PipeVal: light-weight extensible tool for file validation.

MOTIVATION: The volume of biomedical data generated each year is growing exponentially as high-throughput molecular, imaging and mHealth technologies expand. This rise in data volume has contributed to an increasing reliance on and demand for computational methods, and consequently to increased attention to software quality and data integrity. RESULTS: To simplify data verification in diverse data-processing pipelines, we created PipeVal, a light-weight, easy-to-use, extensible tool for file validation. It is open-source, easy to integrate with complex workflows, and modularized for extensibility for new file formats. PipeVal can be rapidly inserted into existing methods and pipelines to automatically validate and verify inputs and outputs. This can reduce wasted compute time attributed to file corruption or invalid file paths, and significantly improve the quality of data-intensive software. AVAILABILITY AND IMPLEMENTATION: PipeVal is an open-source Python package under the GPLv2 license and it is freely available at https://github.com/uclahs-cds/package-PipeVal. The docker image is available at: https://github.com/uclahs-cds/package-PipeVal/pkgs/container/pipeval.

Lactate- and immunomagnetic-purified hiPSC-derived cardiomyocytes generate comparable engineered cardiac tissue constructs.

Three-dimensional engineered cardiac tissue (ECT) using purified human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has emerged as an appealing model system for the study of human cardiac biology and disease. A recent study reported widely used metabolic (lactate) purification of monolayer hiPSC-CM cultures results in an ischemic cardiomyopathy-like phenotype compared with magnetic antibody-based cell sorting (MACS) purification, complicating the interpretation of studies using lactate-purified hiPSC-CMs. Herein, our objective was to determine if use of lactate relative to MACS-purified hiPSC-CMs affects the properties of resulting hiPSC-ECTs. Therefore, hiPSC-CMs were differentiated and purified using either lactate-based media or MACS. Global proteomics revealed that lactate-purified hiPSC-CMs displayed a differential phenotype over MACS hiPSC-CMs. hiPSC-CMs were then integrated into 3D hiPSC-ECTs and cultured for 4 weeks. Structurally, there was no significant difference in sarcomere length between lactate and MACS hiPSC-ECTs. Assessment of isometric twitch force and Ca2+ transient measurements revealed similar functional performance between purification methods. High-resolution mass spectrometry-based quantitative proteomics showed no significant difference in protein pathway expression or myofilament proteoforms. Taken together, this study demonstrates that lactate- and MACS-purified hiPSC-CMs generate ECTs with comparable structural, functional, and proteomic features, and it suggests that lactate purification does not result in an irreversible change in a hiPSC-CM phenotype.

Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.

BACKGROUND: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. METHODS: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. RESULTS: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. CONCLUSIONS: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.

Racial disparity in tumor microenvironment and distant recurrence in residual breast cancer after neoadjuvant chemotherapy.

Black, compared to white, women with residual estrogen receptor-positive (ER+) breast cancer after neoadjuvant chemotherapy (NAC) have worse distant recurrence-free survival (DRFS). Such racial disparity may be due to difference in density of portals for systemic cancer cell dissemination, called TMEM doorways, and pro-metastatic tumor microenvironment (TME). Here, we evaluate residual cancer specimens after NAC from 96 Black and 87 white women. TMEM doorways are visualized by triple immunohistochemistry, and cancer stem cells by immunofluorescence for SOX9. The correlation between TMEM doorway score and pro-metastatic TME parameters with DRFS is examined using log-rank and multivariate Cox regression. Black, compared to white, patients are more likely to develop distant recurrence (49% vs 34.5%, p = 0.07), receive mastectomy (69.8% vs 54%, p = 0.04), and have higher grade tumors (p = 0.002). Tumors from Black patients have higher TMEM doorway and macrophages density overall (p = 0.002; p = 0.002, respectively) and in the ER+/HER2- (p = 0.02; p = 0.02, respectively), but not in the triple negative disease. Furthermore, high TMEM doorway score is associated with worse DRFS. TMEM doorway score is an independent prognostic factor in the entire study population (HR, 2.02; 95%CI, 1.18-3.46; p = 0.01), with a strong trend in ER+/HER2- disease (HR, 2.38; 95%CI, 0.96-5.95; p = 0.06). SOX9 expression is not associated with racial disparity in TME or outcome. In conclusion, higher TMEM doorway density in residual breast cancer after NAC is associated with higher distant recurrence risk, and Black patients are associated with higher TMEM doorway density, suggesting that TMEM doorway density may contribute to racial disparities in breast cancer.

Lactate and Immunomagnetic-purified iPSC-derived Cardiomyocytes Generate Comparable Engineered Cardiac Tissue Constructs.

Three-dimensional engineered cardiac tissue (ECT) using purified human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has emerged as an appealing model system for the study of human cardiac biology and disease. A recent study reported widely-used metabolic (lactate) purification of monolayer hiPSC-CM cultures results in an ischemic cardiomyopathy-like phenotype compared to magnetic antibody-based cell sorting (MACS) purification, complicating the interpretation of studies using lactate-purified hiPSC-CMs. Herein, our objective was to determine if use of lactate relative to MACs-purified hiPSC-CMs impacts the properties of resulting hiPSC-ECTs. Therefore, hiPSC-CMs were differentiated and purified using either lactate-based media or MACS. After purification, hiPSC-CMs were combined with hiPSC-cardiac fibroblasts to create 3D hiPSC-ECT constructs maintained in culture for four weeks. There were no structural differences observed, and there was no significant difference in sarcomere length between lactate and MACS hiPSC-ECTs. Assessment of isometric twitch force, Ca 2+ transients, and ß-adrenergic response revealed similar functional performance between purification methods. High-resolution mass spectrometry (MS)-based quantitative proteomics showed no significant difference in any protein pathway expression or myofilament proteoforms. Taken together, this study demonstrates lactate- and MACS-purified hiPSC-CMs generate ECTs with comparable molecular and functional properties, and suggests lactate purification does not result in an irreversible change in hiPSC-CM phenotype.

Addressing the Operational Challenges for Outpatient Stroke Rehabilitation.

ABSTRACT: The traditional model of rehabilitation services includes clear requirements for provision of services in the acute inpatient rehabilitation setting. However, there are fewer guidelines on the frequency and duration of rehabilitation services beyond the acute setting. Recent research has suggested that neurorehabilitation interventions that are provided frequently enough upon discharge from acute inpatient rehabilitation to facilitate repeated practice and feedback improve long-term stroke outcomes. However, it is challenging to provide high-frequency outpatient rehabilitation, as the logistics of scheduling and insurance limitations often do not allow it. The Sheikh Khalifa Stroke Institute at Johns Hopkins Medicine innovated a new model to provide the appropriate frequency of therapy for stroke rehabilitation in the outpatient setting. This article describes the restructured operational infrastructure for outpatient stroke rehabilitation to facilitate high-frequency transdisciplinary stroke rehabilitation in the real world, including the development of the outpatient postacute therapy programs and the identification of appropriate patients for each program, the development of scheduling matrices and treating teams to deliver the postacute therapy programs, the implementation of transdisciplinary neurorehabilitation, and the steps taken to empower patients to engage in rehabilitation at home and address barriers to accessing the programs. We assessed the effect of the operational restructuring on schedule utilization, no-show rates, and cancellation rates in the 3 mos before and after implementation of the program and show that it increased schedule utilization and reduced no-show rates and cancellation rates, suggesting that it may increase compliance with rehabilitation. It is possible to create the infrastructure needed to bridge the continuum of care for poststroke recovery and rehabilitation.

Pregnancy-Onset Ulcerative Colitis in a Pediatric Patient Presenting With Altered Mental Status and Severe Anemia.

Ulcerative colitis (UC) classically presents with abdominal pain, hematochezia, or diarrhea. However, it can present atypically in pediatric and pregnant patients, posing a diagnostic challenge. A healthy, 16-year-old primigravida presented at 18 weeks and six days of gestation with sudden-onset altered mental status and severe anemia. Hematochezia began about 12 hours after admission. She underwent extensive workup, leading to an endoscopic and histopathologic diagnosis of UC, and achieved prenatal remission with high-dose steroids and infliximab. Her pregnancy, however, was complicated by severe preeclampsia, and her child's post-delivery course was medically complex from an unrelated etiology. Pregnancy-onset inflammatory bowel disease (IBD) in the pediatric population is an uncommon but important consideration. Early diagnosis, treatment, and counseling are vital to achieve results comparable to those of patients without IBD.

Association Between Socioeconomic and Insurance Status and Delayed Diagnosis of Gastrointestinal Cancers.

INTRODUCTION: Association between socioeconomic status (SES) and stage at diagnosis in gastrointestinal (GI) cancers is poorly described. Relationship between low SES and stage at diagnosis as well as the mediating role of insurance status (IS) was examined. METHODS: The Surveillance, Epidemiology, and End Results database was queried for esophageal, gastric, liver, biliary, pancreatic, colon, and rectal cancers diagnosed in 2012-2016. Relationship between census-tract SES index quintiles and late diagnosis (distant disease at diagnosis) was examined. Uni and multivariable logistic regressions were performed. Mediation analyses were conducted to determine the degree to which IS (private/Medicare versus Medicaid/uninsured) mediates the relationship between SES and late diagnosis of cancer. RESULTS: Analysis included 236,713 adult patients from 18 Surveillance, Epidemiology, and End Results areas. In univariable analysis, lowest SES quintile was significantly associated with late diagnosis for all cancers except gastric and biliary cancers. In multivariable analysis controlling for age, gender, marital status and race, this association remained significant for liver (odds ratio (OR) 1.41 [95% confidence interval (CI) 1.25-1.58]), pancreatic (OR 1.13 [95% CI 1.06-1.21]), and rectal (OR 1.31 [95% CI 1.20-1.42]) cancers. Further controlling for IS showed the largest effect size reduction for rectal cancer (OR 1.18 [95% CI 1.09-1.29]), with IS mediating 36.5% (P < 0.0001) of SES effect. CONCLUSIONS: Low SES is an independent risk factor for late diagnosis in liver, pancreas, and rectal cancers. Insurance is not a critical mediator of difference by SES for most GI cancers, with the exception of rectal cancer. Further research is needed to understand factors beyond IS that can account for SES differences in late diagnosis for GI cancers. Insurance related differences for rectal cancer deserves further attention.

Cardiac differentiation of human pluripotent stem cells using defined extracellular matrix proteins reveals essential role of fibronectin.

Research and therapeutic applications using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) require robust differentiation strategies. Efforts to improve hPSC-CM differentiation have largely overlooked the role of extracellular matrix (ECM). The present study investigates the ability of defined ECM proteins to promote hPSC cardiac differentiation. Fibronectin (FN), laminin-111, and laminin-521 enabled hPSCs to attach and expand. However, only addition of FN promoted cardiac differentiation in response to growth factors Activin A, BMP4, and bFGF in contrast to the inhibition produced by laminin-111 or laminin-521. hPSCs in culture produced endogenous FN which accumulated in the ECM to a critical level necessary for effective cardiac differentiation. Inducible shRNA knockdown of FN prevented Brachyury+ mesoderm formation and subsequent hPSC-CM generation. Antibodies blocking FN binding integrins α4ß1 or αVß1, but not α5ß1, inhibited cardiac differentiation. Furthermore, inhibition of integrin-linked kinase led to a decrease in phosphorylated AKT, which was associated with increased apoptosis and inhibition of cardiac differentiation. These results provide new insights into defined matrices for culture of hPSCs that enable production of FN-enriched ECM which is essential for mesoderm formation and efficient cardiac differentiation.

Racial disparity in distant recurrence-free survival in patients with localized breast cancer: A pooled analysis of National Surgical Adjuvant Breast and Bowel Project trials.

BACKGROUND: Black race is associated with worse outcome in patients with breast cancer. The distant relapse-free survival (DRFS) between Black and White women with localized breast cancer who participated in National Cancer Institute-sponsored clinical trial was evaluated. METHODS: Pooled data were analyzed from 8 National Surgical Adjuvant Breast and Bowel Project (NSABP) trials including 9702 women with localized breast cancer treated with adjuvant chemotherapy (AC, n = 7485) or neoadjuvant chemotherapy (NAC, n = 2217), who self-reported as Black (n = 1070) or White (n = 8632) race. The association between race and DRFS was analyzed using log-rank tests and multivariate Cox regression. RESULTS: After adjustment for covariates including age, tumor size, nodal status, body mass index and taxane use, and treatment (AC vs NAC), Black race was associated with an inferior DRFS in estrogen receptor-positive (ER+; hazard ratio [HR], 1.24; 95% CI, 1.05-1.46; P = .01), but not in ER- disease (HR, 0.97; 95% CI, 0.83-1.14; P = .73), and significant interaction between race and ER status was observed (P = .03). There was no racial disparity in DRFS among patients with pathologic complete response (pCR) (log-rank P = .8). For patients without pCR, Black race was associated with worse DRFS in ER+ (HR, 1.67; 95% CI, 1.14-2.45; P = .01), but not in ER- disease (HR, 0.91; 95% CI, 0.65-1.28; P = .59). CONCLUSIONS: Black race was associated with significantly inferior DRFS in ER+ localized breast cancer treated with AC or NAC, but not in ER- disease. In the NAC group, racial disparity was also observed in patients with residual ER+ breast cancer at surgery, but not in those who had pCR. LAY SUMMARY: Black women with breast cancer have worse outcomes compared with White women. We investigated if this held true in the context of clinical trials that provide controlled treatment setting. Black women with cancer expressing estrogen receptors (ERs) had worse outcome than White women. If breast cancers did not express ERs, there was no racial disparity in outcome. We also observed racial disparity in women who received chemotherapy before their cancer was removed, but only if they had cancer expressing ERs and residual disease on completion of treatment. If the cancer disappeared with presurgical chemotherapy, there was no racial disparity.

Acute kidney injury and kidney recovery after cardiopulmonary bypass in children.

BACKGROUND: Acute kidney injury (AKI) that improves in the pediatric intensive care unit (PICU) is associated with better outcomes compared to AKI that persists, but no study has investigated whether this also occurs in children undergoing cardiopulmonary bypass (CPB). METHODS: A retrospective study of children ≤18 years who underwent CPB in three children's hospitals was conducted. Patients were classified into groups by kidney recovery after AKI according to Acute Disease Quality Initiative (ADQI) guidelines. Adjusted regression models evaluated associations between kidney recovery group and hospital outcomes. RESULTS: Among 3620 children, AKI developed in 701 (19.4%): 610 transient AKI, 47 persistent AKI, and 44 acute kidney disease (AKD). Mortality increased with severity of kidney recovery group: 4.5% in the never developed AKI group, 8.9% in the transient AKI group, 25.5% in the persistent AKI group, and 31.8% in the AKD group (p <0.0001). In adjusted analysis, transient AKI (HR 1.4, CI 1.02, 2), persistent AKI (HR 22.4, CI 10.2, 49.2), and AKD (HR 3.7, CI 1.7, 7.9) had a greater hazard of mortality when compared to the never developed AKI group. Patients with transient AKI had a longer length of PICU stay than those with never developed AKI (HR 5.1, CI 2.9, 7.3). CONCLUSIONS: Patterns of kidney recovery after AKI were associated with worse PICU outcomes in children after CPB compared to those who did not develop AKI, even after rapid AKI recovery. Identification of factors that increase risk for these AKI patterns is necessary for prevention of AKI during CPB in children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination.

Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites.

Reduction in Foreign Body Response and Improved Antimicrobial Efficacy via Silicone-Oil-Infused Nitric-Oxide-Releasing Medical-Grade Cannulas.

Foreign body response and infection are two universal complications that occur with indwelling medical devices. In response, researchers have developed different antimicrobial and antifouling surface strategies to minimize bacterial colonization and fibrous encapsulation. In this study, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and silicone oil were impregnated into silicone rubber cannulas (SR-SNAP-Si) using a solvent swelling method to improve the antimicrobial properties and decrease the foreign body response. The fabricated SR-SNAP-Si cannulas demonstrated a stable, prolonged NO release, exhibited minimal SNAP leaching, and maintained sliding angles < 15° for 21 days. SR-SNAP-Si cannulas displayed enhanced antimicrobial efficacy against Staphylococcus aureus in a 7-day biofilm bioreactor study, reducing the viability of adhered bacteria by 99.2 ± 0.2% compared to unmodified cannulas while remaining noncytotoxic toward human fibroblast cells. Finally, SR-SNAP-Si cannulas were evaluated for the first time in a 14- and 21-day subcutaneous mouse model, showing significantly enhanced biocompatibility compared to control cannulas by reducing the thickness of fibrous encapsulation by 60.9 ± 6.1 and a 60.8 ± 10.5% reduction in cell density around the implant site after 3 weeks. Thus, this work demonstrates that antifouling, NO-releasing surfaces can improve the lifetime and safety of indwelling medical devices.

The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy.

Although cancer immunotherapy has resulted in unpreceded survival benefits to subsets of oncology patients, accumulating evidence from preclinical animal models suggests that the immunosuppressive tumor microenvironment remains a detrimental factor limiting benefit for many patient subgroups. Recent efforts on lymphocyte-mediated immunotherapies are primarily focused on eliminating cancer foci at primary and metastatic sites, but few studies have investigated the impact of these therapies on the highly complex process of cancer cell dissemination. The metastatic cascade involves the directional streaming of invasive/migratory tumor cells toward specialized blood vessel intravasation gateways, called TMEM doorways, to the peripheral circulation. Importantly, this process occurs under the auspices of a specialized tumor microenvironment, herewith referred to as "Dissemination Trajectory", which is supported by an ample array of tumor-associated macrophages (TAMs), skewed towards an M2-like polarization spectrum, and which is also vital for providing microenvironmental cues for cancer cell invasion, migration and stemness. Based on pre-existing evidence from preclinical animal models, this article outlines the hypothesis that dissemination trajectories do not only support the metastatic cascade, but also embody immunosuppressive niches, capable of providing transient and localized immunosubversion cues to the migratory/invasive cancer cell subpopulation while in the act of departing from a primary tumor. So long as these dissemination trajectories function as "immune deserts", the migratory tumor cell subpopulation remains efficient in evading immunological destruction and seeding metastatic sites, despite administration of cancer immunotherapy and/or other cytotoxic treatments. A deeper understanding of the molecular and cellular composition, as well as the signaling circuitries governing the function of these dissemination trajectories will further our overall understanding on TAM-mediated immunosuppression and will be paramount for the development of new therapeutic strategies for the advancement of optimal cancer chemotherapies, immunotherapies, and targeted therapies.

Long QT Syndrome KCNH2 Variant Induces hERG1a/1b Subunit Imbalance in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

[Figure: see text].

Functionally Integrated Top-Down Proteomics for Standardized Assessment of Human Induced Pluripotent Stem Cell-Derived Engineered Cardiac Tissues.

Three-dimensional (3D) human induced pluripotent stem cell-derived engineered cardiac tissues (hiPSC-ECTs) have emerged as a promising alternative to two-dimensional hiPSC-cardiomyocyte monolayer systems because hiPSC-ECTs are a closer representation of endogenous cardiac tissues and more faithfully reflect the relevant cardiac pathophysiology. The ability to perform functional and molecular assessments using the same hiPSC-ECT construct would allow for more reliable correlation between observed functional performance and underlying molecular events, and thus is critically needed. Herein, for the first time, we have established an integrated method that permits sequential assessment of functional properties and top-down proteomics from the same single hiPSC-ECT construct. We quantitatively determined the differences in isometric twitch force and the sarcomeric proteoforms between two groups of hiPSC-ECTs that differed in the duration of time of 3D-ECT culture. Importantly, by using this integrated method we discovered a new and strong correlation between the measured contractile parameters and the phosphorylation levels of alpha-tropomyosin between the two groups of hiPSC-ECTs. The integration of functional assessments together with molecular characterization by top-down proteomics in the same hiPSC-ECT construct enables a holistic analysis of hiPSC-ECTs to accelerate their applications in disease modeling, cardiotoxicity, and drug discovery. Data are available via ProteomeXchange with identifier PXD022814.

Recommendations for Therapy following Nerve Transfer for Children with Acute Flaccid Myelitis.

AIM: To provide recommendations for pre- and post-operative occupational and physical therapy for children with acute flaccid myelitis (AFM). METHODS: Writing panel members consisted of an interdisciplinary team of seven healthcare professionals specializing in the care of children with AFM. The panel reviewed background material on AFM, nerve transfer, and rehabilitation principles applied to pediatrics. Recommendations were prioritized if evidence was available. Where there was no known evidence to support a recommendation, this was noted. RECOMMENDATIONS: Communication and coordination among interprofessional team members are vital to a comprehensive family-centered rehabilitation program. Surgical planning should include team preparation accounting for frequency, duration, and timing of treatment, as well as individual characteristics and developmental status of the child. Recommendations for pre-operative and six phases of post-operative therapy address assessment, strengthening, range of motion, orthoses, performance of functional activity, and support of the family. CONCLUSION: Rehabilitation following nerve transfer in children with AFM requires interdisciplinary collaboration and a multisystem approach to assessment and treatment. As new evidence becomes available, recommendations may be revised or replaced accordingly.

Characteristics of Upper Extremity Recovery in Acute Flaccid Myelitis: A Case Series.

BACKGROUND: Clinical characteristics and timing associated with nonsurgical recovery of upper extremity function in acute flaccid myelitis are unknown. METHODS: A single-institution retrospective case series was analyzed to describe clinical features of acute flaccid myelitis diagnosed between October of 2013 and December of 2016. Patients were consecutively sampled children with a diagnosis of acute flaccid myelitis who were referred to a hand surgeon. Patient factors and initial severity of paralysis were compared with upper extremity muscle strength outcomes using the Medical Research Council scale every 3 months up to 18 months after onset. RESULTS: Twenty-two patients with acute flaccid myelitis (aged 2 to 16 years) were studied. Proximal upper extremity musculature was more frequently and severely affected, with 56 percent of patients affected bilaterally. Functional recovery of all muscle groups (≥M3) in an individual limb was observed in 43 percent of upper extremities within 3 months. Additional complete limb recovery to greater than or equal to M3 after 3 months was rarely observed. Extraplexal paralysis, including spinal accessory (72 percent), glossopharyngeal/hypoglossal (28 percent), lower extremity (28 percent), facial (22 percent), and phrenic nerves (17 percent), was correlated with greater severity of upper extremity paralysis and decreased spontaneous recovery. There was no correlation between severity of paralysis or recovery and patient characteristics, including age, sex, comorbidities, prodromal symptoms, or time to paralysis. CONCLUSIONS: Spontaneous functional limb recovery, if present, occurred early, within 3 months of the onset of paralysis. The authors recommend that patients without signs of early recovery warrant consideration for early surgical intervention and referral to a hand surgeon or other specialist in peripheral nerve injury. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

The Contribution of Race to Breast Tumor Microenvironment Composition and Disease Progression.

Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer. Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients. This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles. There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well. Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME. Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (e.g., M2 macrophages, regulatory T cells) and microvasculature. Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM). Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME. Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry. Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality.

A Health System Response to COVID-19 in Long-Term Care and Post-Acute Care: A Three-Phase Approach.

BACKGROUND: The Seattle, WA, area was ground zero for coronavirus disease 2019 (COVID-19). Its initial emergence in a skilled nursing facility (SNF) not only highlighted the vulnerability of its patients and residents, but also the limited clinical support that led to national headlines. Furthermore, the coronavirus pandemic heightened the need for improved collaboration among healthcare organizations and local and state public health. METHODS: The University of Washington Medicine's (UWM's) Post-Acute Care (PAC) Network developed and implemented a three-phase approach within its pre-existing network of SNFs to help slow the spread of the disease, support local area SNFs from becoming overwhelmed when inundated with COVID-19 cases or persons under investigation, and help decrease the burden on area hospitals, clinics, and emergency medical services. RESULTS: Support of local area SNFs consisted of the following phases that were implemented at various times as COVID-19 impacted each facility at different times. Initial Phase: This phase was designed to (1) optimize communication, (2) review infection control practices, and (3) create a centralized process to track and test the target population. Delayed Phase: The goals of the Delayed Phase were to slow the spread of the disease once it is present in the SNF by providing consistent education and reinforcing infection prevention and control practices to all staff. Surge Phase: This phase aimed to prepare facilities in response to an outbreak by deploying a "Drop Team" within 24 hours to the facility to expeditiously test patients and exposed employees, triage symptomatic patients, and coordinate care and supplies with local public health authorities. CONCLUSIONS: The COVID-19 Three-Phase Response Plan provides a standardized model of care that may be implemented by other health systems and SNFs to help prepare and respond to COVID-19. J Am Geriatr Soc 68:1155-1161, 2020.