Effects of involuntary and voluntary attention on critical spacing of visual crowding.

Visual spatial attention can be allocated in two distinct ways: one that is voluntarily directed to behaviorally relevant locations in the world, and one that is involuntarily captured by salient external stimuli. Precueing spatial attention has been shown to improve perceptual performance on a number of visual tasks. However, the effects of spatial attention on visual crowding, defined as the reduction in the ability to identify target objects in clutter, are far less clear. In this study, we used an anticueing paradigm to separately measure the effects of involuntary and voluntary spatial attention on a crowding task. Each trial began with a brief peripheral cue that predicted that the crowded target would appear on the opposite side of the screen 80% of the time and on the same side of the screen 20% of the time. Subjects performed an orientation discrimination task on a target Gabor patch that was flanked by other similar Gabor patches with independent random orientations. For trials with a short stimulus onset asynchrony between cue and target, involuntary capture of attention led to faster response times and smaller critical spacing when the target appeared on the cue side. For trials with a long stimulus onset asynchrony, voluntary allocation of attention led to faster reaction times but no significant effect on critical spacing when the target appeared on the opposite side to the cue. We additionally found that the magnitudes of these cueing effects of involuntary and voluntary attention were not strongly correlated across subjects for either reaction time or critical spacing.

Qualification of Hemophilia Treatment Centers to Enable Multi-Center Studies of Gene Expression Signatures in Blood Cells from Pediatric Patients.

Hemophilia A is a rare congenital bleeding disorder caused by a deficiency of functionally active coagulation factor VIII (FVIII). Most patients with the severe form of the disease require FVIII replacement therapies, which are often associated with the development of neutralizing antibodies against FVIII. Why some patients develop neutralizing antibodies while others do not is not fully understood. Previously, we could demonstrate that the analysis of FVIII-induced gene expression signatures in peripheral blood mononuclear cells (PBMC) obtained from patients exposed to FVIII replacement therapies provides novel insights into underlying immune mechanisms regulating the development of different populations of FVIII-specific antibodies. The aim of the study described in this manuscript was the development of training and qualification test procedures to enable local operators in different European and US clinical Hemophilia Treatment Centers (HTC) to produce reliable and valid data for antigen-induced gene expression signatures in PBMC obtained from small blood volumes. For this purpose, we used the model antigen Cytomegalovirus (CMV) phosphoprotein (pp) 65. We trained and qualified 39 local HTC operators from 15 clinical sites in Europe and the US, of whom 31 operators passed the qualification at first attempt, and eight operators passed at the second attempt.

Prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures during FVIII inhibitor eradication.

Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.

Hyponatremia as a Marker of Complicated Appendicitis: A Retrospective Analysis.

Background The aim of this study is to investigate the potential role of hyponatremia as a biochemical predictor of complicated appendicitis. The effective employment of biochemical markers to identify early and predict progression to complicated appendicitis would be beneficial in triaging those most requiring urgent appendicectomy. A marker of interest and subject of recent study in the literature is sodium. Methods and Materials This study was designed as a single-center, retrospective analysis of all appendicectomies performed between January 1, 2018 and March 10, 2021. Patients were categorized into pediatric and adult groups and subdivided into uncomplicated or complicated appendicitis. We utilized the Chi-square test and crude odds ratio (OR) rates to assess significance of serum sodium level values. Results In total, 890 patients underwent appendicectomy (181 pediatric, 709 adult cases). Within the pediatric group, 10 uncomplicated cases and 16 complicated cases were found to be hyponatremic. The result for hyponatremia as a diagnostic marker for complicated cases in this group was not significant at p<0.05, with a Chi-square test result of 1.6067 and p-value 0.204963 (OR 1.7538, 95% confidence interval (CI) 0.7312-4.2070). Adults displaying hyponatremia comprised four uncomplicated and 34 complicated cases, with calculated OR 7.915 (95% CI 2.7656-22.6521). Chi-square test result was 20.1687 with a p-value of <0.00001 and, thus, statistically significant. Conclusion Our findings suggest that hyponatremia can be employed as an indicator of complicated appendicitis in an adult population. This correlates with the findings of a recent systematic review of this topic and implicates this as a subject worthy of further study.

Spatial Attention Enhances Crowded Stimulus Encoding Across Modeled Receptive Fields by Increasing Redundancy of Feature Representations.

Any visual system, biological or artificial, must make a trade-off between the number of units used to represent the visual environment and the spatial resolution of the sampling array. Humans and some other animals are able to allocate attention to spatial locations to reconfigure the sampling array of receptive fields (RFs), thereby enhancing the spatial resolution of representations without changing the overall number of sampling units. Here, we examine how representations of visual features in a fully convolutional neural network interact and interfere with each other in an eccentricity-dependent RF pooling array and how these interactions are influenced by dynamic changes in spatial resolution across the array. We study these feature interactions within the framework of visual crowding, a well-characterized perceptual phenomenon in which target objects in the visual periphery that are easily identified in isolation are much more difficult to identify when flanked by similar nearby objects. By separately simulating effects of spatial attention on RF size and on the density of the pooling array, we demonstrate that the increase in RF density due to attention is more beneficial than changes in RF size for enhancing target classification for crowded stimuli. Furthermore, by varying target/flanker spacing, as well as the spatial extent of attention, we find that feature redundancy across RFs has more influence on target classification than the fidelity of the feature representations themselves. Based on these findings, we propose a candidate mechanism by which spatial attention relieves visual crowding through enhanced feature redundancy that is mostly due to increased RF density.

The B-Natural study-The outcome of immune tolerance induction therapy in patients with severe haemophilia B.

INTRODUCTION: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. AIM: To evaluate the use and outcome of ITI in patients with HB and inhibitors. METHODS: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. RESULTS: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. CONCLUSION: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.

Endoloops in laparoscopic appendicectomy: A retrospective, cost effectiveness analysis.

BACKGROUND: Over 50,000 appendicectomies are performed in the UK annually. Despite this highvolume. status, and the endoloop being commonly employed, there is a scarcity of literature studying differences in outcomes depending on numbers used.The aim of this study was to investigate whether a significant difference in complication rate exists where different numbers of endoloop ligatures have been applied to the appendiceal base during laparoscopic appendicectomy, and to analyse for potential cost saving. METHODS: We performed a retrospective analysis of appendicectomies at our centre in one year, providing a sample of 254 patients. Each was followed up for complications in the 30 days post discharge and graded using the Clavien-Dindo system. Our null hypothesis of no difference in complication rate was tested using Fisher's exact test. RESULTS: Of 254 patients, 59 were excluded due to open approach, non-endoloop method, or lack of available record, leaving a population of 195. The result of the two-tailed P value equalled 1.000, indicating no statistically significant difference in complication rate whether one or two endoloops were used. An endoloop costs £13.59. If the 62 cases in which 2 endoloops were used to secure the base had utilised a single endoloop, this would amount to a saving of £842.58. CONCLUSION: Our study set out to assess whether the complication rate differs in cases where one or two endoloops have been applied. Retrospective statistical analysis found no significant difference between groups. Therefore, we recommend use of one endoloop to secure the base in laparoscopic appendicectomy.

Selectivity and robustness of sparse coding networks.

We investigate how the population nonlinearities resulting from lateral inhibition and thresholding in sparse coding networks influence neural response selectivity and robustness. We show that when compared to pointwise nonlinear models, such population nonlinearities improve the selectivity to a preferred stimulus and protect against adversarial perturbations of the input. These findings are predicted from the geometry of the single-neuron iso-response surface, which provides new insight into the relationship between selectivity and adversarial robustness. Inhibitory lateral connections curve the iso-response surface outward in the direction of selectivity. Since adversarial perturbations are orthogonal to the iso-response surface, adversarial attacks tend to be aligned with directions of selectivity. Consequently, the network is less easily fooled by perceptually irrelevant perturbations to the input. Together, these findings point to benefits of integrating computational principles found in biological vision systems into artificial neural networks.

An international registry of patients with plasminogen deficiency (HISTORY).

Plasminogen deficiency is an ultra-rare multisystem disorder characterized by the development of fibrin-rich pseudomembranes on mucous membranes. Ligneous conjunctivitis, which can result in vision impairment or loss, is the most frequent symptom reported. Affected systems may also include the respiratory tract, oropharynx, female reproductive tract, gingiva, middle ear, renal collecting system, skin and central nervous system. Untreated, plasminogen deficiency may result in significant reduction in quality of life and morbidity with potential life-threatening complications. Non-specific therapies are inadequate and plasminogen concentrates are not commercially available. The current understanding of plasminogen deficiency and management of disease symptoms and its progression are based on case reports/series and two small clinical trials. To date there has never been a comprehensive, international study to examine the natural history or optimal therapeutic intervention; knowledge gaps include identification of contributing factors and triggers of disease manifestations, inability to predict disease course, and insufficient real-world data for use of therapeutics. We have created an international, observational study (HISTORY) in a large cohort of persons with plasminogen deficiency and first-degree family members to address these gaps and to advance knowledge and care. HISTORY will build upon the established relationship between the Indiana Hemophilia and Thrombosis Center and the Fondazione Angelo Bianchi Bonomi, IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan and will utilize a modified version of the Prospective Rare Bleeding Disorders Database (PRO-RBDD). A biorepository containing samples from subjects with plasminogen deficiency will be established. This article describes the rationale behind the study and efforts towards its goals.

The preprophase band-associated kinesin-14 OsKCH2 is a processive minus-end-directed microtubule motor.

In animals and fungi, cytoplasmic dynein is a processive minus-end-directed motor that plays dominant roles in various intracellular processes. In contrast, land plants lack cytoplasmic dynein but contain many minus-end-directed kinesin-14s. No plant kinesin-14 is known to produce processive motility as a homodimer. OsKCH2 is a plant-specific kinesin-14 with an N-terminal actin-binding domain and a central motor domain flanked by two predicted coiled-coils (CC1 and CC2). Here, we show that OsKCH2 specifically decorates preprophase band microtubules in vivo and transports actin filaments along microtubules in vitro. Importantly, OsKCH2 exhibits processive minus-end-directed motility on single microtubules as individual homodimers. We find that CC1, but not CC2, forms the coiled-coil to enable OsKCH2 dimerization. Instead, our results reveal that removing CC2 renders OsKCH2 a nonprocessive motor. Collectively, these results show that land plants have evolved unconventional kinesin-14 homodimers with inherent minus-end-directed processivity that may function to compensate for the loss of cytoplasmic dynein.

Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network.

Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed in severe haemophilia A, may also be observed. The bleeding patterns of VWD can affect quality of life, and may be life-threatening. The von Willebrand Disease Prophylaxis Network is an international study group formed with the goal of investigating the role of prophylaxis in clinically severe VWD. The objective of the present study is to investigate the response to prophylaxis focusing primarily on epistaxis, joint bleeding, gastrointestinal bleeding, and heavy bleeding associated with menses. Data from 105 subjects, 10 enrolled in a prospective study and 95 in a retrospective study between 2008 and 2013, were available for analysis. The median annualized rate reductions in bleeding were significant for epistaxis (P < 0.0001), gastrointestinal bleeding (P = 0.0003), joint bleeding (P < 0.0001), and menorrhagia (P = 0.008). Doses on a group level were approximately the same prior to and during prophylaxis, but more patients with gastrointestinal bleeding had prophylaxis three or more times per week as well as higher dosages. Our study, which primarily used retrospective data, indicates that prospective studies are needed to better delineate the doses and dose intervals that should be used for prophylactic treatment of VWD.

Prevalence of equinus in diabetic versus nondiabetic patients.

BACKGROUND: There are no conclusive data to support the contention that diabetic patients have an increased frequency of ankle equinus compared with their nondiabetic counterparts. Additionally, a presumed contributing cause of foot ulceration is ankle joint equinus. Therefore, we sought to determine whether persons with diabetes have a higher prevalence of ankle joint equinus than do nondiabetic persons. METHODS: A prospective pilot survey of 102 outpatients (43 diabetic and 59 nondiabetic) was conducted. Demographic and historical data were obtained. Each patient underwent a standard lower-extremity examination, including the use of a biplane goniometer to measure ankle joint range of motion. RESULTS: Equinus, defined as ankle dorsiflexion measured at 0° or less, was found in 24.5% of the overall population. In the diabetes cohort, 16 of 43 patients (37.2%) were affected compared with 9 of 59 nondiabetic participants (15.3%) (P = .011). There was a threefold risk of equinus in the diabetic population (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.28-8.44; P < .013). The equinus group had a history of ulceration in 52.0% compared with 20.8% of the nonequinus group (P = .003). Equinus, therefore, imparted a fourfold risk of ulceration (OR, 4.13; 95% CI, 1.58-10.77; P < .004). We also found a 2.8 times risk of equinus in patients with peripheral neuropathy (OR, 2.8; 95% CI, 1.11-7.09; P < .029). CONCLUSIONS: Equinus may be more prevalent in diabetic patients than previously reported. Although we cannot prove causality, we found a significant association between equinus and ulceration.