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Ir-NSi species stable under catalytic FADH conditions!.

Background Adolescent antisocial behavior (AB) is a public health concern due to the high financial and social costs of AB on victims and perpetrators. Neural systems involved in reward and loss processing are thought to contribute to AB. However, investigations into these processes are limited: few have considered anticipatory and consummatory components of reward, response to loss, nor whether associations with AB may vary by level of callous-unemotional (CU) traits. Methods A population-based community sample of 128 predominantly low-income youth (mean age = 15.9 years; 42% male) completed a monetary incentive delay task during fMRI. A multi-informant, multi-method latent variable approach was used to test associations between AB and neural response to reward and loss anticipation and outcome and whether CU traits moderated these associations. Results AB was not associated with neural response to reward but was associated with reduced frontoparietal activity during loss outcomes. This association was moderated by CU traits such that individuals with higher levels of AB and CU traits had the largest reductions in frontoparietal activity. Co-occurring AB and CU traits were also associated with increased precuneus response during loss anticipation. Conclusions Findings indicate that AB is associated with reduced activity in brain regions involved in cognitive control, attention, and behavior modification during negative outcomes. Moreover, these reductions are most pronounced in youth with co-occurring CU traits. These findings have implications for understanding why adolescents involved in AB continue these behaviors despite severe negative consequences (e.g. incarceration).

Stressful events, such as the COVID-19 pandemic, are major contributors to anxiety and depression, but only a subset of individuals develop psychopathology. In a population-based sample (N = 174) with a high representation of marginalized individuals, this study examined adolescent functional network connectivity as a marker of susceptibility to anxiety and depression in the context of adverse experiences.Data-driven network-based subgroups were identified using an unsupervised community detection algorithm within functional neural connectivity. Neuroimaging data collected during emotion processing (age 15) were extracted from a priori regions of interest linked to anxiety and depression. Symptoms were self-reported at ages 15, 17, and 21 (during COVID-19). During COVID-19, participants reported on pandemic-related economic adversity. Differences across subgroup networks were first examined, then subgroup membership and subgroup-adversity interaction were tested to predict change in symptoms over time.Two subgroups were identified: Subgroup A, characterized by relatively greater neural network variation (i.e., heterogeneity) and density with more connections involving the amygdala, subgenual cingulate, and ventral striatum; and the more homogenous Subgroup B, with more connections involving the insula and dorsal anterior cingulate. Accounting for initial symptoms, subgroup A individuals had greater increases in symptoms across time (β = .138, p = .042), and this result remained after adjusting for additional covariates (β = .194, p = .023). Furthermore, there was a subgroup-adversity interaction: compared with Subgroup B, Subgroup A reported greater anxiety during the pandemic in response to reported economic adversity (β = .307, p = .006), and this remained after accounting for initial symptoms and many covariates (β = .237, p = .021).A subgrouping algorithm identified young adults who were susceptible to adversity using their personalized functional network profiles derived from a priori brain regions. These results highlight potential prospective neural signatures involving heterogeneous emotion networks that predict individuals at the greatest risk for anxiety when experiencing adverse events.

Gonorrhoea infections are frequently diagnosed at extragenital locations in asymptomatic individuals and are historically related to poor recovery in culture, which hinders antimicrobial susceptibility testing. The aim of this study was to evaluate recovery rates of Neisseria gonorrhoeae by culture among asymptomatic individuals who tested positive by nucleic acid amplification tests between 2018 and 2019 in Barcelona (Spain). In total, 10 396 individuals were tested for N. gonorrhoeae on first-void urine, rectal, pharyngeal and/or vaginal swabs depending on sexual behaviour. Overall infection prevalence was 5·5% (95% confidence interval [CI] 5·0–5·9). Seven hundred and ten samples were positive corresponding to 567 individuals. The most common site of infection was the pharynx (71·3%), followed by rectum (23·1%) and genitals (4·7%) (P < 0·0001). The N. gonorrhoeae recovery rate in culture, time from positive screening to culture specimen and inoculation delay were calculated. Recovery rate was 21·7% in pharynx, 66·9% in rectum and 37·0% in genitals (25·0% vagina, 71·4% urethra) (P < 0·0001). Median culture collection time was 1 [0; 3] days, and median inoculation delay was 5·01 [4·99–7·99] h, with no impact on N. gonorrhoeae recovery, P = 0·8367 and P = 0·7670, respectively. Despite efforts towards optimizing pre-analytical conditions, the N. gonorrhoeae recovery rate in asymptomatic individuals is unacceptably low (especially for pharynx), representing a problem for monitoring antimicrobial-resistant infections.

We have designed a workflow to apply full-waveform inversion (FWI) to a new type of acquisition recorded on ocean-bottom nodes (OBNs) in the Brazilian presalt area. The data set consists of three large-radius concentric circles of seismic source points recorded on OBN placed within the area of the circles. This geometry provides full azimuth distribution and benefits from long offsets in which the effect of diving waves is strong. These diving waves carry information about the presalt targets of interest. In the FWI workflow, we retrieve the P-wave velocity using the density as a propagation parameter. We test three objective functions: ℓ2-norm, ℓ1-norm, and nonparametric residuals objective function (NPR-FWI), which have different abilities to handle low signal-to-noise ratio data. In our inversion tests, the ℓ1-norm and NPR-FWI retrieve more information about the presalt reservoir than the ℓ1-norm. We find through several inversion experiments that we can recover structures related to the presalt reservoir, demonstrating the potential for this new type of OBN circular source geometry. We also discuss implications for low-cost data acquisition that take advantage of the sparse nature of sources and receivers needed in this survey geometry, including its extension to time-lapse target-oriented reservoir monitoring.

Background: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. Objective: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. Methods: Pooled cohort study of individual participant data from six cohorts (1971–2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1–Q3, 5.2–20.1) years. Results: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. Conclusion: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

Automated imaging techniques have been in increasing demand for the more advanced analysis and efficient characterization of cellular phenotypes. The success of the image-based profiling method hinges on assays that can rapidly and simultaneously capture a wide range of phenotypic features. We have developed an automated image acquisition method for fungal cytological profiling (FCP) using an imaging flow cytometer that can objectively measure over 250 features of a single fungal cell. Fungal cells were labeled with calcofluor white and FM4-64FX, which bind to the cell wall and lipophilic membrane, respectively. Images of single cells were analyzed using IDEAS® software. We first acquired FCPs of fungal cells treated with fluconazole, amphotericin B, and caspofungin, each with a distinct mode of action, to establish FCP databases of profiles associated with specific antifungal treatment. Once fully established, we investigated the potential application of this technique as a screening methodology to identify compounds with novel antifungal activity against Candida albicans and Cryptococcus neoformans. Altogether, we have developed a rapid, powerful, and novel image-profiling method for the phenotypic characterization of fungal cells, also with potential applications in antifungal drug development.

An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Sociedad Española de Cardiología. Background Fatigue and exercise intolerance are the most common symptoms in patients with long COVID. Purpose This study aimed to evaluate whether a home-based inspiratory muscle training (IMT) program improves maximal functional capacity in patients long COVID after a previous admission due to SARS-CoV-2 pneumonia. Methods This study was a single-centre, blinded assessor, randomised controlled trial. Twenty-six patients with long COVID and a previous admission due to SARS-CoV-2 pneumonia were randomly assigned to receive either a 12-week program of IMT or usual care alone. The physiotherapist and participants were not blinded. Patients allocated to the IMT arm were instructed to train at home twice daily using a threshold inspiratory muscle trainer and to maintain diaphragmatic breathing during the training session. The usual care arm received no intervention. The primary endpoint was changes in peak oxygen consumption (peakVO2). Secondary endpoints were changes in quality of life (QoL), ventilatory efficiency and chronotropic response during exercise (evaluated by chronotropic index-CIx- formula). We used linear mixed regression analysis for evaluating changes in primary and secondary endpoints. Results The median (interquartile range) age of the sample and time to first visit after discharge were 52 (42-59) years and 405 (301-435) days, respectively. A total of 11 (42.3%) were female. At baseline, the median of peakVO2, ventilatory efficiency and CIx were 17.4 (15.6-21.1) mL/kg/min, 29 (24.5-33.3), and 0.64 (0.54-0.87), respectively. The IMT arm improved their peakVO2 significantly compared to usual care (+Δ 4.46 mL/kg/min, 95% CI 3.10 to 5.81; p Conclusion In long COVID patients with a previous admission due to SARS-CoV-2 pneumonia, IMT was associated with marked improvement in exercise capacity and QoL.

Background Obturator hernia is infrequent (incidence 1%). This condition usually occurs in older, multiparous women. Case Report We report two cases of this pathology: The first one deals with a woman that presents insidious abdominal pain, who underwent an abdominal CT scan compatible with mechanical intestinal obstruction secondary to present the ileum trapped in a right obturator hernia. Treatment consisted of a laparoscopic approach creating a peritoneal flap, hernioplasty with polypropylene mesh and closure of the flap with V-lock 3/0. The last one is about an elderly woman who presents nausea and vomiting accompanied by severe pain in the left lower limb. An abdominal CT scan was performed, which revealed a distal jejunal loop into the left obturator accompanied by intestinal obstruction. Open henioplasty was performed due to significant adhesive syndrome. The hernia sac was reduced, preperitoneal plug was placed and the orifice was closed with vycril suture. Discussion Diagnosis is complex due to the characteristics of the patients. There are 3 signs of strangulated hernia: obturator neuralgia, pain in the medial thigh due to obturator nerve compression and the absence of the adductor reflex in the thigh. The most accurate diagnostic test is the CT scan. Three treatment techniques are described: transabdominal, extraperitoneal and laparoscopic. Conclusion Despite of obturator hernia is not a frequent cause of intestinal obstruction, we should consider the laparoscopic approach as an option with fewer postoperative complications, when possible.

IntroductionBeta oscillations in sensorimotor structures contribute to the planning, sequencing, and stopping of movements, functions that are typically associated with the role of the basal ganglia. The presence of beta oscillations (13–30 Hz) in the cerebellar zone of the thalamus (the ventral intermediate nucleus – Vim) indicates that this rhythm may also be involved in cerebellar functions such as motor learning and visuomotor adaptation.MethodsTo investigate the possible role of Vim beta oscillations in visuomotor coordination, we recorded local field potential (LFP) and multiunit activity from the Vim of essential tremor (ET) patients during neurosurgery for the implantation of deep brain stimulation (DBS) electrodes. Using a computer, patients performed a visuomotor adaptation task that required coordinating center-out movements with incongruent visual feedback imposed by inversion of the computer display.ResultsThe results show that, in ET, Vim beta oscillations of the LFP were lower during the incongruent center-out task than during the congruent orientation. Vim firing rates increased significantly during periods of low beta power, particularly on approach to the peripheral target. In contrast, beta power in the subthalamic nucleus of Parkinson’s disease (PD) patients did not differ significantly between the incongruent and the congruent orientation of the center-out task.DiscussionThe findings support the hypothesis that beta oscillations of the Vim are modulated by novel visuomotor tasks. The inverse relationship between the power of Vim-LFP beta oscillations and Vim firing rates suggest that the suppression of beta oscillations may facilitate information throughput to the thalamocortical circuit by modulation of Vim firing rates.

Animal studies suggest that the apolipoprotein E ε4 ( APOE ε4) allele is a culprit of early microglial activation in Alzheimer’s disease (AD). Here, we tested the association between APOE ε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [ 18 F]AZD4694), tau ([ 18 F]MK6240), and microglial activation ([ 11 C]PBR28). We found that APOE ε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOE ε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE ε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE ε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

Transected peripheral nerve injury (PNI) affects the quality of life of patients, which leads to socioeconomic burden. Despite the existence of autografts and commercially available nerve guidance conduits (NGCs), the complexity of peripheral nerve regeneration requires further research in bioengineered NGCs to improve surgical outcomes. In this work, we introduce multidomain peptide (MDP) hydrogels, as intraluminal fillers, into electrospun poly(ε-caprolactone) (PCL) conduits to bridge 10 mm rat sciatic nerve defects. The efficacy of treatment groups was evaluated by electromyography and gait analysis to determine their electrical and motor recovery. We then studied the samples' histomorphometry with immunofluorescence staining and automatic axon counting/measurement software. Comparison with negative control group shows that PCL conduits filled with an anionic MDP may improve functional recovery 16 weeks postoperation, displaying higher amplitude of compound muscle action potential, greater gastrocnemius muscle weight retention, and earlier occurrence of flexion contracture. In contrast, PCL conduits filled with a cationic MDP showed the least degree of myelination and poor functional recovery. This phenomenon may be attributed to MDPs' difference in degradation time. Electrospun PCL conduits filled with an anionic MDP may become an attractive tissue engineering strategy for treating transected PNI when supplemented with other bioactive modifications.

Purpose:The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.Experimental Design:TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).Results:The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.Conclusions:The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.

Pharmacodynamic effects of alisertib and TAK-228 in patient tissue samples

The neurophysiology of selective attention in visual and auditory systems has been studied in animal models but not with single unit recordings in human. Here, we recorded neuronal activity in the ventral intermediate nucleus as well as the ventral oral anterior, and posterior nuclei of the motor thalamus in 25 patients with parkinsonian (n = 6) and non-parkinsonian tremors (n = 19) prior to insertion of deep brain stimulation electrodes while they performed an auditory oddball task. In this task, patients were requested to attend and count the randomly occurring odd or “deviant” tones, ignore the frequent standard tones and report the number of deviant tones at trial completion. The neuronal firing rate decreased compared to baseline during the oddball task. Inhibition was specific to auditory attention as incorrect counting or wrist flicking to the deviant tones did not produce such inhibition. Local field potential analysis showed beta (13–35 Hz) desynchronization in response to deviant tones. Parkinson’s disease patients off medications had more beta power than the essential tremor group but less neuronal modulation of beta power to the attended tones, suggesting that dopamine modulates thalamic beta oscillations for selective attention. The current study demonstrated that ascending information to the motor thalamus can be suppressed during auditory attending tasks, providing indirect evidence for the searchlight hypothesis in humans. These results taken together implicate the ventral intermediate nucleus in non-motor cognitive functions, which has implications for the brain circuitry for attention and the pathophysiology of Parkinson’s disease.

The number of people suffering from Alzheimer’s disease (AD) is increasing rapidly every year. One aspect of AD that is often overlooked is the disproportionate incidence of AD among African American/Black populations. With the recent development of novel assays for lipidomics analysis in recent times, there has been a drastic increase in the number of studies focusing on changes of lipids in AD. However, very few of these studies have focused on or even included samples from African American/Black individuals samples. In this study, we aimed to determine if the lipidome in AD is universal across non-Hispanic White and African American/Black individuals. To accomplish this, a targeted mass spectrometry lipidomics analysis was performed on plasma samples (N = 113) obtained from cognitively normal (CN, N = 54) and AD (N = 59) individuals from African American/Black (N = 56) and non-Hispanic White (N = 57) backgrounds. Five lipids (PS 18:0_18:0, PS 18:0_20:0, PC 16:0_22:6, PC 18:0_22:6, and PS 18:1_22:6) were altered between AD and CN sample groups (p value < 0.05). Upon racial stratification, there were notable differences in lipids that were unique to African American/Black or non-Hispanic White individuals. PS 20:0_20:1 was reduced in AD in samples from non-Hispanic White but not African American/Black adults. We also tested whether race/ethnicity significantly modified the association between lipids and AD status by including a race × diagnosis interaction term in a linear regression model. PS 20:0_20:1 showed a significant interaction (p = 0.004). The discovery of lipid changes in AD in this study suggests that identifying relevant lipid biomarkers for diagnosis will require diversity in sample cohorts.