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Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

BackgroundNo trials have compared cabozantinib and regorafenib for the second-line treatment of advanced hepatocellular carcinoma (HCC).ObjectivesConduct a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of second-line cabozantinib and regorafenib in patients with advanced HCC and disease progression after prior sorafenib.MethodsThe CELESTIAL and RESORCE trials were used for indirect comparison of second-line cabozantinib and regorafenib in advanced HCC. Population-level data were available for RESORCE, individual patient data (IPD) for CELESTIAL. To align with RESORCE, the CELESTIAL population was limited to patients who received first-line sorafenib only. To minimize potential effect-modifying population differences, the CELESTIAL IPD were weighted to balance the distribution of clinically relevant baseline characteristics with those of RESORCE. Overall survival (OS) and progression-free survival (PFS) were evaluated for the matching-adjusted second-line CELESTIAL population and compared with those for RESORCE using weighted Kaplan-Meier curves and parametric modeling. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) affecting > 5% of patients in any study arm were compared.ResultsIn the matching-adjusted second-line populations (CELESTIAL, effective sample size = 266; RESORCE, n = 573), median (95% confidence interval) OS was similar for cabozantinib and regorafenib (11.4 [8.9-17.0] versus 10.6 [9.1-12.1] months; p = 0.3474, log-rank test). Median PFS was longer for cabozantinib than regorafenib (5.6 [4.9-7.3] versus 3.1 [2.8-4.2] months; p = 0.0005, log-rank test). There was a trend for lower rates of some grade 3/4 TEAEs with regorafenib than with cabozantinib, which may reflect the exclusion of sorafenib-intolerant patients from RESORCE but not from CELESTIAL, a difference that the MAIC methods could not remove. Only diarrhea rates were statistically significantly lower for regorafenib (p  ≤ 0.001).ConclusionsCabozantinib may achieve similar OS and prolonged PFS compared with regorafenib in patients with progressive advanced HCC after prior sorafenib.

IntroductionThe cocktail-party problem refers to the difficulty listeners face when trying to attend to relevant sounds that are mixed with irrelevant ones. Previous studies have shown that solving these problems relies on perceptual as well as cognitive processes. Previously, we showed that speech-reception thresholds (SRTs) on a cocktail-party listening task were influenced by genetic factors. Here, we estimated the degree to which these genetic factors overlapped with those influencing cognitive abilities.MethodsWe measured SRTs and hearing thresholds (HTs) in 493 listeners, who ranged in age from 18 to 91 years old. The same individuals completed a cognitive test battery comprising 18 measures of various cognitive domains. Individuals belonged to large extended pedigrees, which allowed us to use variance component models to estimate the narrow-sense heritability of each trait, followed by phenotypic and genetic correlations between pairs of traits.ResultsAll traits were heritable. The phenotypic and genetic correlations between SRTs and HTs were modest, and only the phenotypic correlation was significant. By contrast, all genetic SRT–cognition correlations were strong and significantly different from 0. For some of these genetic correlations, the hypothesis of complete pleiotropy could not be rejected.DiscussionOverall, the results suggest that there was substantial genetic overlap between SRTs and a wide range of cognitive abilities, including abilities without a major auditory or verbal component. The findings highlight the important, yet sometimes overlooked, contribution of higher-order processes to solving the cocktail-party problem, raising an important caveat for future studies aiming to identify specific genetic factors that influence cocktail-party listening.

Summary: Animal testing is the current standard for drug and chemicals safety assessment, but hazards translation to human is uncertain. Human in vitro models can address the species translation but might not replicate in vivo complexity. Herein, we propose a network-based method addressing these translational multiscale problems that derives in vivo liver injury biomarkers applicable to in vitro human early safety screening. We applied weighted correlation network analysis (WGCNA) to a large rat liver transcriptomic dataset to obtain co-regulated gene clusters (modules). We identified modules statistically associated with liver pathologies, including a module enriched for ATF4-regulated genes as associated with the occurrence of hepatocellular single-cell necrosis, and as preserved in human liver in vitro models. Within the module, we identified TRIB3 and MTHFD2 as a novel candidate stress biomarkers, and developed and used BAC-eGFPHepG2 reporters in a compound screening, identifying compounds showing ATF4-dependent stress response and potential early safety signals.

Abstract Alpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods.

Summary: Communicating in everyday situations requires solving the cocktail-party problem, or segregating the acoustic mixture into its constituent sounds and attending to those of most interest. Humans show dramatic variation in this ability, leading some to experience real-world problems irrespective of whether they meet criteria for clinical hearing loss. Here, we estimated the genetic contribution to cocktail-party listening by measuring speech-reception thresholds (SRTs) in 425 people from large families and ranging in age from 18 to 91 years. Roughly half the variance of SRTs was explained by genes (h2 = 0.567). The genetic correlation between SRTs and hearing thresholds (HTs) was medium (ρG = 0.392), suggesting that the genetic factors influencing cocktail-party listening were partially distinct from those influencing sound sensitivity. Aging and socioeconomic status also strongly influenced SRTs. These findings may represent a first step toward identifying genes for “hidden hearing loss,” or hearing problems in people with normal HTs.

Resistance to thyroid hormone β (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year-old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHβ had died of cardiac failure at age 13 years. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass, and improved growth and cardiac function. A combination of antithyroid drug and TRIAC therapy may prevent thyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate.

Resistance to thyroid hormone β (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year-old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHβ had died of cardiac failure at age 13 years. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass, and improved growth and cardiac function. A combination of antithyroid drug and TRIAC therapy may prevent thyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate.

This paper belongs to a Focus Series dedicated to Challenges in Granular Matter. As such, it does not report any new finding, but rather offers an overview of the state of the art and of current and future challenges for the granular physics community. The focus is placed on the case of confined sheared flows of granular samples with particular complexities, such as soft, angular, or cemented grains, with applications in tribology and fault mechanics. We first explain why granular science may help to improve our understanding of dry friction in these two applications, and illustrate some recently unveiled aspects regarding the complexity of the problem. We then describe a few avenues for future research on the topic, focusing on the dialogue between simulations and experiments, on scale-related challenges, and on some pivotal computational aspects.

Introduction The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2−) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety.Methods PADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients.Ethics and dissemination The study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals.Trial registration numbers EudraCT: 2016-004360-18; NCT03079011.

Wastewater (WW) is considered a source of antibiotic-resistant bacteria with clinical relevance and may, thus, be important for their dissemination into the environment, especially in countries with poor WW treatment. To obtain an overview of the occurrence and characteristics of carbapenem-resistant Gram-negative bacteria (CR-GNB) in WW of Belgrade, we investigated samples from the four main sewer outlets prior to effluent into international rivers, the Sava and the Danube. Thirty-four CR-GNB isolates were selected for antimicrobial susceptibility testing (AST) and whole-genome sequencing (WGS). AST revealed that all isolates were multidrug-resistant. WGS showed that they belonged to eight different species and 25 different sequence types (STs), seven of which were new. ST101 K. pneumoniae (blaCTX-M-15/blaOXA-48) with novel plasmid p101_srb was the most frequent isolate, detected at nearly all the sampling sites. The most frequent resistance genes to aminoglycosides, quinolones, trimethroprim-sulfamethoxazole, tetracycline and fosfomycin were aac(6′)-Ib-cr (55.9%), oqxA (32.3%), dfrA14 (47.1%), sul1 (52.9%), tet(A) (23.5%) and fosA (50%), respectively. Acquired resistance to colistin via chromosomal-mediated mechanisms was detected in K. pneumoniae (mutations in mgrB and basRS) and P. aeruginosa (mutation in basRS), while a plasmid-mediated mechanism was confirmed in the E. cloacae complex (mcr-9.1 gene). The highest number of virulence genes (>300) was recorded in P. aeruginosa isolates. Further research is needed to systematically track the occurrence and distribution of these bacteria so as to mitigate their threat.

Introduction: Bevacizumab-containing therapy is considered a standard-of-care front-line option for stage IIIB–IV ovarian cancer based on results of randomized phase 3 trials. The multicenter non-interventional ENCOURAGE prospective cohort study assessed treatment administration and outcomes in the French real-world setting.Patients and Methods: Eligible patients were aged ≥ 18 years with planned bevacizumab-containing therapy for newly diagnosed ovarian cancer. The primary objective was to assess the safety profile of front-line bevacizumab in routine clinical practice; secondary objectives were to describe patient characteristics, indications/contraindications for bevacizumab, treatment regimens and co-medications, follow-up and monitoring, progression-free survival, and treatment at recurrence. In this non-interventional study, treatment was administered as chosen by the investigator and participation in the trial had no influence on the management of the disease.Results: Of 1,290 patients screened between April 2013 and February 2015, 468 were eligible. Most patients (86%) received bevacizumab 15 mg/kg every 3 weeks or equivalent, typically with carboplatin (99%) and paclitaxel (98%). The median duration of bevacizumab was 12.2 (range 0–28, interquartile range 6.9–14.9) months; 8% of patients discontinued bevacizumab because of toxicity. The most common adverse events were hypertension (38% of patients), fatigue (35%), and bleeding (32%). There were no treatment-related deaths. Most physicians (90%) reported blood pressure measurement immediately before each bevacizumab infusion and almost all (97%) reported monitoring for proteinuria before each bevacizumab infusion. Median progression-free survival was 17.4 (95% CI, 16.4–19.1) months. The 3-year overall survival rate was 62% (95% CI, 58–67%). The most commonly administered chemotherapies at recurrence were carboplatin and pegylated liposomal doxorubicin.Discussion: Clinical outcomes and tolerability with bevacizumab in this real-life setting are consistent with randomized trial results, notwithstanding differences in the treated patient population and treatment schedule.Clinical Trial Registration:ClinicalTrials.gov, Identifier NCT01832415.

Spinal cord injury (SCI) is a devastating condition characterized by loss of function, secondary to damaged spinal neurons, disrupted axonal connections, and myelin loss. Spontaneous recovery is limited, and there are no approved pharmaceutical treatments to reduce ongoing damage or promote repair. Repulsive guidance molecule A (RGMa) is upregulated following injury to the central nervous system (CNS), where it is believed to induce neuronal apoptosis and inhibit axonal growth and remyelination. We evaluated elezanumab, a human anti-RGMa monoclonal antibody, in a novel, newly characterized non-human primate (NHP) hemicompression model of thoracic SCI. Systemic intravenous (IV) administration of elezanumab over 6 months was well tolerated and associated with significant improvements in locomotor function. Treatment of animals for 16 weeks with a continuous intrathecal infusion of elezanumab below the lesion was not efficacious. IV elezanumab improved microstructural integrity of extralesional tissue as reflected by higher fractional anisotropy and magnetization transfer ratios in treated vs. untreated animals. IV elezanumab also reduced SCI-induced increases in soluble RGMa in cerebrospinal fluid, and membrane bound RGMa rostral and caudal to the lesion. Anterograde tracing of the corticospinal tract (CST) from the contralesional motor cortex following 20 weeks of IV elezanumab revealed a significant increase in the density of CST fibers emerging from the ipsilesional CST into the medial/ventral gray matter. There was a significant sprouting of serotonergic (5-HT) fibers rostral to the injury and in the ventral horn of lower thoracic regions. These data demonstrate that 6 months of intermittent IV administration of elezanumab, beginning within 24 h after a thoracic SCI, promotes neuroprotection and neuroplasticity of key descending pathways involved in locomotion. These findings emphasize the mechanisms leading to improved recovery of neuromotor functions with elezanumab in acute SCI in NHPs.

Abstract Background Older surgical patients are at high risk of developing postoperative delirium. Non-pharmacological strategies are recommended for delirium prevention, but no pharmacological agents have compelling evidence to decrease the incidence of delirium. The purpose of this study was to assess whether perioperative melatonin decreases the incidence of delirium in older adults undergoing surgical procedures. Methods A systematic search using PubMed/Medline, Embase, PsycINFO, CINAHL, and references of identified articles published in English between January 1990 and October 2017 was performed. Two independent reviewers screened titles and abstracts, and then extracted data following a full-text review of included articles with consensus generation and bias assessment. Studies reporting outcomes for melatonin or ramelteon use to prevent delirium in postoperative hospitalized patients (mean age ≥ 50 years) were eligible for inclusion. Data were pooled using a fixed-effects model to generate a forest plot and obtain a summary odds ratio for the outcome of interest (delirium incidence). Cochran’s Q and I2 values were used to investigate heterogeneity. Results Of 335 records screened, 6 studies were selected for the qualitative analysis and 6 were included in the meta-analysis (n = 1155). The mean age of patients in included studies ranged from 59 to 84 years. Patients in intervention groups typically received melatonin or ramelteon at daily doses of two to eight milligrams around cardiothoracic, orthopedic, or hepatic surgeries for one to nine days, starting on the evening before or the day of surgery. The incidence of delirium ranged from 0 to 30% in the intervention groups versus 4–33% in the comparator groups, and was significantly reduced in the melatonin group, with a summary effect of the meta-analysis yielding an odds ratio of 0.63 (95% CI 0.46 to 0.87; 0.006; I2 = 72.1%). A one study removed analysis reduced overall odds ratio to 0.310 (95% CI 0.19 to 0.50), while reducing heterogeneity (Cochran’s Q = 0.798, I2 = 0.000). Conclusion Perioperative melatonin reduced the incidence of delirium in older adults in the included studies. While optimal dosing remains an unanswered question, the potential benefit of melatonin and melatonin receptor agonists may make them a reasonable option to use for delirium prevention in older adults undergoing surgical procedures.

Retinal ganglion cells (RGCs) are the bridging neurons that connect the retinal input to the visual processing centres within the central nervous system. There is a remarkable diversity of RGCs and the various subtypes have unique morphological features, distinct functions, and characteristic pathways linking the inner retina to the relevant brain areas. A number of psychophysical and electrophysiological tests have been refined to investigate this large and varied population of RGCs. Technological advances, such as high-resolution optical coherence tomography imaging, have provided additional tools to define the pattern of RGC involvement and the chronological sequence of events in both inherited and acquired optic neuropathies. The mechanistic insights gained from these studies, in particular the selective vulnerability and relative resilience of particular RGC subtypes, are of fundamental importance as they are directly relevant to the development of targeted therapies for these invariably progressive blinding diseases. This review provides a comprehensive description of the various types of RGCs, the developments in proposed methods of classification, and the current gaps in our knowledge of how these RGCs are differentially affected depending on the underlying aetiology. The synthesis of the current body of knowledge on the diversity of RGCs and the pathways that are potentially amenable to therapeutic modulation will hopefully lead to much needed effective treatments for patients with optic neuropathies.

AbstractBackgroundQuestions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation.MethodsUsing data from 9,421 individuals aged 8–21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation.ResultsExternalizing was heritable (h2 = 0.46, p = 1 × 10−6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = −0.412, p = 0.004), verbal reasoning (ρg = −0.485, p = 0.001), spatial reasoning (ρg = −0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10−4), verbal knowledge (ρg = −0.314, p = 0.002), and general cognitive ability (g)(ρg = −0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = −0.146, p = 0.004) and increasing environmental variance (γe = 0.059, p = 0.009) on externalizing.ConclusionsCognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.

In this report, we describe a male subject who presents with a complex phenotype of myopia associated with cone dysfunction and a protan vision deficiency. Retinal imaging demonstrates extensive cone disruption, including the presence of non-waveguiding cones, an overall thinning of the retina, and an irregular mottled appearance of the hyper-reflective band associated with the inner segment ellipsoid portion of the photoreceptor. Mutation screening revealed a novel p.Glu41Lys missense mutation in a hybrid L/M opsin gene. Spectral analysis shows that the mutant opsin fails to form a pigment in vitro and fails to be trafficked to the cell membrane in transfected Neuro2a cells. Extensive sequence and quantitative PCR analysis identifies this mutant gene as the only gene present in the affected subject's L/M opsin gene array, yet the presence of protanopia indicates that the mutant opsin must retain some activity in vivo. To account for this apparent contradiction, we propose that a limited amount of functional pigment is formed within the normal cellular environment of the intact photoreceptor, and that this requires the presence of chaperone proteins that promote stability and normal folding of the mutant protein.

We measured psychophysical thresholds for discriminating the speeds of two arrays of moving dots. The arrays could be juxtaposed or could be spatially separated by up to 10 degrees of visual angle, eccentricity being held constant. We found that the precision of the judgments varied little with separation. Moreover, the function relating threshold to separation was similar whether the arrays moved in the same, in opposite or in orthogonal directions. And there was no significant difference in threshold whether the two stimuli were initially presented to the same cerebral hemisphere or to opposite ones. How are human observers able to compare stimuli that fall at well separated positions in the visual field? We consider two classes of explanation: (i) Observers' judgments might be based directly on the signals of dedicated 'comparator neurons', i.e. neurons drawing inputs of opposite sign from local regions of the visual field. (ii) Signals about local features might be transmitted to the site of comparison by a shared 'cerebral bus', where the same physical substrate carries different information from moment to moment. The minimal effects of proximity and direction (which might be expected to influence local detectors of relative motion), and the combinatorial explosion in the number of comparator neurons that would be required by (i), lead us to favor models of type (ii).

PIK3CA mutation frequency varies among breast cancer (BC) subtypes. Recent evidence suggests combination therapy with the PI3K inhibitor (PI3Ki) alpelisib and endocrine therapy (ET) improves response rates and progression-free survival (PFS) in PIK3CA-mutant, hormone receptor positive (HR+) BC versus ET alone; thus, better understanding the clinical and epidemiologic elements of these mutations is warranted. This systematic review characterizes the PIK3CA mutation epidemiology, type of testing approaches (e.g., liquid or tissue tumor biopsy), and stability/concordance (e.g., consistency in results by liquid versus solid tumor sample, by the same method over time) in patients with HR+/HER2– advanced (locally unresectable) or metastatic disease (HR+/HER2– mBC) and explores performance (e.g., pairwise concordance, sensitivity, specificity, or predictive value) of respective mutation findings. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts (i.e., AACR, ASCO, SABCS, ECCO, and ESMO conferences between 2014 and 2017) identified 39 studies of patients with HR+, HER2– mBC. The median prevalence of PIK3CA mutation was 36% (range: 13.3% to 61.5%); identified testing approaches more commonly used tissue over liquid biopsies and primarily utilized next-generation sequencing (NGS), polymerase chain reaction (PCR), or Sanger sequencing. There was concordance and stability between tissues (range: 70.4% to 94%) based on limited data. Given the clinical benefit of the PI3Ki alpelisib in patients with PIK3CA mutant HR+/HER2– mBC, determination of tumor PIK3CA mutation status is of importance in managing patients with HR+/HER2– mBC. Prevalence of this mutation and utility of test methodologies likely warrants PIK3CA mutation testing in all patients with this breast cancer subtype via definitive assessment of PIK3CA mutational status.

Abstract Background Little is known regarding the health-related quality of life among myocardial infarction (MI) survivors in the United States. The purpose of this population-based study was to identify differences in health-related quality of life domains between MI survivors and propensity score matched controls. Methods This retrospective, cross-sectional matched case-control study examined differences in health-related quality of life (HRQoL) among MI survivors of myocardial infarction compared to propensity score matched controls using data from the 2015 Behavioral Risk Factor Surveillance System (BRFSS) survey. Propensity scores were generated via logistic regression for MI survivors and controls based on gender, race/ethnicity, age, body mass index (BMI), smoking status, and comorbidities. Chi-square tests were used to compare differences between MI survivors to controls for demographic variables. A multivariate analysis of HRQoL domains estimated odds ratios. Life satisfaction, sleep quality, and activity limitations were estimated using binary logistic regression. Social support, perceived general health, perceived physical health, and perceived mental health were estimated using multinomial logistic regression. Significance was set at p 15 days in the month (AOR = 1.63, 95% CI: 1.46–1.83) and poor mental health >15 days in the month (AOR = 1.25, 95% CI: 1.07–1.46) compared to matched controls. There was no difference in survivors compared to controls in level of emotional support (rarely/never: AOR = 0.75, 95% CI: 0.48–1.18; sometimes: AOR = 0.73, 95% CI: 0.41–1.28), hours of recommended sleep (AOR = 1.14, 95% CI: 0.94–1.38), or life satisfaction (AOR = 1.62, 95% CI: 0.99–2.63). Conclusion MI survivors experienced lower HRQoL on domains of general health, physical health, daily activity, and mental health compared to the general population.

PurposeTo perform a phenotypic assessment of members of three British families with blue cone monochromatism (BCM), and to determine the underlying molecular genetic basis of disease.MethodsAffected members of three British families with BCM were examined clinically and underwent detailed electrophysiological and psychophysical testing. Blood samples were taken for DNA extraction. Molecular analysis involved the amplification of the coding regions of the long (L) and medium (M) wave cone opsin genes and the upstream locus control region (LCR) by polymerase chain reaction (PCR). Gene products were directly sequenced and analyzed.ResultsIn all three families, genetic analysis identified that the underlying cause of BCM involved an unequal crossover within the opsin gene array, with an inactivating mutation. Family 1 had a single 5'-L-M-3' hybrid gene, with an inactivating Cys203Arg (C203R) mutation. Family 3 had an array composed of a C203R inactivated 5'-L-M-3' hybrid gene followed by a second inactive gene. Families 1 and 3 had typical clinical, electrophysiological, and psychophysical findings consistent with stationary BCM. A novel mutation was detected in Family 2 that had a single hybrid gene lacking exon 2. This family presented clinical and psychophysical evidence of a slowly progressive phenotype.ConclusionsTwo of the BCM-causing family genotypes identified in this study comprised different hybrid genes, each of which contained the commonly described C203R inactivating mutation. The genotype in the family with evidence of a slowly progressive phenotype represents a novel BCM mutation. The deleted exon 2 in this family is not predicted to result in a shift in the reading frame, therefore we hypothesize that an abnormal opsin protein product may accumulate and lead to cone cell loss over time. This is the first report of slow progression associated with this class of mutation in the L or M opsin genes in BCM.

We conducted meta-analyses of 67 studies on the association between neonatal proxies of impaired gas exchange and intellectual disability (ID) or autism spectrum disorders (ASD). Neonatal acidosis was associated with an odds ratio (OR) of 3.55 [95% confidence interval (95% CI) 2.23-5.49] for ID and an OR of 1.10 (95% CI 0.91-1.31) for ASD. Children with a 5-min Apgar score of <7 had an OR of 5.39 (95% CI 3.84-7.55) for ID and an OR of 1.67 (95 % CI 1.34-2.09) for ASD. O2 treatment was associated with an OR of 4.32 (95% CI 3.23-5.78) for ID and an OR of 2.02 (95% CI 1.45 to 2.83) for ASD. Our meta-analysis demonstrates an increased risk of ID and (to a lesser extent) ASD in children with neonatal hypoxia. Moreover, our findings raise the possibility that concomitant ID might account for the observed association between the gas exchange proxies and ASD.

Abstract Background Psoriasis is a multifactorial, inflammatory, skin disease associated with various comorbidities. The cost of those comorbidities is not well characterized. The present study assesses the incremental burden of comorbidities on healthcare resource utilization, direct costs and indirect costs associated with short-term disabilities among patients with psoriasis in the United States. Methods A retrospective, U.S. cohort analysis was conducted using a large claims database. Adult psoriasis patients with at least two diagnoses of psoriasis during the years 2010 and 2011 (one psoriasis diagnosis had to happen in the year 2010) and with continuous enrollment of medical and pharmacy benefits in the years 2010 and 2011 were included. Psoriasis patients were categorized and compared according to the presence or absence of pre-selected comorbidities in the year 2010. Adjusted annual direct (costs associated with outpatient, emergency room, and inpatient claims, and outpatient pharmacy claims) and indirect costs (short-term disabilities) was assessed in patients with and without comorbidities using a regression analysis, controlling for age, gender, and psoriasis severity in year 2010. Results In total, 56,406 patients (mean [SD]) age, 51.6 [14.6] years) were included in the analysis. The most prevalent comorbidities were hypertension (34.3%), hyperlipidemia (33.5%), cardiovascular disease (17.7%), diabetes (14.2%), and psoriatic arthritis (9.9%). Psoriasis patients with comorbidities used more healthcare resources than those without comorbidities. The incidence rate ratio (IRR) (95% CI) for patients with cardiovascular disease was 1.5 (1.4 − 1.5) for outpatient visits, 2.6 (2.4 − 2.8) for hospitalizations, and 2.3 (2.2 − 2.5) for ER visits, showing higher IRRs across all three types of resource use. The mean annual adjusted direct cost differences (i.e., incremental adjusted costs) in psoriasis patients with and without comorbidities were $9914.3, $8386.5, and $8275.1 for psoriatic arthritis, peripheral vascular disease, and cardiovascular disease, respectively. The mean annual incremental adjusted indirect costs of short-term disabilities were $1333, $1195, $994.9, and $996.6 for cerebrovascular disease, obesity, peripheral vascular disease, and depression, respectively. Conclusion The presence of comorbidities was associated with higher healthcare resource utilization and costs among patients with psoriasis.

Numerical models of granular materials are useful in tribology, and can be used to predict wear and friction in contacts. DEM-like simulations are used to model particles of third-body, which are partly wear debris from rubbing bodies. It has been shown that the third-body particles can have different flow regimes, depending on their mechanical properties. Among the different characteristics of flow regimes, agglomerate size seems to be crucial. A method based on vortex analysis used in fluid mechanics allows characterizing this cluster size. The results show that different vortex sizes can be observed during the simulation. In particular, it is observed that some vortexes of a characteristic size persist over time, and could be representative of agglomerates. These results pave the way for a better characterisation of the different flow regimes.

We present a novel numerical model allowing to take the best part of continuum-based and discrete modelling in a single framework. This model is applied to the reproduction of laboratory earthquakes in a high-pressure triaxial cell. It allows to represent most of the relevant phenomena at stake, including elastic stress build-up during loading, fast and slow sliding events, seismic waves emission in the surrounding elastic medium and evolution of fault gouge on the sliding interface. We review here some illustrative results obtained with this model and propose further research avenues.

Earthquakes happen with frictional sliding, by releasing all the stresses accumulated in the prestressed surrounding medium. The geological fault gouge, coming from the wear of previous slips, acts on friction stability and plays a key role in this sudden energy release. A large part of slip mechanisms are influenced, if not controlled, by the characteristics and environment of this tribological “third body”. A 2D granular fault (mm scale) is implemented with Discrete Element Modelling (DEM). A displacement-driven model with dry contact is studied to observe kinematics and properties of the slipping zone. Increasing the length of the granular media increases the slip needed to weaken the friction from friction peak to steadystate. Low-angle Riedel shear bands are mostly observed. Their number increases with the inter-particle friction coefficient, which also influences shear bands formation in their orientation angle (higher friction leads to higher angle with the main slip direction).

Arthroscopic SLAP tear repair has become an increasingly used treatment for patients presenting with symptomatic SLAP tears after failed nonoperative management. Debridement, SLAP repair, and open or arthroscopic biceps tenodesis or tenotomy have been used for the treatment of SLAP tears. Various techniques for repair have been described, and furthermore, there is a high incidence of concomitant pathology of the shoulder. Repair remains an excellent option in isolated SLAP tears amenable to repair, with excellent outcomes in well-indicated patients. We present a method for repairing a SLAP tear using standard suture anchor fixation, anterior and posterior portals, and an accessory portal of Wilmington. Adequate labral repair can be achieved with this technique in patients with no concomitant biceps pathology. This report highlights this technique for SLAP repair in patients with isolated symptomatic SLAP tears that have failed conservative management.