Colonic crypt stem cell functions are controlled by tight junction protein claudin-7 through Notch/Hippo signaling.

The tight junction protein claudin-7 is essential for tight junction function and intestinal homeostasis. Cldn7 deletion in mice leads to an inflammatory bowel disease-like phenotype exhibiting severe intestinal epithelial damage, weight loss, inflammation, mucosal ulcerations, and epithelial hyperplasia. Claudin-7 has also been shown to be involved in cancer metastasis and invasion. Here, we test our hypothesis that claudin-7 plays an important role in regulating colonic intestinal stem cell function. Conditional knockout of Cldn7 in the colon led to impaired epithelial cell differentiation, hyperproliferative epithelium, a decrease in active stem cells, and dramatically altered gene expression profiles. In 3D colonoid culture, claudin-7-deficient crypts were unable to survive and form spheroids, emphasizing the importance of claudin-7 in stem cell survival. Inhibition of the Hippo pathway or activation of Notch signaling partially rescued the defective stem cell behavior. Concurrent Notch activation and Hippo inhibition resulted in restored colonoid survival, growth, and differentiation to the level comparable to those of wild-type derived crypts. In this study, we highlight the essential role of claudin-7 in regulating Notch and Hippo signaling-dependent colonic stem cell functions, including survival, self-renewal, and differentiation. These new findings may shed light on potential avenues to explore for drug development in colorectal cancer.

First reported Rhodotorula mucilaginosa brain abscess: Found as coinfection in woman with common variable immune deficiency.

Rhodotorula is a rare pathogen seen in the immunocompromised host; while cases of Rhodotorula meningitis have been reported, there are no published cases of Rhodotorula brain abscess. We describe the diagnosis and management of a woman with common variable immune deficiency presenting with concomitant Rhodotorula and Nocardia brain abscesses.

Novel combination of GammaTile cesium-131 brachytherapy with 5-aminolevulinic acid fluorescence-guided resection in the re-irradiation of pediatric recurrent high-grade glioma: illustrative case.

BACKGROUND: Herein, the authors describe the successful utilization of 5-aminolevulinic acid (5-ALA) and the first case of GammaTile cesium-131 therapy in a pediatric patient with recurrent high-grade glioma. 5-ALA was utilized to optimize gross-total resection prior to GammaTile implantation. After conversion to an equivalent dose in 2-Gy fractions (EQD2), a composite was made of the GammaTile dose with the initial external beam radiotherapy. Two hypothetical plans consisting of a standard hypofractionated strategy for glioma reirradiation and a CyberKnife plan using GammaTile's planning target volume were developed and likewise underwent EQD2 conversion and composite plan generation with the initial radiotherapy. OBSERVATIONS: 5-ALA was useful in achieving gross-total resection with no acute toxicity from the surgery or GammaTile irradiation. When compared with the hypothetical composite doses, GammaTile's composite, axium point dose (D0.03cc) to the brainstem was 32.9 Gy less than the hypofractionated and the CyberKnife composite plans at 38.7 Gy and 40.2 Gy, respectively. The right hippocampus demonstrated a substantially reduced composite plan dose with GammaTile with a D0.03cc of 62.4 Gy versus 71.7 and 80.7 Gy for the hypofractionated and CyberKnife composite plans, respectively. LESSONS: Utilization of 5-ALA and GammaTile therapy yielded clinically superior tumor debulking and effective radiotherapy dose localization with sparing of organs at risk, respectively.

Atrial Myxoma Presenting With Hemorrhage and Multifocal Infarcts in the Brain of a 59-Year-Old Man: An Uncommon Outcome for the Most Common Primary Heart Neoplasm.

Atrial myxomas are the most common primary neoplasm of the heart. Due to their mass effect, they may lead to dysfunction of the heart or mitral valve. Rarely, neoplastic fragments may embolize or a thrombus secondary to stasis may form, which can infarct downstream structures (e.g., the brain). We report the case of a 59-year-old man presenting with headaches, visual changes, and word-finding difficulty secondary to multifocal brain lesions that were identified on computed tomography and magnetic resonance imaging. After an extensive workup, the etiology of the patient's neurological symptoms was determined to be embolization from a large atrial myxoma (2.3x3.5 cm). Histologic and immunohistochemical examination of the atrial myxoma and largest brain lesion yielded similarities, including the presence of spindle-shaped and stellate cells, myxoid regions, Alcian blue pH 2.5 positivity, calretinin positivity, cluster of differentiation 34 (CD34) positivity, and cluster of differentiation 68 (CD68) negativity. This case was remarkable due to the patient's late presentation, the large size of the atrial myxoma, the presence of abundant cerebral hemisphere and cerebellar lesions, and the histologic comparison of the heart and brain lesions. Atrial myxomas have been reported from childhood to late adulthood and when symptoms typically present clinically due to the mass effect. However, neurologic manifestations from embolization or thrombus formation can occur, as in the present case. Therefore, considering the presence of atrial myxomas is important in patients with neurologic manifestations and heart murmurs.

Evaluation of at-home physiotherapy.

An objective technological solution for tracking adherence to at-home shoulder physiotherapy is important for improving patient engagement and rehabilitation outcomes, but remains a significant challenge. The aim of this research was to evaluate performance of machine-learning (ML) methodologies for detecting and classifying inertial data collected during in-clinic and at-home shoulder physiotherapy exercise. A smartwatch was used to collect inertial data from 42 patients performing shoulder physiotherapy exercises for rotator cuff injuries in both in-clinic and at-home settings. A two-stage ML approach was used to detect out-of-distribution (OOD) data (to remove non-exercise data) and subsequently for classification of exercises. We evaluated the performance impact of grouping exercises by motion type, inclusion of non-exercise data for algorithm training, and a patient-specific approach to exercise classification. Algorithm performance was evaluated using both in-clinic and at-home data. The patient-specific approach with engineered features achieved the highest in-clinic performance for differentiating physiotherapy exercise from non-exercise activity (area under the receiver operating characteristic (AUROC) = 0.924). Including non-exercise data in algorithm training further improved classifier performance (random forest, AUROC = 0.985). The highest accuracy achieved for classifying individual in-clinic exercises was 0.903, using a patient-specific method with deep neural network model extracted features. Grouping exercises by motion type improved exercise classification. For at-home data, OOD detection yielded similar performance with the non-exercise data in the algorithm training (fully convolutional network AUROC = 0.919). Including non-exercise data in algorithm training improves detection of exercises. A patient-specific approach leveraging data from earlier patient-supervised sessions should be considered but is highly dependent on per-patient data quality.

Personalized Activity Recognition with Deep Triplet Embeddings.

A significant challenge for a supervised learning approach to inertial human activity recognition is the heterogeneity of data generated by individual users, resulting in very poor performance for some subjects. We present an approach to personalized activity recognition based on deep feature representation derived from a convolutional neural network (CNN). We experiment with both categorical cross-entropy loss and triplet loss for training, and describe a novel loss function based on subject triplets. We evaluate these methods on three publicly available inertial human activity recognition datasets (MHEALTH, WISDM, and SPAR) comparing classification accuracy, out-of-distribution activity detection, and generalization to new activity classes. The proposed triplet algorithm achieved an average 96.7% classification accuracy across tested datasets versus the 87.5% achieved by the baseline CNN algorithm. We demonstrate that personalized algorithms, and, in particular, the proposed novel triplet loss algorithms, are more robust to inter-subject variability and thus exhibit better performance on classification and out-of-distribution detection tasks.

A Case of Metastatic Basal Cell Carcinoma (BCC) With Spinal and Pulmonary Metastases Treated With Vismodegib, Sonedigib, and Radiotherapy.

Basal cell carcinoma (BCC) is the most common malignancy worldwide and has one of the most favorable prognoses due to its tendency to remain local. Clinical presentation with rare distant metastases significantly increases morbidity and mortality. Historically, no effective therapies have existed for locally advanced or metastatic BCC. Recent research highlights the possibility of treating patients with advanced and metastatic BCC with hedgehog pathway inhibitors, such as vismodegib or sonedigib. We present the case of a 62-year-old male with a history of a large left shoulder lesion, which was diagnosed as a nodulocystic BCC following biopsy and histopathologic examination. The primary lesion was managed with surgical excision, and his ensuing metastatic disease was treated with vismodegib, sonedigib, tumor debulking, and radiation therapy. Magnetic resonance imaging and computed tomography of the chest revealed probable metastases to the apical segment of the left upper lobe and thoracic spine, leading to spinal stenosis and probable cause of the patient's ataxia and paresthesias. Due to the ability of BCCs to transform during metastasis, it is impossible to identify the nature of metastatic lesions (i.e., basaloid, squamous, or hybrid) without biopsy. In this case report, we review the etiologies, typical demographics, presentation patterns, and treatment regimens for metastatic BCC and the possibility of metastatic disease transforming to squamous or hybrid variants.

Out-of-Distribution Detection of Human Activity Recognition with Smartwatch Inertial Sensors.

Out-of-distribution (OOD) in the context of Human Activity Recognition (HAR) refers to data from activity classes that are not represented in the training data of a Machine Learning (ML) algorithm. OOD data are a challenge to classify accurately for most ML algorithms, especially deep learning models that are prone to overconfident predictions based on in-distribution (IIN) classes. To simulate the OOD problem in physiotherapy, our team collected a new dataset (SPARS9x) consisting of inertial data captured by smartwatches worn by 20 healthy subjects as they performed supervised physiotherapy exercises (IIN), followed by a minimum 3 h of data captured for each subject as they engaged in unrelated and unstructured activities (OOD). In this paper, we experiment with three traditional algorithms for OOD-detection using engineered statistical features, deep learning-generated features, and several popular deep learning approaches on SPARS9x and two other publicly-available human activity datasets (MHEALTH and SPARS). We demonstrate that, while deep learning algorithms perform better than simple traditional algorithms such as KNN with engineered features for in-distribution classification, traditional algorithms outperform deep learning approaches for OOD detection for these HAR time series datasets.

Adherence Patterns and Dose Response of Physiotherapy for Rotator Cuff Pathology: Longitudinal Cohort Study.

BACKGROUND: Physiotherapy is considered to be essential for the successful operative and nonoperative management of rotator cuff pathology; however, the extent to which patients adhere to assigned physiotherapy activities and how this impacts recovery is unknown. OBJECTIVE: The purpose of this study was to measure the rate and patterns of participation in physiotherapy for rotator cuff disorders, assess the dose response between physiotherapy activity and recovery, and explore patient factors predictive of physiotherapy participation. METHODS: We report a prospective longitudinal study of 42 patients undergoing physiotherapy for symptomatic rotator cuff pathology. The patients were issued a smartwatch that recorded inertial sensor data while they performed physiotherapy exercises both in the clinic and in the home setting. A machine learning approach was used to assess total physiotherapy participation from smartwatch inertial data. Primary outcomes were the Disabilities of the Arm Shoulder and Hand and numeric pain rating scale assessed every 4 weeks until 12 weeks follow-up. The relationships between participation, outcomes, and clinical patient variables were assessed in univariable analyses. RESULTS: Mean physiotherapy exercise participation in clinic and at home were 11 minutes per week and 33 minutes per week, respectively, with patients participating in physiotherapy on 41% of days assigned to treatment. Home physiotherapy participation decreased significantly over time (P=.03). There was a statistically significant and clinically meaningful relationship between cumulative physiotherapy participation and recovery demonstrated by pain scores at 8 weeks (P=.02) and 12 weeks (P=.05) and disability scores at 8 weeks (P=.04) and 12 weeks (P=.04). Low patient expectations and self-efficacy were associated with low rates of physiotherapy participation. CONCLUSIONS: There was a low rate of participation in home shoulder physiotherapy exercise, and a statistically and clinically significant dose response of physiotherapy on treatment outcome in patients with rotator cuff pathology. The findings highlight the opportunity to develop novel methods and strategies to improve the participation in and efficacy of physiotherapy exercises for rotator cuff disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/17841.

Detection of varicella zoster virus antigen and DNA in two cases of cerebral amyloid angiopathy.

OBJECTIVE: Varicella zoster virus (VZV) vasculopathy and cerebral amyloid angiopathy (CAA) have similar clinical presentations: both affect cerebrovasculature in the elderly, produce hemorrhage, and can have a protracted course of cognitive decline and other neurological deficits. The cause of CAA is unknown, but amyloid-beta (Aß) is found within arterial walls. Recent studies show that VZV induces Aß and amylin expression and an amyloid-promoting environment. Thus, we determined if VZV was present in CAA-affected arteries. METHODS: Two subjects with pathologically-verified CAA were identified postmortem and frontal lobes analyzed by immunohistochemistry for arteries containing VZV, Aß, and amylin and H&E for pathological changes. VZV antigen detection was confirmed by PCR for VZV DNA in the same region. RESULTS: In both CAA cases, sections with cerebral arteries containing VZV antigen with corresponding VZV DNA were identified; VZV antigen co-localized with Aß in media of arteries with histological changes characteristic of CAA. Amylin was also seen in the intima of a VZV-positive artery in the diabetic subject. Not all Aß-containing arteries had VZV, but all VZV-positive arteries contained Aß. CONCLUSIONS: VZV antigen co-localized with Aß in some affected arteries from two CAA cases, suggesting a possible association between VZV infection and CAA.

A Required, Combined Neurology-Physical Medicine and Rehabilitation Clerkship Addresses Clinical and Health Systems Knowledge Gaps for Fourth-Year Medical Students.

ABSTRACT: This study evaluated the impact of a 4-wk mandatory neurology-physical medicine and rehabilitation advanced-core clerkship for fourth-year medical students. The combined clerkship encouraged an interdisciplinary and function-based approach to the management of common neurologic, musculoskeletal, and pain complaints. Seventy-three fourth-year medical students participated in the rotation over 1 yr. A survey assessing knowledge and skill set topics was conducted before and after the clerkship. Qualitative feedback regarding the rotation was provided by the students and analyzed. Significant gaps in knowledge and skill sets were identified before the clerkship and successfully addressed by combined teaching modalities. These data demonstrate that an integrated neurology-physical medicine and rehabilitation clerkship can improve students' confidence in multiple domains. Integrating physical medicine and rehabilitation into core clerkships at other medical schools may provide an avenue to address curriculum gaps.

Pathology Informatics Essentials for Residents: A Flexible Informatics Curriculum Linked to Accreditation Council for Graduate Medical Education Milestones.

CONTEXT: -Recognition of the importance of informatics to the practice of pathology has surged. Training residents in pathology informatics has been a daunting task for most residency programs in the United States because faculty often lacks experience and training resources. Nevertheless, developing resident competence in informatics is essential for the future of pathology as a specialty. OBJECTIVE: -To develop and deliver a pathology informatics curriculum and instructional framework that guides pathology residency programs in training residents in critical pathology informatics knowledge and skills, and meets Accreditation Council for Graduate Medical Education Informatics Milestones. DESIGN: -The College of American Pathologists, Association of Pathology Chairs, and Association for Pathology Informatics formed a partnership and expert work group to identify critical pathology informatics training outcomes and to create a highly adaptable curriculum and instructional approach, supported by a multiyear change management strategy. RESULTS: -Pathology Informatics Essentials for Residents (PIER) is a rigorous approach for educating all pathology residents in important pathology informatics knowledge and skills. PIER includes an instructional resource guide and toolkit for incorporating informatics training into residency programs that vary in needs, size, settings, and resources. PIER is available at http://www.apcprods.org/PIER (accessed April 6, 2016). CONCLUSIONS: -PIER is an important contribution to informatics training in pathology residency programs. PIER introduces pathology trainees to broadly useful informatics concepts and tools that are relevant to practice. PIER provides residency program directors with a means to implement a standardized informatics training curriculum, to adapt the approach to local program needs, and to evaluate resident performance and progress over time.

Pathology Informatics Essentials for Residents: A flexible informatics curriculum linked to Accreditation Council for Graduate Medical Education milestones.

CONTEXT: Recognition of the importance of informatics to the practice of pathology has surged. Training residents in pathology informatics have been a daunting task for most residency programs in the United States because faculty often lacks experience and training resources. Nevertheless, developing resident competence in informatics is essential for the future of pathology as a specialty. OBJECTIVE: The objective of the study is to develop and deliver a pathology informatics curriculum and instructional framework that guides pathology residency programs in training residents in critical pathology informatics knowledge and skills and meets Accreditation Council for Graduate Medical Education Informatics Milestones. DESIGN: The College of American Pathologists, Association of Pathology Chairs, and Association for Pathology Informatics formed a partnership and expert work group to identify critical pathology informatics training outcomes and to create a highly adaptable curriculum and instructional approach, supported by a multiyear change management strategy. RESULTS: Pathology Informatics Essentials for Residents (PIER) is a rigorous approach for educating all pathology residents in important pathology informatics knowledge and skills. PIER includes an instructional resource guide and toolkit for incorporating informatics training into residency programs that vary in needs, size, settings, and resources. PIER is available at http://www.apcprods.org/PIER (accessed April 6, 2016). CONCLUSIONS: PIER is an important contribution to informatics training in pathology residency programs. PIER introduces pathology trainees to broadly useful informatics concepts and tools that are relevant to practice. PIER provides residency program directors with a means to implement a standardized informatics training curriculum, to adapt the approach to local program needs, and to evaluate resident performance and progress over time.

Varicella Zoster Virus Infection in Granulomatous Arteritis of the Aorta.

Granulomatous arteritis characterizes the pathology of giant cell arteritis, granulomatous aortitis, and intracerebral varicella zoster virus (VZV) vasculopathy. Because intracerebral VZV vasculopathy and giant cell arteritis are strongly associated with productive VZV infection in cerebral and temporal arteries, respectively, we evaluated human aortas for VZV antigen and VZV DNA. Using 3 different anti-VZV antibodies, we identified VZV antigen in 11 of 11 aortas with pathologically verified granulomatous arteritis, in 1 of 1 cases of nongranulomatous arteritis, and in 5 of 18 control aortas (28%) obtained at autopsy. The presence of VZV antigen in granulomatous aortitis was highly significant (P = .0001) as compared to control aortas, in which VZV antigen was never associated with pathology, indicating subclinical reactivation. VZV DNA was found in most aortas containing VZV antigen. The frequent clinical, radiological, and pathological aortic involvement in patients with giant cell arteritis correlates with the significant detection of VZV in granulomatous aortitis.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.

Pathology Informatics Essentials for Residents: A Flexible Informatics Curriculum Linked to Accreditation Council for Graduate Medical Education Milestones (a secondary publication).

CONTEXT: Recognition of the importance of informatics to the practice of pathology has surged. Training residents in pathology informatics has been a daunting task for most residency programs in the United States because faculty often lacks experience and training resources. Nevertheless, developing resident competence in informatics is essential for the future of pathology as a specialty. OBJECTIVE: To develop and deliver a pathology informatics curriculum and instructional framework that guides pathology residency programs in training residents in critical pathology informatics knowledge and skills, and meets Accreditation Council for Graduate Medical Education Informatics Milestones. DESIGN: The College of American Pathologists, Association of Pathology Chairs, and Association for Pathology Informatics formed a partnership and expert work group to identify critical pathology informatics training outcomes and to create a highly adaptable curriculum and instructional approach, supported by a multiyear change management strategy. RESULTS: Pathology Informatics Essentials for Residents (PIER) is a rigorous approach for educating all pathology residents in important pathology informatics knowledge and skills. PIER includes an instructional resource guide and toolkit for incorporating informatics training into residency programs that vary in needs, size, settings, and resources. PIER is available at http://www.apcprods.org/PIER (accessed April 6, 2016). CONCLUSIONS: PIER is an important contribution to informatics training in pathology residency programs. PIER introduces pathology trainees to broadly useful informatics concepts and tools that are relevant to practice. PIER provides residency program directors with a means to implement a standardized informatics training curriculum, to adapt the approach to local program needs, and to evaluate resident performance and progress over time.