Correction to: Assessment of individual tumor buds using keratin immunohistochemistry: moderate interobserver agreement suggests a role for machine learning.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Assessment of individual tumor buds using keratin immunohistochemistry: moderate interobserver agreement suggests a role for machine learning.

Tumor budding is a promising and cost-effective biomarker with strong prognostic value in colorectal cancer. However, challenges related to interobserver variability persist. Such variability may be reduced by immunohistochemistry and computer-aided tumor bud selection. Development of computer algorithms for this purpose requires unequivocal examples of individual tumor buds. As such, we undertook a large-scale, international, and digital observer study on individual tumor bud assessment. From a pool of 46 colorectal cancer cases with tumor budding, 3000 tumor bud candidates were selected, largely based on digital image analysis algorithms. For each candidate bud, an image patch (size 256 × 256 µm) was extracted from a pan cytokeratin-stained whole-slide image. Members of an International Tumor Budding Consortium (n = 7) were asked to categorize each candidate as either (1) tumor bud, (2) poorly differentiated cluster, or (3) neither, based on current definitions. Agreement was assessed with Cohen's and Fleiss Kappa statistics. Fleiss Kappa showed moderate overall agreement between observers (0.42 and 0.51), while Cohen's Kappas ranged from 0.25 to 0.63. Complete agreement by all seven observers was present for only 34% of the 3000 tumor bud candidates, while 59% of the candidates were agreed on by at least five of the seven observers. Despite reports of moderate-to-substantial agreement with respect to tumor budding grade, agreement with respect to individual pan cytokeratin-stained tumor buds is moderate at most. A machine learning approach may prove especially useful for a more robust assessment of individual tumor buds.

Closed-loop cortical control of virtual reach and posture using Cartesian and joint velocity commands.

OBJECTIVE: Brain-computer interfaces (BCIs) are a promising technology for the restoration of function to people with paralysis, especially for controlling coordinated reaching. Typical BCI studies decode Cartesian endpoint velocities as commands, but human arm movements might be better controlled in a joint-based coordinate frame, which may match underlying movement encoding in the motor cortex. A better understanding of BCI controlled reaching by people with paralysis may lead to performance improvements in brain-controlled assistive devices. APPROACH: Two intracortical BCI participants in the BrainGate2 pilot clinical trial performed a visual 3D endpoint virtual reality reaching task using two decoders: Cartesian and joint velocity. Task performance metrics (i.e. success rate and path efficiency) and single feature and population tuning were compared across the two decoder conditions. The participants also demonstrated the first BCI control of a fourth dimension of reaching, the arm's swivel angle, in a 4D posture matching task. MAIN RESULTS: Both users achieved significantly higher success rates using Cartesian velocity control, and joint controlled trajectories were more variable and significantly more curved. Neural tuning analyses showed that most single feature activity was best described by a Cartesian kinematic encoding model, and population analyses revealed only slight differences in aggregate activity between the decoder conditions. Simulations of a BCI user reproduced trajectory features seen during closed-loop joint control when assuming only Cartesian-tuned features passed through a joint decoder. With minimal training, both participants controlled the virtual arm's swivel angle to complete a 4D posture matching task, and achieved significantly higher success using a Cartesian + swivel velocity decoder compared to a joint velocity decoder. SIGNIFICANCE: These results suggest that Cartesian velocity command interfaces may provide better BCI control of arm movements than other kinematic variables, even in 4D posture tasks with swivel angle targets.

Signal processing methods for reducing artifacts in microelectrode brain recordings caused by functional electrical stimulation.

OBJECTIVE: Functional electrical stimulation (FES) is a promising technology for restoring movement to paralyzed limbs. Intracortical brain-computer interfaces (iBCIs) have enabled intuitive control over virtual and robotic movements, and more recently over upper extremity FES neuroprostheses. However, electrical stimulation of muscles creates artifacts in intracortical microelectrode recordings that could degrade iBCI performance. Here, we investigate methods for reducing the cortically recorded artifacts that result from peripheral electrical stimulation. APPROACH: One participant in the BrainGate2 pilot clinical trial had two intracortical microelectrode arrays placed in the motor cortex, and thirty-six stimulating intramuscular electrodes placed in the muscles of the contralateral limb. We characterized intracortically recorded electrical artifacts during both intramuscular and surface stimulation. We compared the performance of three artifact reduction methods: blanking, common average reference (CAR) and linear regression reference (LRR), which creates channel-specific reference signals, composed of weighted sums of other channels. MAIN RESULTS: Electrical artifacts resulting from surface stimulation were 175 × larger than baseline neural recordings (which were 110 µV peak-to-peak), while intramuscular stimulation artifacts were only 4 × larger. The artifact waveforms were highly consistent across electrodes within each array. Application of LRR reduced artifact magnitudes to less than 10 µV and largely preserved the original neural feature values used for decoding. Unmitigated stimulation artifacts decreased iBCI decoding performance, but performance was almost completely recovered using LRR, which outperformed CAR and blanking and extracted useful neural information during stimulation artifact periods. SIGNIFICANCE: The LRR method was effective at reducing electrical artifacts resulting from both intramuscular and surface FES, and almost completely restored iBCI decoding performance (>90% recovery for surface stimulation and full recovery for intramuscular stimulation). The results demonstrate that FES-induced artifacts can be easily mitigated in FES + iBCI systems by using LRR for artifact reduction, and suggest that the LRR method may also be useful in other noise reduction applications.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

Whipple's Disease in an Afro-Caribbean National.

Whipple's disease is a rare multi-organ infectious disease caused by Tropheryma whipplei. It is fatal without treatment. We report on a 40-year old Afro-Jamaican man who presented with a six-month history of weight loss and diarrhoea. Investigations revealed iron deficiency anaemia and hypoalbuminaemia. Upper gastrointestinal endoscopy revealed white patchy lesions in the duodenum. The duodenal biopsy showed broadening and thickening of the villi by a dense infiltrate of foamy histiocytes within the lamina propria and focally extending into the attached submucosa. Periodic Acid-Schiff stains were positive. Electron microscopy was confirmatory and polymerase chain reaction testing conclusively identified the organisms as T whipplei. Antibiotic treatment resulted in resolution of symptoms. Although the diagnosis of Whipple's disease is difficult, increased awareness should lead to an increase in reported cases with the improvements in diagnostic capabilities.

Whipple's disease in an Afro-Caribbean national / Enfermedad de whipple en un nacional afrocaribeño

Whipple's disease is a rare multi-organ infectious disease caused by Tropheryma whipplei. It is fatal without treatment. We report on a 40-year old Afro-Jamaican man who presented with a six-month history of weight loss and diarrhoea. Investigations revealed iron deficiency anaemia and hypoalbuminaemia. Upper gastrointestinal endoscopy revealed white patchy lesions in the duodenum. The duodenal biopsy showed broadening and thickening of the villi by a dense infiltrate of foamy histiocytes within the lamina propria and focally extending into the attached submucosa. Periodic Acid-Schiff stains were positive. Electron microscopy was confirmatory and polymerase chain reaction testing conclusively identified the organisms as T whipplei. Antibiotic treatment resulted in resolution of symptoms. Although the diagnosis of Whipple's disease is difficult, increased awareness should lead to an increase in reported cases with the improvements in diagnostic capabilities.

La enfermedad deWhipple es una rara enfermedad infecciosa multiorgánica causada por el Tropheryma whipplei. Es fatal sin tratamiento. Reportamos un hombre afro-jamaicano de 40 años que se presentó con una historia de seis meses de pérdida de peso y diarrea. Las investigaciones revelaron hipoalbuminemia y anemia ferropénica. La endoscopia gastrointestinal superior reveló lesiones blancas irregulares en el duodeno. La biopsia duodenal mostró la ampliación y engrosamiento de las vellosidades por un denso infiltrado de histiocitos espumosos dentro de la lámina propia, que se extienden hasta la submucosa adjunta. Las tinciones con ácido peryódico de Schiff fueron positivas. La microscopia electrónica fue confirmatoria y la prueba de la reacción en cadena de la polimerasa, identificó los organismos como T whipplei de forma concluyente El tratamiento antibiótico trajo como resultado la resolución de los síntomas. Si bien el diagnóstico de la enfermedad de Whipple es difícil, un aumento de la conciencia debe conducir a un aumento en los reportes de casos divulgados que reflejan un mejoramiento en la capacidad para hacer el diagnóstico.

Performance of endovenous foam sclerotherapy in the USA for the treatment of venous disorders: ACP/SVM/AVF/SIR quality improvement guidelines.

OBJECTIVE: This report summarizes the findings of the consensus panel based on the results of the comprehensive questionnaire of US American College of Phlebology annual congress attendees and results of the systematic meta-analysis of the literature and provides quality improvement guidelines for the use of endovenous foam sclerotherapy (EFS) for the treatment of venous disorders, as well as identifies areas of needed research. METHODS: Based on the above data, quality improvement guidelines were developed and reviewed by the ten US consensus panel members and approved by their respective societies. RESULTS: EFS is effective for the treatment of truncal and tributary varicose veins, both as primary treatment and for treatment of recurrence. It may improve the signs and symptoms associated with varicose veins including pain and swelling. EFS is contraindicated in patients who have experienced an allergic reaction to previous treatment with foam or liquid sclerosant, and in patients with acute venous thrombosis events secondary to EFS. CONCLUSION: These guidelines for the use of EFS in the treatment of venous disorders provide an initial framework for the safe and efficacious use of this therapy, and the impetus to promote the evaluation of the questions remaining regarding the use of EFS through well-designed randomized and cohort studies.

Performance of endovenous foam sclerotherapy in the USA.

PURPOSE: To assess practice patterns of endovenous foam sclerotherapy (EFS) use in the USA. METHODS: A multidisciplinary panel of US experts was convened and developed a questionnaire to assess use of EFS. US attendees at the American College of Phlebology 2009 Annual Congress were asked to complete the questionnaire. RESULTS: Of 776 questionnaires distributed, 239 were completed (31%). The majority of respondents (87%) reported using EFS for the treatment of venous disorders. Foam sclerotherapy was used by a wide variety of specialists in every region of the USA. The most common indication was sclerosis of recurrent truncal or tributary veins of the leg. There was variation among practitioners in the indications for use, pre- and postprocedural evaluation and procedure methodology. CONCLUSIONS: The results of this questionnaire show widespread usage of EFS and are important in the development of national quality improvement guidelines for the performance of EFS.

Control of a time-delayed 5 degrees of freedom arm model for use in upper extremity functional electrical stimulation.

The goal of this work is to design a controller for a functional electrical stimulation (FES) neuroprosthesis aimed at restoring shoulder and elbow function in individuals who have suffered a high-level cervical (C3-C4) spinal cord injury (SCI). The controller is a mathematical algorithm that coordinates the electrical stimulations applied to the paralyzed muscles such that the arm closely tracks a given desired trajectory. An issue that so far has received little attention is that of time-delays. These delays arise from two sources: (1) the muscle excitation-activation dynamics (10-30 ms) and (2) the sampling of the electrical stimulation (80 ms at the typical 12 Hz stimulation frequency). Using a 5 degrees of freedom (5 DOF) arm model we designed and evaluated a novel controller capable of maintaining stable and accurate tracking performance in the presence of time-delays. For a desired trajectory consisting of 10 randomized reaches, the controller achieved excellent tracking performance as measured by the root-mean-square error (RMSE) between the desired and simulated joint angles (RMSE= [1.48°; 0.81°; 2.14°; 3.11°; 2.29°]).

Continuous neuronal ensemble control of simulated arm reaching by a human with tetraplegia.

Functional electrical stimulation (FES), the coordinated electrical activation of multiple muscles, has been used to restore arm and hand function in people with paralysis. User interfaces for such systems typically derive commands from mechanically unrelated parts of the body with retained volitional control, and are unnatural and unable to simultaneously command the various joints of the arm. Neural interface systems, based on spiking intracortical signals recorded from the arm area of motor cortex, have shown the ability to control computer cursors, robotic arms and individual muscles in intact non-human primates. Such neural interface systems may thus offer a more natural source of commands for restoring dexterous movements via FES. However, the ability to use decoded neural signals to control the complex mechanical dynamics of a reanimated human limb, rather than the kinematics of a computer mouse, has not been demonstrated. This study demonstrates the ability of an individual with long-standing tetraplegia to use cortical neuron recordings to command the real-time movements of a simulated dynamic arm. This virtual arm replicates the dynamics associated with arm mass and muscle contractile properties, as well as those of an FES feedback controller that converts user commands into the required muscle activation patterns. An individual with long-standing tetraplegia was thus able to control a virtual, two-joint, dynamic arm in real time using commands derived from an existing human intracortical interface technology. These results show the feasibility of combining such an intracortical interface with existing FES systems to provide a high-performance, natural system for restoring arm and hand function in individuals with extensive paralysis.

The expression of protoporphyrinogen oxidase in human tissues.

Protoporphyrinogen oxidase is the penultimate enzyme in the haem biosynthetic pathway. In this study, the expression of protoporphyrinogen oxidase in a variety of human organs has been documented by immunohistochemical means at the light microscopy level in order to shed light on its inter- and intra-organ distribution. The expression varied amongst organs and the various cell types within an organ. The pattern of staining generally reflected presumed metabolic functionality and haem demand. Strongest staining was noted in hepatocytes, proximal convoluted tubules of the kidney, serous cells of the peribronchial gland in the lung, parietal cells of the stomach, tips of the villi in the small intestine and interstitial cells of the testis. Our results suggest that there are some significant sites of haem synthesis in addition to the liver and bone marrow, and should be borne in mind in studies related to haem or porphyrin dynamics and flux.

Fission time measurements: a new probe into superheavy element stability.

Reaction mechanism analyses performed with a 4pi detector for the systems 208Pb + Ge, 238U + Ni and 238U + Ge, combined with analyses of the associated reaction time distributions, provide us with evidence for nuclei with Z=120 and 124 living longer than 10(-18) s and arising from highly excited compound nuclei. By contrast, the neutron deficient nuclei with Z=114 possibly formed in 208Pb + Ge reactions have shorter lifetimes, close to or below the sensitivity limit of the experiment.

Review article: the diagnosis and management of Crohn's disease in populations with high-risk rates for tuberculosis.

BACKGROUND: Distinguishing Crohn's disease from intestinal tuberculosis in endemic areas is challenging as both conditions have overlapping clinical, radiological, endoscopic and histological characteristics. Furthermore, high rates of latent tuberculosis confer a considerable risk of reactivation once therapy for established Crohn's disease is started. AIM: To review current strategies in differentiating these two conditions, and in managing Crohn's disease, in populations with high rates of tuberculosis. METHODS: Literature review and clinical experience. RESULTS: While various clinical, radiological, endoscopic and histological parameters may aid in differentiating Crohn's disease from intestinal tuberculosis, these remain imperfect and as treatment options differ misdiagnosis has grave consequences. We propose a diagnostic algorithm, based on currently available evidence and experience, to aid in this dilemma. We also discuss approaches to the management of Crohn's disease, including agents targeting tumour necrosis factor-alpha, in patients at risk of developing tuberculosis. CONCLUSIONS: A diagnosis of Crohn's disease in individuals at risk for tuberculosis should only be made after careful interpretation of clinical signs, abdominal imaging and systematic endoscopic and histological assessment. Newer techniques for the diagnosis of latent tuberculosis still need to be validated in this environment, and guidelines on the treatment of latent tuberculosis in this setting require clarification.

Comparative evaluation of 2D time-of-flight and 3D elliptic centric contrast-enhanced MR venography in patients with presumptive cerebral venous and sinus thrombosis.

We retrospectively evaluated an elliptic centric ordered 3D (ec 3D) magnetic resonance venography (MRV) technique in comparison to 2D time-of-flight (2D TOF) MRV in patients with presumptive cerebral venous sinus thrombosis (CVST). Twenty-five patients (mean age 40.6 +/- 16.5 years) with presumptive CVST underwent cerebral MRI including 2D TOF and ec 3D MRV. Radiologic findings and clinical outcome were correlated. MRV studies were evaluated by two neuroradiologists in a blinded manner for image quality, assessment of various sinus, internal cerebral veins (ICV), vein of Labbé and Galen (VL/VG) as well as for additional imaging procedures required. Sensitivity/specificity of ec 3D MRV amounted to 85.7%/97.2% as compared with 2D TOF 71.4%/55.6 %. Ec 3D MRV performed superior in terms of image quality as well as assessment of all sinus and veins except for the straight sinus. Additional imaging procedures were less often required in ec 3D MRV studies (28% vs. 66% for 2D TOF MRV; P < 0.001). Interobserver agreement was significantly increased by using ec 3D MRV (93.1% vs. 70.9% of readings). The results of our study provide additional evidence for the superiority of ec 3D compared with 2D TOF MR venography for the diagnosis or exclusion of acute CVST in daily clinical practice.

Role of colonoscopic biopsy in distinguishing between Crohn's disease and intestinal tuberculosis.

BACKGROUND: The histological differential diagnosis of Crohn's disease and intestinal tuberculosis can be very challenging, as both are chronic granulomatous disorders with overlapping histological features. AIM: To evaluate selected clinical and histological parameters in colonic biopsy specimens for their ability to discriminate between Crohn's disease and intestinal tuberculosis. METHODS: 25 patients with Crohn's disease and 18 patients with intestinal tuberculosis were selected for this study on the basis of established clinical, radiological and histological criteria. Clinical data and selected histological parameters in colonoscopic biopsy specimens were assessed retrospectively. A total of 103 and 41 biopsy sites were evaluated in patients with Crohn's disease and intestinal tuberculosis, respectively. RESULTS: Clinical parameters helpful in differentiating intestinal tuberculosis from Crohn's disease included chest radiographic features of tuberculosis (56% v 0%), perianal fistulae (0% v 40%) and extraintestinal manifestations of Crohn's disease (0% v 40%). Histopathological features that seemed to reliably differentiate between intestinal tuberculosis and Crohn's disease included confluent granulomas, > or =10 granulomas per biopsy site and caseous necrosis (in biopsy samples of 50%, 33% and 22% of patients with intestinal tuberculosis, respectively, v 0% of patients with Crohn's disease). Features that were observed more often in patients with intestinal tuberculosis than in those with Crohn's disease included granulomas exceeding 0.05 mm(2) (67% v 8%), ulcers lined by conglomerate epithelioid histiocytes (61% v 8%) and disproportionate submucosal inflammation (67% v 10%). CONCLUSION: Clinical features and selected histological parameters in colonoscopic biopsy specimens can help in differentiating between Crohn's disease and intestinal tuberculosis.

The feasibility of a functional neuromuscular stimulation powered mechanical gait orthosis with coordinated joint locking.

The purpose of this study was to examine the feasibility of a hybrid orthosis for walking after spinal cord injury (SCI) that coordinates the locking and unlocking of knee and ankle joints of a reciprocating gait orthosis (RGO), while injecting propulsive forces and controlling unlocked joints with functional neuromuscular stimulation (FNS). The effectiveness of the hybrid system relative to gait stability and posture were determined in this simulation study. A three-dimensional computer model of a hybrid orthosis system (HOS) combining FNS with a RGO incorporating feedback control of muscle activation and coordinated joint locking was developed in Working Model 3D. The simulated hybrid orthosis system achieved gait speeds, stride lengths, and cadences of 0.51 +/- 0.03 m/s, 0.85 +/- 0.04 m, and 72 +/- 4 steps/min respectively, exceeding the performance of other hybrid systems. Forward trunk tilt was found to be necessary during initial step from standing and pro-swing, but posture and stability were significantly improved over FNS-only systems. The results of the model shows that a HOS that coordinates knee and ankle joint locking with electrical stimulation to the paralyzed muscles holds significant advantages over brace- and FNS-only walking systems in terms of enhanced trunk stability and posture.

An artificial neural network approach to predicting arm movements from ECoG.

There are three specific aims. First, demonstrate the practicality of using an artificial neural network based approach to correlate these cortical signals with actual and imagined arm movements. Second, to identify areas of the cortical surface that provide the most useful command information. Third, quantify the information content and information transfer rate of the signals obtained from the subdural grids relative to a set of relevant arm movements. This work presents progress toward these aims.

Model-based development of a user control algorithm for postural control via a FES-based standing neuroprosthesis.

The goal of this study was to devise an algorithm that would allow the user of a functional electrical stimulation (FES)-based neuroprosthesis to command desired transitions in body center of mass (COM) via smooth changes in lower extremity joint angles. Simulations were performed with a musculoskeletal model modified to reflect an individual with thoracic spinal cord injury, as well as the use of a 16 channel FES system. These simulations indicated useful subsets of 16 muscles, and a set of four polynomial surfaces were fit through the space relating COMx, COMy, and each of the four lower extremity joint angles studied. These polynomial surfaces provided a robust method for selecting a particular, smooth trajectory through this space. These results indicate that a 16-channel FES system should be capable of allowing users to shift postures over a significant fraction of the forward-backward range used by able-bodied individuals during typical activities.