First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results.

PUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).

Why might animals remember? A functional framework for episodic memory research in comparative psychology.

One of Clayton's major contributions to our understanding of animal minds has been her work on episodic-like memory. A central reason for the success of this work was its focus on ecological validity: rather than looking for episodic memory for arbitrary stimuli in artificial contexts, focussing on contexts in which episodic memory would serve a biological function such as food caching. This review aims to deepen this insight by surveying the numerous functions that have been proposed for episodic memory, articulating a philosophically grounded framework for understanding what exactly functions are, and drawing on these to make suggestions for future directions in the comparative cognitive psychology of episodic memory. Our review suggests four key insights. First, episodic memory may have more than one function and may have different functions in different species. Second, cross-disciplinary work is key to developing a functional account of episodic memory. Third, there is scope for further theoretical elaboration of proposals relating episodic memory to food caching and, in particular, future-oriented cognition. Finally, learning-related functions suggested by AI (artificial intelligence)-based models are a fruitful avenue for future behavioural research.

Computation via Neuron-like Spiking in Percolating Networks of Nanoparticles.

The biological brain is a highly efficient computational system in which information processing is performed via electrical spikes. Neuromorphic computing systems that work on similar principles could support the development of the next generation of artificial intelligence and, in particular, enable low-power edge computing. Percolating networks of nanoparticles (PNNs) have previously been shown to exhibit critical spiking behavior, with promise for highly efficient natural computation. Here we employ a rate coding scheme to show that PNNs can perform Boolean operations and image classification. Near perfect accuracy is achieved in both tasks by manipulating the spiking activity using certain control voltages. We demonstrate that the key to successful computation is that nanoscale tunnel gaps within the percolating networks transform input data through a powerful modulus-like nonlinearity. These results provide a basis for implementation of further computational schemes that exploit the brain-like criticality of these networks.

Antimony oxide nanostructures in the monolayer limit: self-assembly of van der Waals-bonded molecular building blocks.

Antimony oxide nanostructures have been identified as candidates for a range of electronic and optoelectronic applications. Here we demonstrate the growth of 2-dimensional antimony oxide nanostructures on various substrates, including highly oriented pyrolytic graphite (HOPG), MoS2 and α-Bi(110) nanoislands. Using scanning tunneling microscopy (STM) we show that the nanostructures formed are exclusively highly crystalline α-Sb2O3(111) monolayers with a lattice constant of 796 pm ± 7 pm. The nanostructures are triangular with lateral dimensions of up to ∼30 nm. Even though elemental antimony nanostructures are grown simultaneously mixed phases are not observed and both materials exhibit their own distinct growth modes. Moiré patterns are also observed and simulated, allowing confirmation of the atomic unit cell and an understanding of the orientation of the Sb2O3 structures with respect to the supporting materials. As in the bulk, the Sb2O3 nanostructures are formed from Sb4O6 molecules that are weakly interacting through van der Waals forces. This allows physical modification of the nanostructures with the STM tip. Scanning tunnelling spectroscopy reveals a wide band gap of at least 3.5 eV. Finally, we show that possible alternative structures that have unit cells comparable to those observed can be excluded based on our DFT calculations. The considered structures are a 2 × 2 reconstruction of ß-Sb with one vacancy per unit cell and a van der Waals solid composed of Sb4 clusters. Previous reports have predominantly demonstrated Sb2O3 structures with much larger thicknesses.

Atomic Scale Dynamics Drive Brain-like Avalanches in Percolating Nanostructured Networks.

Self-assembled networks of nanoparticles and nanowires have recently emerged as promising systems for brain-like computation. Here, we focus on percolating networks of nanoparticles which exhibit brain-like dynamics. We use a combination of experiments and simulations to show that the brain-like network dynamics emerge from atomic-scale switching dynamics inside tunnel gaps that are distributed throughout the network. The atomic-scale dynamics emulate leaky integrate and fire (LIF) mechanisms in biological neurons, leading to the generation of critical avalanches of signals. These avalanches are quantitatively the same as those observed in cortical tissue and are signatures of the correlations that are required for computation. We show that the avalanches are associated with dynamical restructuring of the networks which self-tune to balanced states consistent with self-organized criticality. Our simulations allow visualization of the network states and detailed mechanisms of signal propagation.

Positing numerosities may be metaphysically extravagant; positing representation of numerosities is not.

Clarke and Beck (C&B) assume that approximate number system (ANS) representations should be assigned referents from our scientific ontology. However, many representations, both in perception and cognition, do not straightforwardly refer to such entities. If we reject C&B's assumption, many possible contents for ANS representations besides number are compatible with the evidence C&B cite.

Quantum fluctuations in percolating superconductors: an evolution with effective dimensionality.

We investigate percolating films of superconducting nanoparticles and observe an evolution from superconducting to metallic to insulating states as the surface coverage of the nanoparticles is decreased. We demonstrate that this evolution is correlated with a reduction in the effective/dominant dimensionality of the system, from 2D to 1D to 0D, and that the physics in each regime is dominated by vortices, phase slips and tunnelling respectively. Finally we construct phase diagrams that map the various observed states as a function of surface coverage (or, equivalently, normal state resistance), temperature and measurement current.

Covalently anchored carboxyphenyl monolayer via aryldiazonium ion grafting: a well-defined reactive tether layer for on-surface chemistry.

Electrografting of aryl films to electrode surfaces from diazonium ion solutions is a widely used method for preparation of modified electrodes. In the absence of deliberate measures to limit film growth, the usual film structure is a loosely packed multilayer. For some applications, monolayer films are advantageous; our interest is in preparing well-defined monolayers of reactive tethers for further on-surface chemistry. Here, we describe the synthesis of an aryl diazonium salt with a protected carboxylic acid substituent. After electrografting to glassy carbon electrodes and subsequent deprotection, the layer is reacted with amine derivatives. Electrochemistry and atomic force microscopy are used to monitor the grafting, deprotection, and subsequent coupling steps. Attempts to follow the same procedures on gold surfaces suggest that the grafted layer is not stable in these reaction conditions.

Integer Factorization with Stochastic Spiking in Percolating Networks of Nanoparticles.

As growth in global demand for computing power continues to outpace ongoing improvements in transistor-based hardware, novel computing solutions are required. One promising approach employs stochastic nanoscale devices to accelerate probabilistic computing algorithms. Percolating Networks of Nanoparticles (PNNs) exhibit stochastic spiking, which is of particular interest as it meets criteria for criticality which is associated with a range of computational advantages. Here, we show several ways in which spiking PNNs can be used as the core stochastic components of coupled networks that allow successful factorization of integers up to 945. We demonstrate asynchronous operation and show that a single device is sufficient to solve all factorization tasks and to generate multiple solutions simultaneously.

Experimental Demonstration of Reservoir Computing with Self-Assembled Percolating Networks of Nanoparticles.

The complex self-assembled network of neurons and synapses that comprises the biological brain enables natural information processing with remarkable efficiency. Percolating networks of nanoparticles (PNNs) are complex self-assembled nanoscale systems that have been shown to possess many promising brain-like attributes and which are therefore appealing systems for neuromorphic computation. Here experiments are performed that show that PNNs can be utilized as physical reservoirs within a nanoelectronic reservoir computing framework and demonstrate successful computation for several benchmark tasks (chaotic time series prediction, nonlinear transformation, and memory capacity). For each task, relevant literature results are compiled and it is shown that the performance of the PNNs compares favorably to that previously reported from nanoelectronic reservoirs. It is then demonstrated experimentally that PNNs can be used for spoken digit recognition with state-of-the-art accuracy. Finally, a parallel reservoir architecture is emulated, which increases the dimensionality and richness of the reservoir outputs and results in further improvements in performance across all tasks.

Quantized conductance and switching in percolating nanoparticle films.

We demonstrate switching behavior and quantized conductance at room temperature in percolating films of nanoparticles. Our experiments and complementary simulations show that switching and quantization result from the formation of atomic-scale wires in the gaps between particles. These effects occur only when tunnel gaps are present in the film, close to the percolation threshold.

Risk Factors for Radiotherapy Failure in the Treatment of Spinal Metastases.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To build a predictive model for risk factors for failure of radiation therapy, hypothesizing a higher SINS would correlate with failure. METHODS: Patients with spinal metastasis being treated with radiation at a tertiary care academic center between September 2014 and October 2018 were identified. The primary outcome measure was radiation therapy failure as defined by persistent pain, need for re-irradiation, or surgical intervention. Risk factors were primary tumor type, Karnofsky and ECOG scores, time to treatment, biologically effective dose (BED) calculations using α/ß ratio = 10, and radiation modality. A logistic regression was used to construct a prediction model for radiation therapy failure. RESULTS: One hundred and seventy patients were included. Median follow up was 91.5 days. Forty-three patients failed radiation therapy. Of those patients, 10 required repeat radiation and 7 underwent surgery. Thirty-six patients reported no pain relief, including some that required re-irradiation and surgery. Total SINS score for those who failed reduction therapy was <7 for 27 patients (62.8%), between 7-12 for 14 patients (32.6%), and >12 for 2 patients (4.6%). In the final prediction model, BED (OR .451 for BED > 43 compared to BED ≤ 43; P = .174), Karnofksy score (OR .736 for every 10 unit increase in Karnofksy score; P = .008), and gender (OR 2.147 for male compared to female; P = .053) are associated with risk of radiation failure (AUC .695). A statistically significant association between SINS score and radiation therapy failure was not found. CONCLUSIONS: In the multivariable model, BED ≤ 43, lower Karnofksy score, and male gender are predictive for radiotherapy failure. SINS score was among the candidate risk factors included in multivariable model building procedure, but it was not selected in the final model. LEVEL OF EVIDENCE: Prognostic level III.

Association of Brachytherapy Boost with Overall Survival for Gleason 9-10 Prostate Cancer: The Impact of Primary versus Secondary Pattern 5.

PURPOSE: The addition of a brachytherapy (BT) boost to external beam radiotherapy (EBRT) reduces recurrence risk in men with high-risk prostate cancer (PCa) and may reduce PCa-mortality for Gleason grade group 5 (GG5). Whether the extent of pattern five, a risk factor for distant metastases, impacts the benefit of a BT boost is unclear. METHODS: Men with localized GG5 PCa treated with (1) EBRT or (2) EBRT+BT between 2010 and 2016 were identified in the National Cancer Database. EBRT monotherapy group received conventionally fractionated (1.8-2.0 Gy per fraction) ≥74 Gy or moderately hypofractionated (2.5-3.0 Gy per fraction) ≥60 Gy. EBRT + BT group received conventionally fractionated ≥45 Gy or moderately hypofractionated ≥37.5 Gy, and either LDR or HDR BT. All patients received concomitant ADT; none received chemotherapy, immunotherapy, or surgery. OS was compared using Kaplan-Meier, log-rank test, and multivariable Cox proportional hazards in the overall cohort, followed by subgroups based on primary versus secondary pattern 5. Propensity score- and exact-matching was used to corroborate results. RESULTS: A total of 8260 men were eligible: EBRT alone (89%) versus EBRT + BT (11%). 5-year OS for EBRT versus EBRT + BT was 76.3% and 85.0%, respectively (p = 0.002; multivariable adjusted HR 0.84, 95% CI 0.65-0.98; p = 0.04). These results remained consistent after propensity score and exact matching. The OS advantage of a BT boost was more prominent in men with Gleason 4 + 5 PCa (p = 0.001) and not observed in men with Gleason 5 + 5 or 5 + 4 PCa. CONCLUSIONS: Extent of pattern five may be useful in appropriately selecting men for EBRT+BT and should be considered as a pre-randomization stratification variable for future clinical trial design.

Prophylaxis with a recombinant factor VIII Fc in hemophilia A: long-term follow-up on joint health, efficacy, and safety from phase 3 studies in children and adults.

Background: Recurrent joint bleeds are a major cause of morbidity in severe hemophilia. Prophylaxis with efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, [rFVIIIFc]) has demonstrated benefits beyond bleed control, including joint health maintenance. Objectives: To assess long-term efficacy and safety of rFVIIIFc prophylaxis in severe hemophilia A in phase 3 pivotal (A-LONG/Kids A-LONG) and extension (ASPIRE) studies. Methods: Longitudinal analysis included pooled data from A-LONG/Kids A-LONG and ASPIRE. Subgroup analyses investigated outcomes in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score and target joints in subjects with 4 to 5 years follow-up on individualized prophylaxis (IP), and those with the highest annualized bleeding rate (ABR) quartile during Year 1 of IP. Results: Overall, rFVIIIFc consumption remained stable and low ABRs were maintained, with a median treatment duration of 4.2/3.4 years in subjects from A-LONG/Kids A-LONG, respectively. Median overall ABR also remained low (1.0-2.0) in subjects on IP for 4 to 5 years. Sustained improvements in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score were demonstrated over a median follow-up of 3.7 years. In subjects from A-LONG/Kids A-LONG, 99.6% (n = 234)/100% (n = 9) of evaluable baseline target joints were resolved, with no recurrence in 95%/100% of target joints. In IP subjects within the highest ABR quartile in Year 1, continued improvements were observed over a median follow-up of 4.3 years in ABR and joint health, without increased factor consumption. No inhibitors or treatment-related serious adverse events were reported. Conclusion: Previously treated subjects of all ages receiving long-term prophylaxis with rFVIIIFc had sustained clinical benefits, including improved joint health and low ABR.

Association between physical activity and risk of bleeding in children with hemophilia.

CONTEXT: Vigorous physical activity is thought to increase risk of bleeds in children with hemophilia, but the magnitude of the risk is unknown. OBJECTIVE: To quantify the transient increase in risk of bleeds associated with physical activity in children with hemophilia. DESIGN, SETTING, AND PARTICIPANTS: A case-crossover study nested within a prospective cohort study was conducted at 3 pediatric hemophilia centers in Australia between July 2008 and October 2010. A total of 104 children and adolescent boys aged 4 through 18 years with moderate or severe hemophilia A or B were monitored for bleeds for up to 1 year. Following each bleed, the child or parent was interviewed to ascertain exposures to physical activity preceding the bleed. Physical activity was categorized according to expected frequency and severity of collisions. The risk of bleeds associated with physical activity was estimated by contrasting exposure to physical activity in the 8 hours before the bleed with exposures in two 8-hour control windows, controlling for levels of clotting factor in the blood. MAIN OUTCOME MEASURES: Association of physical activity and factor level with risk of bleeding. RESULTS: The participants were observed for 4839 person-weeks during which time 436 bleeds occurred. Of these, 336 bleeds occurred more than 2 weeks after the preceding bleed and were used in the primary analysis of risk. Compared with inactivity and category 1 activities (eg, swimming), category 2 activities (eg, basketball) were associated with a transient increase in the risk of bleeding (30.6% of bleed windows vs 24.8% of first control windows; odds ratio, 2.7; 95% CI, 1.7-4.8, P < .001). Category 3 activities (eg, wrestling) were associated with a greater transient increase in risk (7.0% of bleed windows vs 3.4% of first control windows; odds ratio, 3.7; 95% CI, 2.3-7.3, P < .001). To illustrate absolute risk increase, for a child who bleeds 5 times annually and is exposed on average to category 2 activities twice weekly and to category 3 activities once weekly, exposure to these activities was associated with only 1 of the 5 annual bleeds. For every 1% increase in clotting factor level, bleeding incidence was lower by 2% (95% CI, 1%-3%; P = .004). CONCLUSIONS: In children and adolescents with hemophilia, vigorous physical activity was transiently associated with a moderate relative increase in risk of bleeding. Because the increased relative risk is transient, the absolute increase in risk of bleeds associated with physical activity is likely to be small.

Neuromorphic behaviour in discontinuous metal films.

Physical systems that exhibit brain-like behaviour are currently under intense investigation as platforms for neuromorphic computing. We show that discontinuous metal films, comprising irregular flat islands on a substrate and formed using simple evaporation processes, exhibit correlated avalanches of electrical signals that mimic those observed in the cortex. We further demonstrate that these signals meet established criteria for criticality. We perform a detailed experimental investigation of the atomic-scale switching processes that are responsible for these signals, and show that they mimic the integrate-and-fire mechanism of biological neurons. Using numerical simulations and a simple circuit model, we show that the characteristic features of the switching events are dependent on the network state and the local position of the switch within the complex network. We conclude that discontinuous films provide an interesting potential platform for brain-inspired computing.

Realization of unpinned two-dimensional dirac states in antimony atomic layers.

Two-dimensional (2D) Dirac states with linear dispersion have been observed in graphene and on the surface of topological insulators. 2D Dirac states discovered so far are exclusively pinned at high-symmetry points of the Brillouin zone, for example, surface Dirac states at [Formula: see text] in topological insulators Bi2Se(Te)3 and Dirac cones at K and [Formula: see text] points in graphene. The low-energy dispersion of those Dirac states are isotropic due to the constraints of crystal symmetries. In this work, we report the observation of novel 2D Dirac states in antimony atomic layers with phosphorene structure. The Dirac states in the antimony films are located at generic momentum points. This unpinned nature enables versatile ways such as lattice strains to control the locations of the Dirac points in momentum space. In addition, dispersions around the unpinned Dirac points are highly anisotropic due to the reduced symmetry of generic momentum points. The exotic properties of unpinned Dirac states make antimony atomic layers a new type of 2D Dirac semimetals that are distinct from graphene.

Treatment Patterns and Overall Survival Outcomes Among Patients Aged 80 yr or Older with High-risk Prostate Cancer.

BACKGROUND: Elderly patients diagnosed with high-risk prostate cancer (PCa) present a therapeutic dilemma of balancing treatment of a potentially lethal malignancy with overtreatment of a cancer that may not threaten life expectancy. OBJECTIVE: To investigate treatment patterns and overall survival outcomes in this group of patients. DESIGN SETTING AND PARTICIPANTS: A retrospective cohort study was conducted. We queried the National Cancer Database for high-risk PCa in patients aged 80 yr or older diagnosed during 2004-2016. INTERVENTION: Eligible patients underwent no treatment following biopsy (ie, observation), androgen deprivation therapy (ADT) alone, radiation therapy (RT) alone, RT + ADT, or surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier, log rank, and multivariate Cox proportional hazard regression was performed to compare overall survival (OS). RESULTS AND LIMITATIONS: A total of 19 920 men were eligible for analysis, and the most common treatment approach was RT + ADT (7401 patients; 37.2%). Observation and ADT alone declined over time (59.3% in 2004 vs 47.5% in 2016). There was no observed difference in OS between observation and ADT alone (adjusted hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.99-1.09; p = 0.105). Definitive local treatment was associated with improved OS compared with ADT alone (RT alone, HR 0.54, 95% CI, 0.50-0.59, p < 0.0001; ADT + RT, HR 0.48, 95% CI, 0.46-0.50, p < 0.0001; surgery, HR 0.50, 95% CI, 0.42-0.59, p < 0.0001). CONCLUSIONS: This analysis demonstrates that the use of definitive local therapy, including surgery or RT ± ADT, is increasing and is associated with a 50% reduction in overall mortality compared with observation or ADT alone. While prospective validation is warranted, elderly men with high-risk disease eligible for definitive management should be counseled on the risks, including a possible compromise in OS, with deferring definitive management. PATIENT SUMMARY: Elderly men are more often diagnosed with higher-risk prostate cancer but are less likely to receive curative treatment options than younger men. Our analysis demonstrates that for men ≥80 yr of age with high-risk prostate cancer, definitive local therapy, including surgery or radiation therapy and/or androgen deprivation therapy, is associated with a 50% reduction in overall mortality compared with observation or androgen deprivation therapy alone. We therefore recommend that life expectancy (ie, physiologic age) be taken into account, over chronologic age, and that elderly men with good life expectancy (eg, >5 yr; minimal comorbidity) should be offered definitive, life-prolonging therapy.

Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor.

Investigation of 3 families with bleeding symptoms demonstrated a defect in the collagen-binding activity of von Willebrand factor (VWF) in association with a normal VWF multimeric pattern. Genetic analysis showed affected persons to be heterozygous for mutations in the A3 domain of VWF: S1731T, W1745C, and S1783A. One person showed compound heterozygosity for W1745C and R760H. W1745C and S1783A have not been reported previously. The mutations were reproduced by site-directed mutagenesis and mutant VWF expressed in HEK293T cells. Collagen-binding activity measured by immunosorbent assay varied according to collagen type: W1745C and S1783A were associated with a pronounced binding defect to both type I and type III collagen, whereas the principal abnormality in S1731T patients was a reduction in binding to type I collagen only. The multimer pattern and distribution of mutant proteins were indistinguishable from wild-type recombinant VWF, confirming that the defect in collagen binding resulted from the loss of affinity at the binding site and not impairment of high-molecular-weight multimer formation. Our findings demonstrate that mutations causing an abnormality in the binding of VWF to collagen may contribute to clinically significant bleeding symptoms. We propose that isolated collagen-binding defects are classified as a distinct subtype of von Willebrand disease.