times and 78.6% continued to prescribe monoclonal antibodies against calcitonin gene-related peptide. Altogether 78.5% are generally satisfied with the use of teleconsultation and 57.1% think it could be quite useful in the future. The main advantages reported were avoiding the need for the patient to travel and time savings; the disadvantages were the absence of physical examinations and difficulties in communicating. The most frequently expressed need for improvement was the use of video-calls., Conclusions: Some of the changes adopted during this time could continue to be useful in the future and, in the case of headaches, teleconsultation could be used as an option for following up patients who have already been diagnosed and do not require any invasive techniques.

Aim: Cross-culturally adapt the PDMS-2 scale from Spanish-Mexican to Spanish-Spanish and evaluate its validity. To determine the efficacy of physiotherapy treatment (number of physiotherapy sessions and activities proposed by the physiotherapist and performed by the parents) in children with neurodevelopmental disorders between the ages of 0 and 3 years., Subjects and Methods: A first prospective descriptive study of validation of the PDMS-2 scale including 74 subjects with neurodevelopmental disorder with aged from 0 and 3 years old. A second randomized clinical trial to evaluate the physiotherapy (Bobath concept) intervention in the experimental group (EG) (n = 37) who received unique 30-minute weekly sessions for 8 weeks against the control group (CG) (n = 37) that did not receive physiotherapy using the PDMS-2 scale for evaluation., Results: An adequate inter-rater reliablity was found (ICC = 0.76). The scale showed also a very good internal consistency (alpha = 0,99). Significant differences between both groups at 8 weeks. EG obtained better scores in the postest after administrating the physiotherapy treatment (p < 0.001) Moderate and significant correlation coefficients were found between the number of physiotherapy sessions and Total Motor Quotient (TMQ) (r = 0.38; p < 0.05) and the home actitvities with TMQ (r = 0.46; p = 0.005)., Conclusions: The Peabody PDMS-2 scale is a valid and reliable instrument to measure gross and fine motor development in children with neurodevelopmental disorder aged from 0 and 3 years old. Physiotherapy is useful for helping children with delayed neurodevelopment improve. The number of physiotherapy sessions and the activities proposed by the physiotherapist and performed at home by the parents show a direct and positive relationship with the results obtained in motor development.

Small-bowel atresias are among the most common causes of intestinal obstruction in newborns, and they often require urgent surgical treatment. Imaging techniques play a very important role in their diagnosis, which is often suspected on prenatal obstetric ultrasound and confirmed on postnatal plain-film X-rays. Abdominal ultrasound's lack of ionizing radiation, wide availability, low cost, and high resolution is making this technique increasingly important in confirming atresias and in detecting possible complications in newborns. This review analyzes a series of cases seen at our center. It summarizes the different types of small-bowel atresias, focusing on the clinical presentation, imaging findings on different modalities, presence of associated disease, management, clinical course, and outcomes., (Copyright © 2021 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.)

The management of wavelength routed optical mesh networks is complex with many potential light path routes and numerous physical layer impairments to transmission performance. This complexity can be reduced by applying the ideas of abstraction from computer science where different equipment is described in the same basic terms. The noise-to-signal ratio can be used as a metric to describe the quality of transmission performance of a signal propagated through a network element and accumulates additively through a sequence of such elements allowing the estimation of end-to-end performance. This study aims to explore the robustness of the noise-to-signal ratio metric in an installed fibre infrastructure. We show that the abstracted noise-to-signal ratio is independent of the observers and their location. We confirm that the abstracted noise-to-signal ratio can reasonably predict the performance of light-paths subsequently set in our network. Having a robust network element abstraction that can be incorporated into routeing engines allows the network management controller to make decisions on the most effective way to use the network resources in terms of the routeing and data coding format.

Background: Myeloid-derived suppressor cells (MDSCs) are relevant in prostate cancer microenvironment collaborating in tumor development. The main tumor marker used in this disease, prostate-specific antigen (PSA), does not provide information related to this tumor microenvironment. Cancer cells secrete exosomes carrying bioactive molecules contributing to MDSCs recruitment and induction. The aim of this study was to characterize the perioperative changes of exosomal cytokines relevant in MDSCs recruitment induced by prostatectomy in prostate cancer patients., Methods: Blood was drawn from 26 early-stage prostate cancer patients before and after radical prostatectomy and from 16 healthy volunteers. Serum exosomes were separated by precipitation. Cytokines related with MDSC cell recruitment and activation CCL2, CXCL2, CXCL5, CXCL8, CXCL12, MIF, S100A9 and TGF-ß were measured in serum and serum-derived exosomes using immunometric assays., Results: All cytokines were detected both in serum and exosomes, except for CXCL12, which was detected only in serum. Exosomes were enriched specially in MIF, TGF-ß and CXCL2. Presurgical MIF levels in exosomes correlated negatively with serum PSA. Also, presurgical TGF-ß decreased both in serum and exosomes as Gleason score rises. Patientś presurgical exosomes had increased CCL2, CXCL5 and TGF-ß levels than exosomes from healthy controls. These differences were not observed when cytokines were analyzed in serum, except for TGF-ß. Cytokine levels of CCL2, CXCL5 decreased in patients' postsurgical exosomes, while TGF-ß further increased. On the contrary, S100A9 levels were lower in patientś presurgical exosomes but increased after radical prostatectomy., Conclusions: Blood exosomal content in cytokines constitute an attractive source to evaluate MDSCs immunomodulators providing additional information related to tumor microenvironment in prostate cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Total dietary protein intake has been associated with better physical function in older adults. However, it is unclear whether an even mealtime distribution of protein intake also has an impact on physical functioning. The aim of this study was to examine the prospective association between distribution of daily protein intake across meals and the risk of impaired lower extremity function (ILEF)., Methods: We used information of 2975 individuals ≥ 60 years from the Seniors-ENRICA cohort. Habitual dietary protein intake was assessed in 2008-2010 with a validated diet history. For each participant, dietary protein intake across meals was determined using the coefficient of variation (CV) of the distribution. Study participants were followed up until 2017 to identify incident ILEF, assessed with the short physical performance battery (SPPB)., Results: Over a median follow-up of 6.3 years, we identified 521 participants with ILEF (SPPB ≤ 6). After adjusting for potential confounders including total protein intake/kg/day, a higher CV (less even distribution) of protein intake did not show an association with the risk of ILEF [hazard ratios (HR) and 95% confidence intervals (CI) for second and third vs. the first tertile: 1.08 (0.87-1.34), and 1.06 (0.85-1.32), respectively; p trend = 0.60]. When assessing each component of the SPPB, a higher CV of protein intake was associated with higher risk of impaired standing balance (HR for tertile 3 vs. tertile 1: 1.26 (1.03-1.54); p trend = 0.02)., Conclusion: The mealtime distribution of protein intake was not associated with ILEF. The possibility of a detrimental effect of uneven distribution of protein on standing balance needs to be further investigated.

Aims: To investigate potential age, period and birth cohort effects in the prevalence of suicide ideation in European ageing population., Methods: A total of 50 782 community-dwelling adults (aged + 50) from 20 different European countries were collected in the Survey Health Ageing and Retirement study. A multilevel logistic regression model of repeated measures was modelled to assess the effects of age and other variables, including the variability of observations over three levels: birth cohort groups, time period assessment and individual differences., Results: The larger effect of variability was attributed to individual-level factors (57.8%). Youngest-old people (65-79 years) showed lower suicide ideation than middle-aged people (50-64 years). No significative differences were found for suicide ideation between middle-aged people and oldest-old (80 + years). Only 0.85% and 0.13% of the total variability of suicide ideation accounted for birth cohort and period effects, respectively. Cohorts born between 1941 and 1944 possessed the lowest estimates of suicide ideation. Conversely, suicide ideation started to rise with post-War generations and reached a significant level for people born from 1953-1957 to 1961-1964. Regarding the time period, participants assessed in 2006-2007 showed a lower likelihood of suicide ideation. The rest of the cohorts and period groups did not show any significant effect on the prevalence of suicide ideation., Conclusions: Our results suggest that age and suicide ideation relationship is not linear in middle and older age. The European Baby boomers born from 50s to mid-60s might report higher suicide ideation than their ancestors. This scenario would imply a greater need for mental healthcare services for older people in the future.

Objective: To analyse the trajectory of empathy throughout the degree programme of medicine in a Spanish school of medicine., Design: Longitudinal, prospective 5-year study, between October 2014 and June 2019., Setting: Students from a Spanish university of medicine., Participants: Two voluntary cohorts of undergraduate medical students from two different school years were invited to participate (n=135 (cohort 1, C1) and 106 (cohort 2, C2) per school year). Finally, a total number of 174 students (102 (C1, 71.6% women) and 72 (C2, 70.8% women) students, respectively) were monitored for 5 years. Each cohort was divided in two subcohorts of paired and unpaired students that were analysed to check possible social desirability bias., Primary Outcome Measure: The Jefferson Scale of Empathy (JSE)., Results: The cohort of 102 students (C1) monitored between their first and fifth years of study (71.6% women) showed an improvement among paired women of 2.15 points in total JSE score (p=0.01) and 2.39 points in cognitive empathy (p=0.01); in the unpaired female cohort the increase was of 2.32 points (cognitive empathy) (p=0.02). The cohort of 72 students (C2) monitored between their second and sixth years of study (70.8% women) displayed a cognitive empathy increase of 2.32 points (p=0.04) in the paired group of women. There were no significant differences between paired and unpaired results for either cohort. Empathy scores among men did not decrease., Conclusions: The empathy of medical students at our school did not decline along grade years. In fact, it improved slightly, particularly cognitive empathy, among women. This paper contributes to enlarge data from Europe, where longitudinal studies are scarce. It supports the idea that there may be global geo-sociocultural differences; however, more studies comparing different school settings are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A 2A R) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and 21 living donors (LD)) were used to analyze expression levels and activated intracellular pathways related to inflammatory and pro-fibrotic processes. A 2A R expression and PKA pathway were enhanced in DD kidneys. A 2A R gene expression correlated with TGF-β1 and other profibrotic markers, as well as CD163, C/EBPβ, and Col1A1, which are highly expressed in DD kidneys. TNF-α mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-β1 and A 2A R. Experiments with THP-1 cells point to the involvement of the TNF-α/NF-κB pathway in the up-regulation of A 2A R, which induces the M2 phenotype increasing CD163 and TGF-β1 expression. In DD kidneys, the TNF-α/NF-κB pathway could be involved in the increase of A 2A R expression, which would activate the PKA-CREB axis, inducing the macrophage M2 phenotype, TGF-β1 production, and ultimately, fibrosis. Thus, in inflamed DD kidneys, an increase in A 2A R expression is associated with the onset of fibrosis, which may contribute to graft dysfunction and prognostic differences between DD and LD transplants.

Iron/silica core-shell microparticles (IMPs) were functionalized by different functional groups including amine, glycidoxy, phenyl, and thiocyanate. Many of the IMPs modifications are reported for the first time. The resulting surface chemistry turned out to affect the properties of magnetic alginate hydrogels fabricated from sodium alginate and dispersed IMPs. Differences in magnetorheological properties of the obtained magnetic hydrogels can be at least partially attributed to the interactions between alginate and surface functionalities of IMPs. Density Functional Theory (DFT) calculations were carried out to get detailed insight into those interactions in order to link them with the observed macroscopic properties of the obtained hydrogels. For example, amine groups on the IMPs surface resulted in well-formed hydrogels while the presence of thiocyanate or phenyl groups - in poorly formed ones. This observation can be used for tuning the properties of various carbohydrate-based hydrogels., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Poststroke depression (PSD) is related to adverse functional and cognitive prognosis in stroke patients. The participation of kynurenine pathway metabolites in depression has been previously proposed; however, there are few studies on its role in PSD and disability in stroke., Objective: To investigate if there is a correlation between serum kynurenines levels with poststroke anxiety and depression symptoms and disability scales., Methods: A cross-sectional case-control study was conducted in patients with first stroke, of >1 month and <1 year of evolution, with no history of previous psychiatric or neurological disorders; the Hospital Anxiety and Depression Scale (HADS), Montreal Cognitive Assessment (MoCA), functional evaluations (Barthel index, Functional Independence Measure [FIM]) were applied and serum kynurenines (Kyns) were determined., Results: Sixty patients were included; significant depressive symptoms were found in 63% of the cases; a significant and positive correlation was obtained between levels of 3-hydroxykynurenine (3-HK) with HADS-T ( r = 0.30, P = .025) and HADS-D ( r = 0.28, P = .039). Depressed patients showed significantly higher levels of 3HK ( P = .048) and KYNA ( P = .0271) than nondepressed patients; the 3HK levels were inversely correlated with functional scales: Barthel index ( r = -0.31, P = .02), FIM ( r = -0.40, P = .01); in addition, serum 3HK levels were significantly higher in patients with poor sleep quality ( P = .0190)., Conclusions: Serum Kyns show correlation with the presence and severity of depressive symptoms and with the disability and sleep quality. Kyns may be a potential marker of depression risk and disability in stroke in future.

We studied the influences of the thickness of the porous silicon layer and the conductivity type on the porous silicon sensors response when exposed to ethanol vapor. The response was determined at room temperature (27 ∘C) in darkness using a horizontal aluminum electrode pattern. The results indicated that the intensity of the response can be directly or inversely proportional to the thickness of the porous layer depending on the conductivity type of the semiconductor material. The response of the porous sensors was similar to the metal oxide sensors. The results can be used to appropriately select the conductivity of semiconductor materials and the thickness of the porous layer for the target gas.

The purpose of this study was to determine the perioperative mortality rate, reintervention rate, and total healthcare costs for head and neck cancer patients who underwent free tissue transfer (FTT) in Colombia. The prognostic factors associated with those results were estimated., Methods: A retrospective cohort study was performed using administrative data from patients of all ages diagnosed with head and neck cancer who underwent FTT between 2013 and 2016 in Colombia's contributory health system. Postoperative mortality rates were estimated at 30, 90, and 180 days, as well as reintervention rates at 30 and 90 days. Total healthcare costs were calculated. Generalized linear models were generated to determine prognostic factors associated with outcomes., Results: A total of 485 patients were included, 215 (44.33%) of which were women. Mean age was 61.4 years. Mortality rate was 3.09 at 30 days, 9.28 at 90 days, and 15.26 at 180 days, per 100 surgeries. Reintervention rate was 5.77 at 30 days and 8.25 at 90 days, per 100 surgeries. The 30-day reintervention rate was lower for 40- to 59-year-old group and for a Charlson Index ≤ 3. The median total healthcare cost of an episode was USD 12,403.68 (interquartile range, 5754-16,736). The bivariate and multivariate models determined that age, the Charlson Index, and geographic region were associated with outcomes., Conclusion: For patients undergoing FTT in Colombia, differences in reintervention and total costs incurred by the national health system exist, and these differences are associated with age, the Charlson Index, and the geographic region., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

The frequency-following response (FFR) is an auditory evoked potential (AEP) that follows the periodic characteristics of a sound. Despite being a widely studied biosignal in auditory neuroscience, the neural underpinnings of the FFR are still unclear. Traditionally, FFR was associated with subcortical activity, but recent evidence suggested cortical contributions which may be dependent on the stimulus frequency. We combined electroencephalography (EEG) with an inhibitory transcranial magnetic stimulation protocol, the continuous theta burst stimulation (cTBS), to disentangle the cortical contribution to the FFR elicited to stimuli of high and low frequency. We recorded FFR to the syllable /ba/ at two fundamental frequencies (Low: 113 Hz; High: 317 Hz) in healthy participants. FFR, cortical potentials, and auditory brainstem response (ABR) were recorded before and after real and sham cTBS in the right primary auditory cortex. Results showed that cTBS did not produce a significant change in the FFR recorded, in any of the frequencies. No effect was observed in the ABR and cortical potentials, despite the latter known contributions from the auditory cortex. Possible reasons behind the negative results include compensatory mechanisms from the non-targeted areas, intraindividual variability of the cTBS effectiveness, and the particular location of our target area, the primary auditory cortex., (Copyright © 2020 López-Caballero, Martin-Trias, Ribas-Prats, Gorina-Careta, Bartrés-Faz and Escera.)

We address the steady-state entropy production rate (EPR) of active scalar ϕ^{4} theories, which lack time-reversal symmetry, close to a phase-separation critical point. We consider both nonconserved (model A) and conserved (model B) dynamics at Gaussian level, and also address the former at leading order in ε=4-d. In each case, activity is irrelevant in the RG sense: the active model lies in the same (dynamic Ising) universality class as its time-reversible counterpart. Hence one might expect that activity brings no new critical behavior. Here we show instead that, on approach to criticality in these models, the singular part of the EPR per (diverging) spacetime correlation volume either remains finite or itself diverges. A nontrivial critical scaling for entropy production thus ranks among universal dynamic Ising-class properties.

Purpose: Continence assessment is an essential component of follow-up after radical prostatectomy (RP). Several methods exist to assess the severity of urinary incontinence (UI). Our study examined the relationship and degree of agreement between International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) scores and the number of pads used in a 24-hour period in the assessment of UI following RP., Methods: Continence was prospectively assessed in 746 men from a Spanish urology clinic 12 months after RP using the ICIQ-SF and pad usage. The relationship between ICIQ-SF scores and pad usage was assessed using Spearman rank correlation coefficients. The Jonckheere-Terpstra trend test was used to determine whether the ICIQ-SF score and the component question scores increased with increasing pad usage. The Bonferroni-corrected pairwise Wilcoxon rank-sum test was used to determine which pairs of pad usage levels differed. The weighted kappa was used to evaluate the agreement between pad usage levels and ICIQ-SF questions., Results: The continence rate was 82% using the "no pad usage" definition of continence versus 78% using the definition of an ICIQ-SF score of 0 (P<0.001). Strong positive correlations were observed between the number of pads and the ICIQ-SF total and component question scores (rs>0.85, P<0.001). The ICIQ-SF total and component question scores increased significantly with increasing pad usage (P<0.001). The ICIQ-SF scores (P<0.018) for all pairs of pad usage levels (0, 1, 2, or 3 or more) differed significantly. The agreement between the ICIQ-SF leakage amount question and pad usage was very good (rs=0.861, P<0.001)., Conclusion: At 12 months post-RP, 24-hour pad usage was closely correlated with ICIQ-SF, although the continence rate differed depending on the definition used. Higher levels of pad usage were associated with higher questionnaire scores, more leakage, and poor quality of life (interference with everyday life).

Introduction: Due to the absence of specific instruments to study the psychosocial sphere of patients undergoing extracorporeal shock wave lithotripsy (SWL), the objective of this study is to develop a satisfaction questionnaire regarding the SWL treatment from a health questionnaire which was already designed and had been previously validated., Material and Methods: The design of the satisfaction questionnaire was carried out in 5 phases, based on a previously validated health scale in patients treated with SWL (ESPTL), including a total cohort of 135 patients treated at our center who received a phone interview. Phase 1: descriptive analysis of the series and scores of the 8 items of ESPTL. Phase 2: U-Mann Whitney comparison of ESPTL based on the patients' sex. Phase 3: study of ESPTL correlation with age using Spearman's Rho. Phase 4: grouping by factors of ESPTL, comparison by sex and correlation with age, as performed in phases 2 and 3 with the global score. Phase 5: obtaining the satisfaction subscale -SATISLIT-, descriptive analysis, comparison according to sex, correlation with age and linear regression model of SATISLIT with respect to ESPTL., Results: 135 patients, 85(63%) men, 50(37%) women. Median (minimum-maximum) age 56 (27-79) and ESPTL score 31 (8-39). Differences in global ESPTL score between men and women (p <.001), as well as in items 1 (p =.029), 3 (p =.002), 6 (p =.006), 7 (p =.005) and 8 (p =.025). Non-significant correlation of ESPTL regarding age. Significant correlation in items 2, 4, 5 and 8 but, very weak (<0.2). 4 factors, each one with 2 items, with statistically significant differences regarding sex in F2 (p =.001), F3 (p =.007) and F4 (p =.001). Significant correlation with age only in F1 and F3, but very weak (<0.2). Median (minimum-maximum) SATISLIT 18 (4-20). Statistically significant differences regarding patients' sex (p =.001). Non- significant correlation with age (p =.836). Significant linear regression of SATISLIT with respect to ESPTL (p <.001)., Conclusions: Based on validated health questionnaire, the present work has provided a new instrument called SATISLIT for assessing patients' satisfaction after treatment with SWL. Future studies with external and temporal validation will be necessary to contrast its real clinical usefulness., (Copyright © 2019 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

Aims: To study the temporal dynamics of depression symptom episodes in old-age and the related influence of risk factors., Methods: Data from 41 362 old adults (54.61% women; mean age = 75.30, SD = 6.20) from the Ageing Trajectories of Health - Longitudinal Opportunities and Synergies (ATHLOS) project were used. Depressive symptoms were followed over an 18-year period. A multi-state model, comprising three statuses (no depression, new clinically relevant episode of symptoms and episode persistence), was fitted. Multinomial regression was used to study the role of risk factors in status transition., Results: Almost 85% of participants showed no depression, but prevalence became lower over time (B = -0.25, P < 0.001). New episode point prevalence was over 5.30% with a significant probability of moving to persistence status (transition probability = 0.27). Episode persistence became evident in 9.86% of episode status transitions, with increasing rate over time (B = 0.54, P < 0.01). Loneliness was proven to be the strongest predictor of episode emergence (OR = 17.76) and persistence (OR = 5.93)., Conclusions: The course of depression tends to become chronic and unremitting in old-age. This study may help to plan interventions to tackle symptom escalation and risk factor influence., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Sewers represent a very important infrastructure of cities whose state should be monitored periodically. However, the length of such infrastructure prevents sensor networks from being applicable. In this paper, we present a mobile platform (SIAR) designed to inspect the sewer network. It is capable of sensing gas concentrations and detecting failures in the network such as cracks and holes in the floor and walls or zones were the water is not flowing. These alarms should be precisely geo-localized to allow the operators performing the required correcting measures. To this end, this paper presents a robust localization system for global pose estimation on sewers. It makes use of prior information of the sewer network, including its topology, the different cross sections traversed and the position of some elements such as manholes. The system is based on a Monte Carlo Localization system that fuses wheel and RGB-D odometry for the prediction stage. The update step takes into account the sewer network topology for discarding wrong hypotheses. Additionally, the localization is further refined with novel updating steps proposed in this paper which are activated whenever a discrete element in the sewer network is detected or the relative orientation of the robot over the sewer gallery could be estimated. Each part of the system has been validated with real data obtained from the sewers of Barcelona. The whole system is able to obtain median localization errors in the order of one meter in all cases. Finally, the paper also includes comparisons with state-of-the-art Simultaneous Localization and Mapping (SLAM) systems that demonstrate the convenience of the approach.

In recent years, the popularity of metal hydrides has increased considerably for hydrogen storage and their applications in hydrogen fuel cells. Their potential applications for clean energy are promissory. However, the temperatures required for adsorption and desorption are extremely high, which range between 500 and 700 K, making their use impractical. To overcome these difficulties, the following work considers using three hydride alloys: magnesium-aluminum (MgAl), magnesium-nickel (MgNi), and magnesium-zinc (MgZn). The Mg concentrations were set to be between 80 and 100 wt% in order to reduce the temperatures of adsorption and desorption in contrast with the temperatures of pure magnesium. The chemisorption and repulsion energies of the hydrogen molecule on the surface (110) of the different metallic alloys were studied at 0, 200, 400, 600, and 700 K, respectively. The study was based on the density functional theory (DFT), with the module DMol 3 of the molecular simulation program Materials Studio, which was used to obtain these energy values. The results confirm that adding aluminum, nickel, or zinc into magnesium matrix increases the chemisorption and decreases the energy repulsion values on surfaces of the metallic alloys, improving the effectiveness of the hydrogen storage.

α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5 N,6 O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2 B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation.

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study compares the fertility effects of inducing ovulation using human chorionic gonadotropin (hCG) versus gonadotropin releasing hormone (GnRH) at the end of a 5-day progesterone(P4)-based protocol for fixed-time artificial insemination (FTAI) in heat-stressed and non-heat stressed anestrous lactating dairy cows. Heat stress (HS) was defined as an environmental temperature-humidity index (THI) > 72. A P4 intravaginal device (CIDR) was fitted for five days and GnRH administered upon CIDR insertion and a double dose (24 h apart) of prostaglandin F 2α upon CIDR removal. Cows then received either GnRH (GnRH group; n = 506), or hCG (hCG group; n = 493) 36 h after CIDR removal and were inseminated 50-56 h after CIDR removal. Ovulation failure was investigated in a subset of 425 cows: 223 and 202 receiving GnRH and hCG, respectively. Based on odds ratios, the interaction between treatment and HS had a significant effect on the ovulation failure rate (P = 0.01). This meant that compared to the rates recorded in non-heat-stressed, GnRH-treated cows (13%), ovulation failure in heat-stressed GnRH-treated cows (25.3%) was more likely by a factor of 2.3 (P = 0.04), in non-heat-stressed hCG-treated cows (2.3%) was less likely by a factor of 0.16 (P = 0.02) and was not significantly different in heat-stressed hCG-treated cows (7%). Interactions between treatment and HS and between treatment and parity had a significant effect on the pregnancy rate (P = 0.0001 and P = 0.001, respectively). The treatment-HS interaction determined that compared to the rates recorded in non-heat-stressed, GnRH-treated cows (30.5%), pregnancy in heat-stressed GnRH-treated cows (17.6%) was less likely by a factor of 0.48 than the remaining cows (P = 0.001), whereas because of the treatment-parity interaction, compared to the rates recorded in primiparous, GnRH-treated cows (31.4%), pregnancy in GnRH-treated multiparous cows (18.9%) was less likely to conceive by a factor of 0.51 than the remaining cows (P = 0.002). No significant effects of treatment on the rates of pregnancy loss or twin pregnancy were identified by binary logistic regression. In conclusion, hCG treatment given at the end of a 5-day P4-based protocol for FTAI improved ovulation and pregnancy rates in anestrous cows under conditions of HS and also had a beneficial impact on the pregnancy rate in anestrous multiparous cows throughout the year., (Copyright © 2018 Elsevier Inc. All rights reserved.)