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To compare event-related oscillations in patients with dementia with Lewy bodies (DLB) who are carriers and non-carriers of glucocerebrosidase (GBA) mutations.EEG was recorded during a visual oddball task in eight Ashkenazi Jewish DLB patients with the N370S mutation in theGBAgene (GBA-DLB) and eleven DLB non-carriers. The time-frequency power and inter-trial phase clustering were calculated from the Morlet wavelet convolution for the midline electrodes.Task performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed delta-band power synchronization relative to the baseline (p = 0.01, Cohen's d = 1.0), the within-GBA-DLB-group analysis detected no event-related changes in power. Both groups showed an increase relative to the baseline in the delta and theta bands inter-trial phase clustering (all p 0.03, d 1.3). The between-group analysis revealed that event-related power - but not clustering - was lower in GBA-DLB compared to non-carriers in the delta band at Fz and Cz (p = 0.04, d = -0.9).GBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase clustering was comparable in both groups.Preserved inter-trial phase clustering possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance.

In December 2019, several patients were hospitalized and diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which subsequently led to a global pandemic. To date, there are no studies evaluating the relationship between the respiratory phageome and the SARS-CoV-2 infection. The current study investigated the phageome profiles in the nasopharyngeal swabs collected from 55 patients during the three different waves of coronavirus disease 2019 (COVID-19) in the Campania Region (Southern Italy). Data obtained from the taxonomic profiling show that phage families belonging to the order Caudovirales have a high abundance in the patient samples. Moreover, the severity of the COVID-19 infection seems to be correlated with the phage abundance.

To evaluate the effectiveness of a multimodal child poverty curriculum for pediatric residents.The Trainee Education in Advocacy and Community Health (TEACH) curriculum trains residents to recognize and address the effects of child poverty, utilizing learning objectives modified from the US Child Poverty Curriculum, new interactive web-based modules, experiential learning, and reflection. This mixed-methods evaluation of the first component, "Epidemiology of Child Poverty," includes nearly 2 years of resident participation. Pre/post knowledge and attitudes regarding child poverty were assessed. Behavior change was evaluated in a subset of participants using an Objective Structured Clinical Examination (OSCE), comparing intervention and control groups of residents. Residents' experience with the curriculum was assessed using qualitative analysis of debrief sessions with faculty.Fifty-two residents completed the curriculum between June 2018 and March 2020. Residents increased in knowledge (P.001) and confidence (P.0001) in recognizing and addressing poverty. They also self-reported greater preparedness (P.001) and effectiveness (P.001) in addressing social determinants of health. Early data from the OSCE have not shown a statistically significant change in skills compared with a control group. Qualitative themes included an increase in empathy for, understanding of, and responsibility to address the effects of poverty in caring for patients.The multimodal "Epidemiology of Child Poverty" portion of the TEACH curriculum increased resident knowledge, confidence, and empathy. Given the ubiquitous nature of poverty and the generalizability of the online modules, the TEACH curriculum can be a resource for other residency programs.

To determine the rate of fetal and neonatal brain lesions and define risk factors for such lesions in pregnancies complicated by Twin Anemia Polycythemia Sequence (TAPS).A retrospective cohort study of monochorionic twin pregnancies which were diagnosed with TAPS in a single tertiary medical center between 2013 and 2021. Pregnancies were followed with fetal brain neurosonogram every 2 weeks and fetal brain MRI (magnetic resonance imaging) was performed when indicated at 28-32 weeks of gestation; post-natal brain imaging included neonatal brain ultrasound. Pregnancies with pre- and post-natal brain lesions were compared to those without such findings.Overall, 23 monochorionic diamniotic pregnancies were diagnosed with TAPS over the study period resulting in perinatal survival of 91.3% (42/46). In 6/23 (26%) pregnancies and 7/46 (15.2%) fetuses pre- or post-natal brain lesions were detected, of whom five were the polycythemic twins and two were the anemic twins. Brain findings included intra-cerebral hemorrhage and ischemic lesions and were diagnosed prenatally in 6/7 (85.7%) cases. No risk factors for severe brain lesions were identified.TAPS may place the fetuses and neonates at increased risk for cerebral injuries. Incorporation of fetal brain imaging protocols may enhance precise prenatal diagnosis and allow for accurate parental counseling and post-natal care.

OBJECTIVE: We examined whether anti-Black cultural racism moderates the efficacy of psychotherapy interventions among youth. METHOD: We analyzed a subset of studies from a previous meta-analysis of five decades of youth psychotherapy randomized controlled trials. Studies were published in English between 1963 and 2017 and identified through a systematic search. The 194 studies (N = 14,081; ages 2–19) across 34 states comprised 2,678 effect sizes (ESs) measuring mental health problems (e.g., depression) targeted by interventions. Anti-Black cultural racism was operationalized using a composite index of 31 items measuring explicit racial attitudes (obtained from publicly available sources; e.g., General Social Survey), aggregated to the state level and linked to the meta-analytic database. Analyses were conducted with samples of majority (i.e., ≥50%) Black (n = 36 studies) and majority-White (n = 158 studies) youth. RESULTS: Two-level random effects meta-regression analyses indicated that higher anti-Black cultural racism was associated with lower ESs for studies with majority-Black youth (β = −0.2, 95% CI: −0.35, −0.04, p = .02) but was unrelated to ESs for studies with majority-White youth (β = 0.0004, 95% CI: −0.03, 0.03, p = .98), controlling for relevant area-level covariates. In studies with majority-Black youth, mean ESs were significantly lower in states with the highest anti-Black cultural racism (>1 SD above the mean; g = 0.19) compared to states with the lowest racism (

Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a widespread gastrointestinal protozoan parasite with debated taxonomic status. Currently, eight distinct genetic sub-groups, termed assemblages A–H, are defined based on a few genetic markers. Assemblages A and B may represent distinct species and are both of human public health relevance. Genomic studies are scarce and the few reference genomes available, in particular for assemblage B, are insufficient for adequate comparative genomics. Here, by combining long- and short-read sequences generated by PacBio and Illumina sequencing technologies, we provide nine annotated genome sequences for reference from new clinical isolates (four assemblage A and five assemblage B parasite isolates). Isolates chosen represent the currently accepted classification of sub-assemblages AI, AII, BIII and BIV. Synteny over the whole genome was generally high, but we report chromosome-level translocations as a feature that distinguishes assemblage A from B parasites. Orthologue gene group analysis was used to define gene content differences between assemblage A and B and to contribute a gene-set-based operational definition of respective taxonomic units. Giardia is tetraploid, and high allelic sequence heterogeneity (ASH) for assemblage B vs. assemblage A has been observed so far. Noteworthy, here we report an extremely low ASH (0.002%) for one of the assemblage B isolates (a value even lower than the reference assemblage A isolate WB-C6). This challenges the view of low ASH being a notable feature that distinguishes assemblage A from B parasites, and low ASH allowed assembly of the most contiguous assemblage B genome currently available for reference. In conclusion, the description of nine highly contiguous genome assemblies of new isolates of G. duodenalis assemblage A and B adds to our understanding of the genomics and species population structure of this widespread zoonotic parasite.

Objective: Loneliness is associated with negative mental health outcomes and is particularly common among adolescents. Yet, little is known about the dynamics of adolescent loneliness in non-Western, low-income nations. Accordingly, we estimated the severity of loneliness in a sample of Kenyan adolescents and used mixed-effects regression modelling to determine the socio-cultural factors associated with loneliness. We also used network analysis to examine the associations between loneliness, depression, and anxiety at the symptom-level. Method: We analyzed data from a large sample (N = 2,192) of school-attending Kenyan adolescents aged 1219 (58.3% Female, 41.7% Male). Standardized measures of loneliness (ULS-8), depression (PHQ-8), and anxiety (GAD-7) were used. Results: Our mixed-effects model revealed that female and lower-income adolescents felt lonelier. The perception of feeling alone emerged as the aspect of loneliness most strongly linked to depression and anxiety symptoms. Conclusions: Our findings establish an estimate of loneliness levels in Kenyan adolescents, and reveal sociocultural factors associated with loneliness. We found that perceptions of isolation more strongly linked loneliness to psychopathology than did objective measures of isolation or preferences for social contact. Finally, we identify specific aspects of loneliness that could prove to be treatment targets for youth psychopathology; however, further research is needed. Limitations, future directions, and clinical implications are discussed.

Multiple pregnancies are at increased risk of placental-related complications. The aim of the study was to investigate the prevalence and cumulative incidence of placental-related complications in twin pregnancies undergoing a late selective termination, compared to matched singleton and twin controls.A retrospective case-control study of post-selective late termination (≥20 weeks of gestation) singletons performed between 2009 and 2020 at a single tertiary center. Each post-termination pregnancy was matched to 2 singleton and 2 dichorionic twin pregnancies for: mode of conception, maternal age group and parity. The prevalence of composite placental related outcome was determined and compared. Kaplan-Meier curves were constructed, and log rank test was performed to compare the cumulative incidence of placental complications among groups.Included were 90 post-selective termination pregnancies and 360 matched singletons and twins. These were subdivided according to trimester at procedure: 1) late 2nd trimester (N = 43, 20-27.6 weeks); 2) 3rd trimester (N = 47, ≥28 weeks). Placental-related complications presented earlier in the 3rd trimester selective termination group compared to singletons (median 35.5 vs median 37.4 weeks of gestation, P = 0.01). The cumulative incidence of placental-related complications in twins and post-selective termination singletons rose significantly earlier compared to singletons (P 0.0001). A late 2nd trimester selective termination resulted in a comparable gestational age and cumulative incidence of placental-related complications as singletons.Compared to singletons, the cumulative incidence of placental complications rises significantly earlier in post-third trimester selective termination singleton pregnancies. While a late 2nd trimester selective termination results in a cumulative incidence comparable to singletons.

BACKGROUND: In the TWILIGHT trial, ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) was shown to be a safe bleeding avoidance strategy in high-risk patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). AIMS: The aim of this study was to evaluate the effects of ticagrelor monotherapy after three-month DAPT in patients undergoing PCI, according to DES type. METHODS: In the current sub-analysis from TWILIGHT, patients were stratified into three groups based on DES type: durable polymer everolimus-eluting stents (DP-EES), durable polymer zotarolimus-eluting stents (DP-ZES), and biodegradable polymer DES (BP-DES). Bleeding and ischaemic outcomes were assessed at one year after randomisation. RESULTS: Out of 5,769 patients, 3,014 (52.2%) had DP-EES, 1,350 (23.4%) had DP-ZES and 1,405 (24.4%) had BP-DES. Compared with ticagrelor plus aspirin, ticagrelor monotherapy had significantly lower BARC type 2, 3 or 5 bleeding compared with DAPT; DP-EES (3.8% vs 6.7%; HR 0.56, 95% CI: 0.41-0.78), DP-ZES (4.6% vs 6.9%; HR 0.66, 95% CI: 0.42-1.04) and BP-DES (4.2% vs 7.9%; HR 0.52, 95% CI: 0.33-0.81; p(interaction)=0.76). Ticagrelor monotherapy resulted in similar rates of death, MI, or stroke: DP-EES (4.2% vs 4.3%; HR 0.97; 95% CI: 0.68-1.37); DP-ZES (4.1% vs 3.1%; HR 1.32; 95% CI: 0.75-2.33); BP-DES (3.9% vs 4.2%; HR 0.92; 95% CI: 0.54-1.55; p(interaction)=0.60). In both unadjusted and covariate-adjusted analyses, DES type was not associated with any differences in ischaemic or bleeding complications. CONCLUSIONS: As compared with ticagrelor plus aspirin, ticagrelor monotherapy after a short DAPT duration lowered bleeding complications without increasing the ischaemic risk, irrespective of DES type. We observed no significant differences among DES types.

Background: Chronic total occlusions (CTO) are common and are associated with lower percutaneous coronary intervention (PCI) success rates, often due to failure of antegrade guidewire crossing. Local, intralesional delivery of collagenase (MZ-004) may facilitate guidewire crossing in CTO. Aims: To evaluate the effect of MZ-004 in facilitating antegrade wire crossing in CTO angioplasty. Methods: A total of 76 patients undergoing CTO PCI were enrolled at 13 international sites: 38 in the randomized training stage (collagenase [MZ-004] 900 or 1200 μg) and 38 in the placebo-controlled stage (MZ-004 900 or 1200 μg or placebo). Patients received the MZ-004 or identical volume saline (placebo group) in a double-blind design, injected via microcatheter directly into the proximal cap of the CTO. The following day patients underwent CTO PCI using antegrade wire techniques only. Results: Patients were generally similar except for a trend for higher Japanese chronic total occlusion (J-CTO) score in the MZ-004 group (MZ-004 J-CTO score 1.9 vs. 1.4, p = 0.07). There was a numerical increase in the rates of guidewire crossing in the MZ-004 groups compared to placebo (74% vs. 63%, p = 0.52). Guidewire crossing with a soft-tip guidewire (≤1.5 g tip load) was significantly higher in the MZ-004 groups (0% in placebo, 17% in 900 μg, and 29% in 1200 μg MZ-004 group, p = 0.03). Rates of the major adverse cardiovascular event were similar between groups. Conclusion: Local delivery of MZ-004 into coronary CTOs appears safe and may facilitate CTO crossing, particularly with softer tipped guidewires. These data support the development of a pivotal trial to further evaluate this agent.

A growing number of emerging SARS-CoV-2 variants is being identified worldwide, potentially impacting the effectiveness of current vaccines. We report the data obtained in several Italian regions involved in the SARS-CoV-2 variant monitoring from the beginning of the epidemic and spanning the period from October 2020 to March 2021.

Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumor in the adult population; its high recurrence rate and resistance to current therapeutics urgently demand a better therapy. Regulation of protein stability by the ubiquitin proteasome system (UPS) represents an important control mechanism of cell growth. UPS deregulation is mechanistically linked to the development and progression of a variety of human cancers, including GBM. Thus, the UPS represents a potentially valuable target for GBM treatment. Using an integrated approach that includes proteomics, transcriptomics and metabolic profiling, we identify praja2, a RING E3 ubiquitin ligase, as the key component of a signaling network that regulates GBM cell growth and metabolism. Praja2 is preferentially expressed in primary GBM lesions expressing the wild-type isocitrate dehydrogenase 1 gene (IDH1). Mechanistically, we found that praja2 ubiquitylates and degrades the kinase suppressor of Ras 2 (KSR2). As a consequence, praja2 restrains the activity of downstream AMP-dependent protein kinase in GBM cells and attenuates the oxidative metabolism. Delivery in the brain of siRNA targeting praja2 by transferrin-targeted self-assembling nanoparticles (SANPs) prevented KSR2 degradation and inhibited GBM growth, reducing the size of the tumor and prolonging the survival rate of treated mice. These data identify praja2 as an essential regulator of cancer cell metabolism, and as a potential therapeutic target to suppress GBM growth.

The architecture of the efferent auditory system enables prioritization of strongly overlapping spatiotemporal cochlear activation patterns elicited by relevant and irrelevant inputs. So far, attempts at finding such attentional modulations of cochlear activity delivered indirect insights in humans or required direct recordings in animals. The extent to which spiral ganglion cells forming the human auditory nerve are sensitive to selective attention remains largely unknown. We investigated this question by testing the effects of attending to either the auditory or visual modality in human cochlear implant (CI) users (3 female, 13 male). Auditory nerve activity was directly recorded with standard CIs during a silent (anticipatory) cue-target interval. When attending the upcoming auditory input, ongoing auditory nerve activity within the theta range (5-8 Hz) was enhanced. Crucially, using the broadband signal (4-25 Hz), a classifier was even able to decode the attended modality from single-trial data. Follow-up analysis showed that the effect was not driven by a narrow frequency in particular. Using direct cochlear recordings from deaf individuals, our findings suggest that cochlear spiral ganglion cells are sensitive to top-down attentional modulations. Given the putatively broad hair-cell degeneration of these individuals, the effects are likely mediated by alternative efferent pathways compared with previous studies using otoacoustic emissions. Successful classification of single-trial data could additionally have a significant impact on future closed-loop CI developments that incorporate real-time optimization of CI parameters based on the current mental state of the user.SIGNIFICANCE STATEMENTThe efferent auditory system in principle allows top-down modulation of auditory nerve activity; however, evidence for this is lacking in humans. Using cochlear recordings in participants performing an audiovisual attention task, we show that ongoing auditory nerve activity in the silent cue-target period is directly modulated by selective attention. Specifically, ongoing auditory nerve activity is enhanced within the theta range when attending upcoming auditory input. Furthermore, over a broader frequency range, the attended modality can be decoded from single-trial data. Demonstrating this direct top-down influence on auditory nerve activity substantially extends previous works that focus on outer hair cell activity. Generally, our work could promote the use of standard cochlear implant electrodes to study cognitive neuroscientific questions.

Few measures of autism-related symptoms have been established as both psychometrically robust and sensitive to the effects of treatment. In the present study, a personalized measure of autism-related symptoms using the Youth Top Problems (YTP) method (Weisz et al., 2011) was evaluated. Participants included 68 children with diagnoses of autism (ages 6-13 years), and their parents, who were randomized to cognitive behavioral therapy (CBT) or enhanced standard community treatment (ESCT) addressing autism-related symptoms. At pretreatment, parents described their child's top autism-related problems (YTPs) in their own words and rated the severity of these problems on a Likert-type scale. Parents also made daily severity ratings on the child's top three YTPs for 5 days prior to treatment and 5 days following treatment while videorecording their child's behavior at home on each of these days. Trained observers coded these videorecordings, focusing on the same YTPs that the parents rated. Parents also completed standardized checklists of autism-related symptoms and general mental health symptoms. There was evidence of convergent and discriminant validity as well as good test-retest reliability for the YTP measures. YTP severity scores converged with the standardized measure of autism-related symptoms. Parent-reported YTP scores predicted observers' YTP scores at the daily level, and both parent-reported and observers' YTP scores decreased from pre- to post treatment. Observers' ratings of the videorecordings exhibited sensitivity to treatment condition. These applications of the YTP method are promising and may complement standardized symptom checklists for clinical trials focusing on autism-related symptoms. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Ongoing fluctuations in neural excitability and connectivity influence whether or not a stimulus is seen. Do they also influence which stimulus is seen? We recorded magnetoencephalography data while 21 human participants viewed face or house stimuli, either one at a time or under bistable conditions induced through binocular rivalry. Multivariate pattern analysis revealed common neural substrates for rivalrous versus nonrivalrous stimuli with an additional delay of ∼36 msec for the bistable stimulus, and poststimulus signals were source-localized to the fusiform face area. Before stimulus onset followed by a face versus house report, fusiform face area showed stronger connectivity to primary visual cortex and to the rest of the cortex in the alpha frequency range (8–13 Hz), but there were no differences in local oscillatory alpha power. The prestimulus connectivity metrics predicted the accuracy of poststimulus decoding and the delay associated with rivalry disambiguation suggesting that perceptual content is shaped by ongoing neural network states.

Background Network analyses have been applied to understand the relationships between individual symptoms of depression and anxiety. However, little is known about which symptoms are most strongly associated with “positive” indicators of mental health, such as happiness. Furthermore, few studies have examined symptom networks in participants from low- and middle-income countries. Methods To address these gaps, we applied network analyses in a sample of Indian adolescents (Study 1; n=1080) and replicated these analyses in a pre-registered study with Kenyan adolescents (Study 2; n=2176). Participants from both samples completed the same measures of depressive symptoms, anxiety symptoms, and happiness. Results Feeling sad and feeling like a failure had the strongest (negative) associations with happiness items. These two symptoms, as well as worrying and feeling nervous, had the strongest associations with other symptoms of depression and anxiety. Symptoms of depression and anxiety formed a single cluster, which was distinct from a cluster of happiness items. Main findings were consistent across the two samples, suggesting a cross-culturally robust pattern. Limitations We used cross-sectional data, and we administered scales assessing a limited subset of symptoms and happiness items. Conclusions Our findings support the idea that some symptoms of depression and anxiety are more strongly associated with happiness. These findings contribute to a body of literature emphasizing the advantages of symptom-level analyses. We discuss how efforts to understand associations between individual symptoms and “positive” mental health indicators, like happiness, could have theoretical and practical implications for clinical psychological science.

BACKGROUND: Prior coronary artery bypass graft surgery (CABG) patients undergoing percutaneous coronary intervention (PCI) are often older and present with multiple comorbidities. Ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) has emerged as an effective bleeding-avoidance strategy among high-risk patients. AIMS: We aimed to examine the effects of ticagrelor with or without aspirin in prior CABG patients undergoing PCI within the TWILIGHT trial. METHODS: After 3 months of ticagrelor plus aspirin, patients were randomised to either aspirin or placebo, in addition to ticagrelor, for 12 months and compared by prior CABG status. The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding. The key secondary endpoint was all-cause death, myocardial infarction (MI), or stroke. RESULTS: Out of 7,119 patients, a total of 703 (10.8%) patients had prior CABG within the randomised cohort. Prior CABG patients had more comorbidities and a higher incidence of BARC type 2, 3, or 5 bleeding and death, MI or stroke at 1 year after randomisation, compared with patients without prior CABG. Ticagrelor monotherapy was associated with significantly less BARC 2, 3, or 5 bleeding among prior CABG patients compared with DAPT (4.9% vs 9.6%, hazard ratio [HR] 0.50, 95% confidence interval [CI]: 0.28 to 0.90; pinteraction=0.676) and similar rates of death, MI or stroke (10.0% vs 8.7%, HR 1.14, 95% CI: 0.70 to 1.87; pinteraction=0.484). When comparing target vessel type, treatment effects were consistent among graft- and native-vessel interventions. CONCLUSIONS: In high-risk patients with prior CABG, ticagrelor monotherapy reduced bleeding without compromising ischaemic outcomes compared with ticagrelor plus aspirin.

Background Neuroendocrine neoplasms (NENs) represent a heterogeneous class of rare tumors with increasing incidence. They are characterized by the ability to secrete peptide hormones and biogenic amines but other reliable biomarkers are lacking, making diagnosis and identification of the primary site very challenging. While in some NENs, such as the pancreatic ones, next generation sequencing technologies allowed the identification of new molecular hallmarks, our knowledge of the molecular profile of NENs from other anatomical sites is still poor. Methods Starting from the concept that NENs from different organs may be clinically and genetically correlated, we applied a multi-omics approach by combining multigene panel testing, CGH-array, transcriptome and miRNome profiling and computational analyses, with the aim to highlight common molecular and functional signatures of gastroenteropancreatic (GEP)-NENs and medullary thyroid carcinomas (MTCs) that could aid diagnosis, prognosis and therapy. Results By comparing genomic and transcriptional profiles, ATM-dependent signaling emerged among the most significant pathways at multiple levels, involving gene variations and miRNA-mediated regulation, thus representing a novel putative druggable pathway in these cancer types. Moreover, a set of circulating miRNAs was also selected as possible diagnostic/prognostic biomarkers useful for clinical management of NENs. Conclusions These findings depict a complex molecular and functional landscape of NENs, shedding light on novel therapeutic targets and disease biomarkers to be exploited.

Introduction: Some abnormal electrocardiographic findings were independently associated with increased mortality in patients admitted for COVID-19; however, no studies have focussed on the prognosis impact of the interatrial block (IAB) in this clinical setting. The aim of our study was to assess the prevalence and clinical implications of IAB, both partial and advanced, in hospitalized COVID-19 patients. Materials: We retrospectively evaluated 300 consecutive COVID-19 patients (63.22±15.16years; 70% males) admitted to eight Italian Hospitals from February 2020 to April 2020 whounderwent twelve lead electrocardiographic recording at admission. The study population has been dichotomized into two groups according to the evidence of IAB at admission, both partial and advanced. The differences in terms of ARDS in need of intubation, in-hospital mortality and thromboembolic events (a composite of myocardial infarction, stroke and transient ischaemic attack) have been evaluated. Results: The presence of IAB was noticed in 64 patients (21%). In the adjusted logistic regression model, the partial interatrial block was found to be an independent predictor of ARDS in need of intubation (HR: 1.92; p:.04) and in-hospital mortality (HR: 2.65; p:.02); moreover, the advanced interatrial block was an independent predictor of thrombotic events (HR: 7.14; p&nbsp

Purpose We conducted the first prospective longitudinal study examining the independent association between patient-reported health-related quality of life (hrQoL) (physical, social/family, emotional, functional, and brain cancer-specific) and neurocognitive function (NCF), while controlling for mood symptoms in patients with primary brain tumors. Methods and Materials Patients with primary brain tumors (n = 59) receiving brain radiation therapy underwent hrQOL (Functional Assessment of Cancer Therapy-Brain), mood (Beck Depression and Anxiety Inventories), and neurocognitive evaluation at baseline and 3, 6, and 12 months postradiation therapy in a prospective clinical trial. Neurocognitive assessments measured attention/processing speed, memory, and executive function, including the Delis-Kaplan Executive Function System Verbal Fluency, Hopkins Verbal Learning Test Revised (HVLT-R), and Brief Visuospatial Memory Test. Subjects underwent neurocognitive, mood, and hrQoL assessments in the same testing session. Multivariable linear mixed-effects models assessed associations between hrQOL and NCF over time, controlling for patient, tumor, and treatment characteristics as well as timepoint-specific patient-reported mood (ie, anxiety and depression symptoms). P values were adjusted for multiple comparisons. Results Higher physical hrQoL was associated with better verbal memory (HVLT-R Total Recall, P = .047), and higher functional hrQoL was associated with better executive function (Delis-Kaplan Executive Function System Verbal Fluency Switching Total, P = .009) and verbal memory (HVLT-R Delayed Recall, P = .006). Higher brain tumor-specific hrQoL was associated with better verbal and nonverbal memory (HVLT-R Total, P = .004 and Delayed Recall, P = .030; Brief Visuospatial Memory Test Total, P = .049 and Delayed Recall, P = .049). There was no association between social/family or emotional hrQoL and NCF after controlling for mood. Conclusions Higher physical, functional, and brain tumor-specific hrQoL were associated with better executive function and memory among patients with primary brain tumors. Physical and functional impairments are correlated with cognitive performance. Interventions to maximize quality of life after treatment may influence neurocognition and vice versa.

Although technical (quality of delivering techniques from a specific treatment) and global (general clinical expertise) competence are believed to be important ingredients of successful psychosocial treatment with youth, there have been few empirical efforts to measure both dimensions. Efforts to understand the role that each competence dimension plays in the process and outcome of youth treatment starts with determining whether the dimensions can be measured separately. This study examined whether scores from measures designed to assess technical and global competence were distinct. Treatment sessions (N = 603) from 38 youths (M age = 9.84 years, SD = 1.65; 60.5% White; 52.6% male) treated for primary anxiety problems within a randomized effectiveness trial were coded. Four coders used observational measures designed to assess technical competence, global competence, protocol adherence, and the alliance. Mean item interrater reliability was .70 (SD = .09) for technical competence and .66 (SD = .05) for global competence. While most components of global competence were distinct from technical competence scores, two components showed redundancy (r > .70). Scores on both competence measures were empirically distinct (r < .70) from scores on measures of protocol adherence and the alliance. Although the measures did not fully distinguish between technical and global competence, our findings do indicate that some components of technical and global competence may provide unique information about competence.

Objective To determine the rate of and risk factors for fetal and neonatal brain lesions following laser ablation for twin-to-twin transfusion syndrome (TTTS). Methods A retrospective cohort study of 83 women with monochorionic twin pregnancies who underwent ablation for TTTS at a single tertiary hospital. Post-laser survivors were followed-up with fetal neurosonogram every 2 weeks and fetal brain MRI at 28-32 weeks of gestation; post-natal brain imaging included neurosonogram. Cases with pre- and post-natal brain lesions were compared to those without. Results 153 fetuses survived the immediate post-laser period and underwent brain imaging. Of these, 17 (11.11%) exhibited brain lesions on prenatal imaging studies, and 36 (32.4%) on post-natal ultrasound. Later gestational age (GA) at the time of ablation (23.0 weeks vs. 21.4 weeks, p=0.0244), post-laser TAPS (29.41% vs. 9.56%, p=0.035) and birthweight discordancy (30% vs 9%, p=0.0025) were associated with prenatal brain lesions. Earlier GA at delivery (31.0 weeks vs. 32.2, p=0.0002) and post-laser TAPS (25% vs. 9.33%, p=0.038) were associated with post-natal brain lesions. Conclusions Survivors of ablation for TTTS are at risk for brain lesions, which can be detected prenatally. Incorporation of neurosonogram and fetal brain MRI into the routine surveillance of such pregnancies should be considered. This article is protected by copyright. All rights reserved.

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the presence of clones of mutated blood cells without overt blood diseases. In the last few years, it has emerged that CHIP is associated with atherosclerosis and coronary calcification and that it is an independent determinant of cardiovascular mortality. Recently, CHIP has been found to occur frequently in patients with calcific aortic valve disease (CAVD) and it is associated with a poor prognosis after valve replacement. We assessed the frequency of CHIP by DNA sequencing in the blood cells of 168 CAVD patients undergoing surgical aortic valve replacement or transcatheter aortic valve implantation and investigated the effect of CHIP on 12 months survival. To investigate the pathological process of CAVD in CHIP carriers, we compared by RNA-Seq the aortic valve transcriptome of patients with or without CHIP and non-calcific controls. Transcriptomics data were validated by immunohistochemistry on formalin-embedded aortic valve samples. We confirm that CHIP is common in CAVD patients and that its presence is associated with higher mortality following valve replacement. Additionally, we show, for the first time, that CHIP is often accompanied by a broad cellular and humoral immune response in the explanted aortic valve. Our results suggest that an excessive inflammatory response in CHIP patients may be related to the onset and/or progression of CAVD and point to B cells as possible new effectors of CHIP-induced inflammation.

Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms regulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles highlighting the markedly variable consequences of the PDA are provided. In most contemporary settings, transcatheter closure is preferable over surgical ligation, but data on longer‐term outcomes, particularly among preterm infants, are lacking. The present review provides recommendations to identify gaps in PDA diagnosis, management, and treatment on which subsequent research can be developed. Ultimately, the combination of refined diagnostic thresholds and expanded treatment options provides the best opportunities to address the burden of PDA. Although fundamental gaps remain unanswered, the present review provides pediatric and adult cardiac care providers with a contemporary framework in PDA care to support the practice of evidence‐based medicine.

From December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly, leading to a global pandemic. Little is known about possible relationships between SARS-CoV-2 and other viruses in the respiratory system affecting patient prognosis and outcomes. This study aims to characterize respiratory virome profiles in association with SARS-CoV-2 infection and disease severity, through the analysis in 89 nasopharyngeal swabs collected in a patient's cohort from the Campania region (Southern Italy). Results show coinfections with viral species belonging to Coronaviridae, Retroviridae, Herpesviridae, Poxviridae, Pneumoviridae, Pandoraviridae, and Anelloviridae families and only 2% of the cases (2/89) identified respiratory viruses.

Since its first appearance, the SARS-CoV-2 has spread rapidly in the human population, reaching the pandemic scale with >280 million confirmed infections and more than 5 million deaths to date (https://covid19.who.int/). These data justify the urgent need to enhance our understanding of SARS-CoV-2 effects in the respiratory system, including those linked to co-infections. The principal aim of our study is to investigate existing correlations in the nasopharynx between the bacterial community, potential pathogens, and SARS-CoV-2 infection. The main aim of this study was to provide evidence pointing to possible relationships between components of the bacterial community and SARS-CoV-2 in the nasopharynx. Meta-transcriptomic profiling of the nasopharyngeal microbial community was carried out in 89 SARS-Cov-2 positive subjects from the Campania Region in Italy. To this end, RNA extracted from nasopharyngeal swabs collected at different times during the initial phases of the pandemic was analyzed by Next-Generation Sequencing (NGS). Results show a consistently high presence of members of the Proteobacteria (41.85%), Firmicutes (28.54%), and Actinobacteria (16.10%) phyla, and an inverted correlation between the host microbiome, co-infectious bacteria, and super-potential pathogens such as Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Neisseria gonorrhoeae. In depth characterization of microbiota composition in the nasopharynx can provide clues to understand its potential contribution to the clinical phenotype of Covid-19, clarifying the interaction between SARS-Cov-2 and the bacterial flora of the host, and highlighting its dysbiosis and the presence of pathogens that could affect the patient's disease progression and outcome.

Objective Evaluate the association of late treatment with acetaminophen vs. immediate surgical ligation with death or neurodevelopmental impairment (NDI) among extremely low gestational age neonates (ELGANs) with persistent patent ductus arteriosus (pPDA). Study design Retrospective comparative epoch study of ELGANs with pPDA being considered for surgical ligation. ELGANs in epoch 1 (2009-2012) were referred for ligation, while infants in epoch 2 (2012-2015) were treated with oral acetaminophen and referred for ligation in the absence of improvement. The primary outcome was a composite of death/NDI at 18-24 months. Results Ninety-two ELGANs with median[IQR] GA 25.2 weeks [24.4, 26.3] had pPDA (43 in epoch 1, 49 in -epoch 2) with acetaminophen-exposed neonates receiving 7 days [7, 7] of treatment. ELGANs in epoch 2 had reduced ligation (aOR 0.30; 95%CI: [0.11, 0.87]), but there was no difference in death/NDI (aOR 1.03; 95%CI: [0.30, 3.56]). Conclusions Late treatment with acetaminophen to avoid surgery for pPDA is associated with reduced ligation but no difference in death/NDI, supporting the safety and effectiveness of this approach.

Hysterosalpingo-foam sonography (HyFoSy) is considered an acceptable alternative for hysterosalpingography (HSG). By combining HyFoSy with two and three-dimensional (2D and 3D) ultrasound and hysterosonography, a complete fertility work-up can be done. We aimed to evaluate the value of a combined ultrasound examination for fertility work-up. During the study period 113 women were examined. Five of 113 (4.4%) examinations were abandoned due to intra-uterine adhesions that were detected by hysterosonography, and five (4.4%) were abandoned due to technical difficulties. Of 103 women who had completed the examination, 2D ultrasound revealed six patients with hydrosalpinx (5.8%) and sonographic signs of adenomyosis in 13 (12.6%) patients. By combining 2D ultrasound with hysterosonography, two (1.9%) fibroids that were penetrating the uterine cavity and seven (6.8%) endometrial polyps were detected. HyFoSy showed bilateral patent tubes in 58 patients (56.3%), unilateral tubal occlusion in 29 (28.1%) and bilateral tubal occlusion in 16 (15.5%). This study shows that the 'one-stop shop' examination is feasible. The combined examination had detected 16 pathological findings that would have not been detected by HyFoSy alone. Hence, it should be offered to couples undergoing routine infertility work-up.IMPACT STATEMENTWhat is already known on this subject? The accuracy of the HyFoSy alone has been evaluated in different studies, but this presented ultrasound scan is integrating 4 different modalities in one exam (2D scanning of the pelvis, 3D scanning of the uterus, hysterosonography and HyFoSy) and we were able to evaluate the female pelvic organs, including the uterine cavity, the tubes and the ovaries, in order to expand the range of diagnosed pathologies.What do the results of this study add? The concept of 'one-stop shop' for the evaluation of female pelvis in couples suffering from infertility is feasible, has comparable accuracy as HSG for tubal occlusion, and higher detection rate for uterine malformations.What are the implications of these findings for clinical practice and/or further research? We suggest to incorporate this examination in routine fertility work-up.

Objective Discrepancies between caregiver and youth reports of emotional and behavioral symptoms are well-documented, with cross-informant correlations often falling in the low to moderate range. Studies have shown that caregiver-youth (dis)agreement in reporting of youth symptoms is related to treatment outcomes. However, commonly used methods for exploring reporter discrepancies (e.g., difference scores) are limited by their inability to assess discrepancies across multiple symptom domains simultaneously, and thus these previous findings do not explore multiple patterns of (dis)agreement. Method We used latent profile analysis (LPA) to identify subgroups of clinically referred youths based on patterns of caregiver- and youth-reported internalizing and externalizing symptoms for 174 caregiver-youth dyads. Longitudinal multilevel models were used to examine changes in weekly caregiver- and youth-reported internalizing symptoms, externalizing symptoms, and top problems for identified subgroups. Results The LPA identified four latent subgroups: (a) Caregiver Internalizing (9%), (b) Caregiver Internalizing-Externalizing (45%), (c) Youth Internalizing (7%), and (d) Caregiver-Youth Internalizing-Externalizing (39%). Clinical outcomes varied across informants and subgroups. Significant improvements in caregiver- and youth-reported outcome measures were documented within the Caregiver Internalizing, Caregiver Internalizing-Externalizing, and Caregiver-Youth Internalizing-Externalizing subgroups. However, only youth-reported improvements were detected in the Youth Internalizing subgroup. The results show differences in treatment outcomes across caregiver-youth informant subgroups. Conclusions These findings suggest how youth and caregiver baseline data could provide guidance for clinicians in interpreting discrepant reporting and its relevance to change during treatment.

Objective We conducted a prospective clinical trial of patients receiving radiation (RT) for brain metastases to identify clinical predictors of pre-RT and post-RT health-related quality of life (hrQoL). Materials and methods Patients with brain metastases completed overall (European Organisation for Research and Treatment of Cancer QLQ C15-PAL) and brain tumor-specific (QLQ-BN20) hrQoL assessments pre-RT (n=127) and 1 (n=56) and 3 (n=45) months post-RT. Linear and proportional-odds models analyzed patient, disease, and treatment predictors of baseline, 1-, and 3-month hrQoL scores. Generalized estimating equations and repeated measures proportional-odds models assessed predictors of longitudinal hrQoL scores. Results Most patients underwent stereotactic radiosurgery (SRS) (69.3%) and had non-small-cell lung (36.0%) metastases. Compared with SRS, receipt of whole brain RT was associated with a higher odds of appetite loss (baseline P=0.04, 1 mo P=0.02) and greater motor dysfunction (baseline P=0.01, 1 mo P=0.003, 3 mo P=0.02). Receipt of systemic therapy was associated with better emotional functioning after RT (1 mo P=0.03, 3 mo P=0.01). Compared with patients with breast cancer, patients with melanoma had higher odds of better global hrQoL (P=0.01) and less pain (P=0.048), while patients with lung cancer reported lower physical function (P=0.048) 3 months post-RT. Nonmarried patients had greater odds of higher global hrQoL (1 mo P=0.01), while male patients had lower odds of reporting more hair loss (baseline P=0.03, 3 mo P=0.045). Patients 60 years and above had lower odds of more drowsiness (P=0.04) and pain (P=0.049) over time. Conclusions Patients receiving SRS versus whole brain RT and systemic therapy reported better posttreatment hrQoL. In addition, melanoma metastases, nonmarried, male, and older patients with reported better hrQoL in various as well as domains after intracranial RT.

Objective: To evaluate the costs and cost-effectiveness of Shamiri-Digital, an online single-session intervention (SSI) for depression among Kenyan adolescents. Method: Data were drawn from a randomized clinical trial with n = 103 Kenyan high school students (64% female, Mage = 15.5). All students were eligible to participate, regardless of baseline depression symptomatology. We estimated delivery costs in 2020 U.S. dollars from multiple perspectives. To account for uncertainty, we performed sensitivity analyses with different cost assumptions and definitions of effectiveness. Using number needed to treat (NNT) estimates, we also evaluated the cost required to achieve a clinically meaningful reduction in depressive symptoms. Results: In the base-case (the most realistic cost estimate), it costs U.S. $3.57 per student to deliver Shamiri-Digital. Depending on the definition of clinically meaningful improvement, 7.1-9.7 students needed to receive the intervention for one student to experience a clinically meaningful improvement, which translated to a cost of U.S. $25.35 to U.S. $34.62 per student. Under a worst-case scenario (i.e., assuming the highest treatment cost and the strictest effectiveness definition), the cost to achieve clinically meaningful improvement was U.S. $92.05 per student. Conclusions:Shamiri-Digital is a low-cost intervention for reducing depression symptomatology. The public health benefit of empirically supported SSIs is especially important in low-income countries, where funding for mental health care is most limited. Future research can compare the cost-effectiveness of online SSIs to higher-cost treatments and estimate the robustness of Shamiri-Digital's effects over a longer time horizon. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. Objective: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. Methods: The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. Results: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. Conclusion: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.