Silicone Embolism Syndrome Causing Altered Mental Status and Respiratory Failure After an Unlicensed Gluteal Silicone Injection: A Case Report.

Introduction: Unlicensed cosmetic procedures, which come at increased risk of infection and potential surgical complications, have introduced new challenges in healthcare. Physicians should be aware of presentations that may arise secondary to these procedures. Case Report: We describe a case in which a previously healthy, 28-year-old female presented with new-onset seizures and acute respiratory distress syndrome (ARDS) in the setting of a recent cosmetic procedure with silicone injections to the gluteal region. The patient's hospital course was complicated by altered mental status, respiratory failure, rapid hemodynamic compromise, and eventual death. Conclusion: In rare cases, one possible complication of cosmetic procedures is silicone embolism syndrome, which is characterized by pneumonitis, alveolar hemorrhage, and ARDS. The patient described in this report also experienced neurologic symptoms including seizure and altered mental status. This is a clinical diagnosis that relies upon thorough history-taking and detailed physical exam. Documentation on this phenomenon is limited, and medical management has not yet been standardized for this condition. Morbidity and mortality remain high.

Using machine-learning to decode postoperative hip mortality Trends: Actionable insights from an extensive clinical dataset.

BACKGROUND: Hip fractures are one of the most common injuries experienced by the general population. Despite advances in surgical techniques, postoperative mortality rates remain high. identifying relevant clinical factors associated with mortality is essential to preoperative risk stratification and tailored post-surgical interventions to improve patient outcomes. The purpose of this study aimed to identify preoperative risk factors and develop predictive models for increased hip fracture-related mortality within 30 days post-surgery, using one of the largest patient cohorts to date. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program database, comprising 107,660 hip fracture patients treated with surgical fixation was used. A penalized regression approach, least absolute shrinkage and selection operator was employed to develop two predictive models: one using preoperative factors and the second incorporating both preoperative and postoperative factors. RESULTS: The analysis identified 68 preoperative factor outcomes associated with 30-day mortality. The combined model revealed 84 relevant factors, showing strong predictive power for determining postoperative mortality, with an AUC of 0.83. CONCLUSIONS: The study's comprehensive methodology provides risk assessment tools for clinicians to identify high-risk patients and optimize patient-specific care.

Tafazzin mediates tamoxifen resistance by regulating cellular phospholipid composition in ER-positive breast cancer.

Tamoxifen is the frontline therapeutic agent for the estrogen receptor-positive (ER + ) subtype of breast cancer patients, which accounts for 70-80% of total breast cancer incidents. However, clinical resistance to tamoxifen has become increasingly common, highlighting the need to identify the underlying cellular mechanisms. In our study, we employed a genome-scale CRISPR-Cas9 loss-of-function screen and validation experiments to discover that Tafazzin (TAZ), a mitochondrial transacylase, is crucial for maintaining the cellular sensitivity of ER+ breast cancer cells to tamoxifen and other chemotherapies. Mechanistically, we found that cardiolipin, whose synthesis and maturation rely on TAZ, is required to maintain cellular sensitivity to tamoxifen. Loss of metabolic enzymatic activity of TAZ causes ERα downregulation and therapy resistance. Interestingly, we observed that TAZ deficiency also led to the upregulation of lysophosphatidylcholine (LPC), which in turn suppressed ERα expression and nuclear localization, thereby contributing to tamoxifen resistance. LPC is further metabolized to lysophosphatidic acid (LPA), a bioactive molecule that supports cell survival. Thus, our findings suggest that the depletion of TAZ promotes tamoxifen resistance through an LPC-LPA phospholipid synthesis axis, and targeting this lipid metabolic pathway could restore cell susceptibility to tamoxifen treatment.

Does Acupuncture Hurt? A Retrospective Study on Pain and Satisfaction during Pediatric Acupuncture.

Previous studies have shown the benefit and safety of pediatric acupuncture, but it is often rejected by patients and their caregivers due to the perception of needling pain associated with acupuncture. A retrospective cohort study of 230 unique patients (1380 sessions) aged 8 to 21 underwent Kiiko Matsumoto Style acupuncture in an outpatient pain clinic. Patients completed a post-acupuncture survey, including the Faces Pain Scale-Revised and Likert-like scales about overall satisfaction, relaxation, and anxiolysis. Univariate analyses were conducted on all outcomes of interest. The mean needling pain score was 1.3 out of 10 with 57.7% of patients reporting no needling pain during their first acupuncture session. The mean score for overall satisfaction was 8.4 out of 10, relaxation was 8.2 out of 10, and anxiety reduction was 7.7 out of 10. The overall satisfaction, relaxation, and anxiolytic effect of acupuncture was increased in patients with more sessions (p = 0.003, 0.022, 0.004, respectively). There was no change in needling pain scores in patients with an increased number of acupuncture sessions (p = 0.776). Patients experience minimal needling pain during acupuncture needling and are highly satisfied with acupuncture. Those with more treatment sessions report feeling increased satisfaction and relaxation.

Mapping Lesion-Related Epilepsy to a Human Brain Network.

Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P < .001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P < .001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P < .001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies.

A transdiagnostic network for psychiatric illness derived from atrophy and lesions.

Psychiatric disorders share neurobiology and frequently co-occur. This neurobiological and clinical overlap highlights opportunities for transdiagnostic treatments. In this study, we used coordinate and lesion network mapping to test for a shared brain network across psychiatric disorders. In our meta-analysis of 193 studies, atrophy coordinates across six psychiatric disorders mapped to a common brain network defined by positive connectivity to anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortex. This network was robust to leave-one-diagnosis-out cross-validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). In 194 patients with penetrating head trauma, lesion damage to this network correlated with the number of post-lesion psychiatric diagnoses. Neurosurgical ablation targets for psychiatric illness (four targets) also aligned with the network. This convergent brain network for psychiatric illness may partially explain high rates of psychiatric comorbidity and could highlight neuromodulation targets for patients with more than one psychiatric disorder.

A comparison of the chest radiographic and computed tomographic features of subclinical pulmonary tuberculosis.

Subclinical pulmonary tuberculosis (PTB) is a recently described intermediate state of great interest, but about which little is known. This study sought to describe and compare the frequency of key radiologic features of subclinical PTB on chest radiograph (CXR) versus computed tomographic scan (CT), and to interpret the clinical and public health relevance of the differences. Diagnostic CXRs and CT scans of the thorax and neck in a 16-year cohort of subclinical PTB patients in Canada were re-acquired and read by two independent readers and arbitrated by a third reader. Logistic regression models were fit to determine how likely CXR features can be detected by CT scan versus CXR after adjustment for age and sex. Among 296 subclinical patients, CXRs were available in 286 (96.6%) and CT scans in 94 (32.9%). CXR features in patients with and without CT scans were comparable. Lung cavitation was 4.77 times (95% CI 1.95-11.66), endobronchial spread 19.36 times (95% CI 8.05-46.52), and moderate/far-advanced parenchymal disease 3.23 times (95% CI 1.66-6.30), more common on CT scan than CXR. We conclude that the extent to which CXRs under-detect key radiologic features in subclinical PTB is substantial. This may have public health and treatment implications.

The Radiographic and Mycobacteriologic Correlates of Subclinical Pulmonary TB in Canada: A Retrospective Cohort Study.

BACKGROUND: Very little is known about subclinical pulmonary TB (PTB), a recently described intermediate state, in high-income countries. RESEARCH QUESTION: What is the prevalence of subclinical PTB in Canada? What are its diagnostic chest radiography features? What is the relationship between those features and time to culture positivity, and what is the association between DNA fingerprint clustering, a measure of local transmission, and radiographic or other features in the foreign-born? STUDY DESIGN AND METHODS: We used primary source data to identify a 16-year retrospective cohort of patients with PTB. Demographic and mycobacteriologic features in patients with subclinical and clinical disease were compared, and the reason for assessment of patients with subclinical disease was described. Diagnostic chest radiographs in patients with subclinical disease were read by two independent readers and were arbitrated by a third reader. Linear regression was used to compute time to culture positivity (in days) in relationship to the change in chest radiograph findings from normal or minimally abnormal to moderately or far advanced, adjusted for age and sex and stratified by reason for assessment. Multivariate logistic regression was used in foreign-born patients with subclinical disease to determine associations between DNA fingerprint clustering of Mycobacterium TB isolates and age, sex, chest radiograph features, and time since arrival. RESULTS: We identified 1,656 patients with PTB, 347 of whom (21%) were subclinical. Compared with patients with clinical disease, patients with subclinical disease were more likely to be foreign-born (90.2% vs 79.6%) and to demonstrate negative smear results (88.2% vs 43.5%). The median time to culture-positivity was 18 days (interquartile range [IQR], 14-25 days) vs 12 days (IQR, 7-17 days). Most patients with PTB (75.2%) were identified during active case finding. Parenchymal disease was absent or minimal on chest radiography in 86.4% of patients. More advanced disease on chest radiography was associated with shorter times to culture positivity in nonstratified (by 3.3 days) and stratified (by 4.5-5.8 days) analysis (active case-finding groups). DNA fingerprint clustering was associated with male sex and a longer time between arrival and diagnosis. INTERPRETATION: Subclinical patients with PTB constitute a substantial and heterogeneous minority of patients with PTB in high-income countries. DNA fingerprint clustering is consistent with some, albeit limited, local transmission.

Network Localization of Unconscious Visual Perception in Blindsight.

OBJECTIVE: Blindsight is a disorder where brain injury causes loss of conscious but not unconscious visual perception. Prior studies have produced conflicting results regarding the neuroanatomical pathways involved in this unconscious perception. METHODS: We performed a systematic literature search to identify lesion locations causing visual field loss in patients with blindsight (n = 34) and patients without blindsight (n = 35). Resting state functional connectivity between each lesion location and all other brain voxels was computed using a large connectome database (n = 1,000). Connections significantly associated with blindsight (vs no blindsight) were identified. RESULTS: Functional connectivity between lesion locations and the ipsilesional medial pulvinar was significantly associated with blindsight (family wise error p = 0.029). No significant connectivity differences were found to other brain regions previously implicated in blindsight. This finding was independent of methods (eg, flipping lesions to the left or right) and stimulus type (moving vs static). INTERPRETATION: Connectivity to the ipsilesional medial pulvinar best differentiates lesion locations associated with blindsight versus those without blindsight. Our results align with recent data from animal models and provide insight into the neuroanatomical substrate of unconscious visual abilities in patients. ANN NEUROL 2022;91:217-224.

Radioactive Iodine-125 in Tumor Therapy: Advances and Future Directions.

Radioactive iodine-125 (I-125) is the most widely used radioactive sealed source for interstitial permanent brachytherapy (BT). BT has the exceptional ability to deliver extremely high doses that external beam radiotherapy (EBRT) could never achieve within treated lesions, with the added benefit that doses drop off rapidly outside the target lesion by minimizing the exposure of uninvolved surrounding normal tissue. Spurred by multiple biological and technological advances, BT application has experienced substantial alteration over the past few decades. The procedure of I-125 radioactive seed implantation evolved from ultrasound guidance to computed tomography guidance. Compellingly, the creative introduction of 3D-printed individual templates, BT treatment planning systems, and artificial intelligence navigator systems remarkably increased the accuracy of I-125 BT and individualized I-125 ablative radiotherapy. Of note, utilizing I-125 to treat carcinoma in hollow cavity organs was enabled by the utility of self-expandable metal stents (SEMSs). Initially, I-125 BT was only used in the treatment of rare tumors. However, an increasing number of clinical trials upheld the efficacy and safety of I-125 BT in almost all tumors. Therefore, this study aims to summarize the recent advances of I-125 BT in cancer therapy, which cover experimental research to clinical investigations, including the development of novel techniques. This review also raises unanswered questions that may prompt future clinical trials and experimental work.

Arterial spin labeling compared to dynamic susceptibility contrast MR perfusion imaging for assessment of ischemic penumbra: A systematic review.

BACKGROUND AND PURPOSE: Dynamic susceptibility contrast (DSC) MR imaging is commonly used to estimate penumbra size in acute ischemic stroke; this technique relies on the administration of gadolinium contrast, which has limited use in certain populations, such as those with impaired renal function or allergies. Arterial spin labeling (ASL) is a relatively new technique that can provide information on cerebral perfusion without need for exogenous contrast agents. This systematic review examines published studies that specifically compared ASL to DSC for assessment of ischemic penumbra. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library for papers which compared ASL with DSC for assessment of ischemic penumbra in acute ischemic stroke among adult human populations. Two independent reviewers screened studies using predefined inclusion and exclusion criteria. Study characteristics and findings regarding the utility of ASL compared to DSC for identification of penumbra were then extracted and anlyzed for results and risk of bias. RESULTS: Seventeen articles met inclusion and exclusion criteria. Studies compared ASL with DSC on a range of metrics (hypoperfusion, hyperperfusion, mismatch, and reperfusion). Most studies concluded that agreement of ASL with DSC was moderate to very high. A small subset of studies found discrepancy in agreement of ASL with DSC for size or location of perfusion abnormalities. A heterogeneity of perfusion parameters studied for DSC was noted, along with the need for more standardization of research methods. CONCLUSION: ASL shows moderate to high agreement with DSC for detection of penumbra among ischemic stroke patients.

Global digital social learning as a strategy to promote engagement in the era of COVID-19.

AIMS AND OBJECTIVES: To assess formative and summative milestones in a digital course and the reach to low- and middle-income countries of a Massive Open Online Course focussing on supporting nurses dealing with an emerging pandemic. BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has ravaged the globe and increased the need for timely and accurate information from reliable sources. Access to reliable and accurate information, as well as support, is important in achieving health systems strengthening. Using a Massive Open Online Course format, an educational resource aimed at large-scale interactive participation via the Internet, and participants were engaged in a course focussing on nursing in a time of crisis and involved using social learning principles. DESIGN: Observational descriptive study. METHOD: Routinely collected data were collated during the period of 18 May-18 July 2020 focused on both formative and summative milestones in the course. Data were separated and classified by income in accordance with the publicly accessible 2020 World Bank Open Dataset. RESULTS: During the 2-month period of observation (18 May-18 July 2020), 10,130 individuals from 156 countries enrolled in the course. More than 51% of participants were Active Learners. Thirty per cent completed over 90% of the course content by the end. There was widespread distribution of learners in low- and middle-income countries across Asia, Africa and Latin America. CONCLUSION: The COVID-19 pandemic has underscored the importance of reliable and valid information sources. The use of Massive Open Online Course format can facilitate dissemination. RELEVANCE TO CLINICAL PRACTICE: In the context of a dynamic global pandemic, leveraging digital resources to allow access to reliable information and resources is important. Incentivising participation through recognition of learning is important. Engaging in a social learning platform also has the power for reflection, promotion of resilience and capacity for health systems strengthening.

The Effect of FAmily-CEntered (FACE®) Pediatric Advanced Care Planning Intervention on Family Anxiety: A Randomized Controlled Clinical Trial for Adolescents With HIV and Their Families.

Clinicians fear pediatric advance care planning (pACP) for adolescents is too distressing for families. Multisite longitudinal randomized controlled trial of adolescents with HIV tested the effect of FAmily-CEntered (FACE®) pACP intervention on families' anxiety and depression. One hundred five adolescent/family dyads were randomized to FACE® (n = 54 dyads) or control (n = 51 dyads). Families were 90% African American, 37% HIV-positive, and 22% less than high school educated. Families reported lower anxiety 3 months post-FACE® intervention than control (ß = -4.71, 95% confidence interval [CI] = [-8.20, -1.23], p = .008). Male family members were less anxious than female family members (ß = -4.55, 95% CI = [-6.96, -2.138], p ≤ .001). Family members living with HIV reported greater depressive symptoms than HIV-uninfected families (ß = 3.32, 95% CI = [0.254, 6.38], p = .034). Clinicians can be assured this structured, facilitated FACE® pACP model minimized family anxiety without increasing depressive symptoms. Adolescent/family dyads should be invited to have access to, and provision of, evidence-based pACP as part of patient-centered/family-supported care in the HIV continuum of care.

COVID-19: the novel coronavirus disease and its manifestations and management in ophthalmology.

Coronavirus disease 2019 (COVID-19), a newly identified acute respiratory disease caused by a strain of novel coronavirus (SARS-CoV-2), has become a worldwide pandemic. From December 2019 to present, millions of cases have been reported, bringing unprecedented pressure on both health and epidemic prevention services in every country. As frontline healthcare workers, ophthalmologists face an increased threat of viral infection, not only because of close contact with patients during examinations or operations, but also due to evidence showing that ocular fluids such as tears or conjunctival secretions may carry the virus. The risk that healthcare workers face is emphasized by the loss of our colleagues who have sacrificed themselves in combating the virus. As a result, it is necessary to have a comprehensive understanding of the threats that we face. In the first part of this review, we start by explaining the structure of SARS-CoV-2 and examining its transmission and means of infection. Next, we summarize the latest scientific advancements of epidemiology, clinical presentations, and current treatments of COVID-19. In the second half of the review, we emphasize the ocular transmission, symptomatic manifestations, and the essential knowledge in an ophthalmology clinic setting. As the pandemic of COVID-19 continues to pose a threat to global health, we hope that this review makes a contribution to combating COVID-19.

A Retrospective Quality Analysis of External Ventricular Drain Infection Rates Following Stroke Diagnoses and Other Brain Injuries: Comparison of Emergency Room and ICU/OR Setting.

Objective The purpose of this study was to analyze the incidence of infections in patients following placement of External Ventricular Drain (EVD) in either the Emergency Room (ER) or the Intensive Care Unit (ICU)/ Operating Room (OR) at a single Comprehensive Stroke Center. Methods Retrospective analysis of post-procedure infection rates in 710 patients with EVDs placed on site between 2010 and 2018 was performed. We analyzed cases between sex, age, stroke and non-stroke related and further requirement of conversion of the EVD to a ventriculoperitoneal (VP) shunt. Results Significant decrease in EVD related infection (ERIs) rates following the shift in EVD placement from ER to ICU/OR (from 13% to 7.7%, p=.03) among all ages, sex and type of brain injury was observed. Furthermore, our data also shows that the rate of conversion of EVDs to VP shunts is independent of the setting where EVD was placed, but increases in patients who develop ERIs. 23.1% of stroke patients that developed an ERI required a conversion to VP shunt while 67.3% of non-stroke patients that developed an ERI required further VP shunt (p<.001) showing that non-stroke EVD patients with infections are more likely to require VP shunt. Conclusion This is one of the larger retrospective studies conducted on EVD related infections. ERIs were significantly higher when EVDs were placed in the ER. Moreover, our results highlight the relation between ERIs and further requirement of conversion EVD to VP shunt. These figures highlight the importance of focusing on infection rates, and the implications CSF infection has on the long-term care of patients.

Segmentation of Glomeruli Within Trichrome Images Using Deep Learning.

INTRODUCTION: The number of glomeruli and glomerulosclerosis evaluated on kidney biopsy slides constitute standard components of a renal pathology report. Prevailing methods for glomerular assessment remain manual, labor intensive, and nonstandardized. We developed a deep learning framework to accurately identify and segment glomeruli from digitized images of human kidney biopsies. METHODS: Trichrome-stained images (n = 275) from renal biopsies of 171 patients with chronic kidney disease treated at the Boston Medical Center from 2009 to 2012 were analyzed. A sliding window operation was defined to crop each original image to smaller images. Each cropped image was then evaluated by at least 3 experts into 3 categories: (i) no glomerulus, (ii) normal or partially sclerosed (NPS) glomerulus, and (iii) globally sclerosed (GS) glomerulus. This led to identification of 751 unique images representing nonglomerular regions, 611 images with NPS glomeruli, and 134 images with GS glomeruli. A convolutional neural network (CNN) was trained with cropped images as inputs and corresponding labels as output. Using this model, an image processing routine was developed to scan the test images to segment the GS glomeruli. RESULTS: The CNN model was able to accurately discriminate nonglomerular images from NPS and GS images (performance on test data: Accuracy: 92.67% ± 2.02% and Kappa: 0.8681 ± 0.0392). The segmentation model that was based on the CNN multilabel classifier accurately marked the GS glomeruli on the test data (Matthews correlation coefficient = 0.628). CONCLUSION: This work demonstrates the power of deep learning for assessing complex histologic structures from digitized human kidney biopsies.

Short-course or long-course radiation therapy as a part of a neoadjuvant regimen for stage II & III rectal adenocarcinoma?

The aim of this mini-review is to compare and contrast the pros and cons of short-course and long-course neoadjuvant chemoradiation therapy regimens for stage II & III rectal adenocarcinoma. Multiple trials have demonstrated the equal efficacy and safety of short-course and long-course radiation therapy as a part of neoadjuvant regimens. Published data also shows that total neoadjuvant therapy could be more successful than neoadjuvant chemoradiation followed by adjuvant chemotherapy. This review points out future research directions for patients with locally advanced rectal adenocarcinoma such as comparing total neoadjuvant therapy that contains a short-course of radiation therapy to the standard of care, and evaluating how the sequence of short-course radiation therapy and chemotherapy in the total neoadjuvant therapy impacts the pathological complete response (pCR) rate, local control, and survival outcomes.

Co-use of Electronic Nicotine Delivery Systems and Combustible Cigarettes, and Their Association with Internalizing Pathology and Vulnerabilities.

Nicotine use and psychological distress exert negative bidirectional effects on one another, and are impacted by shared vulnerabilities. Little work has examined the extent to which these relations differ between adult electronic nicotine delivery system (ENDs) users with varied combustible cigarette use histories. The current study examined differences in internalizing symptoms and vulnerabilities between adult dual and single ENDs users with and without a history of combustible cigarette use. Single ENDs users without combustible use histories reported significantly greater stress and anxiety symptoms than single ENDs users with combustible use histories. Single ENDs users without combustible use histories reported greater anxiety and difficulty regulating their emotions than dual-users. Dual-and single users with prior combustible use histories did not differ in internalizing pathology or vulnerability presentations. This suggests that pathology and vulnerability presentation among nicotine users are influenced by both current and past nicotine use history.

Single-Cell Transcriptomics Reveals Heterogeneity and Drug Response of Human Colorectal Cancer Organoids.

Organoids are three-dimensional cell cultures that mimic organ functions and structures. The organoid model has been developed as a versatile in vitro platform for stem cell biology and diseases modeling. Tumor organoids are shown to share ~ 90% of genetic mutations with biopsies from same patients. However, it's not clear whether tumor organoids recapitulate the cellular heterogeneity observed in patient tumors. Here, we used single-cell RNA-Seq to investigate the transcriptomics of tumor organoids derived from human colorectal tumors, and applied machine learning methods to unbiasedly cluster subtypes in tumor organoids. Computational analysis reveals cancer heterogeneity sustained in tumor organoids, and the subtypes in organoids displayed high diversity. Furthermore, we treated the tumor organoids with a first-line cancer drug, Oxaliplatin, and investigated drug response in single-cell scale. Diversity of tumor cell populations in organoids were significantly perturbed by drug treatment. Single-cell analysis detected the depletion of chemosensitive subgroups and emergence of new drug tolerant subgroups after drug treatment. Our study suggests that the organoid model is capable of recapitulating clinical heterogeneity and its evolution in response to chemotherapy.

Association of Pathological Fibrosis With Renal Survival Using Deep Neural Networks.

INTRODUCTION: Chronic kidney damage is routinely assessed semiquantitatively by scoring the amount of fibrosis and tubular atrophy in a renal biopsy sample. Although image digitization and morphometric techniques can better quantify the extent of histologic damage, we need more widely applicable ways to stratify kidney disease severity. METHODS: We leveraged a deep learning architecture to better associate patient-specific histologic images with clinical phenotypes (training classes) including chronic kidney disease (CKD) stage, serum creatinine, and nephrotic-range proteinuria at the time of biopsy, and 1-, 3-, and 5-year renal survival. Trichrome-stained images processed from renal biopsy samples were collected on 171 patients treated at the Boston Medical Center from 2009 to 2012. Six convolutional neural network (CNN) models were trained using these images as inputs and the training classes as outputs, respectively. For comparison, we also trained separate classifiers using the pathologist-estimated fibrosis score (PEFS) as input and the training classes as outputs, respectively. RESULTS: CNN models outperformed PEFS across the classification tasks. Specifically, the CNN model predicted the CKD stage more accurately than the PEFS model (κ = 0.519 vs. 0.051). For creatinine models, the area under curve (AUC) was 0.912 (CNN) versus 0.840 (PEFS). For proteinuria models, AUC was 0.867 (CNN) versus 0.702 (PEFS). AUC values for the CNN models for 1-, 3-, and 5-year renal survival were 0.878, 0.875, and 0.904, respectively, whereas the AUC values for PEFS model were 0.811, 0.800, and 0.786, respectively. CONCLUSION: The study demonstrates a proof of principle that deep learning can be applied to routine renal biopsy images.