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Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA)., Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks., Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks., Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD., (Copyright © 2022 Society of Biological Psychiatry. All rights reserved.)

Novel approaches for malaria prophylaxis remain important. Synthetic DNA-encoded monoclonal antibodies (DMAbs) are a promising approach to generate rapid, direct in vivo host-generated mAbs with potential benefits in production simplicity and distribution coupled with genetic engineering. Here, we explore this approach in a malaria challenge model. We engineered germline-reverted DMAbs based on human mAb clones CIS43, 317, and L9 which target a junctional epitope, major repeat, and minor repeat of the Plasmodium falciparum circumsporozoite protein (CSP) respectively. DMAb variants were encoded into a plasmid vector backbone and their expression and binding profiles were characterized. We demonstrate long-term serological expression of DMAb constructs resulting in in vivo efficacy of CIS43 GL and 317 GL in a rigorous mosquito bite mouse challenge model. Additionally, we engineered an Fc modified variant of CIS43 and L9-based DMAbs to ablate binding to C1q to test the impact of complement-dependent Fc function on challenge outcomes. Complement knockout variant DMAbs demonstrated similar protection to that of WT Fc DMAbs supporting the notion that direct binding to the parasite is sufficient for the protection observed. Further investigation of DMAbs for malaria prophylaxis appears of importance., (© 2022. The Author(s).)

Accurate diagnosis of colorectal cancer (CRC) still relies on invasive colonoscopy. Noninvasive methods are less sensitive in detecting the disease, particularly in the early stage. In the current work, a metabolomics analysis of fecal samples was carried out by ultra-high-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS). A total of 1380 metabolites were analyzed in a cohort of 120 fecal samples from patients with normal colonoscopy, advanced adenoma (AA) and CRC. Multivariate analysis revealed that metabolic profiles of CRC and AA patients were similar and could be clearly separated from control individuals. Among the 25 significant metabolites, sphingomyelins (SM), lactosylceramides (LacCer), secondary bile acids, polypeptides, formiminoglutamate, heme and cytidine-containing pyrimidines were found to be dysregulated in CRC patients. Supervised random forest (RF) and logistic regression algorithms were employed to build a CRC accurate predicted model consisting of the combination of hemoglobin (Hgb) and bilirubin E,E, lactosyl-N-palmitoyl-sphingosine, glycocholenate sulfate and STLVT with an accuracy, sensitivity and specificity of 91.67% (95% Confidence Interval (CI) 0.7753-0.9825), 0.7 and 1, respectively.

Glucose monitoring technologies allow users to monitor glycemic fluctuations (e.g., blood glucose levels). This is particularly important for individuals who have diabetes mellitus (DM). Traditional self-monitoring blood glucose (SMBG) devices require the user to prick their finger and extract a blood drop to measure the blood glucose based on chemical reactions with the blood. Unlike traditional glucometer devices, noninvasive continuous glucose monitoring (NICGM) devices aim to solve these issues by consistently monitoring users' blood glucose levels (BGLs) without invasively acquiring a sample. In this work, we investigated the feasibility of a novel approach to NICGM using multiple off-the-shelf wearable sensors and learning-based models (i.e., machine learning) to predict blood glucose. Two datasets were used for this study: (1) the OhioT1DM dataset, provided by the Ohio University; and (2) the UofM dataset, created by our research team. The UofM dataset consists of fourteen features provided by six sensors for studying possible relationships between glucose and noninvasive biometric measurements. Both datasets are passed through a machine learning (ML) pipeline that tests linear and nonlinear models to predict BGLs from the set of noninvasive features. The results of this pilot study show that the combination of fourteen noninvasive biometric measurements with ML algorithms could lead to accurate BGL predictions within the clinical range; however, a larger dataset is required to make conclusions about the feasibility of this approach.

Background: Psychotherapy noncompletion rates for veterans and their families are high. This study sought to (a) measure noncompletion rates of such patients at a university-based treatment center, (b) compare veteran and family member attrition rates, (c) identify dropout predictors, and (d) explore clinicians' perspectives on treatment noncompletion., Method: Using quantitative and qualitative approaches, we analyzed demographic and clinical characteristics of 141 patients (90 military veterans; 51 family members) in a university treatment center. We defined dropout as not completing the time-limited therapy contract. Reviewing semistructured interview data assessing clinicians' perspectives on their patients' dropout, three independent raters agreed on key themes, with interrater coefficient kappa range .74 to 1., Results: Patient attrition was 24%, not differing significantly between veterans and family members. Diagnosis of major depression (MDD) and exposure-based therapies predicted noncompletion, as did higher baseline Hamilton Depression Rating Scale (HDRS) total scores, severe depression (HDRS > 20), lack of Beck Depression Inventory weekly improvement, and history of military sexual trauma. Clinicians mostly attributed noncompletion to patient difficulties coping with intense emotions, especially in exposure-based therapies., Conclusion: Noncompletion rate at this study appeared relatively low compared to other veteran-based treatment centers, if still unfortunately substantial. Patients with comorbid MDD/PTSD and exposure-based therapies carried greater noncompletion risk due to the MDD component, and this should be considered in treatment planning. Ongoing discussion of dissatisfaction and patient discontinuation, in the context of a strong therapeutic alliance, might reduce noncompletion in this at-risk population. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The biosynthesis of polyhydroxyalkanoates (PHAs) from industrial wastes by mixed microbial cultures (MMCs) enriched in PHA-accumulating bacteria is a promising technology to replace petroleum-based plastics. However, the populations' dynamics in the PHA-accumulating MMCs are not well known. Therefore, the main objective of this study was to address the shifts in the size and structure of the bacterial communities in two lab-scale sequencing batch reactors (SBRs) fed with fish-canning effluents and operated under non-saline (SBR-N, 0.5 g NaCl/L) or saline (SBR-S, 10 g NaCl/L) conditions, by using a combination of quantitative PCR and Illumina sequencing of bacterial 16S rRNA genes. A double growth limitation (DGL) strategy, in which nitrogen availability was limited and uncoupled to carbon addition, strongly modulated the relative abundances of the PHA-accumulating bacteria, leading to an increase in the accumulation of PHAs, independently of the saline conditions (average 9.04 wt% and 11.69 wt%, maximum yields 22.03 wt% and 26.33% SBR-N and SBR-S, respectively). On the other hand, no correlations were found among the PHAs accumulation yields and the absolute abundances of total Bacteria , which decreased through time in the SBR-N and did not present statistical differences in the SBR-S. Acinetobacter , Calothrix , Dyella , Flavobacterium , Novosphingobium , Qipengyuania , and Tsukamurella were key PHA-accumulating genera in both SBRs under the DGL strategy, which was revealed as a successful tool to obtain a PHA-enriched MMC using fish-canning effluents.

Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD., Method: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site., Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages., Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment., (© 2021. The Author(s).)

Pathogenic Escherichia coli strains are responsible for food-borne disease outbreaks upon consumption of fresh vegetables and fruits. The aim of this study was to establish the transmission route of E. coli strain 0611, as proxy for human pathogenic E. coli , via manure, soil and plant root zones to the above-soil plant compartments. The ecological behavior of the introduced strain was established by making use of a combination of cultivation-based and molecular targeted and untargeted approaches. Strain 0611 CFUs and specific molecular targets were detected in the root zones of lettuce and leek plants, even up to 272 days after planting in the case of leek plants. However, no strain 0611 colonies were detected in leek leaves, and only in one occasion a single colony was found in lettuce leaves. Therefore, it was concluded that transmission of E. coli via manure is not the principal contamination route to the edible parts of both plant species grown under field conditions in this study. Strain 0611 was shown to accumulate in root zones of both species and metagenomic reads of this strain were retrieved from the lettuce rhizosphere soil metagenome library at a level of Log 4.11 CFU per g dry soil.

The ability to visualize cell and tissue morphology at a high magnification using scanning electron microscopy (SEM) has revolutionized plant sciences research. In plant-insect interactions studies, SEM-based imaging has been of immense assistance to understand plant surface morphology including trichomes [plant hairs; physical defense structures against herbivores], spines, waxes, and insect morphological characteristics such as mouth parts, antennae, and legs, that they interact with. While SEM provides finer details of samples, and the imaging process is simpler now with advanced image acquisition and processing, sample preparation methodology has lagged. The need to undergo elaborate sample preparation with cryogenic freezing, multiple alcohol washes, and sputter coating makes SEM imaging expensive, time consuming, and warrants skilled professionals, making it inaccessible to majority of scientists. Here, using a desktop version of SEM (SNE- 4500 Plus Tabletop), we show that the "plug and play" method can efficiently produce SEM images with sufficient details for most morphological studies in plant-insect interactions. We used leaf trichomes of Solanum genus as our primary model, and oviposition by tobacco hornworm ( Manduca sexta ; Lepidoptera: Sphingidae) and fall armyworm ( Spodoptera frugiperda ; Lepidoptera: Noctuidae), and leaf surface wax imaging as additional examples to show the effectiveness of this instrument and present a detailed methodology to produce the best results with this instrument. While traditional sample preparation can still produce better resolved images with less distortion, we show that even at a higher magnification, the desktop SEM can deliver quality images. Overall, this study provides detailed methodology with a simpler "no sample preparation" technique for scanning fresh biological samples without the use of any additional chemicals and machinery., (© The Author(s) 2021. Published by Oxford University Press.)

The rapid spread of viral infections demands early detection strategies to minimize proliferation of the disease. Here, we demonstrate a plasmonic biosensor to detect Dengue virus, which was chosen as a model, via its nonstructural protein NS1 biomarker. The sensor is functionalized with a synthetic single-stranded DNA oligonucleotide and provides high affinity toward NS1 protein present in the virus genome. We demonstrate the detection of NS1 protein at a concentration of 0.1-10 μg/mL in bovine blood using an on-chip microfluidic plasma separator integrated with the plasmonic sensor which covers the clinical threshold of 0.6 μg/mL of high risk of developing Dengue hemorrhagic fever. The conceptual and practical demonstration shows the translation feasibility of these microfluidic optical biosensors for early detection of a wide range of viral infections, providing a rapid clinical diagnosis of infectious diseases directly from minimally processed biological samples at point of care locations.

Food choices are a complex subject of study. This study reviews existing literature on the topic, while also offering new perspectives. It introduces empirical materials that suggest the existence of continuities between childhood memories of food insecurity and current nutritional choices and practices among older adults. This is a qualitative study, based on grounded theory, which explores memories of hunger in the aftermath of the Spanish Civil War through ethnographic fieldwork conducted in 12 rural localities in Extremadura (Spain) - analysing current food practices and ideologies among surviving post-war children and tracing continuities between the past and the present. It provides results in the field of food continuities and shows how experiences and memories of hunger have an impact on food choices many decades later Data analysis and interpretation revealed three main categories: food memories of the so-called "years of hunger"; present-day food practices; and continuities between past and present. The inductive-deductive analysis revealed enduring memories that shaped present-day attitudes towards food - i.e. maximisation of ingredients and "zero-waste" practices; conspicuous consumption at particular times of the year; the central role of bread; and even certain food taboos. More than seventy years later, memories of deprivation and hunger are still pervasive and permeate present-day dietary practices and choices., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Posttraumatic stress disorder (PTSD) is twice as prevalent among females as compared to males following potentially traumatic events. While there is evidence for aberrant functional connectivity between hubs of the central executive network (CEN), salience network (SN), and the default mode network (DMN) in PTSD, little is known regarding sex-specificity of this connectivity. The current study aims to directly examine sex-specific resting-state functional connectivity (rs-FC) in trauma exposed males and females, with and without PTSD., Methods: One hundred and seventy-eight individuals underwent functional magnetic resonance imaging (fMRI) at rest, of them 85 females (45 with PTSD) and 93 males (57 with PTSD). We conducted whole-brain seed-based analysis using CEN (lateral prefrontal cortex [lPFC]), SN (anterior cingulate cortex [ACC], insula, amygdala [AMG]), and DMN (medial prefrontal cortex [mPFC], posterior parietal cortex [PCC], and hippocampus [HIP]) hubs as seed regions. Group-by-Sex ANOVA was conducted., Results: The amygdala-precuneus, ACC-precuneus, and hippocampus-precuneus pathways exhibited significant group-by-sex interaction effects, with females with PTSD consistently differing in connectivity patterns from males with PTSD and from trauma-exposed healthy females., Conclusions: Sex-specific neural connectivity patterns were found within and between key nodes of the CEN, DMN, and the SN, suggesting opposite patterns of connectivity in PTSD and trauma-exposed controls as a function of sex as a biological variable (SABV). This may point to mechanistic sex differences in adaptation following trauma and may inform differential neural targets for treatment of females and males with PTSD., (© 2021 The Authors.)

Introduction: The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab., Methods: Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received., Results: Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients' characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group., Conclusions: Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Objective: As veterans have high rates of posttraumatic stress disorder (PTSD) and historically poor treatment outcomes and high attrition, alternative treatments have gained much popularity despite lack of rigorous research. In this study, a recently developed and manualized 8-session group Equine-Assisted Therapy for PTSD (EAT-PTSD) was tested in an open trial to assess its preliminary feasibility, acceptability, and outcomes for military veterans., Methods: The study was conducted from July 2016 to July 2019. Sixty-three treatment-seeking veterans with PTSD enrolled. PTSD diagnosis was ascertained using the Structured Clinical Interview for DSM-5 , Research Version (SCID-5-RV) and confirmed using the Clinician-Administered PTSD Scale (CAPS-5). Mean age was 50 years, and 23 patients (37%) were women. Clinician and self-report measures of PTSD and depression were assessed at pretreatment, midtreatment, and posttreatment and at a 3-month follow-up. An intent-to-treat analysis and a secondary analysis of those who completed all 4 clinical assessments were utilized., Results: Only 5 patients (8%) withdrew from treatment, 4 before midtreatment and 1 afterward. Posttreatment assessment revealed marked reductions in both clinician-rated and self-reported PTSD and depression symptoms, which persisted at 3-month follow-up. Specifically, mean (SD) CAPS-5 scores fell from 38.6 (8.1) to 26.9 (12.4) at termination. Thirty-two patients (50.8%) showed clinically significant change (≥ 30% decrease in CAPS-5 score) at posttreatment and 34 (54.0%) at follow-up., Conclusions: Manualized EAT-PTSD shows promise as a potential new intervention for veterans with PTSD. It appears safe, feasible, and clinically viable. These preliminary results encourage examination of EAT-PTSD in larger, randomized controlled trials., Trial Registration: ClinicalTrials.gov identifier: NCT03068325., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network., (© 2019. The Author(s), under exclusive licence to Springer Nature Limited.)

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

The COVID-19 pandemic has caused a profound change in health organizations at both the primary and hospital care levels. This cross-sectional study aims to investigate the impact of the COVID-19 pandemic in the annual rate of new cancer diagnosis in two university-affiliated hospitals. This study includes all the patients with a pathological diagnosis of cancer attended in two hospitals in Málaga (Spain) during the first year of pandemic. This study population was compared with the patients diagnosed during the previous year 2019. To analyze whether the possible differences in the annual rate of diagnoses were due to the pandemic or to other causes, the patients diagnosed during 2018 and 2017 were also compared. There were 2340 new cancer diagnosis compared to 2825 patients in 2019 which represented a decrease of -17.2% ( p = 0.0001). Differences in the number of cancer patients diagnosed between 2018 and 2019 (2840 new cases; 0.5% increase) or 2017 and 2019 (2909 new cases; 3% increase) were not statistically significant. The highest number of patients lost from diagnosis in 2020 was in breast cancer (-26.1%), colorectal neoplasms (-16.9%), and head and neck tumors (-19.8%). The study of incidence rates throughout the first year of the COVID-19 pandemic shows that the diagnosis of new cancer patients has been significantly impaired. Health systems must take the necessary measures to restore pre-pandemic diagnostic procedures and to recover lost patients who have not been diagnosed.

Enhancing soil suppressiveness against plant pathogens or pests is a promising alternative strategy to chemical pesticides. Organic amendments have been shown to reduce crop diseases and pests, with chitin products the most efficient against fungal pathogens. To study which characteristics of organic products are correlated with disease suppression, an experiment was designed in which 10 types of organic amendments with different physicochemical properties were tested against the soilborne pathogen Rhizoctonia solani in sugar beet seedlings. Organic amendments rich in keratin or chitin reduced Rhizoctonia solani disease symptoms in sugar beet plants. The bacterial and fungal microbial communities in amended soils were distinct from the microbial communities in nonamended soil, as well as those in soils that received other nonsuppressive treatments. The Rhizoctonia -suppressive amended soils were rich in saprophytic bacteria and fungi that are known for their keratinolytic and chitinolytic properties (i.e., Oxalobacteraceae and Mortierellaceae ). The microbial community in keratin- and chitin-amended soils was associated with higher zinc, copper, and selenium, respectively. IMPORTANCE Our results highlight the importance of soil microorganisms in plant disease suppression and the possibility to steer soil microbial community composition by applying organic amendments to the soil., (Copyright © 2021 Andreo-Jimenez et al.)

Background: While effective treatments for posttraumatic stress disorder (PTSD) exist, many individuals, including military personnel and veterans fail to respond to them. Equine-assisted therapy (EAT), a novel PTSD treatment, may complement existing PTSD interventions. This study employs longitudinal neuro-imaging, including structural magnetic resonance imaging (sMRI), resting state-fMRI (rs-fMRI), and diffusion tensor imaging (DTI), to determine mechanisms and predictors of EAT outcomes for PTSD., Method: Nineteen veterans with PTSD completed eight weekly group sessions of EAT undergoing multimodal MRI assessments before and after treatment. Clinical assessments were conducted at baseline, post-treatment and at 3-month follow-up., Results: At post-treatment patients showed a significant increase in caudate functional connectivity (FC) and reduction in the gray matter density of the thalamus and the caudate. The increase of caudate FC was positively associated with clinical improvement seen immediately at post-treatment and at 3-month follow-up. In addition, higher baseline caudate FC was associated with greater PTSD symptom reduction post-treatment., Conclusions: This exploratory study is the first to demonstrate that EAT can affect functional and structural changes in the brains of patients with PTSD. The findings suggest that EAT may target reward circuitry responsiveness and produce a caudate pruning effect from pre- to post-treatment., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Aging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). There is a need for well characterized animal models that will allow the scientific community to understand and modulate this process., Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their senescence resistant control mice (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and determined the appearance of Iba1 + clustered cells with aging. To analyze specific constant brain areas, we have performed stereology measurements of Iba1 + cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch), and analyzed their response to systemic lipopolysaccharide (LPS)-driven inflammation., Results: Aged 10 months old SAMP8 mice present many of the hallmarks of aging-dependent neuroinflammation when compared with their SAMR1 control, i.e., increase of protein aggregates, presence of Iba1 + clusters, but not an increase in the number of Iba1 + cells. We have further observed an increase of main inflammatory mediator IL-1β, and an augment of border MHCII + Iba1 + cells. Isolated CD45 + bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch) have been analyzed, showing that there is not a significant increase of CD45 + cells from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL-1β) transcription is enhanced in CD45 + BP cells. Furthermore, LPS-driven systemic inflammation produces inflammatory cytokines mainly in border bMyC, sensed to a lesser extent by the BP bMyC, showing that IL-1β expression is further augmented in aged SAMP8 compared to control SAMR1., Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of pro-inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

Background: Real-world data have suggested a detrimental effect of steroid use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents., Patients and Methods: A comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model., Results: For the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001) CONCLUSIONS: In patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Eye-tracking-based attentional research implicates sustained attention to threat in posttraumatic stress disorder (PTSD). However, most of this research employed small stimuli set-sizes, small samples that did not include both trauma-exposed healthy participants and non-trauma-exposed participants, and generally failed to report the reliability of used tasks and attention indices. Here, using an established eye-tracking paradigm, we explore attention processes to different negatively-valenced cues in PTSD while addressing these limitations., Methods: PTSD patients (n = 37), trauma-exposed healthy controls (TEHC; n = 34), and healthy controls (HC; n = 30) freely viewed three blocks of 30 different matrices of faces, each presented for 6 s. Each block consisted of matrices depicting eight negatively-valenced faces (anger, fear, or sadness) and eight neutral faces. Gaze patterns on negative and neural areas of interest were compared. Internal consistency and test-retest reliability were evaluated for the entire sample and within groups., Results: The two trauma-exposed groups dwelled longer on negatively-valenced faces over neutral faces, while HC participants showed the opposite pattern. This attentional bias was more prominent in the PTSD than the TEHC group. Similar results emerged for first-fixation dwell time, but with no differences between the two trauma-exposed groups. No group differences emerged for first-fixation latency or location. Internal consistency and 1-week test-retest reliability were adequate, across and within groups., Conclusions: Sustained attention on negatively-valenced stimuli emerges as a potential target for therapeutic intervention in PTSD designed to divert attention away from negatively-valenced stimuli and toward neutral ones.

Background: CDK4/6 inhibitors plus endocrine therapies are the current standard of care in the first-line treatment of HR+/HER2-negative metastatic breast cancer, but there are no well-established clinical or molecular predictive factors for patient response. In the era of personalised oncology, new approaches for developing predictive models of response are needed., Materials and Methods: Data derived from the electronic health records (EHRs) of real-world patients with HR+/HER2-negative advanced breast cancer were used to develop predictive models for early and late progression to first-line treatment. Two machine learning approaches were used: a classic approach using a data set of manually extracted features from reviewed (EHR) patients, and a second approach using natural language processing (NLP) of free-text clinical notes recorded during medical visits., Results: Of the 610 patients included, there were 473 (77.5%) progressions to first-line treatment, of which 126 (20.6%) occurred within the first 6 months. There were 152 patients (24.9%) who showed no disease progression before 28 months from the onset of first-line treatment. The best predictive model for early progression using the manually extracted dataset achieved an area under the curve (AUC) of 0.734 (95% CI 0.687-0.782). Using the NLP free-text processing approach, the best model obtained an AUC of 0.758 (95% CI 0.714-0.800). The best model to predict long responders using manually extracted data obtained an AUC of 0.669 (95% CI 0.608-0.730). With NLP free-text processing, the best model attained an AUC of 0.752 (95% CI 0.705-0.799)., Conclusions: Using machine learning methods, we developed predictive models for early and late progression to first-line treatment of HR+/HER2-negative metastatic breast cancer, also finding that NLP-based machine learning models are slightly better than predictive models based on manually obtained data., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Established by the Centers for Medicare and Medicaid Services (CMS), the Open Payments Database (OPD) has reported industry payments to physicians since August 2013., Objective: To evaluate the frequency, type, and value of payments received by academic neurosurgeons in the United States over a 5-yr period (2014-2018)., Methods: The OPD was queried for attending neurosurgeons from all neurosurgical training programs in the United States (n = 116). Information from the OPD was analyzed for the entire cohort as well as for comparative subgroup analyses, such as career stage, subspecialty, and geographic location., Results: Of all identified neurosurgeons, 1509 (95.0%) received some payment from industry between 2014 and 2018 for a total of 106 171 payments totaling $266 407 458.33. A bimodal distribution was observed for payment number and total value: 0 to 9 (n = 438) vs > 50 (n = 563) and 0-$1000 (n = 418) vs >$10 000 (n = 653), respectively. Royalty/License was the most common type of payment overall (59.6%; $158 723 550.57). The median number (40) and value ($8958.95) of payments were highest for mid-career surgeons. The South-Central region received the most money ($117 970 036.39) while New England received the greatest number of payments (29 423). Spine surgeons had the greatest median number (60) and dollar value ($20 551.27) of payments, while pediatric neurosurgeons received the least (8; $1108.29). Male neurosurgeons received a greater number (31) and value ($6395.80) of payments than their female counterparts (11, $1643.72)., Conclusion: From 2014 to 2018, payments to academic neurosurgeons have increased in number and value. Dollars received were dependent on geography, career stage, subspecialty and gender., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background/aim: Breast cancer cell lines consist of bulk tumor cells and a small proportion of stem-like cells. While the bulk cells are known to express a distinct combination of Eph receptors and ephrin ligands, the transcript profiles of stem-like cells in these cell lines have not been adequately characterized. The aim of this study was to determine Eph receptor/ephrin ligand profiles of cancer stem cells specific to a triple negative breast carcinoma cell line., Materials and Methods: The normal breast cell line MCF10A and the invasive breast carcinoma cell line MDA-MB-231 were used to isolate CD24 + /CD24 - cell populations. The profiles of Eph receptors and ephrin ligands were determined by real-time PCR and the relative abundance in bulk and stem cells were compared., Results: Based on the mean ΔCT values, the descending order of abundance was as follows. Ephrin-A5 > EPHA2 > (EPHA8, EPHB2) > ephrin-B2 > (EPHA7, EPHB4, ephrin-A4) > ephrin-A3 > ephrin-A1 > (EPHB3, ephrin-B1) > EPHA4 > EPHA1 > EPHA10. EPHA6 and ephrin-A2 transcripts were not detectable in stem cells from either cell line. The expression of EPHA4, EPHA7, EPHA8, and ephrin-A5 in MDA-MB-231 stem cells was up-regulated by 12, 20, ~500, and 6.5-fold respectively., Conclusion: The up-regulation of transcripts for EPHA8 and its cognate ligand, ephrin-A5, in the stem cells isolated from MDA-MB-231, suggest their involvement in the invasiveness of this cell line. Based on literature reports, we propose the role of EPHA8 and ephrin-A5 in MDA-MB-231 stem cells via the PI3K-AKT-mTOR pathway., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The authors conducted a multicenter retrospective study on the outcome of programmed death-ligand 1 tumor proportion score≥50% advanced non-small cell lung cancer patients treated with first-line pembrolizumab according to the presence/absence of brain metastases. A total of 282 patients were included, of whom 56 had brain metastases that were treated with upfront local radiation therapy in 80.3% of cases. The overall response rate was 39.2% and 44.4% in patients with and without brain metastases (P=0.48), respectively, while intracranial response rate and intracranial disease control rate were 67.5% and 85.0%, respectively. The median time-to-treatment failure (TTF) and overall survival (OS) were 4.2 and 9.9 months versus 10.8 and 26.5 months for patients with and without brain metastases (P=0.06 and 0.05, respectively). Drug discontinuation rate due to treatment-related adverse events was 10.7% and 10.2% in patients with and without brain metastases, respectively. Multivariate analysis showed that baseline steroids was an independent predictor for a worse OS (P<0.001), while performance status (PS)≥2 was an independent predictor for a poorer TTF (P<0.001) and OS (P<0.001). In patients with brain metastases, only PS ≥2 was predicted for a worse TTF (P=0.02) and OS (P=0.03). Pembrolizumab has activity against brain metastases from non-small cell lung cancers with programmed death-ligand 1≥50%. Presence of brain metastases per se does not appear to be prognostic, and PS ≥2 seems to be the only factor associated with a worse outcome in patients with brain metastases.

Background: In the network approach to psychopathology, psychiatric disorders are considered networks of causally active symptoms (nodes), with node centrality hypothesized to reflect symptoms' causal influence within a network. Accordingly, centrality measures have been used in numerous network-based cross-sectional studies to identify specific treatment targets, based on the assumption that deactivating highly central nodes would proliferate to other nodes in the network, thereby collapsing the network structure and alleviating the overall psychopathology (i.e., the centrality hypothesis)., Methods: Here, we summarize three types of evidence pertaining to the centrality hypothesis in psychopathology. First, we discuss the validity of the theoretical assumptions underlying the centrality hypothesis in psychopathology. We then summarize the methodological aspects of extant studies using centrality measures as predictors of symptom change following treatment, while delineating their main findings and several of their limitations. Finally, using a specific dataset of 710 treatment-seeking patients with posttraumatic stress disorder (PTSD) as an example, we empirically examine node centrality as a predictor of therapeutic change, replicating the approach taken by previous studies, while addressing some of their limitations. Specifically, we investigated whether three pre-treatment centrality indices (strength, predictability, and expected influence) were significantly correlated with the strength of the association between a symptom's change and the change in the severity of all other symptoms in the network from pre- to post-treatment (Δnode-Δnetwork association). Using similar analyses, we also examine the predictive validity of two simple non-causal node properties (mean symptom severity and infrequency of symptom endorsement)., Results: Of the three centrality measures, only expected influence successfully predicted how strongly changes in nodes/symptoms were associated with change in the remainder of the nodes/symptoms. Importantly, when excluding the amnesia node, a well-documented outlier in the phenomenology of PTSD, none of the tested centrality measures predicted symptom change. Conversely, both mean symptom severity and infrequency of symptom endorsement, two standard non-network-derived indices, were found to be more predictive than expected influence and remained significantly predictive also after excluding amnesia from the network analyses., Conclusions: The centrality hypothesis in its current form is ill-defined, showing no consistent supporting evidence in the context of cross-sectional, between-subject networks.

Background: Strigolactones represent the most recently described group of plant hormones involved in many aspects of plant growth regulation. Simultaneously, root exuded strigolactones mediate rhizosphere signaling towards beneficial arbuscular mycorrhizal fungi, but also attract parasitic plants. The seed germination of parasitic plants induced by host strigolactones leads to serious agricultural problems worldwide. More insight in these signaling molecules is hampered by their extremely low concentrations in complex soil and plant tissue matrices, as well as their instability. So far, the combination of tailored isolation-that would replace current unspecific, time-consuming and labour-intensive processing of large samples-and a highly sensitive method for the simultaneous profiling of a broad spectrum of strigolactones has not been reported., Results: Depending on the sample matrix, two different strategies for the rapid extraction of the seven structurally similar strigolactones and highly efficient single-step pre-concentration on polymeric RP SPE sorbent were developed and validated. Compared to conventional methods, controlled temperature during the extraction and the addition of an organic modifier (acetonitrile, acetone) to the extraction solvent helped to tailor strigolactone isolation from low initial amounts of root tissue (150 mg fresh weight, FW) and root exudate (20 ml), which improved both strigolactone stability and sample purity. We have designed an efficient UHPLC separation with sensitive MS/MS detection for simultaneous analysis of seven natural strigolactones including their biosynthetic precursors-carlactone and carlactonoic acid. In combination with the optimized UHPLC-MS/MS method, attomolar detection limits were achieved. The new method allowed successful profiling of seven strigolactones in small exudate and root tissue samples of four different agriculturally important plant species-sorghum, rice, pea and tomato., Conclusion: The established method provides efficient strigolactone extraction with aqueous mixtures of less nucleophilic organic solvents from small root tissue and root exudate samples, in combination with rapid single-step pre-concentration. This method improves strigolactone stability and eliminates the co-extraction and signal of matrix-associated contaminants during the final UHPLC-MS/MS analysis with an electrospray interface, which dramatically increases the overall sensitivity of the analysis. We show that the method can be applied to a variety of plant species., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Objectives: We retrospectively analysed patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression (>50%) and treated with front-line pembrolizumab, comparing outcomes of patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to those with PS 0-1. Methods: Data were collected by 16 participating centres. All patients with NSCLC and high PD-L1, treated with first-line pembrolizumab were included. We collected medical data from patient files, pathology and laboratory reports. Patient characteristics, comorbidities, PS, and tumour characteristics were reported. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were calculated. Results: 302 patients were included, 246 with PS 0-1, 56 with PS 2. RR was 72% among patients with PS 0-1 compared to 45% with PS2 (odds ratio (OR) 0.31 (95% CI: 0.17-0.57), p  < .001). Median PFS was 2.6 months (95% CI: 1.9-5.1) among patients with PS2 and 11.3 months (95% CI: 8.5-14.4) among those with PS 0-1. Median OS was 7.8 months (95% CI: 2.5-10.7) in the PS2 group, not reached in the PS 0-1 group. PS 2 remained predictive of poor outcomes in multivariate analysis. Conclusion: PS 2 is a strong independent predictor of poor response and survival in NSCLC patients with high PD-L1, treated with front-line pembrolizumab. Prospective randomised trials comparing immunotherapy to chemotherapy in this population would be welcome.

Next-generation ALK TKIs have become the new standard of care in first-line setting in advanced ALK-positive NSCLC patients. However, sequential strategies at progression are relevant, as may have an impact on patients' outcome. In this commentary we discuss whether genomic-tailored strategies at progression would be more suitable for improving outcome of ALK-positive NSCLC patients.

Significance: The hallmarks of digital holographic microscopy (DHM) compared with other quantitative phase imaging (QPI) methods are high speed, accuracy, spatial resolution, temporal stability, and polarization-sensitivity (PS) capability. The above features make DHM suitable for real-time quantitative PS phase imaging in a broad number of biological applications aimed at understanding cell growth and dynamic changes occurring during physiological processes and/or in response to pharmaceutical agents., Aim: The insertion of a Fresnel biprism (FB) in the image space of a light microscope potentially turns any commercial system into a DHM system enabling QPI with the five desired features in QPI simultaneously: high temporal sensitivity, high speed, high accuracy, high spatial resolution, and PS. To the best of our knowledge, this is the first FB-based DHM system providing these five features all together., Approach: The performance of the proposed system was calibrated with a benchmark phase object. The PS capability has been verified by imaging human U87 glioblastoma cells., Results: The proposed FB-based DHM system provides accurate phase images with high spatial resolution. The temporal stability of our system is in the order of a few nanometers, enabling live-cell studies. Finally, the distinctive behavior of the cells at different polarization angles (e.g., PS capability) can be observed with our system., Conclusions: We have presented a method to turn any commercial light microscope with monochromatic illumination into a PS QPI system. The proposed system provides accurate quantitative PS phase images in a new, simple, compact, and cost-effective format, thanks to the low cost (a few hundred dollars) involved in implementing this simple architecture, enabling the use of this QPI technique accessible to most laboratories with standard light microscopes.

Cells adapt to environmental changes, including fluctuations in oxygen levels, through the induction of specific gene expression programs. However, most transcriptomic studies do not distinguish the relative contribution of transcription, RNA processing, and RNA degradation processes to cellular homeostasis. Here we used metabolic labeling followed by massive parallel sequencing of newly transcribed and preexisting RNA fractions to simultaneously analyze RNA synthesis and decay in primary endothelial cells exposed to low oxygen tension. We found that changes in transcription rates induced by hypoxia are the major determinant of changes in RNA levels. However, degradation rates also had a significant contribution, accounting for 24% of the observed variability in total mRNA. In addition, our results indicated that hypoxia led to a reduction of the overall mRNA stability from a median half-life in normoxia of 8.7 h, to 5.7 h in hypoxia. Analysis of RNA content per cell confirmed a decrease of both mRNA and total RNA in hypoxic samples and that this effect is dependent on the EGLN/HIF/TSC2 axis. This effect could potentially contribute to fundamental global responses such as inhibition of translation in hypoxia. In summary, our study provides a quantitative analysis of the contribution of RNA synthesis and stability to the transcriptional response to hypoxia and uncovers an unexpected effect on the latter., (© 2020 Tiana et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Background: Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers., Methods: Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall., Results: Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis., Conclusion: Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD.

Background: Comorbidity between posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) has been commonly overlooked by studies examining resting-state functional connectivity patterns in PTSD. The current study used a data-driven approach to identify resting-state functional connectivity biomarkers to 1) differentiate individuals with PTSD (with or without MDD) from trauma-exposed healthy control subjects (TEHCs), 2) compare individuals with PTSD alone with those with comorbid PTSD+MDD, and 3) explore the clinical utility of the identified biomarkers by testing their associations with clinical symptoms and treatment response., Methods: Resting-state magnetic resonance images were obtained from 51 individuals with PTSD alone, 52 individuals with PTSD+MDD, and 76 TEHCs. Of the 103 individuals with PTSD, 55 were enrolled in prolonged exposure treatment. A support vector machine model was used to identify resting-state functional connectivity biomarkers differentiating individuals with PTSD (with or without MDD) from TEHCs and differentiating individuals with PTSD alone from those with PTSD+MDD. The associations between the identified features and symptomatology were tested with Pearson correlations., Results: The support vector machine model achieved 70.6% accuracy in discriminating between individuals with PTSD and TEHCs and achieved 76.7% accuracy in discriminating between individuals with PTSD alone and those with PTSD+MDD for out-of-sample prediction. Within-network connectivity in the executive control network, prefrontal network, and salience network discriminated individuals with PTSD from TEHCs. The basal ganglia network played an important role in differentiating individuals with PTSD alone from those with PTSD+MDD. PTSD scores were inversely correlated with within-executive control network connectivity (p < .001), and executive control network connectivity was positively correlated with treatment response (p < .001)., Conclusions: Results suggest that unique brain-based abnormalities differentiate individuals with PTSD from TEHCs, differentiate individuals with PTSD from those with PTSD+MDD, and demonstrate clinical utility in predicting levels of symptomatology and treatment response., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Historically, practicing neurosurgeons have been key drivers of neurosurgical innovation. We sought to describe the patents held by U.S. academic neurosurgeons and to explore the relationship between patents and royalties received., Methods: The Centers for Medicare and Medicaid CMS Open Payments Data was used to identify academic neurosurgeons who had received royalties and royalty amounts during a 5-year period (2013-2017). Online patent databases were used to gather patent details. Patent citations and 5-year individual and departmental patent Hirsch (h)-indexes were calculated. Royalties were correlated with the number of patents, patent citations, and patent h-index., Results: We found that 119 academic neurosurgeons (7.8%) from 57 U.S. teaching programs (48.3%) had received royalty payments; 72 (60.5%) had published 648 patents. All surgeons were men, with approximately one half in the "late" stages of their career (45.3%) and subspecializing in spinal surgery (50.4%). The patented products or devices were most commonly used for spinal surgery (72.1%), with 2010-2019 the most productive period (n = 455; 70.2%). The median number of citations per patent was 32 (range, 0-620), with 33% having ≥100 citations. The highest individual and institutional patent h-index was 95; 25 (34.7%) neurosurgeons had a patent h-index of ≥5. The median total royalty payment per individual neurosurgeon was $111,011 (range, $58.05-$76,715,750.34). Royalties were correlated with the number of patents (Spearman r = 0.37; P ≤ 0.001), citations (Spearman r, 0.38; P ≤ 0.001), and inventor h-index (Spearman r = 0.38; P ≤ 0.001)., Conclusions: Few U.S. academic neurosurgeons (7.8%) receive royalties and hold patents (4.7%), with an even smaller select group having a patent h-index of ≥5 (1.6%)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)]., Methods: Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes., Results: Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome., Conclusions: This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the 'limbic' AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.

Background: Delays in clinical trial enrollment and difficulties enrolling representative samples continue to vex sponsors, sites, and patient populations. Here we investigated use of an artificial intelligence-powered technology, Mendel.ai, as a means of overcoming bottlenecks and potential biases associated with standard patient prescreening processes in an oncology setting., Methods: Mendel.ai was applied retroactively to 2 completed oncology studies (1 breast, 1 lung), and 1 study that failed to enroll (lung), at the Comprehensive Blood and Cancer Center, allowing direct comparison between results achieved using standard prescreening practices and results achieved with Mendel.ai. Outcome variables included the number of patients identified as potentially eligible and the elapsed time between eligibility and identification., Results: For each trial that enrolled, use of Mendel.ai resulted in a 24% to 50% increase over standard practices in the number of patients correctly identified as potentially eligible. No patients correctly identified by standard practices were missed by Mendel.ai. For the nonenrolling trial, both approaches failed to identify suitable patients. An average of 19 days for breast and 263 days for lung cancer patients elapsed between actual patient eligibility (based on clinical chart information) and identification when the standard prescreening practice was used. In contrast, ascertainment of potential eligibility using Mendel.ai took minutes., Conclusions: This study suggests that augmentation of human resources with artificial intelligence could yield sizable improvements over standard practices in several aspects of the patient prescreening process, as well as in approaches to feasibility, site selection, and trial selection.

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data., Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific)., Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively)., Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: In this real-world multicenter study we addressed the activity of post-progression anticancer treatments after first-line pembrolizumab in advanced non-small cell lung cancer (NSCLC) patients with PD-L1 ≥50%., Methods: Clinico-pathological data of PD-L1 ≥50% advanced NSCLCs who failed first-line pembrolizumab were collected in 14 Oncologic Centers from different European countries. Types of subsequent anticancer treatment and outcomes on salvage chemotherapy or pembrolizumab beyond progression with or without the addition of local ablative therapies were reported., Results: Out of 173 patients, 100 had progressed on pembrolizumab, of which 60 patients (60%) met eligibility criteria and were treated with either salvage chemotherapy (42/60, 70%) or pembrolizumab beyond progression (18/60, 30%). Overall, median age was 66 years, 63.3% were male, 60.0% had a performance status of 0-1, 88.3% were smokers and 61.7% had adenocarcinoma histology. In patients evaluable for response, objective response rate to salvage chemotherapy was 41.9%, with no significant difference according to the type of regimen (42.9% for platinum-based and 40.0% for single-agent chemotherapy). Median progression-free survival (PFS) to salvage chemotherapy was 4.5 months. Among patients treated with pembrolizumab beyond progression, 13 out of 18 patients (72.2%) had progressive disease in ≤2 organ sites, of whom 9 (69.2%) were managed with the addition of local ablative therapies consisting of radiation at progressive lesion(s). No significant difference was noted in terms of post-progression survival between the salvage chemotherapy and the pembrolizumab beyond progression groups of patients (6.9 versus 8.1 months, respectively, P=0.08)., Conclusions: In PD-L1 ≥50% advanced NSCLCs who progress on first-line pembrolizumab, salvage chemotherapy is associated with a remarkable anticancer activity, while select patients may benefit from continuation of pembrolizumab beyond progression, with the possible addition of local ablative radiotherapy in oligoprogressive cases., Competing Interests: Conflict of Interest: This work was presented in abstract form at World Conference on Lung Cancer 2019. Giulio Metro has had consulting/advisory relationship with Boehringher-Ingelheim; Giuseppe Banna has had consulting/advisory relationships with Boehringher-Ingelheim, Janssen-Cilag, Roche; Athina Christopoulou has had consulting/advisory relationships with Bristol Myers Squibb, Merck, Novartis, Pfizer, Roche, Sanofi; Antonio Calles received honorary/consulting fees from AstraZeneca, Boehringher-Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche; Helena Linardou has had consulting/advisory relationships with AstraZeneca, Boehringher-Ingelheim, Bristol Myers Squibb, Merck, Novartis, Roche; Paris Kosmidis has had consulting/advisory relationships with Bristol Myers Squibb, Merck, Novartis, Pfizer. The other authors have no conflicts of interest to declare., (2019 Journal of Thoracic Disease. All rights reserved.)

Under conditions in which budding yeast form colonies and then undergo meiosis/sporulation, the resulting colonies are organized such that a sharply defined layer of meiotic cells overlays a layer of unsporulated cells termed "feeder cells." This differentiation pattern requires activation of both the Rlm1/cell-wall integrity pathway and the Rim101/alkaline-response pathway. In the current study, we analyzed the connection between these two signaling pathways in regulating colony development by determining expression patterns and cell-autonomy relationships. We present evidence that two parallel cell-nonautonomous positive-feedback loops are active in colony patterning, an Rlm1-Slt2 loop active in feeder cells and an Rim101-Ime1 loop active in meiotic cells. The Rlm1-Slt2 loop is expressed first and subsequently activates the Rim101-Ime1 loop through a cell-nonautonomous mechanism. Once activated, each feedback loop activates the cell fate specific to its colony region. At the same time, cell-autonomous mechanisms inhibit ectopic fates within these regions. In addition, once the second loop is active, it represses the first loop through a cell-nonautonomous mechanism. Linked cell-nonautonomous positive-feedback loops, by amplifying small differences in microenvironments, may be a general mechanism for pattern formation in yeast and other organisms., (Copyright © 2019 by the Genetics Society of America.)

Background: Double blockade with pertuzumab and trastuzumab combined with chemotherapy is the standard neoadjuvant treatment for HER2-positive early breast cancer. Data derived from clinical trials indicates that the response rates differ among intrinsic subtypes of breast cancer. The aim of this study is to determine if these results are valid in real-world patients. Methods: A total of 259 patients treated in eight Spanish hospitals were included and divided into two cohorts: Cohort A (132 patients) received trastuzumab plus standard neoadjuvant chemotherapy (NAC), and Cohort B received pertuzumab and trastuzumab plus NAC (122 patients). Pathological complete response (pCR) was defined as the complete disappearance of invasive tumor cells. Assignment of the intrinsic subtype was realized using the research-based PAM50 signature. Results: There were more HER2-enriched tumors in Cohort A (70 vs. 56%) and more basal-like tumors in Cohort B (12 vs. 2%), with similar luminal cases in both cohorts (luminal A 12 vs. 14%; luminal B 14 vs. 18%). The overall pCR rate was 39% in Cohort A and 61% in Cohort B. Better pCR rates with pertuzumab plus trastuzumab than with trastuzumab alone were also observed in all intrinsic subtypes (luminal PAM50 41 vs. 11.4% and HER2-enriched subtype 73.5 vs. 50%) but not in basal-like tumors (53.3 vs. 50%). In multivariate analysis the only significant variables related to pCR in both luminal PAM50 and HER2-enriched subtypes were treatment with pertuzumab plus trastuzumab (Cohort B) and histological grade 3. Conclusions: With data obtained from patients treated in clinical practice, it has been possible to verify that the addition of pertuzumab to trastuzumab and neoadjuvant chemotherapy substantially increases the rate of pCR, especially in the HER2-enriched subtype but also in luminal subtypes, with no apparent benefit in basal-like tumors., (Copyright © 2019 Díaz-Redondo, Lavado-Valenzuela, Jimenez, Pascual, Gálvez, Falcón, Alamo, Morales, Amerigo, Pascual, Sanchez-Muñoz, González-Guerrero, Vicioso, Laborda, Ortega, Perez, Fernandez-Martinez, Chic, Jerez, Alvarez, Prat, Ribelles and Alba.)

Background: Randomized control trials (RCTs) comparing attention control training (ACT) and attention bias modification (ABM) in posttraumatic stress disorder (PTSD) have shown mixed results. The current RCT extends the extant literature by comparing the efficacy of ACT and a novel bias-contingent-ABM (BC-ABM), in which direction of training is contingent upon the direction of pre-treatment attention bias (AB), in a sample of civilian patients with PTSD., Methods: Fifty treatment-seeking civilian patients with PTSD were randomly assigned to either ACT or BC-ABM. Clinician and self-report measures of PTSD and depression, as well as AB and attention bias variability (ABV), were acquired pre- and post-treatment., Results: ACT yielded greater reductions in PTSD and depressive symptoms on both clinician-rated and self-reported measures compared with BC-ABM. The BC-ABM condition successfully shifted ABs in the intended training direction. In the ACT group, there was no significant change in ABV or AB from pre- to post-treatment., Conclusions: The current RCT extends previous results in being the first to apply ABM that is contingent upon AB at pre-treatment. This personalized BC-ABM approach is associated with significant reductions in symptoms. However, ACT produces even greater reductions, thereby emerging as a promising treatment for PTSD.

Background and Aim: Water is an increasingly scarce resource while some crops, such as paddy rice, require large amounts of water to maintain grain production. A better understanding of rice drought adaptation and tolerance mechanisms could help to reduce this problem. There is evidence of a possible role of root-associated fungi in drought adaptation. Here, we analyzed the endospheric fungal microbiota composition in rice and its relation to plant genotype and drought., Methods: Fifteen rice genotypes ( Oryza sativa ssp. indica) were grown in the field, under well-watered conditions or exposed to a drought period during flowering. The effect of genotype and treatment on the root fungal microbiota composition was analyzed by 18S ribosomal DNA high throughput sequencing. Grain yield was determined after plant maturation., Results: There was a host genotype effect on the fungal community composition. Drought altered the composition of the root-associated fungal community and increased fungal biodiversity. The majority of OTUs identified belonged to the Pezizomycotina subphylum and 37 of these significantly correlated with a higher plant yield under drought, one of them being assigned to Arthrinium phaeospermum ., Conclusion: This study shows that both plant genotype and drought affect the root-associated fungal community in rice and that some fungi correlate with improved drought tolerance. This work opens new opportunities for basic research on the understanding of how the host affects microbiota recruitment as well as the possible use of specific fungi to improve drought tolerance in rice., Competing Interests: The authors declare there are no competing interests., (©2019 Andreo-Jimenez et al.)

The present work aims to use aerobic granular sludge technology for the treatment of wastewater containing high organic matter loads and a mixture of phenolic compounds normally present in olive washing water. The physicochemical performance of five bioreactors treating different concentrations of mixture of phenolic acid was monitored to observe the response of the systems. The bioreactors that operated at 50, 100 and 300 mg L -1 did not show relevant changes in terms of performance and granules properties, showing high ratio of phenolic compound removal ratio. However, the bioreactors operated with high phenolic compound concentrations showed low rates of organic matter, nitrogen and phenolic acid removal. In the same way, high concentrations of phenolic compounds determined the disintegration of the granular biomass. Next-generation sequencing studies showed a stable community structure in the bioreactors operating with 50, 100 and 300 mg L -1 of phenolic acids, with the genera Lampropedia and Arenimonas, family Xanthobacteraceae and Fungi Pezizomycotina as the dominant phylotypes. Conversely, the reactors operated at 500 and 600 mg L -1 of phenolic substances promoted the proliferation of Oligohymenophorea ciliates. Thus, this study suggests that aerobic granular sludge technology could be useful for the treatment of wastewaters such as olive washing water., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to analyze the publication output of postgraduate pediatric neurosurgery fellows for a 10-year period as well as identify 25 individual highly productive pediatric neurosurgeons. The correlation between academic productivity and the site of fellowship training was studied., Methods: Programs certified by the Accreditation Council for Pediatric Neurosurgery Fellowships that had 5 or more graduating fellows from 2006 to 2015 were included for analysis. Fellows were queried using Scopus for publications during those 10 years with citation data through 2017. Pearson correlation coefficients were calculated, comparing program rankings of faculty against fellows using the revised Hirsch index (r-index; primary) and Hirsch index (h-index; secondary). A list of 25 highly accomplished individual academicians and their fellowship training locations was compiled., Results: Sixteen programs qualified with 152 fellows from 2006 to 2015; 136 of these surgeons published a total of 2009 articles with 23,735 citations. Most publications were pediatric-specific (66.7%) clinical articles (93.1%), with middle authorship (55%). Co-investigators were more likely from residency than fellowship. There was a clustering of the top 7 programs each having total publications of around 120 or greater, publications per fellow greater than 12, more than 1200 citations, and adjusted ir10 (revised 10-year institutional h-index) and ih10 (10-year institutional h-index) values of approximately 2 or higher. Correlating faculty and fellowship program rankings yielded correlation coefficients ranging from 0.53 to 0.80. Fifteen individuals (60%) in the top 25 (by r5 index) list completed their fellowship at 1 of these 7 institutions., Conclusions: Approximately 90% of fellowship-trained pediatric neurosurgeons have 1 or more publications, but the spectrum of output is broad. There is a strong correlation between where surgeons complete their fellowships and postgraduate publications.