Increased mTOR activation in idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904).

A Systematic Review and Meta-analysis of Depression, Anxiety, and Sleep Disorders in US Adults with Food Insecurity.

INTRODUCTION: A large number of peer-reviewed studies, with various methodologies and populations, have addressed the effects of food insecurity (FIS) on mental health conditions such as depression, anxiety, and sleep disorders. There are currently, however, no published systematic assessments or meta-analyses of this literature. METHODS: A systematic search of the literature was conducted in PubMed, PsycInfo, Embase, Scopus, and Web of Science. Cross-sectional studies assessing the association between food insecurity and depression, anxiety, or sleep disorders were identified. For each of the three health outcomes, we extracted (or calculated when possible) the following effect sizes: odds ratio (OR), Hedges' g, Pearson correlation coefficients r, or bivariate coefficients. Then, for each mental health-outcome/effect-size pair, the available studies were combined using the random effect model. Heterogeneity, publication bias, and subgroup dependence, for each meta-analysis, were also assessed. RESULTS: Fifty-seven studies provided cross-sectional data on the relationship between FIS and depression (n = 169,433), 13 on anxiety and psychological distress (n = 91,957), and 8 studies provided data on sleep disorders (n = 85,788). Meta-analysis showed that FIS is associated with an increased risk of testing positive for depression OR = 2.74 [95% CI 2.52-2.97, n = 135,500, Q(df = 41) = 69, I2 = 40%], anxiety OR = 2.41 [95% CI 1.81-3.22, n = 51,541, Q(df = 3) = 8, I2 = 63%], and sleep disorders OR = 1.80 [95% CI 1.51-2.15, n = 84,800, Q(df = 5) = 13, I2 = 62%]. The highest risks were found for depression and anxiety which had statistically similar values. The results were robust to covariates and population groups. DISCUSSION: This systematic review and meta-analysis demonstrates a strong association between FIS and depression, anxiety, and sleep disorders, for which more longitudinal studies addressing effect sizes are warranted to further study causation.

Virtual biopsies: Proof of concept for a novel quantitative approach to liver biopsy adequacy and pathology education.

OBJECTIVES: To quantitatively measure liver biopsy adequacy requirements and the effect of a teaching intervention that uses a virtual biopsy platform. METHODS: A library of virtual liver biopsies was created using digital whole-slide, trichrome-stained tissue sections from liver resection material and QuPath image analysis software. Blinded participants staged fibrosis on the virtual biopsies before and after a teaching intervention. RESULTS: This platform both modeled adequacy requirements for cirrhosis diagnosis on biopsy material and measured the effect of a teaching intervention on participant performance. Using this platform, diagnostic accuracy for cirrhosis could be modeled according to the function y = λ(1 ‒ e‒x/γ). The platform demonstrated that the relationship between biopsy size and diagnostic accuracy was statistically significant and that biopsies smaller than 6 mm long and 0.8 mm wide were insufficient to diagnosis cirrhosis. The platform also measured improvement in fibrosis staging accuracy among participants following a teaching intervention. CONCLUSIONS: These results provide proof of concept for a virtual biopsy method by which outstanding questions in anatomic pathology can be addressed quantitatively using open source software. Future work is needed to validate these findings in clinical practice.

A low appendiceal mucinous neoplasm lesion in an inflamed appendix within an inguinal hernia.

Amyand's hernia, an incarcerated appendix inside an inguinal hernia, accounts for <1% of hernias in children and even less in adults. Similarly, low-grade appendiceal mucinous (LAMN) lesions are only found in <1% of removed appendices. We present the case of a 72-year-old man with a 15-year history of a large right inguinoscrotal hernia that presented with right lower quadrant pain, was found by computed tomography imaging to have an incarcerated appendix with a large fluid collection, and was post-operatively diagnosed with an LAMN lesion. Although our case is rare due to the simultaneity of the Amyand's hernia and LAMN conditions, each separate condition is prevalent enough for most surgical providers to encounter at least one of these. For our case, we discuss the decisions made in the pre-operative and post-operative management and relevant literature.

Food insecurity, type 2 diabetes, and hyperglycaemia: A systematic review and meta-analysis.

AIMS: Food insecurity (FIS) is a major public health issue with possible implications for type 2 diabetes mellitus (T2DM) risk. We conducted a systematic review and meta-analysis to explore the association between FIS and T2DM. METHODS: We performed a systematic search in PubMed, Embase, Scopus, and Web of Science. All cross-sectional, peer-reviewed studies investigating the link between FIS and T2DM were included. Population characteristics, study sizes, covariates, T2DM diagnoses, and diabetes-related clinical measures such as fasting blood glucose (FBG) and HbA1c were extracted from each study. Outcomes were compared between food insecure and food secure individuals. Effect sizes were combined across studies using the random effect model. RESULTS: Forty-nine peer-reviewed studies investigating the link between FIS and T2DM were identified (n = 258,250). Results of meta-analyses showed no association between FIS and clinically determined T2DM either through FBG or HbA1c: OR = 1.22 [95%CI: 0.96, 1.55], Q(df = 5) = 12.5, I2  = 60% and OR = 1.21 [95%CI: 0.95, 1.54], Q(df = 5) = 14; I2  = 71% respectively. Standardized mean difference (SMD) meta-analyses yielded no association between FIS and FBG or HbA1c: g = 0.06 [95%CI: -0.06, 0.17], Q(df = 5) = 15.8, I2  = 68%; g = 0.11 [95% CI: -0.02, 0.25], Q(df = 7) = 26.8, I2  = 74% respectively. For children, no association was found between FIS and HbA1c: g = 0.06 [95%CI: 0.00, 0.17], Q(df = 2) = 5.7, I2  = 65%. CONCLUSIONS: Despite multiple proposed mechanisms linking FIS to T2DM, integration of the available literature suggests FIS is not associated with clinically determined T2DM or increases in FBG or HbA1c among adult patients.

A Systematic Review and Meta-Analysis of Food Insecurity and Dyslipidemia.

PURPOSE: There is considerable interest in the association between food insecurity (FIS) and various cardiovascular risk factors such as dyslipidemia. Although the association between FIS and dyslipidemia has been studied across various methodologies and populations, there is no comprehensive systematic review and meta-analysis of these data. METHODS: A systematic literature search was conducted. Cross-sectional peer-review studies assessing the association between FIS and dyslipidemia were identified. Data extracted included population characteristics, study sizes, covariates explored, and laboratory assessments of dyslipidemia. Effect sizes were extracted or calculated, then synthesized across studies using a random effect model, and the heterogeneity, publication bias, and subgroup dependence for each meta-analysis were assessed. RESULTS: For adults, meta-analysis demonstrated no significantly elevated odds for FIS individuals to have a concomitant abnormal lipid measurement. Covariate-unadjusted analysis of standardized mean differences showed no significant differences in lipid measurements between food-insecure and food-secure individuals. In contrast to quantitative laboratory results, food-insecure patients were more likely to self-report previous diagnoses of dyslipidemia. CONCLUSIONS: Although current data do not suggest an association between FIS and dyslipidemia, more longitudinal studies and studies targeting women, children, the elderly, and patients with chronic diseases such as diabetes are needed to further address this issue.

Associations of Race, Insurance, and Zip Code-Level Income with Nonadherence Diagnoses in Primary and Specialty Diabetes Care.

INTRODUCTION: Evidence suggests that clinicians may view or label patients as nonadherent in a biased manner. Therefore, we performed a retrospective cohort analysis exploring associations between patient demographics and zip code-level income with the International Classification of Diseases, Tenth Version (ICD-10) diagnoses for nonadherence among type 2 diabetes mellitus (T2DM) patients, comparing primary and specialty care settings. Providers in the primary care group included internal medicine and family medicine physicians. In the specialty care group, providers included endocrinologists and diabetologists only. METHODS: Participants were identified from 5 primary care and 4 endocrinology sites in the University of Pennsylvania Health System between January 1, 2015, and January 1, 2019. Demographics, hemoglobin A1c (HbA1c), and ICD-10 codes for T2DM and nonadherence were extracted from the electronic health record and analyzed in October 2019. Log-binomial regression models were used to estimate patients' risk of nonadherence labeling by race, insurance, and zip code-level median household income, controlling for patient characteristics and HbA1c as a proxy for diabetes self-management. Results were compared between primary and specialty care sites. RESULTS: A total of 6072 patients aged 18-70 years were included in this study. Black race, Medicare, and Medicaid were associated with increased nonadherence labeling while controlling for patient characteristics ([ARR = 2.48, 95% CI: 2.01, 3.04], [ARR = 1.82, 95% CI: 1.50, 2.18], [ARR = 1.61, 95% CI: 1.32, 1.93], respectively). The results remained significant on adjustment with zip code-level income and showed no differences between primary and specialty sites. Lower-income zip codes showed a significant association with increased rates of nonadherence labeling. CONCLUSIONS: Black race, non-private insurance, and lower-income zip codes were associated with disproportionately high rates of nonadherence labeling in both primary and specialty management of T2DM, possibly suggestive of racial or class bias.

Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.

Comparison of solution and crystal properties of Co(II)-substituted human carbonic anhydrase II.

The visible absorption of crystals of Co(II)-substituted human carbonic anhydrase II (Co(II)-HCA II) were measured over a pH range of 6.0-11.0 giving an estimate of pK(a) 8.4 for the ionization of the metal-bound water in the crystal. This is higher by about 1.2 pK(a) units than the pK(a) near 7.2 for Co(II)-CA II in solution. This effect is attributed to a nonspecific ionic strength effect of 1.4M citrate in the precipitant solution used in the crystal growth. A pK(a) of 8.3 for the aqueous ligand of the cobalt was measured for Co(II)-HCA II in solution containing 0.8M citrate. Citrate is not an inhibitor of the catalytic activity of Co(II)-HCA II and was not observed in crystal structures. The X-ray structures at 1.5-1.6A resolution of Co(II)-HCA II were determined for crystals prepared at pH 6.0, 8.5 and 11.0 and revealed no conformational changes of amino-acid side chains as a result of the use of citrate. However, the studies of Co(II)-HCA II did reveal a change in metal coordination from tetrahedral at pH 11 to a coordination consistent with a mixed population of both tetrahedral and penta-coordinate at pH 8.5 to an octahedral geometry characteristic of the oxidized enzyme Co(III)-HCA II at pH 6.0.

Cocaine, cardiomyopathy, and heart failure: a systematic review and meta-analysis.

Although the cardiotoxic effects of cocaine are universally recognized, the association between cocaine and cardiomyopathy and/or heart failure is poorly understood. To conduct a comprehensive review and meta-analysis on the association between cocaine, heart failure, and cardiomyopathy, we first conducted a broad-term search in PubMed, Embase, Web of Science, and Scopus for human studies containing primary data on the relationship between cocaine and heart failure or cardiomyopathy. We were interested in studies with data beyond acute coronary syndromes. Retrieved studies were grouped into different categories based on possible hypotheses to test by meta-analysis. A second search with specific terms was then conducted. For grouped studies with sufficient clinical and methodological homogeneity, effect sizes were calculated and combined for meta-analysis by the Random Effects model. There is in general a need for more primary data studies that investigate heart failure and/or cardiomyopathy in cocaine users for mechanisms independent of ischemia. There were, however, enough studies to combine by meta-analyses that showed that chronic cocaine use is associated with anatomical and functional changes more consistent with diastolic heart failure instead of the commonly taught dilated cardiomyopathy pathway. In patients without a history of ACS, chronic cocaine use was not associated with significantly reduced EF. The few studies on acute cocaine had conflicting results on whether single-dose intravascular cocaine results in acute heart failure. Studies identified that included beta-blockade therapy in cocaine users with cardiac disease suggest that beta-blockers are not unsafe and that may be effective in the treatment of cocaine-associated heart failure. Chronic cocaine use is associated with anatomical and physiological changes of the heart muscle that are potentially reversible with beta-blockade therapy.

Food insecurity and hypertension: A systematic review and meta-analysis.

BACKGROUND: Food insecurity (FIS) is an important public health issue associated with cardiovascular risk. Given the association of FIS with diets of poorer nutritional quality and higher salt intake as well as chronic stress, numerous studies have explored the link between FIS and hypertension. However, no systematic review or meta-analysis has yet to integrate or analyze the existing literature. METHODS: We performed a wide and inclusive search of peer-reviewed quantitative data exploring FIS and hypertension. A broad-terms, systematic search of the literature was conducted in PubMed, Embase, Scopus, and Web of Science for all English-language, human studies containing primary data on the relationship between FIS and hypertension. Patient population characteristics, study size, and method to explore hypertension were extracted from each study. Effect sizes including odds ratios and standardized mean differences were extracted or calculated based on studies' primary data. Comparable studies were combined by the random effects model for meta-analyses along with assessment of heterogeneity and publication bias. RESULTS: A total of 36 studies were included in the final analyses. The studies were combined into different subgroups for meta-analyses as there were important differences in patient population characteristics, methodology to assess hypertension, and choice of effect size reporting (or calculability from primary data). For adults, there were no significantly increased odds of elevated blood pressures for food insecure individuals in studies where researchers measured the blood pressures: OR = 0.91 [95%CI: 0.79, 1.04; n = 29,781; Q(df = 6) = 7.6; I2 = 21%]. This remained true upon analysis of studies which adjusted for subject BMI. Similarly, in studies for which the standardized mean difference was calculable, there was no significant difference in measured blood pressures between food secure and FIS individuals: g = 0.00 [95%CI: -0.04, 0.05; n = 12,122; Q(df = 4) = 3.6; I2 = 0%]. As for retrospective studies that inspected medical records for diagnosis of hypertension, there were no significantly increased odds of hypertension in food insecure adults: OR = 1.11 [95%CI: 0.86, 1.42; n = 2,887; Q(df = 2) = 0.7; I2 = 0%]. In contrast, there was a significant association between food insecurity and self-reports of previous diagnoses of hypertension: 1.46 [95%CI: 1.13, 1.88; n = 127,467; Q(df = 7) = 235; I2 = 97%]. Only five pediatric studies were identified which together showed a significant association between FIS and hypertension: OR = 1.44 [95%CI: 1.16, 1.79; n = 19,038; Q(df = 4) = 5.7; I2 = 30%]. However, the small number of pediatric studies were not sufficient for subgroup meta-analyses based on individual study methodologies. DISCUSSION: In this systematic review and meta-analysis, an association was found between adult FIS and self-reported hypertension, but not with hypertension determined by blood pressure measurement or chart review. Further, while there is evidence of an association between FIS and hypertension among pediatric subjects, the limited number of studies precluded a deeper analysis of this association. These data highlight the need for more rigorous and longitudinal investigations of the relationship between FIS and hypertension in adult and pediatric populations.

Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. METHODS: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. RESULTS: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. CONCLUSION: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904). FUNDING: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.

A Monte Carlo simulation approach for estimating the health and economic impact of interventions provided at a student-run clinic.

BACKGROUND: Student Run Clinics (SRCs) are a common aspect of medical education, present at more than half of US medical schools, and noted for providing care to communities that might otherwise lack access, including the uninsured and underinsured. To date, few studies have rigorously quantified the health and economic benefits of SRCs, and the present study remedies that. METHODS AND FINDINGS: We used Monte Carlo simulations to estimate the health impact of common preventive health interventions applied to individuals in quality-adjusted life-years (QALYs). We then used those measurements to estimate the health and economic impact of United Community Clinic (UCC), a student-run clinic in Philadelphia, PA. We found that with an annual operating budget of $50,000, UCC saves 6.5 QALYs, corresponding to over $850,000 saved. CONCLUSIONS: Using Monte Carlo simulation methods, the health and economic impact of SRCs can be reasonably estimated to demonstrate the utility of SRCs and justify their growing importance in the healthcare delivery landscape of the US.

A Structure-free Method for Quantifying Conformational Flexibility in proteins.

All proteins sample a range of conformations at physiologic temperatures and this inherent flexibility enables them to carry out their prescribed functions. A comprehensive understanding of protein function therefore entails a characterization of protein flexibility. Here we describe a novel approach for quantifying a protein's flexibility in solution using small-angle X-ray scattering (SAXS) data. The method calculates an effective entropy that quantifies the diversity of radii of gyration that a protein can adopt in solution and does not require the explicit generation of structural ensembles to garner insights into protein flexibility. Application of this structure-free approach to over 200 experimental datasets demonstrates that the methodology can quantify a protein's disorder as well as the effects of ligand binding on protein flexibility. Such quantitative descriptions of protein flexibility form the basis of a rigorous taxonomy for the description and classification of protein structure.

Multi-Walled Carbon Nanotube Growth in Multi-Walled Carbon Nanotubes by Chemical Vapor Deposition.

We report chemical vapor deposition (CVD) growth of a multi-walled carbon nanotube (MWCNT) inside another MWCNTs from a cementite (Fe3C) catalyst nanoparticles. The CNTs have bi or tri-layered core(s)-sheath structure with various crystallinity. The sheath grows first at a lower temperature, and then the catalyst nanoparticle works again to grow the core(s) at a higher temperature in the tip or root growth mode. Transmission electron microscopy (TEM) observation provides a clear piece of evidence of reverse-inward growth.

Low-band-gap platinum acetylide polymers as active materials for organic solar cells.

We report on two pairs of platinum acetylide based polymers and model oligomers utilizing a 2,1,3-benzothiadiazole (BTD) acceptor moiety flanked on either side by either 2,5-thienyl donor units (Pt2BTD-Th and p-PtBTD-Th) or (3,4-ethylenedioxy)-2,5-thienyl donors (Pt2BTD-EDOT and p-PtBTD-EDOT). Both oligomer/polymer pairs absorb strongly throughout the visible region; however, because the (ethylenedioxy)thiophene moiety is a stronger donor than thiophene, the latter oligomer/polymer pair has a correspondingly lower band gap and, therefore, harvests light more efficiently at longer wavelengths. p-PtBTD-Th exhibits a relatively narrow molecular weight distribution with a number-average molecular weight (Mn) of 22 kDa, while p-PtBTD-EDOT exhibits a comparable Mn of 33 kDa but has a high polydispersity index likely due to aggregation. We provide a complete report of the photophysical and electrochemical characterization of the two oligomer/polymer pairs. The photophysical studies reveal that the materials undergo relatively efficient intersystem crossing. In a discussion of the energetics of photoinduced electron transfer from the platinum polymers to [6,6]-phenyl C61 butyric acid methyl ester (PCBM), it is noted that while the singlet state is quenched efficiently, the triplet state is not quenched, indicating that charge generation in the photovoltaic materials must ensue from the singlet manifold. Finally, organic photovoltaic devices based on blends of p-PtBDT-Th or p-PtBDT-EDOT with PCBM were characterized under monochromatic and simulated solar (AM1.5) illumination. Optimized devices exhibit an open-circuit voltage (Voc) of approximately 0.5 V, a short-circuit current density (Isc) of approximately 7.2 mA cm(-2), and a fill factor of approximately 35%, which yields overall power conversion efficiencies of 1.1-1.4%.