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Purpose of Review: Proteolysis-targeted chimeras (PROTACs) are heterobifunctional compounds that selectively target proteins for degradation and are an emerging therapeutic modality to treat diseases such as cancer and neurodegenerative disorders. This review will widen the area of application by highlighting the ability of PROTACs to remove proteins from the anucleate platelets and evaluate their antithrombotic potential., Recent Findings: Proteomic and biochemical studies demonstrated that human platelets possess the Ubiquitin Proteasomal System as well as the E3 ligase cereblon (CRBN) and therefore may be susceptible to PROTAC-mediated protein degradation. Recent findings confirmed that CRBN ligand-based PROTACs targeting generic tyrosine kinases, Btk and/or Fak lead to efficacious and selective protein degradation in human platelets. Downregulation of Btk, a key player involved in signalling to thrombosis, but not haemostasis, resulted in impaired in-vitro thrombus formation., Summary: Platelets are susceptible to targeted protein degradation by CRBN ligand-based PROTACs and have limited ability to resynthesise proteins, ensuring long-term downregulation of target proteins. Therefore, PROTACs serve as an additional research tool to study platelet function and offer new therapeutic potential to prevent thrombosis. Future studies should focus on enhancing cell specificity to avoid on-target side effects on other blood cells., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Distal radius fractures are the most common skeletal injuries requiring intervention in children. These injuries are classified by fracture pattern, location, displacement, and angulation. While each unique fracture pattern warrants slightly modified treatment plans and follow-up, the goals of treatment remain constant. Successful outcomes depend on restoration of motion and function, and attaining acceptable sagittal and coronal alignment is a necessary first step. For displaced fractures, closed reduction is often necessary to restore alignment; well-molded cast application is important to maintain fracture alignment. Fractures with bayonet apposition, if well aligned, may not need formal reduction in some patients. Special attention should be paid to the physis-not only for physeal-involving fractures but also for all distal radius fractures-given that the proximity to the physis and amount of remaining skeletal growth help guide treatment decisions. Casting technique is essential in optimizing the best chance in maintaining fracture reduction. Surgical intervention may be indicated for a subset of fractures when acceptable alignment is not achieved or is lost at subsequent follow-up. Even among experts in the field, there is little consensus as to the optimal treatment of displaced metaphyseal fractures, illustrating the need for prospective, randomized studies to establish best practices., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Genome editing technologies, clustered regularly interspaced short palindromic repeats (CRISPR)-Cas in particular, have revolutionized the field of genetic engineering, providing promising avenues for treating various genetic diseases. Chronic kidney disease (CKD), a significant health concern affecting millions of individuals worldwide, can arise from either monogenic or polygenic mutations. With recent advancements in genomic sequencing, valuable insights into disease-causing mutations can be obtained, allowing for the development of new treatments for these genetic disorders. CRISPR-based treatments have emerged as potential therapies, especially for monogenic diseases, offering the ability to correct mutations and eliminate disease phenotypes. Innovations in genome editing have led to enhanced efficiency, specificity and ease of use, surpassing earlier editing tools such as zinc-finger nucleases and transcription activator-like effector nucleases (TALENs). Two prominent advancements in CRISPR-based gene editing are prime editing and base editing. Prime editing allows precise and efficient genome modifications without inducing double-stranded DNA breaks (DSBs), while base editing enables targeted changes to individual nucleotides in both RNA and DNA, promising disease correction in the absence of DSBs. These technologies have the potential to treat genetic kidney diseases through specific correction of disease-causing mutations, such as somatic mutations in PKD1 and PKD2 for polycystic kidney disease; NPHS1, NPHS2 and TRPC6 for focal segmental glomerulosclerosis; COL4A3, COL4A4 and COL4A5 for Alport syndrome; SLC3A1 and SLC7A9 for cystinuria and even VHL for renal cell carcinoma. Apart from editing the DNA sequence, CRISPR-mediated epigenome editing offers a cost-effective method for targeted treatment providing new avenues for therapeutic development, given that epigenetic modifications are associated with the development of various kidney disorders. However, there are challenges to overcome, including developing efficient delivery methods, improving safety and reducing off-target effects. Efforts to improve CRISPR-Cas technologies involve optimizing delivery vectors, employing viral and non-viral approaches and minimizing immunogenicity. With research in animal models providing promising results in rescuing the expression of wild-type podocin in mouse models of nephrotic syndrome and successful clinical trials in the early stages of various disorders, including cancer immunotherapy, there is hope for successful translation of genome editing to kidney diseases., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Little is known about the prevalence of intraspinal pathology in children who toe walk, but magnetic resonance imaging (MRI) may be part of the diagnostic workup. The purpose of this study was to examine the role of MRI for children who toe walk with a focus on the rate of positive findings and associated neurosurgical interventions performed for children with said MRI findings., Methods: A single-center tertiary hospital database was queried to identify a cohort of 118 subjects with a diagnosis of toe walking who underwent spinal MRI during a 5-year period. Patient and MRI characteristics were summarized and compared between subjects with a major abnormality, minor abnormality, or no abnormality on MRI using multivariable logistic regression. Major MRI abnormalities included those with a clear spinal etiology, such as fatty filum, tethered cord, syrinx, and Chiari malformation, while minor abnormalities had unclear associations with toe walking., Results: The most common primary indications for MRI were failure to improve with conservative treatment, severe contracture, and abnormal reflexes. The prevalence of major MRI abnormalities was 25% (30/118), minor MRI abnormalities was 19% (22/118), and normal MRI was 56% (66/118). Patients with delayed onset of toe walking were significantly more likely to have a major abnormality on MRI ( P =0.009). The presence of abnormal reflexes, severe contracture, back pain, bladder incontinence, and failure to improve with conservative treatment were not significantly associated with an increased likelihood of major abnormality on MRI. Twenty-nine (25%) subjects underwent tendon lengthening, and 5 (4%) underwent neurosurgical intervention, the most frequent of which was detethering and sectioning of fatty filum., Conclusions: Spinal MRI in patients who toe walk has a high rate of major positive findings, some of which require neurosurgical intervention. The most significant predictor of intraspinal pathology was the late onset of toe walking after the child had initiated walking. MRI of the spine should be considered by pediatric orthopedic surgeons in patients with toe walking who present late with an abnormal clinical course., Level of Evidence: Level III Retrospective Comparative Study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS. Here, the role of PAR-1 was studied in human podocytes in vitro, and using a mouse model with developmental or inducible expression of podocyte-specific constitutively active PAR-1, and using biopsies from patients with nephrotic syndrome. In vitro podocyte PAR-1 activation caused a pro-migratory phenotype with phosphorylation of the kinase JNK, VASP protein and docking protein Paxillin. This signaling was mirrored in podocytes exposed to patient relapse-derived NS plasma and in patient disease biopsies. Both developmental and inducible activation of transgenic PAR-1 (NPHS2 Cre PAR-1 Active+/- ) caused early severe nephrotic syndrome, FSGS, kidney failure and, in the developmental model, premature death. We found that the non-selective cation channel protein TRPC6 could be a key modulator of PAR-1 signaling and TRPC6 knockout in our mouse model significantly improved proteinuria and extended lifespan. Thus, our work implicates podocyte PAR-1 activation as a key initiator of human NS circulating factor and that the PAR-1 signaling effects were partly modulated through TRPC6., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Orthopaedic and related care has the potential to present unique obstacles for patients with a range of autism manifestations. In this review, we aim to describe and analyze the literature on autistic patients' experience within orthopaedics and closely related fields. This literature search utilized the PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature databases. Three major concepts were built into the search terms: (1) patients on the autism spectrum; (2) patient experience; and (3) movement sciences, including orthopaedics, physical medicine and rehabilitation (PM&R), occupational therapy (OT), and physical therapy (PT). Our search yielded 35 topical publications, with the major topic areas addressed as follows: (1) clinical and perioperative management, (2) therapy interventions, (3) participation in exercise and social play, (4) sensory management and accommodations, (5) caregiver/parent training and involvement in care, (6) healthcare needs and barriers to care, and (7) utilization of technology. In the current literature, there are no studies that attempt to directly assess autistic patient experience with care practices and clinical environments in orthopaedics. Rigorous, direct examination of the experience of autistic patients within clinical orthopaedic settings is urgently needed to address this gap.

We introduce a soft fundamental measure theory functional for the purely repulsive Weeks-Chandler-Andersen (WCA) fluid. This classical density functional could serve as a reference fluid for functionals created using thermodynamic perturbation theory instead of the hard-sphere fluid. Our functional incorporates temperature-dependent parameters describing the length scale and effective softness of the particle interaction, and which reproduce the second virial coefficient of the WCA fluid. We find that this approach is comparable in accuracy to the Barker-Henderson approach combined with the White Bear density functional for the hard-sphere fluid.

The number of melanoma diagnoses has increased dramatically over the past three decades, outpacing almost all other cancers. Nearly 1 in 4 skin biopsies is of melanocytic lesions, highlighting the clinical and public health importance of correct diagnosis. Deep learning image analysis methods may improve and complement current diagnostic and prognostic capabilities. The histologic evaluation of melanocytic lesions, including melanoma and its precursors, involves determining whether the melanocytic population involves the epidermis, dermis, or both. Semantic segmentation of clinically important structures in skin biopsies is a crucial step towards an accurate diagnosis. While training a segmentation model requires ground-truth labels, annotation of large images is a labor-intensive task. This issue becomes especially pronounced in a medical image dataset in which expert annotation is the gold standard. In this paper, we propose a two-stage segmentation pipeline using coarse and sparse annotations on a small region of the whole slide image as the training set. Segmentation results on whole slide images show promising performance for the proposed pipeline., (© 2022. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Invasive melanoma, a common type of skin cancer, is considered one of the deadliest. Pathologists routinely evaluate melanocytic lesions to determine the amount of atypia, and if the lesion represents an invasive melanoma, its stage. However, due to the complicated nature of these assessments, inter- and intra-observer variability among pathologists in their interpretation are very common. Machine-learning techniques have shown impressive and robust performance on various tasks including healthcare. In this work, we study the potential of including semantic segmentation of clinically important tissue structure in improving the diagnosis of skin biopsy images. Our experimental results show a 6% improvement in F-score when using whole slide images along with epidermal nests and cancerous dermal nest segmentation masks compared to using whole-slide images alone in training and testing the diagnosis pipeline.

Purpose: The purpose of this study was to quantify the anxiety experienced by patients undergoing pin removal in clinic following closed reduction and percutaneous pinning for supracondylar humerus fractures., Methods: We prospectively enrolled 53 patients (3-8 years) treated for supracondylar humerus fracture with closed reduction and percutaneous pinning between July 2018 and February 2020. Demographic and injury data were recorded. Heart rate and the Face, Legs, Activity, Cry, and Consolability scale were measured immediately before pin removal and after pin removal, and crossover control values were obtained at the subsequent follow-up clinic visit., Results: All patients experienced anxiety immediately prior to pin removal (95% confidence interval, 94%-100%) with a median Face, Legs, Activity, Cry, and Consolability score of 7 (interquartile range, 6-8). In addition, 98% of subjects experienced an elevated heart rate (95% confidence interval, 88%-100%). Patients experienced a median 73% reduction in Face, Legs, Activity, Cry, and Consolability score and mean 21% reduction in heart rate from prior to pin removal to after pin removal ( p  < 0.001). All 45 patients who completed their follow-up visit had a control Face, Legs, Activity, Cry, and Consolability score of 0 and a mean control heart rate of 89.7 bpm. Twenty-five of these 45 subjects (56%) had an elevated control heart rate for their age and sex. Mean heart rate prior to pin removal was 36% higher than control heart rate. There were no sex differences detected in Face, Legs, Activity, Cry, and Consolability scores or heart rate., Conclusions: Pediatric patients experience high levels of anxiety when undergoing pin removal following closed reduction and percutaneous pinning for supracondylar humerus fractures. This is an area of clinical practice where intervention may be warranted to decrease patient anxiety., Level of Evidence: II., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

This report describes a combined immunofluorescence and fluorescence viability stain applied as one staining solution for rapid detection of live Legionella pneumophila in mixed bacterial populations. Instead of sequential viability staining with the Invitrogen BacLight LIVE/DEAD staining kit followed by antibody-Alexa Fluor (AF) 647 conjugate staining to identify live L. pneumophila, a combined single cocktail solution staining protocol was developed to simplify and accelerate the time to detection of viable L. pneumophila serogroup-1 (SG-1) in mixed species populations on a filter membrane. The stain cocktail will aid in accelerating fluorescence microscopic analysis of cooling tower, air conditioner and water fountain or other liquid samples for the presence of L. pneumophila and its viability status. Visibly red stained cells were identified as dead non-L. pneumophila SG-1 cells, while green fluorescing cells represented viable non-L. pneumophila SG-1 cells. Due to also staining red with antibody-AF 647, L. pneumophila SG-1 cells were pseudocolorized as blue to distinguish them from other dead cells. Fluorescence color emission mixing from the viability dyes (SYTO 9 and propidium iodide) with antibody-AF 647 stained L. pneumophila led to other fluorescent colors. For example, green plus pseudocolorized blue AF 647-antibody- labeled cells were identified as live cyan-colored L. pneumophila SG-1 cells. Magenta-colored cells resulted from dead L. pneumophila cells that combined red propidium iodide with blue pseudocolorized AF 647-antibody emissions. Analysis of measured RGB (red, green, blue) color values in microscopic images of mixed bacterial populations suggests the possibility of facile automated discrimination of subpopulations of live and dead L. pneumophila and non-L. pneumophila species by computers in 3-dimensional RGB color space after staining in the combined cocktail which will save time for more rapid microscopic detection of potential sources of Legionnaire's disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Displaced supracondylar humeral fractures (SCHFs) benefit from closed reduction and percutaneous pinning. In Malawi, many SCHFs are treated nonoperatively because of limited surgical capacity. We sought to assess clinical and functional outcomes of nonoperatively treated SCHFs in a resource-limited setting., Methods: We retrospectively reviewed all patients with SCHFs treated at Nkhotakota District Hospital (NKKDH) in Malawi between January 2014 and December 2016. Patients subsequently underwent clinical and functional follow-up assessment., Results: We identified 182 children (54% male, mean age of 7 years) with an SCHF; 151 (83%) of the fractures were due to a fall, and 178 (98%) were extension-type (Gartland class distribution: 63 [35%] type I, 52 [29%] type II, and 63 [35%] type III). Four patients with type-I fractures were treated with an arm sling alone, and 59 were treated with straight-arm traction to reduce swelling and then splint immobilization until union. All 119 of the patients with Gartland type-II and III or flexion-type injuries were treated with straight-arm traction, manipulation under anesthesia without fluoroscopy, and then splint immobilization until union. A total of 137 (75%) of the patients were available for follow-up, at a mean of 3.9 years after injury. The Flynn functional outcome was excellent for 39 (95%) with a type-I fracture, 30 (70%) with type-II, and 14 (29%) with type-III. The Flynn cosmetic outcome was excellent for 40 (98%) with a type-I fracture, 42 (98%) with type-II, and 41 (84%) with type-III. Forty (98%) of the children with a type-I fracture, 41 (95%) with type-II, and 32 (65%) with type-III returned to school without limitation. Controlling for sex, delayed presentation, medical comorbidities, injury mechanism, and skin blistering/superinfection during traction, patients with type-II fractures were 5.82-times more likely (95% confidence interval [CI], 1.71 to 19.85) and those with type-III fractures were 9.81-times more likely (95% CI, 3.00 to 32.04), to have a clinical complication or functional limitation compared with patients with type-I fractures., Conclusions: Nonoperative treatment of type-III SCHFs resulted in a high risk of clinical complications or functional impairment. These results illustrate the urgent need to increase surgical capacity in low-income countries like Malawi to improve pediatric fracture care., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A310)., (Copyright © 2021 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Background: The prevalence of venous thromboembolism (VTE) may be increasing in children; however, scarce literature exists comparing incidence rates between pediatric orthopaedic patients and other pediatric patients. The purpose of this study was to compare the incidence, anatomic locations, and risk factors of VTEs between orthopaedic and nonorthopaedic pediatric related patients to determine if important differences exist., Methods: Computed tomography and ultrasound data were reviewed for children (below 19 y old) with a diagnosed VTE between January 1, 2009 and December 31, 2016. Demographic and clinical data, including VTE anatomic location and risk factors, were recorded. Two major cohorts were identified: orthopaedic-related (ORTH) and nonorthopaedic-related (NORTH) VTEs. Incidence rates were estimated and risk factors were compared using χ2 testing., Results: There were 373 children diagnosed with a VTE (average age 10.3 y) of a total of 810,097 treated as in-patients for an incidence rate of 4.60 per 10,000 cases (95% confidence interval=4.15 to 5.10 per 10,000 cases). The rate of ORTH VTEs (28 of 188,669 orthopaedic patients, 1.48 per 10,000 cases) was significantly lower than that of NORTH VTEs (345 of 621,428 nonorthopaedic patients, 5.55 per 10,000 cases; P<0.001). For the ORTH cohort, there was a significant difference in the proportion of deep vein thrombosis in the lower extremity (91%) compared with the upper extremity (9%) (P<0.001), while a more even distribution of NORTH deep vein thrombosis in the upper (50%) and lower (41%) extremities was appreciated. The primary risk factors for ORTH VTEs included surgery (93%; P<0.001), change in ambulatory status (61%; P<0.001), and trauma (18%; P<0.001), while the primary risk factors for NORTH VTEs included intravenous peripheral inserted central catheter/central line (61%; P<0.001) and cancer (27%; P=0.001)., Conclusions: Pediatric ORTH VTEs have a significantly lower incidence rate and different primary risk factors than those of NORTH VTEs. This information is useful for health care providers when making decisions regarding risk and prophylaxis in pediatric patients with orthopaedic and nonorthopaedic conditions., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Fracture of the medial epicondyle is a common pediatric injury, with an estimated annual incidence of 40 to 60 per 100,000 people per year 1-3 . Medial epicondylar fractures are associated with elbow dislocation in about 60% of cases, and ulnar nerve dysfunction is reported to occur nearly 10% of the time 2,4 . No standard of care for medial epicondylar fracture exists, as similar outcomes have been demonstrated in observational studies with both operative and nonoperative treatment 5,6 . Increasingly, however, these injuries are being treated with surgical intervention, which in most cases consists of a single screw affixing the osseous piece back to its donor site on the humerus 7-9 . There is broad consensus on the absolute indications for operative treatment, including an open fracture and an incarcerated epicondylar fragment 1,10-13 . The relative indications are more controversial and include ulnar nerve dysfunction, elbow instability, increased fragment displacement, and high-level throwing or upper-extremity weight-bearing athletes 2,9,14-16 ., Description: The patient is placed in the prone position with the operative arm on a radiolucent arm board. A milking maneuver with an Esmarch bandage is utilized. A posteromedial incision is made over the medial epicondyle. The ulnar nerve is protected posteriorly. The fracture is easily reduced under minimal tension, and then 1 or 2 guidewires from the 4.0-mm cannulated screw kit are placed to fix the fragment. The central guidewire is overreamed, and then a partially threaded 4.0-mm screw is placed in a relative posterior-to-anterior trajectory within the medial column of the elbow., Alternatives: Nonoperative treatment includes immobilization in a long arm cast until fragment healing. Complications associated with nonoperative treatment include nonunion and late instability. Supine positioning is a reasonable alternative to the prone position described here. In that case, the fracture is fixed with the arm in external rotation of the shoulder and with the elbow extended., Rationale: Prone positioning for operative treatment of medial epicondylar fractures is preferred because the tension from the flexor pronator mass associated with supine positioning is negated, facilitating an easier fracture reduction and improved anatomic reduction., Expected Outcomes: To our knowledge, there are currently no Level-I or Level-II prospective studies reporting on the outcomes of operative versus nonoperative treatment of medial epicondylar fractures. A systematic review of retrospective results suggested no difference in pain or clinical outcomes, but >9-times greater odds of union with operative treatment 5,6 . Expectations following operative treatment of a medial epicondylar fracture have been explored in multiple studies. Generally, return to full levels of activity and near-normal range of motion of the elbow have been demonstrated by most. Minor rates of range-of-motion limitation, including extension deficit (4% with deficit up to 20°) are reported in some studies 8 . In the setting of preoperative instability, the expectation is that elbow stability will be achieved by operative treatment 7,8 ., Important Tips: Perform and document an accurate preoperative neurovascular examination of the arm.Test the shoulder in internal rotation prior to prone positioning.Protect the ulnar nerve during surgical fixation and drilling.Confirm that the screw trajectory is relatively posterior to anterior and only in the medial column of the elbow., Competing Interests: Disclosure: The authors indicated that no external funding was received for any aspect of this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSEST/A331)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Pathologists analyze biopsy material at both the cellular and structural level to determine diagnosis and cancer stage. Mitotic figures are surrogate biomarkers of cellular proliferation that can provide prognostic information; thus, their precise detection is an important factor for clinical care. Convolutional Neural Networks (CNNs) have shown remarkable performance on several recognition tasks. Utilizing CNNs for mitosis classification may aid pathologists to improve the detection accuracy., Methods: We studied two state-of-the-art CNN-based models, ESPNet and DenseNet, for mitosis classification on six whole slide images of skin biopsies and compared their quantitative performance in terms of sensitivity, specificity, and F-score. We used raw RGB images of mitosis and non-mitosis samples with their corresponding labels as training input. In order to compare with other work, we studied the performance of these classifiers and two other architectures, ResNet and ShuffleNet, on the publicly available MITOS breast biopsy dataset and compared the performance of all four in terms of precision, recall, and F-score (which are standard for this data set), architecture, training time and inference time., Results: The ESPNet and DenseNet results on our primary melanoma dataset had a sensitivity of 0.976 and 0.968, and a specificity of 0.987 and 0.995, respectively, with F-scores of .968 and .976, respectively. On the MITOS dataset, ESPNet and DenseNet showed a sensitivity of 0.866 and 0.916, and a specificity of 0.973 and 0.980, respectively. The MITOS results using DenseNet had a precision of 0.939, recall of 0.916, and F-score of 0.927. The best published result on MITOS (Saha et al. 2018) reported precision of 0.92, recall of 0.88, and F-score of 0.90. In our architecture comparisons on MITOS, we found that DenseNet beats the others in terms of F-Score (DenseNet 0.927, ESPNet 0.890, ResNet 0.865, ShuffleNet 0.847) and especially Recall (DenseNet 0.916, ESPNet 0.866, ResNet 0.807, ShuffleNet 0.753), while ResNet and ESPNet have much faster inference times (ResNet 6 s, ESPNet 8 s, DenseNet 31 s). ResNet is faster than ESPNet, but ESPNet has a higher F-Score and Recall than ResNet, making it a good compromise solution., Conclusion: We studied several state-of-the-art CNNs for detecting mitotic figures in whole slide biopsy images. We evaluated two CNNs on a melanoma cancer dataset and then compared four CNNs on a public breast cancer data set, using the same methodology on both. Our methodology and architecture for mitosis finding in both melanoma and breast cancer whole slide images has been thoroughly tested and is likely to be useful for finding mitoses in any whole slide biopsy images., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Congenital tibial pseudarthrosis is a rare condition seen in neurofibromatosis type 1 (NF1), and treatment is complex. A randomized, placebo-controlled trial of bone morphogenetic protein (rhBMP-2; INFUSE bone graft) at time of tibial surgery was developed by the Neurofibromatosis Clinical Trials Consortium. Patients were randomized to receive rhBMP-2 that would, or would not, be added to the standard surgical procedure consisting of resection of pseudarthrosis tissue, insertion of a rigid intramedullary rod, and placement of autogenous iliac crest bone graft. Despite involvement of 16 centers with wide experience with NF1 orthopaedic management, only 5 patients (of 54 required) were able to be enrolled in the study during a 3-year time period. Because of the inability to recruit sufficient patients, this study was closed in June 2019, with plans to terminate. The obstacles that were encountered during the study are summarized. The authors question whether a randomized, placebo-controlled trial of a rare pediatric orthopaedic condition is possible to accomplish. Recommendations are provided to guide future studies of orthopaedic manifestations of NF1.Level of Evidence: Level V.

Diagnosing melanocytic lesions is one of the most challenging areas of pathology with extensive intra- and inter-observer variability. The gold standard for a diagnosis of invasive melanoma is the examination of histopathological whole slide skin biopsy images by an experienced dermatopathologist. Digitized whole slide images offer novel opportunities for computer programs to improve the diagnostic performance of pathologists. In order to automatically classify such images, representations that reflect the content and context of the input images are needed. In this paper, we introduce a novel self-attention-based network to learn representations from digital whole slide images of melanocytic skin lesions at multiple scales. Our model softly weighs representations from multiple scales, allowing it to discriminate between diagnosis-relevant and -irrelevant information automatically. Our experiments show that our method outperforms five other state-of-the-art whole slide image classification methods by a significant margin. Our method also achieves comparable performance to 187 practicing U.S. pathologists who interpreted the same cases in an independent study. To facilitate relevant research, full training and inference code is made publicly available at https://github.com/meredith-wenjunwu/ScATNet.

Background: Melanocytic tumors are often challenging and constitute almost one in four skin biopsies. Immunohistochemical (IHC) studies may assist diagnosis; however, indications for their use are not standardized., Methods: A test set of 240 skin biopsies of melanocytic tumors was examined by 187 pathologists from 10 US states, interpreting 48 cases in Phase I and either 36 or 48 cases in Phase II. Participant and diagnosis characteristics were compared between those who reported they would have ordered, or who would have not ordered IHC on individual cases. Intraobserver analysis examined consistency in the intent to order when pathologists interpreted the same cases on two occasions., Results: Of 187 participants interpreting 48 cases each, 21 (11%) did not request IHC tests for any case, 85 (45%) requested testing for 1 to 6 cases, and 81 (43%) requested testing for ≥6 cases. Of 240 cases, 229 had at least one participant requesting testing. Only 2 out of 240 cases had more than 50% of participants requesting testing. Increased utilization of testing was associated with younger age of pathologist, board-certification in dermatopathology, low confidence in diagnosis, and lesions in intermediate MPATH-Dx classes 2 to 4. The median intraobserver concordance for requesting tests among 72 participants interpreting the same 48 cases in Phases I and II was 81% (IQR 73%-90%) and the median Kappa statistic was 0.20 (IQR 0.00, 0.39)., Conclusion: Substantial variability exists among pathologists in utilizing IHC., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Congenital pseudarthrosis of the fibula (CPF) is a rare disorder characterized by a deficiency in the continuity of the fibula and can lead to progressive ankle valgus malalignment. An existing classification system for CPF is imperfect and may contribute to heterogeneity in reporting and discrepancy of outcomes in the literature., Methods: Fifteen patients with CPF treated at our institution between 1995 and 2017 were retrospectively identified. Only patients with dysplasia leading to spontaneous fracture or pseudarthrosis were included in this series. The median age at presentation was 2.5 years (range: 3 mo to 13.4 y). The median duration of follow-up from the initial presentation was 11.8 years (range: 2.0 to 24 y). Chart review and serial radiographs were analyzed to assess natural history and outcomes following surgery., Results: The coexistence of tibial dysplasia in CPF is very common. Patients were classified into 3 groups based on the degree of tibial involvement-group 1: no evidence of tibial dysplasia, group 2: mild tibial dysplasia, and group 3: significant tibial dysplasia. Age at presentation and age at which fibular fracture occurred were progressively younger with a greater degree of tibial involvement (P<0.05). In the absence of surgical intervention, group 1 patients did not undergo progressive ankle valgus (defined as the valgus change in tibiotalar angle by ≥4 degrees), whereas all patients in groups 2 and 3 did (P<0.001). Fibular osteosynthesis was performed in 6 patients, with union seen only in group 1 patients. Ten patients underwent distal tibiofibular fusion, with no cases of nonunion seen. Distal tibiofibular fusion with or without medial distal tibial hemiepiphysiodesis halted the progression of ankle valgus in 8 of the 10 patients. Further progression of ankle valgus occurred only in patients who did not undergo concurrent medial distal tibial hemiepiphysiodesis and with considerable wedging of the distal tibial epiphysis at the time of fusion., Conclusions: Tibial dysplasia and CPF are intimately related. Grouping patients on this basis may help guide natural history and treatment and may explain discrepancies in findings in the literature. Fibular osteosynthesis, distal tibiofibular fusion, and medial distal tibial hemiepiphysiodesis may all have an important role in the treatment of CPF., Level of Evidence: Level IV-case series.

Background: Recent adult literature has demonstrated that in the setting of acute compartment syndrome (ACS), if fasciotomy wounds are not closed after the first debridement, they are unlikely to be closed via delayed primary closure (DPC). The purpose of this study was to report the success of DPC through serial debridement in children with fasciotomy wounds secondary to ACS and to determine whether length of hospital stay is negatively affected by adopting a DPC strategy., Methods: We identified all patients treated with fasciotomy for ACS (aged 0 to18 y). Patient, injury, and treatment characteristics were summarized by fasciotomy treatment type. Patients were grouped as: primary closure, DPC, and flap or skin graft (F/SG). For patients who required additional debridements after initial fasciotomy, treatment success was defined as closure by DPC (without requiring F/SG). Multivariable logistic regression was used to determine factors associated with additional surgeries, complications, and treatment success., Results: A total of 82 children underwent fasciotomies for ACS. Fifteen (18%) patients were treated with primary closure at the time of their initial fasciotomy and were excluded from the remainder of the analysis, 48 (59%) patients underwent DPC, and 19 (23%) patients were treated with F/SG. The majority of delayed fasciotomy wounds were successfully closed by DPC (48/67, 72%) and the rate of successful closure remained consistent with each successive operative debridement. There were no differences across DPC and F/SG groups with respect to age, method of injury, or injury severity. Patients who underwent F/SG remained in the hospital for an average of 12 days compared with 8 days for those who underwent DPC (P<0.001)., Conclusions: In the setting of ACS, pediatric fasciotomy wounds that are not closed after the first postfasciotomy debridement still have a high likelihood of being closed through DPC with serial surgical debridement. In children, persisting with DPC strategy for fasciotomy closure after ACS is more successful than it is in adults., Level of Evidence: Level III.

The specific pathogenesis of idiopathic nephrotic syndrome (NS) is poorly understood, and the role of immune mediators remains contentious. However, there is good evidence for the role of a circulating factor, and we recently postulated circulating proteases as candidate factors. Immunosuppressive therapy with glucocorticoids (GCs) and T cell inhibitors are widely used in the clinical treatment of NS. Given that T helper (CD4 + ) cells expressing IL-17A (so-called Th17 cells) have recently been reported to be resistant to GC treatment, and GC resistance remains a major challenge in the management of NS, we hypothesized that Th17 cells produce a circulating factor that is capable of signaling to the podocyte and inducing deleterious phenotypic changes. To test this, we generated human Th17 cells from healthy volunteers and added the supernatants from these T cell cultures to conditionally immortalized human podocytes in vitro. This demonstrated that podocytes treated with Th17 cell culture supernatant, as well as with patient disease plasma, showed significant stimulation of JNK and p38 MAPK pathways and an increase in motility, which was blocked using a JNK inhibitor. We have previously shown that nephrotic plasma elicits a podocyte response via protease-activated receptor-1 (PAR-1). Stimulation of PAR-1 in podocytes elicited the same signaling response as Th17 cell culture supernatant treatment. Equally, protease inhibitors with Th17 cell culture treatment blocked the signaling response. This was not replicated by the reagents added to Th17 cell cultures or by IL-17A. Hence, we conclude that an undefined soluble mediator produced by Th17 cells mimics the deleterious effect of PAR-1 activation in vitro. Given the association between pathogenic subsets of Th17 cells and GC resistance, these observations have potential therapeutic relevance for patients with NS.

Purpose: The presence of a clubfoot is often found prenatally and some families seek counselling with a specialist. The purpose of this study was to compare the parental anxiety levels in families that: a) knew prenatally and had prenatal counselling; b) knew prenatally but did not seek prenatal counselling; and c) did not know until after delivery., Methods: This prospective cohort study evaluated the anxiety of parents as they presented to the paediatric orthopaedic clinic with their newborn with a foot disorder (prior to the diagnostic confirmation of clubfoot). Each family filled out the 'Pre-visit orthopaedic surgeon questionnaire' and then after the initial visit with the orthopaedic surgeon (confirming the clubfoot diagnosis) the family filled out the 'Immediately post-visit orthopaedic surgeon questionnaire'. Through these questionnaires, anxiety level was assessed prior to meeting postnatally with the paediatric orthopaedic specialist, as well as after the meeting and compared across groups., Results: A total of 121 parents completed questionnaires: 71% (86/121) confirmed clubfoot; 69% of families (59/86) received prenatal counselling (Group A); 16% (14/86) knew prenatally but had no counselling (Group B); and 15% (13/86) found out at birth (Group C). There was no difference in anxiety levels across groups before (p = 0.78) or after (p = 0.57) meeting with the paediatric orthopaedic surgeon; however, overall anxiety reduced significantly (p < 0.001)., Conclusion: We found no difference in the anxiety levels of across the three groups. Prenatal counselling for parents of children with likely clubfoot may not decrease parental anxiety, but nonetheless is very appreciated by the families who receive it., Level of Evidence: Prognostic Level II., (Copyright © 2019, The author(s).)

Background: The etiology of hip pain in pediatric and adolescent patients can be unclear. Osteoid osteoma (OO) about the hip in children has only been described in case reports or small studies. The present study assessed the clinical presentation and diagnostic course, imaging, and treatment approaches in a large cohort of pediatric cases of OO about the hip., Methods: Medical record and imaging results were reviewed for all cases of OO identified within or around the hip joint in patients <20 years old between January 1, 2003, and December 31, 2015, at a tertiary-care pediatric center. Demographic, clinical, and radiographic data were analyzed., Results: Fifty children and adolescents (52% female; mean age, 12.4 years; age range, 3 to 19 years) were identified. Night pain (90%) and symptom relief with nonsteroidal anti-inflammatory drugs (NSAIDs) (88%) were common clinical findings. Sclerosis/cortical thickening was visible in 58% of radiographs, although a radiolucent nidus was visible in only 42%. Diagnostic imaging findings included perilesional edema and a radiolucent nidus on 100% of available magnetic resonance imaging (MRI) and computed tomography (CT) scans, respectively. Initial alternative diagnoses were given in 23 cases (46%), the most common of which was femoroacetabular impingement (FAI). Delay in diagnosis of >6 months occurred in 43% of patients. Three patients underwent operative procedures for other hip diagnoses, but all had persistent postoperative pain until the OO was treated. Of the 41 patients (82%) who ultimately underwent radiofrequency ablation (RFA), 38 (93%) achieved complete post-RFA symptom resolution., Conclusions: Initial misdiagnosis, the most common of which was FAI, and delayed correct diagnosis are common in pediatric OO about the hip. Presenting complaints were variable and nonspecific MRI findings were frequent. Night pain and relief with NSAIDs were present in the vast majority of cases. CT scans provided definitive diagnosis in all patients who received them. As increasing numbers of young, active patients are being evaluated for various causes of hip pain, such as FAI, OO should not be overlooked in the differential diagnosis., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Purpose: The Ponseti Method has dramatically altered the management of clubfoot, with particular implications for limited-resource settings. We sought to describe outcomes of care and risk factors for sub-optimal results using the Ponseti Method in Haiti., Methods: We conducted a records review of patients presenting from 2011-2015 to a CURE Clubfoot clinic in Port-au-Prince, Haiti. We report patient characteristics (demographics and clinical), treatment patterns (cast number/duration and tenotomy rates), and outcomes (relapse and complications). We compared treatment with benchmarks in high-income nations and used generalized linear models to identify risk factors for delayed presentation, increased number of casts, and relapse., Results: Amongst 168 children, age at presentation ranged from 0 days (birth) to 4.4 years, 62% were male, 35% were born at home, 63% had bilateral disease, and 46% had idiopathic clubfeet. Prior treatment (RR 6.33, 95% CI 3.18-12.62) was associated with a higher risk of delayed presentation. Risk factors for requiring ≥ 10 casts included having a non-idiopathic diagnosis (RR 2.28, 95% CI 1.08-4.83) and higher Pirani score (RR 2.78 per 0.5 increase, 95% CI 1.17-6.64). Female sex (RR 1.54, 95% CI 1.01-2.34) and higher Pirani score (RR 1.09 per 0.5 increase, 95% CI 1.00-1.17) were risk factors for relapse. Compared to North American benchmarks, children presented later (median 4.1 wks [IQR 1.6-18.1] vs. 1 wk), with longer casting (12.5 wks [SD 9.8] vs. 7.1 wks), and higher relapse (43% vs. 22%)., Conclusions: Higher Pirani score, prior treatment, non-idiopathic diagnosis, and female sex were associated with a higher risk of sub-optimal outcomes in this low-resource setting. Compared to high-income nations, serial casting began later, with longer duration and higher relapse. Identifying patients at risk for poor outcomes in a low-resource setting can guide counseling, program development, and resource allocation., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Treatment of idiopathic clubfoot with the Ponseti method is now standard, but predicting relapse can be difficult. Most experts recommend bracing to the age of four years, but this can be challenging for families, and may not be necessary in all patients. The purpose of this study is to compare patterns of bracing and age of relapse to help determine if predictable patterns exist., Methods: The 70 patients with idiopathic clubfoot treated initially with the Ponseti technique who had relapse of their clubfoot were identified. Relapse was defined as a return to casting or surgery due to recurrent deformity. Data collected included demographics, treatment and brace adherence. Patients who sustained initial relapse before the age of two years were compared with those who sustained initial relapse after the age of two years., Results: In total 56% (39/70) had their initial relapse prior to age two years while 44% (31/70) were after age two years. Of the patients who relapsed prior to the age of two years, 28% (11/39) were adherent with bracing while 72% were non--adherent. For patients who initially relapsed after age two, 74% (23/31) were adherent with bracing while 26% were non-adherent (p < 0.001). Of those who had initial -relapse -prior to age two, a subsequent relapse was seen in 69% (27/39)., Conclusion: Patients with idiopathic clubfoot who experienced recurrence prior to age two years are significantly more likely to be non-adherent with bracing than those who sustain recurrence after age two. After initial relapse prior to age two, bracing adherence does not affect likelihood of subsequent recurrence.

Soil-transmitted helminths (STHs) are intestinal parasitic nematodes that infect humans, and are transmitted through contaminated soil. These nematodes include the large roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworm (Ancylostoma ceylanicum, Ancylostoma duodenale, and Necator americanus). Nearly 1.5 billion people (~24% of the population) worldwide are infected with at least one species of these parasites, burdening the poor, in particular, children and pregnant women. To combat these diseases, the WHO only recognizes four anthelmintic drugs, including the preferred drug, albendazole, for mass drug administration (MDA). These four drugs have a total of two different mechanisms of action, and, as expected, resistance has been observed. This problem calls for new drugs with different mechanisms of action. Although there is precedence for the use of Caenorhabditis elegans (C. elegans), a free-living nematode, as a model for drug screening and anthelmintic testing, their usefulness for such anthelmintic study is not clear as past research has shown that C. elegans did not show a strong response to albendazole, the MDA drug of choice, in comparison with various STHs under similar treatment. To further examine if C. elegans has the potential to be a good model organism for anthelmintic drug study, we employed a health rating scale in order to tease out potential effects of albendazole, and other anthelmintics, that may have been missed using a binary, dead/alive scale. Using the health-rating scale we found that although the worms may have not been dying, they were sick, showing dose responses to anthelmintic drugs, including albendazole, reinforcing C. elegans as a useful model for anthelmintic study.

Context: Carcinoid heart disease (NET-CHD) is associated with the development of symptom-limited exercise capacity and high rates of morbidity and mortality., Objective: This study sought to determine the survival, cardiac function, and functional class following surgery., Design and Setting, and Patients: This was a retrospective observational cohort study between 2005 and 2015 at a European Centre of Excellence for Neuroendocrine Tumours, Queen Elizabeth Hospital Birmingham. England consisting of 62 consecutive patients referred to the NET-Cardiology Service., Interventions: Subjects were assessed at referral using transthoracic echocardiography (with saline contrast) and transesophageal echocardiography, and 77% with confirmed NET-CHD underwent cardiovascular magnetic resonance imaging. Symptomatic patients with concomitant severe valvular dysfunction were referred for surgery with stable NET disease., Main Outcome Measure: Survival of patients with proven NET-CHD following medical and surgical treatments was measure., Results: In total, 47/62 patients were diagnosed with NET-CHD. Thirty-two patients (68%) underwent surgery with bioprosthetic valve replacements in all subjects; tricuspid, n = 31; pulmonary, n = 30; mitral, n = 3; and aortic, n = 3. Four patients underwent concomitant coronary artery bypass grafting. There were 4 (13%) early post-operative deaths. One- and 2-y survival rates after surgery were 75 and 69% compared with 45 and 15% in un-operated patients. Post-operatively, functional class was improved (pre-New York Heart Association Classification [NYHA], 2.6 [0.5] vs post-NYHA, 1.7 [1.1]), P < .05, right-ventricular (RV) size was reduced (136 ml/m(2) [25] vs 71 ml/m(2) [7]; P < .01) with preserved RV ejection fraction (61% ± 9 vs 55% ± 10; P = .26)., Conclusion: Valve surgery improved functional class and resulted in RV reverse remodelling with improved survival rates at 2 y compared with those not proceeding to operation. These data highlight the importance of close collaboration between NET clinicians, cardiology, and cardiothoracic surgery teams. Early referral can improve functional capacity but more research is needed to define the selection of appropriate candidates and randomized data are needed to define the effect of surgery on prognosis.

Background & Aims: We studied new-onset diabetes after transplantation (NODAT) in liver transplantation with grafts donated after brain death (DBD) or circulatory death (DCD), focusing on the early post-transplant period., Methods: A total of 430 non-diabetic primary liver transplant recipients [DCD, n = 90 (21%)] were followed up for 30 months (range 5-69). NODAT was defined as the composite endpoint of one of following: (i) Two non-fasting plasma glucose levels > 11.1 mmol/L ≥ 30 days apart, (ii) oral hypoglycaemic drugs ≥ 30 days consecutively (iii) insulin therapy ≥ 30 days and (iv) HbA1c ≥ 48 mmol/L. Resolution of NODAT was defined as cessation of treatment or hyperglycaemia., Results: Total of 81/430 (19%) patients developed NODAT. Incidence and resolution of NODAT over time showed significantly different patterns between DCD and DBD liver graft recipients; early occurrence, high peak incidence and early resolution were seen in DCD. In multivariate logistic regression including age, ethnicity, HCV, tacrolimus level and pulsed steroids, only DCD was independently associated with NODAT at day 15 post-transplant (OR 6.5, 95% CI 2.3-18.4, P < 0.001), whereas age and pulsed steroids were significant factors between 30-90 days. Combined in multivariate Cox regression model for NODAT-free survival, graft type, age and pulsed steroids were each independent predictor for decreased NODAT-free survival in the first 90-postoperative days., Conclusion: Early peak of NODAT in DCD graft recipients is a novel finding, occurring independently from known risk factors. Donor warm ischaemia and impact on insulin sensitivity should be further studied and could perhaps be associated with graft function., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The podocyte is one of the two cell types that contribute to the formation of the glomerular filtration barrier (GFB). It is a highly specialized cell with a unique structure. The key feature of the podocyte is its foot processes that regularly interdigitate. A structure known as the slit diaphragm can be found bridging the interdigitations. This molecular sieve comprises the final layer of the GFB. It is well accepted that the podocyte is the target cell in the pathogenesis of nephrotic syndrome. In nephrotic syndrome, the GFB no longer restricts the passage of macromolecules and protein is lost into the urine. A number of phenotypic and morphological changes are seen in the diseased podocyte and in the literature these have been described as an epithelial-mesenchymal transition (EMT). However, there is a growing appreciation that this term does not accurately describe the changes that are seen. Definitions of type-2 EMT are based on typical epithelial cells. While the podocyte is known as a visceral epithelial cell, it is not a typical epithelial cell. Moreover, podocytes have several features that are more consistent with mesenchymal cells. Therefore, we suggest that the term podocyte disease transformation is more appropriate.

Introduction: Following surgical procedures in thoracic surgery a chest X-ray is routinely performed and its necessity is rarely questioned. However, there are differences in the time frame of such radiological procedures. Especially after minor procedures such as mediastinoscopy there is a wide variation from a chest X-ray immediately after surgical intervention to an image only on the following day. Also, in some hospitals patients undergo only clinical but no radiological examination. No recommendations are available in the literature., Aim and Method: Following video-mediastinoscopy with good visualisation of all structures it appeared that a chest X-ray could be waived. 95 consecutive patients were prospectively randomised into two groups, either receiving chest X-ray four hours postoperatively or no chest X-ray. All patients were clinically examined on the evening of the day of mediastinoscopy., Results: 48 % of the patients had a chest X-ray, 52 % did not and underwent only clinical examination. No surgical revision was necessary in either group, no difference in therapeutic consequences was noted. As a result we discontinued chest X-rays after mediastinoscopy., Discussion: There are only sparse data concerning postoperative chest X-rays in thoracic surgery patients. In a study on children and young adults undergoing a Nuss procedure routine radiological examination was substituted by clinical indication resulting in a lower rate of thoracic drain placement. A chest X-ray to document the location of the metal bar prior to discharge was felt to be sufficient. In patients undergoing cardiac procedures daily routine chest X-rays on the intensive care ward were replaced by on-demand X-ray in a study without any change in length of stay, readmission or mortality. The same was found for chest X-rays following drain removal in cardiac patients: routine radiological examination seems not to be indicated. As a consequence of our own observational study on mediastinoscopy we have discontinued postoperative X-ray as the patients are examined clinically. All other patients undergoing thoracic surgery procedures who are observed in the intensive care unit receive the first chest X-ray in the morning following surgery. Only if complete expansion of the lung is warranted (pleurodesis, pneumothorax) an X-ray is performed on the day of surgery., (Georg Thieme Verlag KG Stuttgart · New York.)

Because bottom substrate composition is an important control on the temporal and spatial location of the aquatic community, accurate maps of benthic habitats of inland lakes and reservoirs provide valuable information to managers, recreational users, and scientists. Therefore, we collected vertical, split-beam sonar data (roughness [E1], hardness [E2], and bathymetry) and sediment samples to make such maps. Statistical calibration between sonar parameters and sediment classes was problematic because the E1:E2 ratios for soft (muck and clay) sediments overlapped a lower and narrower range for hard (gravel) substrates. Thus, we used indicator kriging (IK) to map the probability that unsampled locations did not contain coarse sediments. To overcome the calibration issue we tested proxies for the natural processes and anthropogenic history of the reservoir as potential predictive variables. Of these, a geologic map proved to be the most useful. The central alluvial valley and mudflats contained mainly muck and organic-rich clays. The surrounding glacial till and shale bedrock uplands contained mainly poorly sorted gravels. Anomalies in the sonar data suggested that the organic-rich sediments also contained trapped gases, presenting additional interpretive issues for the mapping. We extended the capability of inexpensive split-beam sonar units through the incorporation of historic geologic maps and other records as well as validation with dredge samples. Through the integration of information from multiple data sets, were able to objectively identify bottom substrate and provide reservoir users with an accurate map of available benthic habitat.

David Marr famously proposed three levels of analysis (implementational, algorithmic, and computational) for understanding information processing systems such as the brain. While two of these levels are commonly taught in neuroscience courses (the implementational level through neurophysiology and the computational level through systems/cognitive neuroscience), the algorithmic level is typically neglected. This leaves an explanatory gap in students' understanding of how, for example, the flow of sodium ions enables cognition. Neural networks bridge these two levels by demonstrating how collections of interacting neuron-like units can give rise to more overtly cognitive phenomena. The demonstrations in this paper are intended to facilitate instructors' introduction and exploration of how neurons "process information."

The great diversity of techniques to synthesize and use DNA microarrays has made them extremely flexible for a variety of applications. This flexibility also has made standardization difficult, leading to problems comparing data from these different systems. In this work, we use the surface science techniques of X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS) to analyze the components of DNA. The atomic ratios of the components of nucleobases, nucleosides, and nucleotides were characterized by XPS. The chemical shifts in the high-resolution XPS spectra allow for their relatively easy resolution. The unique positive and negative ions from the nucleobases, nucleosides, and nucleotides in their TOF-SIMS spectra were identified. This information was used to build a comprehensive table of all of the molecular ions. These standard spectra of DNA components can be used to predict the relative amounts of the bases within more complex molecules either by univariate analysis (i.e., by relating the base molecular ions to the sugar fragment ions within the nucleotides) or by multivariate analysis (e.g., principal component analysis). Our preliminary examination of four oligonucleotides shows promising results in that we can distinguish between two oligomers of similar composition using univariate and multivariate analysis, although additional studies are needed to expand this method to more complex oligomers.