A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression.

The diverse roles of the dynein motor in shaping microtubule networks and cargo transport complicate in vivo analysis of its functions significantly. To address this issue, we have generated a series of missense mutations in Drosophila Dynein heavy chain. We show that mutations associated with human neurological disease cause a range of defects, including impaired cargo trafficking in neurons. We also describe a novel microtubule-binding domain mutation that specifically blocks the metaphase-anaphase transition during mitosis in the embryo. This effect is independent from dynein's canonical role in silencing the spindle assembly checkpoint. Optical trapping of purified dynein complexes reveals that this mutation only compromises motor performance under load, a finding rationalized by the results of all-atom molecular dynamics simulations. We propose that dynein has a novel function in anaphase progression that depends on it operating in a specific load regime. More broadly, our work illustrates how in vivo functions of motors can be dissected by manipulating their mechanical properties.

Stress testing the Centiloid: Precision and variability of PET quantification of amyloid pathology.

INTRODUCTION: Assessing the potential sources of bias and variability of the Centiloid (CL) scale is fundamental for its appropriate clinical application. METHODS: We included 533 participants from AMYloid imaging to Prevent Alzheimer's Disease (AMYPAD DPMS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. Thirty-two CL pipelines were created using different combinations of reference region (RR), RR and target types, and quantification spaces. Generalized estimating equations stratified by amyloid positivity were used to assess the impact of the quantification pipeline, radiotracer, age, brain atrophy, and harmonization status on CL. RESULTS: RR selection and RR type impact CL the most, particularly in amyloid-negative individuals. The standard CL pipeline with the whole cerebellum as RR is robust against brain atrophy and differences in image resolution, with 95% confidence intervals below ± 3.95 CL for amyloid beta positivity cutoffs (CL < 24). DISCUSSION: The standard CL pipeline is recommended for most scenarios. Confidence intervals should be considered when operationalizing CL cutoffs in clinical and research settings. HIGHLIGHTS: We developed a framework for evaluating Centiloid (CL) variability to different factors. Reference region selection and delineation had the highest impact on CL values. Whole cerebellum (WCB) and whole cerebellum plus brainstem (WCB+BSTM) as reference regions yielded consistent results across tracers. The standard CL pipeline is robust against atrophy and image resolution variation. Estimated within- and between-pipeline variability (95% confidence interval) in absolute CL units.

Continuous ß-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity.

BACKGROUND AND OBJECTIVES: Discordance between CSF and PET biomarkers of ß-amyloid (Aß) might reflect an imbalance between soluble and aggregated species, possibly reflecting disease heterogeneity. Previous studies generally used binary cutoffs to assess discrepancies in CSF/PET biomarkers, resulting in a loss of information on the extent of discordance. In this study, we (1) jointly modeled Aß-CSF/PET data to derive a continuous measure of the imbalance between soluble and fibrillar pools of Aß, (2) investigated factors contributing to this imbalance, and (3) examined associations with cognitive trajectories. METHODS: Across 822 cognitively unimpaired (n = 261) and cognitively impaired (n = 561) Alzheimer's Disease Neuroimaging Initiative individuals (384 [46.7%] females, mean age 73.0 ± 7.4 years), we fitted baseline CSF-Aß42 and global Aß-PET to a hyperbolic regression model, deriving a participant-specific Aß-aggregation score (standardized residuals); negative values represent more soluble relative to aggregated Aß and positive values more aggregated relative to soluble Aß. Using linear models, we investigated whether methodological factors, demographics, CSF biomarkers, and vascular burden contributed to Aß-aggregation scores. With linear mixed models, we assessed whether Aß-aggregation scores were predictive of cognitive functioning. Analyses were repeated in an early independent validation cohort of 383 Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study individuals (224 [58.5%] females, mean age 65.2 ± 6.9 years). RESULTS: The imbalance model could be fit (pseudo-R2 = 0.94) in both cohorts, across CSF kits and PET tracers. Although no associations were observed with the main methodological factors, lower Aß-aggregation scores were associated with larger ventricular volume (ß = 0.13, p < 0.001), male sex (ß = -0.18, p = 0.019), and homozygous APOE-ε4 carriership (ß = -0.56, p < 0.001), whereas higher scores were associated with increased uncorrected CSF p-tau (ß = 0.17, p < 0.001) and t-tau (ß = 0.16, p < 0.001), better baseline executive functioning (ß = 0.12, p < 0.001), and slower global cognitive decline (ß = 0.14, p = 0.006). In the validation cohort, we replicated the associations with APOE-ε4, CSF t-tau, and, although modestly, with cognition. DISCUSSION: We propose a novel continuous model of Aß CSF/PET biomarker imbalance, accurately describing heterogeneity in soluble vs aggregated Aß pools in 2 independent cohorts across the full Aß continuum. Aß-aggregation scores were consistently associated with genetic and AD-associated CSF biomarkers, possibly reflecting disease heterogeneity beyond methodological influences.

Salud sin Fronteras: Identifying Determinants of Frequency of Healthcare Use among Mexican immigrants in Southern Arizona.

BACKGROUND: Guided by Andersen's Behavioral Model of Health Services Use (BMHSU), this study aimed to identify determinants of post-migration healthcare use among a sample of Mexican immigrants in a US-Mexico border region in Southern Arizona, while considering pre-migration health and healthcare experiences. METHODS: A non-probabilistic convenience sample of 300 adult Mexican immigrants completed a telephone survey to assess healthcare practices. Multivariable logistic regressions were fitted to determine adjusted relationships between frequency of care and predisposing, enabling, need, and contextual factors as well as personal health practices. RESULTS: Overall, participants had a 79% probability of receiving healthcare "at least once a year" after migrating to Southern Arizona. Receiving post-migration healthcare was associated with predisposing, enabling, need, contextual factors, and personal health practices (p < 0.05). DISCUSSION: Consistent with BMHSU, our findings suggest that frequency of healthcare is not only a function of having post-migration health insurance but is also shaped by a complex array of other factors. The results of this study shed light onto potential areas to be leveraged by multifactorial sociocultural interventions to increase Mexican immigrants' frequency of healthcare services use.

Amyloid-PET imaging predicts functional decline in clinically normal individuals.

BACKGROUND: There is good evidence that elevated amyloid-ß (Aß) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aß burden and decline in daily living activities in this population. Moreover, Aß-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established. METHODS: Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aß groups (CL < 12 = Aß-, 12 ≤ CL ≤ 50 = Aß-intermediate/Aß± , CL > 50 = Aß+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample. RESULTS: Participants included 765 Aß- (61%, Mdnage = 66.0, IQRage = 61.0-71.0; 59% women), 301 Aß± (24%; Mdnage = 69.0, IQRage = 64.0-75.0; 53% women) and 194 Aß+ individuals (15%, Mdnage = 73.0, IQRage = 68.0-78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB (bCL*Time = 0.001/CL/year, 95% CI [0.0005,0.0024], p = .003) and A-IADL-Q (bCL*Time = -0.010/CL/year, 95% CI [-0.016,-0.004], p = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aß+ CN individuals (HRAß+ vs Aß- = 2.55, 95% CI [1.16,5.60], p = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB (bAß+ vs Aß- = 0.137/year, 95% CI [0.069,0.206], p < .001) and 28 CL using the A-IADL-Q (bAß+ vs Aß- = -0.693/year, 95% CI [-1.179,-0.208], p = .005). CONCLUSIONS: Amyloid-PET quantification supports the identification of CN individuals at risk of functional decline. TRIAL REGISTRATION: The AMYPAD PNHS is registered at www.clinicaltrialsregister.eu with the EudraCT Number: 2018-002277-22.

Disparities in hepatocellular carcinoma incidence among Hispanic and non-Hispanic adults in Arizona: Trends between 2009-2017.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly lethal cancer with few treatment options available to patients. Most HCC cases in Arizona, a state with a high proportion of Hispanic adults, have not been included in recent reports of HCC incidence. This study describes trends in HCC incidence and stage at diagnosis among Arizona residents between 2009-2017 and reports on racial and ethnic disparities for these outcomes. METHODS: The Arizona Cancer Registry was used to identify Arizonans aged 19 or older diagnosed with liver cell carcinoma diagnosed between 2009-2017. A total of 5043 cases were examined. Adjusted annual and 3-year HCC incidence rates (per 100,000) were examined for non-Hispanic White (NHW) and Hispanic adults. RESULTS: The total age-adjusted HCC incidence rate increased significantly between 2009-2012 and then declined significantly between 2012-2017. Across nearly all years, age-adjusted HCC incidence in Hispanic adults was twice that of NHW adults. Hispanic adults were more likely to be diagnosed at a later stage across all time periods. The disparity in 3-year age-adjusted HCC incidence rate between NHW and Hispanic adults decreased between 2009-2017. CONCLUSION: Whe total age-adjusted HCC incidence rate increased significantly between 2009-2012 and then declined significantly between 2012-2017. Across nearly all years, age-adjusted HCC incidence in Hispanic adults was twice that of NHW adults. Hispanic adults were more likely to be diagnosed at a later stage across all time periods. The disparity in 3-year age-adjusted HCC incidence rate between NHW and Hispanic adults decreased between 2009-2017.

A comprehensive, predictive mortality score for patients with bloodstream infections (PROBAC): a prospective, multicentre cohort study.

OBJECTIVES: Bloodstream infections (BSI) are an important cause of mortality, although they show heterogeneity depending on patients and aetiological factors. Comprehensive and specific mortality scores for BSI are scarce. The objective of this study was to develop a mortality predictive score in BSI based on a multicentre prospective cohort. METHODS: A prospective cohort including consecutive adults with bacteraemia recruited between October 2016 and March 2017 in 26 Spanish hospitals was randomly divided into a derivation cohort (DC) and a validation cohort (VC). The outcome was all-cause 30-day mortality. Predictors were assessed the day of blood culture growth. A logistic regression model and score were developed in the DC for mortality predictors; the model was applied to the VC. RESULTS: Overall, 4102 patients formed the DC and 2009 the VC. Mortality was 11.8% in the DC and 12.34% in the CV; the patients and aetiological features were similar for both cohorts. The mortality predictors selected in the final multivariate model in the DC were age, cancer, liver cirrhosis, fatal McCabe underlying condition, polymicrobial bacteraemia, high-risk aetiologies, high-risk source of infection, recent use of broad-spectrum antibiotics, stupor or coma, mean blood pressure <70 mmHg and PaO2/FiO2 ≤ 300 or equivalent. Mortality in the DC was <2% for ≤2 points, 6%-14% for 3-7 points, 26%-45% for 8-12 points and ≥60% for ≥13 points. The predictive score had areas under the receiving operating curves of 0.81 (95% CI 0.79-0.83) in the DC and 0.80 (0.78-0.83) in the VC. CONCLUSIONS: A 30 day mortality predictive score in BSI with good discrimination ability was developed and internally validated.

The maintenance of mexican traditional medicine practices among mexicans in southern Arizona.

Mexicans in the United States have been reported to maintain practices of Mexican traditional medicine at comparably higher rates than most other populations, including other Latino sub-groups. In this cross-sectional study, we examined the pre- and post-migration traditional medicine practices of first-generation immigrants from Mexico living in southern Arizona. Our objective was to assess how migration affected Mexican immigrants' ethnomedical practices and to better understand the mechanisms and motivating factors for the post-migration maintenance of practice. We designed a survey instrument based off prior qualitative data on traditional medicine practices and translated it into Spanish. The survey measured the rates and frequency of six domains of lay healing practices: herbal medicine, healing foods, self-medication with over-the-counter medicine, and three types of specialty healers (curandero/a, and sobador/a, or partero/a), and asked questions about knowledge sources, reasons for maintaining practice post-migration, and to what extent participants believed the remedies were effective. The research team fielded the telephone-based survey from April 2022 to February 2023 to 300 first-generation adult Mexican immigrants residing in southern Arizona. A series of proportions tests were conducted to examine differences in reliance on lay healing pre- and post-migration as well as to assess differences between women's and men's lay practices. The data indicate a general, but moderated decline in lay medical practices post-migration, with the usage of expert healers declining at much higher rates than the three self-care domains. Women tend to use herbal medicine and healing foods at higher rates than men post-migration. This cross-sectional quantitative study confirms prior research indicating that traditional medicine practices are heavily relied upon by Mexican origin people both pre- and post-migration. These findings suggest that public health messaging and medical providers should better address and harness Mexican immigrants' lay medical practices in order to optimize health in this population.

Proactive selective attention across competition contexts.

Selective attention is a cognitive function that helps filter out unwanted information. Theories such as the biased competition model (Desimone & Duncan, 1995) explain how attentional templates bias processing towards targets in contexts where multiple stimuli compete for resources. However, it is unclear how the anticipation of different levels of competition influences the nature of attentional templates, in a proactive fashion. In this study, we used electroencephalography (EEG) to investigate how the anticipated demands of attentional selection (either high or low stimuli competition contexts) modulate target-specific preparatory brain activity and its relationship with task performance. To do so, participants performed a sex/gender judgment task in a cue-target paradigm where, depending on the block, target and distractor stimuli appeared simultaneously (high competition) or sequentially (low competition). Multivariate Pattern Analysis (MVPA) showed that, in both competition contexts, there was a preactivation of the target category to select, with a ramping-up profile at the end of the preparatory interval. However, cross-classification showed no generalization across competition conditions, suggesting different preparatory formats. Notably, time-frequency analyses showed differences between anticipated competition demands, with higher theta band power for high than low competition, which mediated the impact of subsequent stimuli competition on behavioral performance. Overall, our results show that, whereas preactivation of the internal templates associated with the category to select are engaged in advance in high and low competition contexts, their underlying neural patterns differ. In addition, these codes could not be associated with theta power, suggesting that they reflect different preparatory processes. The implications of these findings are crucial to increase our understanding of the nature of top-down processes across different contexts.

Alzheimer's Disease and Small Vessel Disease Differentially Affect White Matter Microstructure.

OBJECTIVE: Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non-invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE-ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non-demented older adults. METHODS: Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid ß1-42 and p-Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow-up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed-effects model for each tract. RESULTS: AD pathology, APOE-ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE-ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect. INTERPRETATION: Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.

Modeling the Regional Distribution of International Travelers in Spain to Estimate Imported Cases of Dengue and Malaria: Statistical Inference and Validation Study.

BACKGROUND: Understanding the patterns of disease importation through international travel is paramount for effective public health interventions and global disease surveillance. While global airline network data have been used to assist in outbreak prevention and effective preparedness, accurately estimating how these imported cases disseminate locally in receiving countries remains a challenge. OBJECTIVE: This study aimed to describe and understand the regional distribution of imported cases of dengue and malaria upon arrival in Spain via air travel. METHODS: We have proposed a method to describe the regional distribution of imported cases of dengue and malaria based on the computation of the "travelers' index" from readily available socioeconomic data. We combined indicators representing the main drivers for international travel, including tourism, economy, and visits to friends and relatives, to measure the relative appeal of each region in the importing country for travelers. We validated the resulting estimates by comparing them with the reported cases of malaria and dengue in Spain from 2015 to 2019. We also assessed which motivation provided more accurate estimates for imported cases of both diseases. RESULTS: The estimates provided by the best fitted model showed high correlation with notified cases of malaria (0.94) and dengue (0.87), with economic motivation being the most relevant for imported cases of malaria and visits to friends and relatives being the most relevant for imported cases of dengue. CONCLUSIONS: Factual descriptions of the local movement of international travelers may substantially enhance the design of cost-effective prevention policies and control strategies, and essentially contribute to decision-support systems. Our approach contributes in this direction by providing a reliable estimate of the number of imported cases of nonendemic diseases, which could be generalized to other applications. Realistic risk assessments will be obtained by combining this regional predictor with the observed local distribution of vectors.

Quality of life, craniomandibular function, and psychosocial factors related to pain and movement in patients with head and neck cancer.

PURPOSE: To describe the characteristics of and the associations between health-related quality of life, pain, craniomandibular function, and psychosocial factors related to pain and fear of movement in patients with head and neck cancer. METHODS: Seventy-eight patients diagnosed with HNC were recruited. Measurements of the maximum mouth opening range and pressure pain thresholds on the masseter muscle and the distal phalanx of the thumb were conducted, as well as a battery of self-report questionnaires were administrated, including the QoL Questionnaire (EORT QLQ-H&N35), Numeric Rating Scale (NRS), Pain Catastrophizing Scale (PCS), the Spanish translation of the Tampa Scale for Kinesiophobia for Temporomandibular Disorders (TSK-TMD), and the short version of the Craniofacial Pain and Disability Inventory (CF-PDI-11). RESULTS: The study sample (66.7% men, mean age 60.12 [11.95] years) experienced a moderate impact on their QoL levels (57.68 [18.25] EORT QLQ-H&N35) and high kinesiophobia values (20.49 [9.11] TSK-TMD). Pain was present in 41% of the patients, but only 3.8% reported severe pain. 26.4% had a restricted mouth opening range, and 34.62% showed significant catastrophism levels. There were strong positive correlations between EORT QLQ-H&N35 and CF-PDI-11 (r = 0.81), between NRS and CF-PDI-11 (r = 0.74), and between PCS and CF-PDI-11 (r = 0.66). CONCLUSION: Patients with HNC experience negative effects in their QoL, related to their impairment in craniomandibular function. Fear of movement, pain intensity, and catastrophism are associated with poorer functionality; relationships that should be considered when attempting to improve health care.

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits.

G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HT2AR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT2AR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HT2AR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by Gαq protein activation, whereas psychosis-related behavior is modulated through Gαi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.

Functional imaging guided stereotactic ablative body radiotherapy (SABR) with focal dose escalation and bladder trigone sparing for intermediate and high-risk prostate cancer: study protocol for phase II safo trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment alternative for patients with localized low and intermediate risk prostate cancer patients. As already explored by some authors in the context of conventional moderate hypofractionated radiotherapy, focal boost of the index lesion defined by magnetic resonance imaging (MRI) is associated with an improved biochemical outcome. The objective of this phase II trial is to determine the effectiveness (in terms of biochemical, morphological and functional control), the safety and impact on quality of life, of prostate SABR with MRI guided focal dose intensification in males with intermediate and high-risk localized prostate cancer. METHODS: Patients with intermediate and high-risk prostate cancer according to NCCN definition will be treated with SABR 36.25 Gy in 5 fractions to the whole prostate gland with MRI guided simultaneous integrated focal boost (SIB) to the index lesion (IL) up to 50 Gy in 5 fractions, using a protocol of bladder trigone and urethra sparing. Intra-fractional motion will be monitored with daily cone beam computed tomography (CBCT) and intra-fractional tracking with intraprostatic gold fiducials. Androgen deprivation therapy (ADT) will be allowed. The primary endpoint will be efficacy in terms of biochemical and local control assessed by Phoenix criteria and post-treatment MRI respectively. The secondary endpoints will encompass acute and late toxicity, quality of life (QoL) and progression-free survival. Finally, the subgroup of high-risk patients will be involved in a prospective study focused on immuno-phenotyping. DISCUSSION: To the best of our knowledge, this is the first trial to evaluate the impact of post-treatment MRI on local control among patients with intermediate and high-risk prostate cancer undergoing SABR and MRI guided focal intensification. The results of this trial will enhance our understanding of treatment focal intensification through the employment of the SABR technique within this specific patient subgroup, particularly among those with high-risk disease, and will help to clarify the significance of MRI in monitoring local responses. Hopefully will also help to design more personalized biomarker-based phase III trials in this specific context. Additionally, this trial is expected to be incorporated into a prospective radiomics study focused on localized prostate cancer treated with radiotherapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05919524; Registered 17 July 2023. TRIAL SPONSOR: IRAD/SEOR (Instituto de Investigación de Oncología Radioterápica / Sociedad Española de Oncología Radioterápica). STUDY SETTING: Clinicaltrials.gov identifier: NCT05919524; Registered 17 July 2023. TRIAL STATUS: Protocol version number and date: v. 5/ 17 May-2023. Date of recruitment start: August 8, 2023. Date of recruitment completion: July 1, 2024.

AlloViz: A tool for the calculation and visualisation of protein allosteric communication networks.

Allostery, the presence of functional interactions between distant parts of proteins, is a critical concept in the field of biochemistry and molecular biology, particularly in the context of protein function and regulation. Understanding the principles of allosteric regulation is essential for advancing our knowledge of biology and developing new therapeutic strategies. This paper presents AlloViz, an open-source Python package designed to quantitatively determine, analyse, and visually represent allosteric communication networks on the basis of molecular dynamics (MD) simulation data. The software integrates well-known techniques for understanding allosteric properties simplifying the process of accessing, rationalising, and representing protein allostery and communication routes. It overcomes the inefficiency of having multiple methods with heterogeneous implementations and showcases the advantages of using MD simulations and multiple replicas to obtain statistically sound information on protein dynamics; it also enables the calculation of "consensus-like" scores aggregating methods that consider multiple structural aspects of allosteric networks. We demonstrate the features of AlloViz on two proteins: ß-arrestin 1, a key player for regulating G protein-coupled receptor (GPCR) signalling, and the protein tyrosine phosphatase 1B, an important pharmaceutical target for allosteric inhibitors. The software includes comprehensive documentation and examples, tutorials, and a user-friendly graphical interface.

Discordance between aPTT and anti-Xa in monitoring heparin anticoagulation in mechanical circulatory support.

AIMS: It is unclear whether activated partial thromboplastin time (aPTT) or anti-Xa is more accurate for monitoring heparin anticoagulation in mechanical circulatory support (MCS) patients. This study investigates the relationship between aPTT and anti-Xa in MCS patients and identifies predictors of discordance. METHODS AND RESULTS: aPTT and anti-Xa were simultaneously measured in a prospective cohort of MCS patients receiving unfractionated heparin at a tertiary academic medical centre. Therapeutic aPTT and anti-Xa levels were 60-100 s and 0.3-0.7 IU/mL, respectively, and concordance was defined as both levels being subtherapeutic, therapeutic, or supratherapeutic. To identify predictors of discordance, both a machine learning random forest model and a multivariate regression model were applied to patient demographics, device type, and 14 laboratory variables; 23 001 pairs of simultaneously measured aPTT/anti-Xa were collected from 699 MCS patients. aPTT and anti-Xa were concordant in 35.5% of paired observations and discordant in 64.5% (aPTT > antiXa 61.5%; aPTT < antiXa 3.0%). Discordance with a high aPTT relative to anti-Xa (aPTT > antiXa) was associated with high INR, eGFR, and total bilirubin, as well as low platelets, haemoglobin, pre-albumin, white blood cell count, and haptoglobin. Total artificial heart and durable ventricular assist devices were more likely to be associated with aPTT > anti-Xa than temporary MCS devices. CONCLUSIONS: aPTT and anti-Xa were frequently discordant in MCS patients receiving heparin anticoagulation. Clinical conditions common in MCS patients such as concurrent warfarin use, malnutrition, haemolysis, and thrombocytopenia, as well as durable type of MCS devices were associated with a high aPTT relative to anti-Xa.

Adapting a dyadic exercise program to be culturally relevant for Hispanic men with prostate cancer using community engagement studio: a brief report.

Background: Cancer disparities exist for Hispanic men with prostate cancer and their caregivers that could be reduced through exercise. Exercising Together© is a six-month, evidence-based dyadic resistance training program that promotes teamwork between prostate cancer survivors and their spouses to improve physical, mental, and relational health outcomes. The purpose of this study was to elicit feedback and recommendations from stakeholders on the Exercising Together© intervention to inform the cultural adaptation of this program for Hispanic men with prostate cancer. Methods: We conducted a virtual Community Engagement Studio (V-CES) with community expert stakeholders representing the Hispanic and cancer care communities in Southern Arizona. The V-CES process included orientation, presentation of the research, guided discussion, and evaluation. The V-CES was audio recorded, transcribed, and rapidly analyzed to identify actionable feedback and contextual adaptations. Results: Nine stakeholders (6/9 male; 5/9 Hispanic) completed all V-CES activities. Through stakeholder engagement and feedback from the V-CES, adaptations to the original Exercising Together© intervention included: (1) inclusion of the cancer survivor's identified caregiver, who may not be a spouse; (2) availability in English and Spanish; (3) shortening the intervention to 3 months; (4) remote delivery of the intervention; and (5) incorporation of low burden procedures. Conclusion: Findings from our V-CES informed the adaptation of a culturally relevant dyadic progressive resistance training program for Hispanic men with prostate cancer and their caregivers.

A machine learning approach to detect potentially harmful and protective suicide-related content in broadcast media.

Suicide-related media content has preventive or harmful effects depending on the specific content. Proactive media screening for suicide prevention is hampered by the scarcity of machine learning approaches to detect specific characteristics in news reports. This study applied machine learning to label large quantities of broadcast (TV and radio) media data according to media recommendations reporting suicide. We manually labeled 2519 English transcripts from 44 broadcast sources in Oregon and Washington, USA, published between April 2019 and March 2020. We conducted a content analysis of media reports regarding content characteristics. We trained a benchmark of machine learning models including a majority classifier, approaches based on word frequency (TF-IDF with a linear SVM) and a deep learning model (BERT). We applied these models to a selection of more simple (e.g., focus on a suicide death), and subsequently to putatively more complex tasks (e.g., determining the main focus of a text from 14 categories). Tf-idf with SVM and BERT were clearly better than the naive majority classifier for all characteristics. In a test dataset not used during model training, F1-scores (i.e., the harmonic mean of precision and recall) ranged from 0.90 for celebrity suicide down to 0.58 for the identification of the main focus of the media item. Model performance depended strongly on the number of training samples available, and much less on assumed difficulty of the classification task. This study demonstrates that machine learning models can achieve very satisfactory results for classifying suicide-related broadcast media content, including multi-class characteristics, as long as enough training samples are available. The developed models enable future large-scale screening and investigations of broadcast media.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.