Miracle-dz/UniFAR-FTUs huggingface dataset:
Association between Functional Small Airway Disease and FEV 1 Decline in Chronic Obstructive Pulmonary Disease

Rationale: The small conducting airways are the major site of air ﬂ ow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. Objectives: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV 1 decline. Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV 1 (ml/yr) over 5 years. Separate models for subjects without and with air ﬂ ow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to de ﬁ ne emphysema (PRM emph ) and functional small airways disease (PRM fSAD ), a measure of nonemphysematous air trapping. Measurements and Main Results: decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0 – 4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1 – 4; P , 0.001). In multivariable linear regression, for participants without air ﬂ ow obstruction, PRM fSAD but not PRM emph was associated with FEV 1 decline ( P , 0.001). In GOLD 1 – 4 participants, both PRM fSAD and PRM emph were associated with FEV 1 decline ( P , 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV 1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM fSAD and PRM emph in GOLD 1/2 and 3/4, respectively. Conclusions: CT-assessed functional small airway disease and emphysemaare associated with FEV 1 decline, butthe association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV 1 decline is the greatest. Clinical trial registered with www.clinicaltrials. gov (NCT 00608764).
Loss of anti-Mu¨llerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classical polycystic ovary syndrome (PCOS) CASE REPORT Reproductive endocrinology

: Anti-Mu¨llerian hormone (AMH) is produced by granulosa cells of pre-antral and small antral ovarian follicles. In polycystic ovary syndrome (PCOS), higher levels of serum AMH are usually encountered due to the ample presence of small antral follicles and a high AMH production per follicular unit which have led to the proposal of AMH as a serum diagnostic marker for PCOS or as a surrogate for polycystic ovarian morphology (PCOM). However, heterozygous coding mutations of the AMH gene with decreased in vitro bioactivity have been described in some women with PCOS. Such mutation carriers have a trend toward reduced serum AMH levels compared to noncarriers, although both types of women with PCOS have similar circulating gonadotropin and testosterone (T) levels. This report describes a normal-weight woman with PCOS by NIH criteria with severely reduced AMH levels (index woman with PCOS). Our objective was to examine the molecular basis for her reduced serum AMH levels and to compare her endocrine characteristics to similar-weight women with PCOS and detectable AMH levels. Twenty normoandrogenic ovulatory (control) and 13 age- and BMI-matched women with PCOS (19–35 years; 19–25 kg/m 2 ) underwent transvaginal sonography and serum hormone measures including gonadotro-pins, sex hormone-binding globulin, total and free T, androstenedione, dehydroepiandrosterone sulfate, estrone, estradiol and AMH. The latter was measured by ELISA (Pico-AMH: Ansh Labs, Webster, TX, USA). Women with PCOS and detectable AMH had higher serum AMH (10.82 (6.74–13.40) ng/ml, median (interquartile range)), total and free T (total T: 55.5 (49.5–62.5) ng/dl; free T: 5.65 (4.75–6.6) pg/ml) levels and greater total antral follicle count (AFC) (46 (39–59) follicles) than controls (AMH: 4.03 (2.47–6.11) ng/ml; total T: 30 (24.5–34.5) ng/dl; free T: 2.2 (1.8–2.45) pg/ml; AFC 16 (14.5–21.5) follicles, P < 0.05, all values), along with a trend toward LH hypersecretion ( P ¼ 0.06). The index woman with PCOS had severely reduced serum AMH levels ( (cid:2) 0.1 ng/ml), although she also had a typical NIH-deﬁned PCOS phenotype resembling that of the other women with PCOS and elevated AMH levels. All women with PCOS, including the index woman with PCOS, exhibited LH hypersecretion, hyperandrogenism, reduced serum estrogen/androgen ratios and PCOM. A homozygous Ala 515 Val variant (rs10417628) in the mature region of AMH was identiﬁed in the index woman with PCOS. Recombinant hAMH- 515 Val displayed normal processing and bioactivity, yet had severely reduced immunoactivity when measured by the commercial pico-AMH ELISA assay by Ansh Labs. In conclusion, homozygous AMH variant rs10417628 may severely impair serum AMH immunoactivity without affecting its bioactivity or PCOS phenotypic expression. Variants in AMH can interfere with serum AMH immunoactivity without affecting the phenotype in PCOS. This observation can be accompanied by discordance between AMH immunoactivity and bioactivity.
C1q Reduces the Stoichiometric Threshold for Antibody-Mediated Neutralization of West Nile Virus

Summary Virus neutralization is governed by the number of antibodies that bind a virion during the cellular entry process. Cellular and serum factors that interact with antibodies have the potential to modulate neutralization potency. Although the addition of serum complement can increase the neutralizing activity of antiviral antibodies in vitro, the mechanism and significance of this augmented potency in vivo remains uncertain. Herein, we show that the complement component C1q increases the potency of antibodies against West Nile virus by modulating the stoichiometric requirements for neutralization. The addition of C1q does not result in virolysis, but instead reduces the number of antibodies that must bind the virion to neutralize infectivity. For IgG subclasses that bind C1q avidly, this reduced stoichiometric threshold falls below the minimal number of antibodies required for antibody-dependent enhancement (ADE) of infection of K562 cells expressing Fc- γ receptors (CD32), and explains how C1q restricts the ADE of flavivirus infection. Author Contributions. S.J. generated hu-E16 IgG subclass-switch variants and characterized antibody affinity; E.M. , C.J. and S.N. analyzed neutralization of mouse and human mAbs; S.N. performed the stoichiometry studies; S.J. and S. G. characterized antibody-affinity measurements by SPR; E.M. analyzed the in vivo protective capacity of E16 variants; E.M. , S.N. , D.H. F. , M.S.D. and T.C. P. designed the studies, analyzed the data, and wrote the paper; all authors discussed the data and commented on the manuscript. Conflict of Interest Statement. S.G. and S.J. are employees of MacroGenics, a company that has licensed the E16 antibody from Washington University for commercial use. M.S.D. is a consultant for MacroGenics. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and in vivo studies with neutralizing yellow fever virus antibodies that showed enhanced protection correlated with IgG subclasses that efficiently fix complement
Rapid CKD progression in a new mouse kidney remnant model: strain-dependent resistance is overcome by angiotensin II

The remnant kidney model in C57BL6 mice does not develop progressive chronic kidney disease (CKD). In this study we modified the model to mimic features of human CKD and to define accelerants of disease progression using three strains of mice. Following the procedure there was a progressive increase in albuminuria, progressive loss in renal function, severe glomerulosclerosis and interstitial fibrosis, hypertension, cardiac fibrosis, and anemia by 4 weeks in CD-1 mice and by 12 weeks in 129S3 mice. In contrast, even after 16 weeks, the C57BL/6 mice with a remnant kidney had modestly increased albuminuria without increased blood pressure and without developing CKD or cardiac fibrosis. The baseline blood pressure, determined by radiotelemetry in conscious animals, correlated with CKD progression rates in each strain. Administering angiotensin II overcame the resistance of C57BL/6 mice to CKD following renal mass reduction displaying high blood pressure and albuminuria, severe glomerulosclerosis, and loss of renal function by 4 weeks. Decreasing blood pressure with olmesartan but not hydralazine in CD-1 mice with a remnant kidney reduced CKD progression and cardiac fibrosis. C57BL/6 mice with a remnant kidney and DOCA-salt hypertension developed modest CKD. Each strain had similar degrees of interstitial fibrosis in three different normotensive models of renal fibrosis. Thus reducing renal mass in CD-1 or 129S3 mice mimics many features of human CKD. Angiotensin II can convert the C57BL/6 strain from CKD-resistant to susceptible in this disease model.
Echocardiographic left atrial reverse remodeling after catheter ablation of atrial fibrillation is predicted by pre-ablation delayed enhancement of left atrium by MRI

regression analysis, pre-ablation LA wall fibrosis predicted recurrence after adjusting for, paroxysmal vs. persistent AF, pre-ablation LA AP diameter, superior-inferior diameter, LA maximum biplane volume index, LA emptying fraction, average LA strain and LVEF (p<0.02, hazard ratio (HR): 1.04, 95% confidence interval (CI): 1.01-1.08). Post-ablation predictors of recurrence of AF: Using Cox multivariate stepwise regression analysis, early post-ablation LA emptying fraction predicted long-term recurrence at 12 months, after adjusting for paroxysmal vs. persistent AF, post-ablation LA AP diameter, superior-inferior diameter, LA maximum biplane volume index, average LA strain and LVEF (p<0.006, HR: 0.97, 95% CI: 0.96-1.0).
Adhesion Prevention in Myomectomy REVIEW

Adhesions are abnormal fibrous connections, joining tissue surfaces in abnormal locations. Adhesions form after any trauma involving the peritoneum and the injured tissue surface or directly between the injured tissue surfaces. The ideal anti-adhesion agent should be safe, efficacious, easy to use in all types of surgery, and economical. It should prevent adhesions at the site of surgery as well as throughout the peritoneal cavity. Needless to say, the ideal agent is still elusive.
Polysulfated Hyaluronan GlycoMira-1111 Inhibits Elastase and Improves Rheology in Cystic Fibrosis Sputum

Cystic ﬁ brosis (CF) lung disease is marked by high concentrations of neutrophil elastase (NE) and DNA polymers; both factors contribute to airway disease. Although inhaled recombinant human dornase alfa reduces the frequency of CF pulmonary exacerbations, it also increases free NE activity in the sputum. There are no approved anti-NE therapies for patients with CF. We investigated whether synthetic, low – molecular weight polysulfated hyaluronan GlycoMira-1111 (GM-1111) would be effective as an anti-NE drug using ex vivo CF sputum. Anti-NE activity of GM-1111 was tested in CF sputum in the presence or absence of dornase alfa and/or hypertonic saline using a spectrophotometric assay speci ﬁ c for human NE and was compared with unfractionated heparin. We tested whether GM-1111 disaggregated DNA from CF sputum (using gel electrophoresis analysis) or modi ﬁ ed CF sputum viscoelastic properties (using a dynamic rheometer). GM-1111 and unfractionated heparin had near equivalent anti-NE activity in CF sputum in the presence of dornase alfa. Both GM-1111 and unfractionated heparin retained anti-NE activity in hypertonic saline but with decreased activity. GM-1111 increased the release of soluble DNA in CF sputum, resulting in improved depolymerization ef ﬁ cacy of dornase alfa. GM-1111 decreased CF sputum elasticity. GM-1111 inhibited NE activity, enhanced DNA depolymerization by deoxyribonuclease, and decreased viscoelastic properties of CF sputum, similar to effects reported previously for unfractionated heparin. Unlike heparins, GM-1111 is synthetic, with minimal anticoagulant activity, and is not derived from animal products. These key attributes provide advantages over unfractionated heparin as a potential therapeutic for CF.
CMR Quantification of Structure-Function Relationships in Heart Failure

Classification of heart failure is based on the left ventricular ejection fraction (LVEF): preserved EF, mid-range EF, and reduced EF. There remains an unmet need for further heart failure phenotyping of ventricular structure-function relationships. Due to high spatiotemporal resolution, cardiac magnetic resonance (CMR) remains the reference modality for quantification of ventricular contractile function. Recent technical advancements in CMR have shifted the paradigm for quantification of ventricular function beyond the EF to include myocardial mechanics, in vivo tissue microstructure, and intraventricular flow analysis. Advanced methods in image reconstruction, post-processing, and off-label use of iron-based contrast agents such as ferumoxytol have enhanced the clinical CMR workflow. We aim to highlight novel frameworks including theranostic use of ferumoxytol to enable more efficient evaluation of ventricular function in heart failure patients who are also frequently anemic, and to discuss emerging quantitative CMR approaches for evaluation of ventricular structure-function relationships in heart failure.
BJRD14847 1..5

Objective: The purpose of this study was to calculate the costs associated with the evaluation of breast incidentalomas (BI) identified on CT. Methods: All CT scans of the thorax performed at the radiological department of the University Hospital of the Martin-Luther-University Halle-Wittenberg between the years 2006 and 2014 were reanalysed retrospectively. 111 patients with BI were identified. The radiological and clinical reports of these cases were examined, and the costs of all further diagnostic procedures performed to clarify the detected BI were calculated. Results: In 31 (27.9%) of the 111 patients, BI were not further investigated. Of the remaining 80 (72.1%) cases of BI, primary breast carcinoma was diagnosed in 10 (12.5%) cases, breast involvement by lymphoma in 7 (8.8%) cases, intramammary metastases in 19 (23.7%) cases and different benign findings in 44 (55.0%) cases. The total costs associated with clarification of BI in our institution (n553) amounted to €14,045.71. The costs per BI were €265.01 and per newly identified breast cancer €1560.63. Conclusion: Breast lesions incidentally detected on CT should be categorized as major incidental findings because of the high frequency of malignancy. The radiologist should carefully evaluate the breast on CT images and all identified BI should be clarified. The clarification of BI is associated with a low economic burden in comparison with screening programmes for primary breast cancer. Advances in knowledge: The radiologist should carefully evaluate the breast on CT and all identified BI should be clarified. The evaluation of BI is associated with a low economic burden.
C E : Common Structural Themes in Viral Cell Entry Pathways

Structural studies of polio- and closely related viruses have provided a series of snapshots along their cell entry pathways. Based on the structures and related kinetic, biochemical, and genetic studies, we have proposed a model for the cell entry pathway for polio- and closely related viruses. In this model a maturation cleavage of a capsid protein precursor locks the virus in a metastable state, and the receptor acts like a transition-state catalyst to overcome an energy barrier and release the mature virion from the metastable state. This initiates a series of conformational changes that allow the virus to attach to membranes, form a pore, and finally release its RNA genome into the cytoplasm. This model has striking parallels with emerging models for the maturation and cell entry of more complex enveloped viruses such as influenza virus and HIV. A entry. ( d ability of the A
Myelodysplastic syndrome and acute myeloid leukemia in patients with Shwachman Diamond syndrome: a multicentre, retrospective, cohort study

Background: Data to inform surveillance and treatment for leukemia predisposition syndromes are limited and recommendations largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of myelodysplastic syndrome and acute myeloid leukemia in Shwachman Diamond syndrome, an inherited marrow failure disorder with high risk of myeloid malignancy. Methods: We performed a multicentre, retrospective cohort study in 17 centres in the USA and Canada. Patients with a genetic or clinical diagnosis of Shwachman Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukemia were eligible without additional restriction. Medical records from March 1, 2001 to October 5, 2017 were reviewed for 36 patients. Blinded central review of bone marrow pathology was performed in 27 available cases. Description of clinical features and survival assessment was performed. Median follow-up was 4·9 years (range: 0.3–10.1, IQR: 3.9–8.4). Findings: Median age was 18 years (range: 0.5–47.0, IQR:10–24). Central pathology review concurred with local diagnosis in 56% (n=15/27). Treatment was heterogeneous with 10 chemotherapy regimens and 16 hematopoietic stem monitored with bone marrow surveillance prior to myelodysplastic syndrome / leukemia diagnosis had a 3-year OS of 62% (95% CI: 32–82, n=14) compared with 28% without surveillance (95% CI:10–50, n=19) (p=0·13). Several patients developed myelodysplastic syndrome in the setting of stable blood counts (n=6). Interpretation: Prognosis is poor for Shwachman Diamond syndrome patients with leukemia due to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms for early disease detection/risk stratification, biological studies of clonal evolution and prospective clinical trials are needed to inform effective prevention and treatment strategies for leukemia predisposition. We conducted a multi-institutional retrospective study of patients with Shwachman Diamond syndrome and myelodysplastic syndrome or acute myeloid leukemia. We describe demographics, disease characteristics, challenges of pathologic diagnosis, surveillance practices, therapy response, and overall survival. These data are critical to inform medical management of this leukemia-predisposition syndrome.
STUDIES ON THE EFFECT OF THE ACTION OF DIGITALIS ON THE OUTPUT OF BLOOD FROM THE HEART THE ON THE OF THE DOG'S HEART IN HEART-LUNG PREPARATIONS1

A satisfactory solution of the problem concerning the effect of giving digitalis, especially on the volume output of the heart, but of other problems concerning its action, is still outstanding. Difficulties in the way of complete understanding depend, it seems, on the circumstances in which digitalis is administered. Among these are the species of animal which is studied and the state of the heart, whether healthy or diseased. The value of digitalis as a therapeutic agent, being on many accounts a constant source of concern, is viewed as being involved in these issues. Discussion is often confused, action of the drug and the beneficence of that action being regarded as the same things. This inference need not necessarily be correct. The pulse rate may be lowered, the blood pressure raised, the excretion of water unchanged, the volume output of blood from the heart either decreased or increased; the effect of not one of these actions can supply a clue, a priori, to whether giving this agent is advisable. In terms of no one of these functions can its value or benefit be described. The situation is different in an infectious fever. Barring the artificial lowering of temperature as a single effect without influence on the general course of the illness, defervescence is usually, and perhaps justly, regarded as a sign of value. If the success of an agent cannot be measured in terms of a " test " of its efficacy, how can it be measured? Is it necessary to rely on the report of its effect by patients or is there something in the totality of their demeanor which permits the drawing of a relevant inference? In whatever way this phase of the matter is decided, an outstanding consideration is this, that a judgment is desirable which is not dependent on the measurement of some function, involved no doubt in the total action, but yet not characteristic of a result regarded as satisfactory. In the case of giving digitalis for example, patients may, conceivably, report
Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for CML: Refined HLA-matching shows more GVHD but not less relapse Blood Marrow

Purpose— Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor:recipient-histoincompatibility can augment the graft vs. leukemia (GvL) effect. We previously reported similar, but not equivalent outcomes of URD vs. sibling donor HCT for CML using an older, less precise classification of HLA-matching. HCT. Acute and chronic GVHD are significantly more frequent with all levels of recategorized URD HLA-matching. Importantly, survival and leukemia-free survival remain significantly worse following URD-HCT at any matching level. No augmented GvL effect accompanied URD HLA-mismatch. Compared to sibling donor transplants, we observed marginally increased, but not significantly different risks of relapse in either well-matched, partially-matched or mismatched URD-HCT. Conclusions— These data confirm the utility of our revised HLA-matching schema as applicable for analysis of retrospective data sets when fully informative, allele level-typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD but does not improve protection against relapse thus the best donor is still the most closely matched.
A Word of Caution Regarding Patient Self-inflicted Lung Injury and Prophylactic Intubation To the Editor: We read the Critical Care Perspective “Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure” by Brochard and colleagues with great interest

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