COMPARING FUNCTIONAL DATA ANALYSIS AND HYSTERESIS LOOPS WHEN TESTING TREATMENTS FOR REDUCING HEAT STRESS IN DAIRY COWS

Various techniques are commonly used to reduce heat stress, including sprayers and misters, shading, and changes in feed. Oftentimes studies are performed where researchers do not control the times when animals use shading or other means available to reduce heat stress, making it hard to test differences between treatments. Two methods are used on data from a study where Holstein cows were given free access to weight activated “cow showers.” Functional data analysis can be used to model body temperature as a function of time and environmental variables such as the Heat Load Index. Differences between treatment groups can be tested using a Functional Bayesian MCMC model. Alternatively hysteresis loops, such as the ellipse, formed by a plot of air temperature or the Heat Load Index against body temperature over the course of a day can be estimated and their parameters used to test differences between cows with access to showers and cows without. Results from an R package hysteresis, which can estimate these loops and their parameters are illustrated. Functional data analysis allows for looser assumptions regarding the body temperature curve and the ability to look for differences between groups at specific time points, while hysteresis loops give the ability to look at heat stress over the course of a day holistically in terms of parameters such as amplitude, lag, internal heat load and central values

Continuous-flow left ventricular assist device outflow graft stenting: Indications and outcomes

Introduction: Stenosis in the continuous-flow left ventricular assist device (CF-LVAD) outflow graft can be caused by various mechanical and anatomical factors. Increasingly, percutaneous management has been utilized to re-establish adequate CF-LVAD flow. We sought to evaluate indications for such interventions and their outcomes. Methods: An electronic search was performed to identify all studies in the English literature reporting CF-LVAD outflow graft stenting for various etiologies. Twenty-one studies consisting of 26 patients were included in the analysis. Results: Median patient age was 59 years [45.8-67.0] and 65.4% (17/26) were male. 58.3% (14/24) of patients had HeartWare HVAD, 37.5% (9/24) had HeartMate II LVAD, and 4.2% (1/24) had HeartMate III LVAS. Median time from device placement to outflow graft stenting was 24.0 months [7.8-30.4]. 76.9% of patients (20/26) presented with heart failure. 34.6% (9/26) had outflow graft thrombosis, 34.6% (9/26) stenosis, 11.5% (3/26) kinking, 11.5% (3/26) pseudoaneurysm, 3.8% (1/26) external graft compression, and 3.8% (1/26) had a bronchialarterial fistula. 88.5% (23/26) procedures led to immediate flow improvement with the remaining 11.5% (3/26) receiving additional stenting. Post-intervention flows were significantly improved (4.7 L/min [4.1-4.8] post-intervention vs 2.9 L/min [2.0-3.5] initial, p=0.01). 96.2% (25/26) patients were discharged from the hospital. The 30-day mortality was 6.7% (1/15). Overall mortality during the median follow-up of 90 days [7.0-240.0] was 9.5% (2/21). Discussion: Outflow graft stenting appears to effectively alleviate CF-LVAD outflow graft obstruction with low mortality. Longer-term follow up is necessary to determine the longevity of such an intervention but early results are promising

Thin, fine and with sensitivity: a metamethodology of intuitions

Do philosophers use intuitions? Should philosophers use intuitions? Can philosophical methods (where intuitions are concerned) be improved upon? In order to answer these questions we need to have some idea of how we should go about answering them. I defend a way of going about methodology of intuitions: a metamethodology. I claim the following: (i) we should approach methodological questions about intuitions with a thin conception of intuitions in mind; (ii) we should carve intuitions finely; and, (iii) we should carve to a grain to which we are sensitive in our everyday philosophising. The reason is that, unless we do so, we don’t get what we want from philosophical methodology. I argue that what we want is information that will aid us in formulating practical advice concerning how to do philosophy responsibly/well/better

Bronchial artery revascularization in lung transplantation: a systematic review and meta-analysis.

Background: Bronchial artery revascularization (BAR) during lung transplantation has been hypothesized to improve early tracheal healing and delay the onset of bronchiolitis obliterans syndrome (BOS). We aimed to assess the outcomes of BAR after lung transplantation. Methods: Electronic search in Ovid Medline, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Scopus, and Cochrane Controlled Trials Register (CCTR) databases was performed to identify all relevant studies published about lung transplantation with BAR. Studies discussing lung transplantation utilizing BAR were included while those without outcome data such as BOS and survival were excluded. Cohort-level data were extracted and pooled for analysis. A binary outcome meta-analysis of proportions with logit transformation was conducted. Newcastle-Ottawa scale was used for risk of bias assessment. Results: Seven studies were selected for the analysis comprising 143 patients. Mean patient age was 47 (95% CI: 40-55) years. Sixty-one percent (48-72%) were male. Seventy-three percent (65-79%) of patients underwent double lung transplant while 27% (21-25%) underwent single lung transplant. In patients with postoperative angiography, successful BAR was demonstrated in 93% (82-97%) of all assessed conduits. The 30-day/in-hospital mortality was 6% (3-11%). Seventy-nine percent (63-89%) of patients were free from rejection at three months. Eighty-three percent (29-98%) of patients were free from signs of airway ischemia at three and six months. Pooled survival at one year and five years was 87% (78-92%) and 71% (46-87%), respectively, with a mean follow-up time of 21 (3-38) months. Pooled freedom from bronchiolitis obliterans was 86% (77-91%) at two years. Conclusions: While this systematic review and meta-analysis is limited by the available surgeons, institutions, and papers discussing a highly specialized technique, it does show that BAR is a viable technique to minimize BOS and early anastomotic intervention following lung transplantation

Endovascular Intervention for Tracheo-Innominate Fistula: A Systematic Review and Meta-analysis

Introduction: Fistula formation between the trachea and the innominate artery is a life-threatening complication rarely seen with existing or previous tracheostomy. Fatal upon rupture, swift diagnosis and immediate intervention are paramount for survival. We aim to identify feasibility and outcomes of endovascular intervention for trachea-innominate fistula (TIF). Methods: Patient-level data of reported individuals above the age of 14 that underwent endovascular intervention for TIF was extracted and analyzed. Identification of 25 patients from 27 studies was accomplished by electronic database search of Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Ovid Medline, and Scopus. Survival data was evaluated by Kaplan-Meier analysis. Results: Median patient age was 39.0 years [IQR 16.0, 47.5]. Median time to TIF presentation following tracheostomy was 2.2 months [0.5, 42.5]. 84.6% (22/27) exhibited tracheal hemorrhage at presentation. Covered stent graft placement was performed in 96.3% (26/27) and coil embolization in 3.8% (1/27). Repeat endovascular intervention was necessary in 18.5% (5/27) and rescue sternotomy was required in 11.1% (3/27). Overall mortality was 29.6% (8/27) with a median follow-up time of 5 months [1.2, 11.5]. Discussion: Endovascular intervention may be an effective method of TIF repair at presentation. As an alternative to conventional surgical repair, endovascular intervention may be an appropriate method for TIF repair particularly in patients unfit for open sternotomy repair

DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration

Purpose: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). Methods: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). Results: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). Conclusion: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD

Structural Basis for Dual-Inhibition Mechanism of a Non-Classical Kazal-Type Serine Protease Inhibitor from Horseshoe Crab in Complex with Subtilisin

Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki = 1.43 nM). CrSPI has been grouped with the non-classical Kazal-type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 Å resolution and the results of biophysical interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1∶2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation

Understanding management gurus and historical narratives: The benefits of a historic turn in management and organization studies

A historic turn in organization studies requires a basic theoretical understanding of ‘doing history’ and an appreciation of the centrality of narrative in history. Following the cultural turn in history, narrativist historians and philosophers of history such as Hayden White, Frank Ankersmit and Paul Ricoeur have made the case that narrative is an essential and unavoidable component in history. We demonstrate the persuasive capacity of narrative through a narrativist critique of three best-selling ‘management gurus’. This analysis illustrates the following: (1) the narrative features of popular organizational theories; (2) the basis of the success of guru literature; and (3) why gurus and organizational scientists themselves do not understand the narratological mechanisms behind their success. Finally, we maintain that historical narrativism offers the possibility for positioning organizational history as a highly relevant field for management academics, gurus and even managers, providing support for a historic turn

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery