A Rare Cause of Low Back Pain.

This is the case of a 60-year-old man with no known medical history who presented with progressively worsening lumbar pain and was found to have idiopathic dorsal epidural lipomatosis. The patient's condition improved significantly with pain management. Therefore, no surgical intervention was warranted at the time, but the patient was advised to keep close follow-up as an outpatient. Being familiar with this potential cause of lumbar pain is vital, as it can lead to severe morbidity if left unrecognized.

Anion-exchange membranes with internal microchannels for water control in CO2 electrolysis.

Electrochemical reduction of carbon dioxide (CO2R) poses substantial promise to convert abundant feedstocks (water and CO2) to value-added chemicals and fuels using solely renewable energy. However, recent membrane-electrode assembly (MEA) devices that have been demonstrated to achieve high rates of CO2R are limited by water management within the cell, due to both consumption of water by the CO2R reaction and electro-osmotic fluxes that transport water from the cathode to the anode. Additionally, crossover of potassium (K+) ions poses concern at high current densities where saturation and precipitation of the salt ions can degrade cell performance. Herein, a device architecture incorporating an anion-exchange membrane (AEM) with internal water channels to mitigate MEA dehydration is proposed and demonstrated. A macroscale, two-dimensional continuum model is used to assess water fluxes and local water content within the modified MEA, as well as to determine the optimal channel geometry and composition. The modified AEMs are then fabricated and tested experimentally, demonstrating that the internal channels can both reduce K+ cation crossover as well as improve AEM conductivity and therefore overall cell performance. This work demonstrates the promise of these materials, and operando water-management strategies in general, in handling some of the major hurdles in the development of MEA devices for CO2R.

Skin Biopsy in Pediatric Oncology/Hematopoietic Stem Cell Transplantation Patients.

ABSTRACT: The aim of this study was to review the dermatopathological findings in skin biopsy specimens from pediatric oncology and hematopoietic stem cell transplantation patients over a 20-year period. Three hundred fifty-two skin biopsies from 240 patients were reviewed, and the findings were grouped into 6 categories: index neoplasms, nonindex neoplasms, infections, graft-versus-host disease, other treatment complications, and others. Among the index neoplasms identified on skin biopsy, the most common conditions were Langerhans cell histiocytosis (14 patients) and melanoma (7 patients), with other hematological malignancies and an array of soft-tissue tumors accounting for the bulk of the remainder. Neoplastic conditions common in general dermatopathological practice such as basal cell carcinoma and squamous cell carcinoma were uncommon, each being identified in only 1 patient younger than the age of 18, although basal cell carcinomas developing subsequently in young adult life were identified in 7 patients. Infections were common, with infectious agents or viral cytopathic effects (not including human papillomavirus) identified in 34 biopsies. A significant proportion (74%) represented invasive fungal infections, which are of very significant clinical importance. Biopsies performed for a clinical suspicion of graft-versus-host seldom showed histological features to suggest an alternative diagnosis, with only a single case suggesting a diagnosis of toxic erythema of chemotherapy identified.

Continuum Modeling of Porous Electrodes for Electrochemical Synthesis.

Electrochemical synthesis possesses substantial promise to utilize renewable energy sources to power the conversion of abundant feedstocks to value-added commodity chemicals and fuels. Of the potential system architectures for these processes, only systems employing 3-D structured porous electrodes have the capacity to achieve the high rates of conversion necessary for industrial scale. However, the phenomena and environments in these systems are not well understood and are challenging to probe experimentally. Fortunately, continuum modeling is well-suited to rationalize the observed behavior in electrochemical synthesis, as well as to ultimately provide recommendations for guiding the design of next-generation devices and components. In this review, we begin by presenting an historical review of modeling of porous electrode systems, with the aim of showing how past knowledge of macroscale modeling can contribute to the rising challenge of electrochemical synthesis. We then present a detailed overview of the governing physics and assumptions required to simulate porous electrode systems for electrochemical synthesis. Leveraging the developed understanding of porous-electrode theory, we survey and discuss the present literature reports on simulating multiscale phenomena in porous electrodes in order to demonstrate their relevance to understanding and improving the performance of devices for electrochemical synthesis. Lastly, we provide our perspectives regarding future directions in the development of models that can most accurately describe and predict the performance of such devices and discuss the best potential applications of future models.

Engineering Catalyst-Electrolyte Microenvironments to Optimize the Activity and Selectivity for the Electrochemical Reduction of CO2 on Cu and Ag.

The electrochemical reduction of carbon dioxide (CO2R) driven by renewably generated electricity (e.g., solar and wind) offers a promising means for reusing the CO2 released during the production of cement, steel, and aluminum as well as the production of ammonia and methanol. If CO2 could be removed from the atmosphere at acceptable costs (i.e., <$100/t of CO2), then CO2R could be used to produce carbon-containing chemicals and fuels in a fully sustainable manner. Economic considerations dictate that CO2R current densities must be in the range of 0.1 to 1 A/cm2 and selectivity toward the targeted product must be high in order to minimize separation costs. Industrially relevant operating conditions can be achieved by using gas diffusion electrodes (GDEs) to maximize the transport of species to and from the cathode and combining such electrodes with a solid-electrolyte membrane by eliminating the ohmic losses associated with liquid electrolytes. Additionally, high product selectivity can be attained by careful tuning of the microenvironment near the catalyst surface (e.g., the pH, the concentrations of CO2 and H2O, and the identities of the cations in the double layer adjacent to the catalyst surface).We begin this Account with a discussion of our experimental and theoretical work aimed at optimizing catalyst microenvironments for CO2R. We first examine the effects of catalyst morphology on the production of multicarbon (C2+) products over Cu-based catalysts and then explore the role of mass transfer combined with the kinetics of buffer reactions in the local concentration of CO2 and pH at the catalyst surface. This is followed by a discussion of the dependence of the local CO2 concentration and pH on the dynamics of CO2R and the formation of specific products over both Cu and Ag catalysts. Next, we explore the impact of electrolyte cation identity on the rate of CO2R and the distribution of products. Subsequently, we look at utilizing pulsed electrolysis to tune the local pH and CO2 concentration at the catalyst surface. The last part of the discussion demonstrates that ionomer-coated catalysts in combination with pulsed electrolysis can enable the attainment of very high (>90%) selectivity to C2+ products over Cu in an aqueous electrolyte. This part of the Account is then extended to consider the difference in the catalyst-nanoparticle microenvironment, present in the catalyst layer of a membrane electrode assembly (MEA), with respect to that of a planar electrode immersed in an aqueous electrolyte.

Risk Factors for Readmissions After Total Joint Replacement: A Meta-Analysis.

¼: We performed a systematic review and meta-analysis of predictive modeling studies examining the risk of readmission after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in order to synthesize key risk factors and evaluate their pooled effects. Our analysis entailed 15 compliant studies for qualitative review and 17 compliant studies for quantitative meta-analysis. ¼: A qualitative review of 15 predictive modeling studies highlighted 5 key risk factors for risk of readmission after THA and/or TKA: age, length of stay, readmission reduction policy, use of peripheral nerve block, and type of joint replacement procedure. ¼: A meta-analysis of 17 studies unveiled 3 significant risk factors: discharge to a skilled nursing facility rather than to home (approximately 61% higher risk), surgery at a low- or medium-procedure-volume hospital (approximately 26% higher risk), and the presence of patient obesity (approximately 34% higher risk). We demonstrated clinically meaningful relationships between these factors and moderator variables of procedure type, source of data used for model-building, and the proportion of male patients in the cohort. ¼: We found that many studies did not adhere to gold-standard criteria for reporting and study construction based on the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) and NOS (Newcastle-Ottawa Scale) methodologies. ¼: We recommend that these risk factors be considered in clinical practice and future work alike as they relate to surgical, discharge, and care decision-making. Future work should also prioritize greater observance of gold-standard reporting criteria for predictive models.

Understanding Multi-Ion Transport Mechanisms in Bipolar Membranes.

Bipolar membranes (BPMs) have the potential to become critical components in electrochemical devices for a variety of electrolysis and electrosynthesis applications. Because they can operate under large pH gradients, BPMs enable favorable environments for electrocatalysis at the individual electrodes. Critical to the implementation of BPMs in these devices is understanding the kinetics of water dissociation that occurs within the BPM as well as the co- and counter-ion crossover through the BPM, which both present significant obstacles to developing efficient and stable BPM-electrolyzers. In this study, a continuum model of multi-ion transport in a BPM is developed and fit to experimental data. Specifically, concentration profiles are determined for all ionic species, and the importance of a water-dissociation catalyst is demonstrated. The model describes internal concentration polarization and co- and counter-ion crossover in BPMs, determining the mode of transport for ions within the BPM and revealing the significance of salt-ion crossover when operated with pH gradients relevant to electrolysis and electrosynthesis. Finally, a sensitivity analysis reveals that the performance and lifetime of BPMs can be improved substantially by using of thinner dissociation catalysts, managing water transport, modulating the thickness of the individual layers in the BPM to control salt-ion crossover, and increasing the ion-exchange capacity of the ion-exchange layers in order to amplify the water-dissociation kinetics at the interface.

Risk Factors for Readmission After Knee Arthroplasty Based on Predictive Models: A Systematic Review.

BACKGROUND: An increase in the aging yet active US population will continue to make total knee arthroplasty (TKA) procedures routine in the coming decades. For such joint procedures, the Centers for Medicare and Medicaid Services introduced programs such as the Comprehensive Care for Joint Replacement to emphasize accountable and efficient transitions of care. Accordingly, many studies have proposed models using risk factors for predicting readmissions after the procedure. We performed a systematic review of TKA literature to identify such models and risk factors therein using a reliable appraisal tool for their quality assessment. METHODS: Five databases were searched to identify studies that examined correlations between post-TKA readmission and risk factors using multivariate models. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis methodology and Transparent Reporting of a multivariate prediction model for Individual Prognosis Or Diagnosis criteria established for quality assessment of prognostic studies. RESULTS: Of 29 models in the final selection, 6 models reported performance using a C-statistic, ranging from 0.51 to 0.76, and 2 studies used a validation cohort for assessment. The average 30-day and 90-day readmission rates across the studies were 5.33% and 7.12%, respectively. Three new significant risk factors were discovered. CONCLUSIONS: Current models for TKA readmissions lack in performance measurement and reporting when assessed with established criteria. In addition to using new techniques for better performance, work is needed to build models that follow the systematic process of calibration, external validation, and reporting for pursuing their deployment in clinical settings.

Predictive models for identifying risk of readmission after index hospitalization for hip arthroplasty: A systematic review.

BACKGROUND: An aging United States population profoundly impacts healthcare from both a medical and financial standpoint, especially with an increase in related procedures such as Total Hip Arthroplasty (THA). The Hospital Readmission Reduction Program and Comprehensive Care for Joint Replacement Program incentivize hospitals to decrease post-operative readmissions by correlating reimbursements with smoother care transitions, thereby decreasing hospital burden and improving quantifiable patient outcomes. Many studies have proposed predictive models built upon risk factors for predicting 30-day THA readmissions. QUESTIONS: (1) Are there validated statistical models that predict 30-day readmissions for THA patients when appraised with a standards-based, reliable assessment tool?. (2) Which evidence-based factors are significant and have support across models for predicting risk of 30-day readmissions post-THA? METHODS: Five major electronic databases were searched to identify studies that examined correlations between post-THA readmission and risk factors using multivariate models. We rigorously applied the PRISMA methodology and TRIPOD criteria for assessment of the prognostic studies. RESULTS: We found 26 studies that offered predictive models, of which two presented models tested with validation cohorts. In addition to the many factors grouped into demographic, administrative, and clinical categories, bleeding disorder, higher ASA status, discharge disposition, and functional status appeared to have broad and significant support across the studies. CONCLUSIONS: Reporting of recent predictive models establishing risk factors for 30-day THA readmissions against the current standard could be improved. Aside from building better performing models, more work is needed to follow the thorough process of undergoing calibration, external validation, and integration with existing EHR systems for pursuing their use in clinical settings. There are several risk factors that are significant in multiple models; these factors should be closely examined clinically and leveraged in future risk modeling efforts.

Tortuosity-powered microfluidic device for assessment of thrombosis and antithrombotic therapy in whole blood.

Accurate assessment of blood thrombosis and antithrombotic therapy is essential for the management of patients in a variety of clinical conditions, including surgery and on extracorporeal life support. However, current monitoring devices do not measure the effects of hemodynamic forces that contribute significantly to coagulation, platelet function and fibrin formation. This limits the extent to which current assays can predict clotting status in patients. Here, we demonstrate that a biomimetic microfluidic device consisting stenosed and tortuous arteriolar vessels would analyze blood clotting under flow, while requiring a small blood volume. When the device is connected to an inline pressure sensor a clotting time analysis is applied, allowing for the accurate measurement of coagulation, platelets and fibrin content. Furthermore, this device detects a prolonged clotting time in clinical blood samples drawn from pediatric patients on extracorporeal membrane oxygenation receiving anticoagulant therapy. Thus, this tortuosity activated microfluidic device could lead to a more quantitative and rapid assessment of clotting disorders and their treatment.

Predicting Survival for Patients With Metastatic Disease.

PURPOSE: This prospective study aimed to determine the accuracy of radiation oncologists in predicting the survival of patients with metastatic disease receiving radiation therapy and to understand factors associated with their accuracy. METHODS AND MATERIALS: This single-institution study surveyed 22 attending radiation oncologists to estimate patient survival. Survival predictions were defined as accurate if the observed survival (OS) was within the correct survival prediction category (0-6 months, >6-12 months, >12-24 months, and >24 months). The physicians made survival estimates for each course of radiation, yielding 877 analyzable predictions for 689 unique patients. Data analysis included Stuart's Tau C, logistic regression models, ordinal logistic regression models, and stepwise selection to examine variable interactions. RESULTS: Of the 877 radiation oncologists' predictions, 39.7% were accurate, 26.5% were underestimations, and 33.9% were overestimations. Stuart's Tau C showed low correlation between OS and survival estimates (0.3499), consistent with the inaccuracy reported in the literature. However, results showed less systematic overprediction than reported in the literature. Karnofsky performance status was the most significant predictor of accuracy, with greater accuracy for patients with shorter OS. Estimates were also more accurate for patients with lower Karnofsky performance status. Accuracy by patient age varied by primary site and race. Physician years of experience did not correlate with accuracy. CONCLUSIONS: The sampled radiation oncologists have a 40% accuracy in predicting patient survival. Future investigation should explore how survival estimates influence treatment decisions and how to improve survival prediction accuracy.

Mechanochemical Coupling and Junctional Forces during Collective Cell Migration.

Cell migration, a fundamental physiological process in which cells sense and move through their surrounding physical environment, plays a critical role in development and tissue formation, as well as pathological processes, such as cancer metastasis and wound healing. During cell migration, dynamics are governed by the bidirectional interplay between cell-generated mechanical forces and the activity of Rho GTPases, a family of small GTP-binding proteins that regulate actin cytoskeleton assembly and cellular contractility. These interactions are inherently more complex during the collective migration of mechanically coupled cells because of the additional regulation of cell-cell junctional forces. In this study, we adapted a recent minimal modeling framework to simulate the interactions between mechanochemical signaling in individual cells and interactions with cell-cell junctional forces during collective cell migration. We find that migration of individual cells depends on the feedback between mechanical tension and Rho GTPase activity in a biphasic manner. During collective cell migration, waves of Rho GTPase activity mediate mechanical contraction/extension and thus synchronization throughout the tissue. Further, cell-cell junctional forces exhibit distinct spatial patterns during collective cell migration, with larger forces near the leading edge. Larger junctional force magnitudes are associated with faster collective cell migration and larger tissue size. Simulations of heterogeneous tissue migration exhibit a complex dependence on the properties of both leading and trailing cells. Computational predictions demonstrate that collective cell migration depends on both the emergent dynamics and interactions between cellular-level Rho GTPase activity and contractility and multicellular-level junctional forces.

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.

PURPOSE: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. METHODS: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. RESULTS: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05). CONCLUSION: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.

IMPORTANCE: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. OBJECTIVE: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. DESIGN, SETTING, AND PARTICIPANTS: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017. MAIN OUTCOMES AND MEASURES: The DFS and OS among patients with resected pancreatic adenocarcinoma. RESULTS: Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations. CONCLUSIONS AND RELEVANCE: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.

Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival.

BACKGROUND: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). METHODS: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. RESULTS: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both Pinteraction<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence. CONCLUSIONS: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.

Metastatic Cellular Blue Nevus: A Rare Case With Metastasis Beyond Regional Nodes.

In this study, we present a rare case of a 35-year-old man with a long-standing blue-black lesion on his left hand with subsequent infraclavicular and axillary lymph node tumor deposits. The hand lesion and lymph nodes were excised revealing histological, immunohistochemical, and molecular findings consistent with cellular blue nevus. Despite nonregional lymph node involvement, there has been no progression at 12-months follow-up. This is an index case of a cellular blue nevus with metastasis to both regional and nonregional lymph nodes. The lack of atypical/malignant features in this lesion makes the metastatic behavior extraordinary, and hence the prognosis of lesions of this type is indeterminate.