bluuebunny/crossref_metadata_2025 huggingface dataset:
Hand washing behavior change effect of community-based hygiene and sanitation intervention in low resource setting
Authors: Qazi Umair , Anwar Saeed
Published: September 2019

Background

Lack of hygiene and sanitation causes significant disease, disability and death. Majority of diarrheal diseases are related to hygiene and drinking water. Hand washing with soap after toilet use and before eating reduces these risks significantly.

Methods

This report is based on a behavior change project in the rural community setting (union council Nahqi), Peshawar, Pakistan aimed to improve hygiene- and sanitation-related behavior. A pre-intervention survey was conducted at household level (n = 958), followed by a structured behavior change communication program with motivational and educational material and key health messages for three months. Lastly, an end-line survey was conducted measuring change in practice domains.

Results

All the domains of hygiene and sanitation showed statistically significant improvement (11–59% P < 0.001), including handwashing before meals (28.2%), before cooking (54.1%), before child feeding (21.2%), after defecation (30.6%); tooth brushing twice daily (7.3%); nail clipping at least weekly (16.3%); bathing daily (11.3%); change of clothing twice weekly (24.7%); covering the water containers (59.3%) and house orderliness (30.6%).

Conclusion

The findings conclude that a behavior change communication program that is in accord with community needs, level of their understanding, beliefs and sociocultural norms is well received for positive behavior change.
Pathology of immune-mediated tissue lesions following treatment with immune checkpoint inhibitors
Authors: Ibraheim Hajir , Perucha Esperanza , Powell Nick
Published: September 2019

Immune check point inhibitor (CPI) therapy has revolutionized treatment paradigms for several cancers, but at the cost of triggering a diverse spectrum of immune-mediated injury to non-cancer tissues. The complex biology of these toxicities remains incompletely understood, partly because tissue acquisition from affected areas can be challenging to retrieve, thus hindering development of targeted therapy. Here, we review the literature describing pathology of immune-mediated tissue lesions including gastrointestinal, skin, rheumatic, pulmonary, cardiac, renal and hepatic lesions and highlight key immunological insights.
Young Adult Caregiver Strain and Benefits
Authors: King McLaughlin Jessica , Greenfield Jennifer C , Hasche Leslie , De Fries Carson
Published: September 2019

Young adult caregivers (YACs) of older adults are an often-overlooked subset of the caregiver population, though they make up more than a quarter of all caregivers. Because of their stage in life and their economic and work status, YACs (ages 21 to 40) are likely to face different caregiving challenges than other age cohorts of caregivers. Using the life course perspective and role conflict theory as foundational frameworks, this article compares the resources and strains of YACs with those of their middle-age caregiver (MAC) (ages 41 to 60) and older adult caregiver (OAC) (ages 61 and older) counterparts. Authors used data from a cross-sectional pilot study of caregivers recruited across one western state through community agencies. Through multivariate regression analysis, findings indicated that YACs reported more financial strain than MACs and OACs, despite being more likely to be employed. In contrast, YACs reported greater positive feelings toward caregiving than both MACs and OACs. These findings remained while controlling for employment status, education, and hours per week spent caregiving. Although YACs may find great value in caregiving, they may also be in more financially precarious situations. The article concludes with recommendations for caregiver support programs to reach YACs in the workplace.
Site of Occlusion May Influence Decision to Perform Thrombectomy Under General Anesthesia or Conscious Sedation
Authors: Steinberg Jeffrey A. , Somal Jaspreet , Brandel Michael G. , Kang Keiko M. , Wali Arvin R. , Rennert Robert C. , Santiago-Dieppa David R. , Olson Scott E. , Pannell J. Scott , Khalessi Alexander A.
Published: September 2019

Background:

Although mechanical thrombectomy has become the standard of care for large-vessel occlusion, the role of conscious sedation versus general anesthesia (GA) with intubation during thrombectomy remains controversial. Aphasia may increase patient agitation or apparent uncooperativeness/confusion and thereby lead to higher use of GA. The purpose of this study was to identify risk factors for GA and determine if the side of vessel occlusion potentially impacts GA rates.

Materials and Methods:

Patients who underwent mechanical thrombectomy of the middle cerebral artery (MCA) for acute ischemic stroke at our institution between April 2014 and July 2017 were retrospectively reviewed. Patient characteristics, procedural factors, and outcomes were assessed using multivariate regression analyses. Mediation analysis was utilized to investigate whether aphasia lies on the causal pathway between left-sided MCA stroke and GA.

Results:

Overall, 112 patients were included: 62 with left-sided and 50 with right-sided MCA occlusion. Patients with left-sided MCA occlusion presented with aphasia significantly more often those with right-sided occlusion (90.3% vs. 32.0%; P<0.001). GA rates were significantly higher for patients with left-sided compared with right-sided MCA occlusion (45.2% vs. 20.0%; P=0.028). Aphasia mediated 91.3% of the effect of MCA stroke laterality on GA (P=0.02). GA was associated with increased door-to-groin-puncture time (106.4% increase; 95% confidence interval, 24.1%-243.4%; P=0.006) and adverse discharge outcome (odds ratio, 1.04; 95% confidence interval, 1.01-1.07; P=0.019).

Conclusions:

Patients who had a stroke with left-sided MCA occlusion are more likely to undergo GA for mechanical thrombectomy than those with right-sided MCA occlusion. Aphasia may mediate this effect and understanding this relationship may decrease GA rates through modification of management protocols, potentially leading to improved clinical outcomes. Our study suggests that GA should preferentially be considered for the subset of patients with acute ischemic stroke undergoing mechanical thrombectomy for left-sided MCA occlusion.
Optimizing Multisource Feedback Implementation for Australasian Physicians
Authors: Pooley Michael , Pizzuti Carol , Daly Michele
Published: September 2019

Introduction:

Medical regulatory bodies in Australasia are encouraging greater use of continuing professional development activities, such as multisource feedback (MSF), which are practice-based, include facilitated feedback, and improve performance. The aim of this study was to explore the feasibility, effectiveness, and sustainability of an MSF process that includes a telephone/videoconference debrief, to better design future MSF implementation.

Method:

Thirty-seven Australasian physician participants sought feedback from patients and colleagues and debriefed their feedback report with a trained facilitator. The impact was evaluated using quantitative and qualitative measures including surveys and semistructured interviews.

Results:

The feasibility of the MSF process was impacted by the level of support for the participant to complete the MSF, the nature and location of participants' work, and the use of telephone/videoconference to deliver the debrief. Regarding effectiveness, the MSF stimulated reflection on practice and action on areas identified for improvement. In addition, the quality of rater feedback and the inclusion of a debrief impacted participant and facilitator reports of effectiveness. The absence of a culture of feedback, the formative nature of the MSF, and the confidentiality of the results were factors impacting sustainability.

Discussion:

Optimizing MSF is important to encourage broad uptake in the wider medical community in Australasia. Although several factors were identified as having an impact, it is clear that inclusion of a quality debrief will increase the perceived value and the effectiveness of MSF. Delivering that debrief through telephone/videoconference can be effective and will increase the overall feasibility and sustainability.
Right ventricular–pulmonary arterial uncoupling in mild-to-moderate systemic hypertension
Authors: Vriz Olga , Pirisi Mario , Bossone Eduardo , Fadl ElMula Fadl ElMula Mohammed , Palatini Paolo , Naeije Robert
Published: September 2019

Background:

Mild-to-moderate hypertension with preserved left ventricular (LV) function may be associated with right ventricular (RV) dysfunction and increased pulmonary vascular resistance (PVR).

Methods:

The present study explored the adequacy of RV–pulmonary arterial (PA) coupling in 211 never-treated hypertensive patients (mean blood pressure, BP 112 ± 12 mmHg) and 246 controls (BP 93 ± 12 mmHg). They underwent a comprehensive transthoracic Doppler echocardiography, and RV–PA coupling was estimated by the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio (TAPSE/PASP).

Results:

Compared with the controls, hypertensive patients had increased LV wall thickness and decreased trans-mitral E/A with only slight but significant increase in transmitral Doppler E wave to tissue Doppler mitral annulus e′ wave ratio (6.3 ± 1.9 vs. 5.8 ± 1. 5, P < 0.05). RV dimensions and indices of either systolic or diastolic function were not different. PASP was increased in the hypertensive patients (25 ± 7 vs. 21 ± 7 mmHg, P < 0.001), as was PVR estimated from the tricuspid regurgitation velocity to right ventricular outflow tract velocity ratio (1.7 ± 0.4 vs. 1.5 ± 0.5 Wood units, P < 0.001). The TAPSE/PASP ratio was decreased (1.08 ± 0.35 vs. 1.43 ± 0.67 mm/mmHg, P < 0.001). This difference was mainly driven by male hypertensive patients. At multivariable analysis, the only independent predictors of decreased TAPSE/PASP were age and blood pressure.

Conclusion:

The TAPSE/PASP is markedly decreased in hypertension without heart failure, chiefly in men, with only slight increases in estimates of LV filling pressure or PVR, suggesting RV–PA uncoupling.
Making a Correct Diagnosis of Glaucoma: Data From the EMGT
Authors: Öhnell HannaMaria , Bengtsson Boel , Heijl Anders
Published: September 2019

Précis:

A correct diagnosis of glaucoma established at initial visits.

Purpose:

It has been suggested that a diagnosis of glaucoma cannot be certain until progression has been demonstrated. Our aim was to evaluate the correctness of a glaucoma diagnosis established after 2 initial visits.

Patients and Methods:

Patients included in the Early Manifest Glaucoma Trial (EMGT) who had continued follow-up for at least 15 years were included in this analysis. The patients had been recruited primarily through a population screening and were diagnosed with glaucoma if the Glaucoma Hemifield Test was outside normal limits in the same sector at two consecutive visits. A Glaucoma Hemifield Test classification of borderline was also diagnostic if corresponding optic disc findings were present. At least one of the following criteria had to be fulfilled during follow-up to confirm the initial diagnosis: (1) visual field progression in at least one eye according to the EMGT criterion; (2) development of manifest glaucoma in an initially ineligible fellow eye; (3) optic disc progression in at least one eye; (4) optic disc hemorrhages in at least 1 eye.

Results:

Of the 255 patients included in the EMGT, 117 were followed for at least 15 years, representing 147 eyes eligible for our study. During follow-up, 134 eyes (91%) showed visual field progression, and, of the remaining 13 eyes, only 4 (3%) did not fulfill any of the criteria to confirm the diagnosis.

Conclusions:

A diagnosis made applying strict criteria to 2 initial visual field tests, supported by optic disc findings if visual field findings were borderline, was almost always correct.
Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series
Authors: Buness James Gage , Ali Ahmad Hassan , Tabibian James H. , Buness Cynthia W. , Cox Kenneth L. , Lindor Keith D.
Published: September 2019

Background:

Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD.

Areas of Uncertainty:

The etiopathogenesis of PSC remains an enigma.

Data Sources:

We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed.

Results:

We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months.

Therapeutic Hypothesis:

We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.
Clinical Experience With 75-mg Dose of Erlotinib for Mutated Metastatic EGFR Non-small Cell Lung Cancer
Authors: Aren Osvaldo , Samtani Suraj , Frelinghuysen Micahel , Burotto Mauricio
Published: September 2019

Background:

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide, although important advances in target therapy have been developed in the past few years. Erlotinib is a reversible epidermal growth factor receptor (EGFR) inhibitor, which was approved at its maximum tolerated dose of 150 mg/d determined from the initial phase I study. Studies suggest that the optimal biological dose of erlotinib should be lower and dependent on different variables.

Study Question:

We aimed to evaluate the response rates and toxicity with 75 mg/d dose of erlotinib in South American patients.

Method:

We performed a retrospective review of 18 patients with histologically proven (+) EGFR (+) mutation metastatic NSCLC (mNSCLC) treated with 75 mg/d erlotinib as starting dose.

Measures and Outcomes:

Clinical information, including toxicity grade 1–4, drug discontinuation, clinical evolution and radiological evaluation, and overall survival (OS), was revised.

Results:

Patients received 75 mg/d of erlotinib as starting dose. Sixteen (89%) patients were treated in first-line treatment and 2 (11%) in second-line treatment. Mean age was 62 years (range 36–89 years), and 50% patients were female. Sixteen percent of the patients had brain metastases at first diagnosis. All patients had mutation positive EGFR, 12 (66%) had Del19 and 6 (34%) exon 21 mutation. Median progression-free survival was 17 months and OS 23 months. The main grade 1–2 toxicities were rash (44%) and diarrhea (22%). No grade 3–4 toxicity and no cases of drug discontinuation were reported.

Conclusions:

In South American population with mutated mNSCLC, a dose of 75 mg/d of erlotinib was well tolerated. This dose resulted in comparable benefits in progression-free survival and OS when compared to those reported in the literature with the standard dose. More studies are needed to explore the use of adjusted doses of biological agents in different ethnic backgrounds.
Is autologous stem cell transplantation still relevant for multiple myeloma?
Authors: Choi Taewoong
Published: September 2019

Purpose of review

Autologous stem cell transplantation has been the standard of care in myeloma treatment for many years, but the availability of newer antimyeloma drugs and the emerging data from chimeric antigen receptor (CAR) T-cell clinical studies make us question the relevance of it. The purpose of this review is to go over recent data and to reassess the current status of autologous stem cell transplantation as a standard of care.

Recent findings

Autologous stem cell transplantation can be safely performed for elderly patients and there is no absolute age limit. Recent data on BEAM (Carmustine, Etoposide, Cytarabine, and Melphalan), Busulfan/Melphalan, and Carmustine/Melphalan conditioning when compared with Melphalan showed favorable survival outcomes with manageable toxicities although we need to see data from randomized, multicenter studies. Posttransplant maintenance and consolidation can maximize the benefit of transplant by prolonging progression-free survival. Current B-cell maturation antigen CAR T-cell therapy showed remarkably high response rates, but didn’t seem to provide durable response yet.

Recent advances in myeloma therapy and autologous stem cell transplantation are described. Although we’ve seen many new developments including CAR T-cell therapies, autologous stem cell transplantation remains as the standard of care. However, it may be replaced by or combined with newer therapies in the future.
Corticosteroids
Authors: Kapugi Michelle , Cunningham Kathleen
Published: September 2019

Corticosteroids are commonly prescribed for a variety of indications due to the wide range of effects on the human body. Although they exhibit many therapeutic uses, corticosteroids are unfortunately known for their many dose- and duration-dependent toxicities. The purpose of this review is to explore indications for corticosteroid use, differences among formulations, and adverse effects and their management.
Discharge Processes
Authors: Luther Brenda , Wilson Rebecca D. , Kranz Clare , Krahulec Melody
Published: September 2019

The quality of discharge teaching is statistically linked to decreased readmission rates. Nursing most often bears the major responsibility of patient and caregiver teaching. Currently, discharge teaching is complicated by problems including time constraints, patient and caregiver overload, and coexisting comorbidities that add complexity to the patient's care needs at home. Not only are readmissions a preventable cost, more importantly, but they also are a negative patient experience signifying to our patients that they are unable to optimally care for themselves or that their disease or healing is not something they can care for alone. The following is a review of Agency for Healthcare Research and Quality's IDEAL discharge process, common problems in discharge teaching, and nursing's responsibilities with assessing a patient and his or her caregiver for discharge readiness. IDEAL is a structured discharge process with tools to help healthcare organizations improve their discharge process to decrease readmissions rates.
SOX9 Immunohistochemistry in the Distinction of Angiomatoid Fibrous Histiocytoma From Histologic Mimics: Diagnostic Utility and Pitfalls
Authors: Berklite Lara , John Ivy , Ranganathan Sarangarajan , Parafioriti Antonina , Alaggio Rita
Published: September 2019

Angiomatoid fibrous histiocytoma (AFH) can be diagnostically difficult because of its varied histologic appearance and potential to occur at unusual sites. The identification of recurrent rearrangements (EWSR1-CREB1, EWSR1-ATF1, and FUS-ATF1) is a helpful diagnostic tool. Additional immunohistochemical markers in AFH could aid in restricting the differential diagnosis and selecting appropriate cases for targeted molecular studies. SOX9 is a transcription factor that is crucial for chondrogenesis and is expressed in neoplasms with chondroid differentiation, and other malignant bone and soft tissue tumors. Recently a role of EWS in regulation of SOX9 expression has been reported, the rearrangements typical of AFH may play a role in SOX9 expression. In this study, we analyzed SOX9 expression in 13 pediatric AFH with varying histology, and an additional 80 cases of other myofibroblastic or fibrohistiocytic lesions. SOX9 expression was present in 11 of 13 AFH, 2 of 53 dermatofibroma (1 aneurysmal and 1 cellular) and 1 calcifying aponeurotic fibroma. The remaining tumors were negative. SOX9 is selectively expressed in AFH and may be a useful maker in combination with desmin, CD99, CD68, and EMA in small biopsies, especially in cases with unusual morphologic features. SOX9 appears to be highly specific for AFH, being weakly expressed in a subset of aneurysmal dermatofibroma and absent in other myofibroblastic lesions, except calcifying aponeurotic fibroma. It should be used with caution when differentiating AFH from malignant neoplasms such as Ewing sarcoma.
Milan-out Criteria and Worse Intention-to-Treat Outcome Postliver Transplantation
Authors: Herreras Julia , Di Maira Tommaso , Vinaixa Carmen , San Juan Fernando , Rubín Ángel , Berenguer Marina
Published: September 2019

Background.

Milan criteria are widely used for liver transplantation selection in hepatocellular carcinoma but have been recognized to be too restrictive. Milan-out criteria are increasingly being adopted. Our aim was to analyze if liver transplantation waitlisted Milan-out hepatocellular carcinoma patients have different outcome than Milan patients.

Methods.

Retrospective study including all consecutive patients with hepatocellular carcinoma admitted in the waiting list for liver transplantation between January 2012 and January 2015. We included 177 patients, 146 of which eventually transplanted. Downstaging was achieved in the Milan-out cases (n = 29) before waitlisting.

Results.

From diagnosis to last follow-up, 29% patients died. Survival at 1 and 5 years from diagnosis was 93% and 75%, respectively in the within Milan group compared with 91% and 61% in the Milan-out group (P = 0.03). Treatment failure occurred in 20% of cases due to tumor progression in the waiting list (44%), death on the waiting list (20%), and hepatocellular carcinoma recurrence postliver transplantation (9%). Milan-out criteria was the only variable predictive of treatment failure remaining in the multivariate analysis with a hazard ratio (HR) of 1.7 (HR, 1.7; 95% confidence interval, 1.34-4.55; P = 0.010) and HR of 1.43 (1.23-6.5) in the hepatocellular carcinoma recurrence.

Conclusions.

Milan-out criteria are associated with a higher intention-to-treat liver transplantation failure from time of inclusion in the waiting list. However, survival rates are still >50% at 5 years of follow-up.
Outcomes of Liver Transplantation in Patients on Renal Replacement Therapy: Considerations for Simultaneous Liver Kidney Transplantation Versus Safety Net
Authors: Pita Alejandro , Kaur Navpreet , Emamaullee Juliet , Lo Mary , Nguyen Brian , Sabour Andrew , Tristan Vincent , Nadim Mitra , Genyk Yuri , Sher Linda
Published: September 2019

Background.

As the liver transplant (LT) waiting list continues to outpace organ availability, many patients require renal replacement therapy (RRT) before LT. It is unclear which patients will benefit from simultaneous liver kidney (SLK) transplant as opposed to awaiting a Safety Net kidney transplant (KT) post-LT.

Methods.

In this study, a retrospective analysis of the United Network for Organ Sharing dataset was performed to identify risk factors associated with poor outcome for patients on RRT before LT who were listed for SLK and received either SLK vs LT alone (LTA).

Results.

Between January 2003 and December 2016, 8971 adult LT recipients were on RRT at the time of LT. 5359 were listed for and received LTA (Group 1). Of 3612 patients listed for SLK, 3414 (38.1%) received SLK (Group 2) and 198 (2.2%) received LTA (Group 3). Overall, Group 3 had lower graft and patient survival post-LT when compared with Groups 1 and 2 (P < 0.001). Serum creatinine at 1 year post-LT and cumulative incidence for KT at 3 years post-LT were higher for Group 3 (P < 0.001). On multivariate analysis, pre-LT diabetes (P = 0.002), Model of End-Stage Liver Disease score (P = 0.01), and donor kidney donor profile index (P = 0.025) were significant in Group 2. Recipient age >60 (P < 0.001) and RRT pre-LT (>90 days; P = 0.001) were associated with lower patient survival in Group 3.

Conclusions.

Among LT recipients on RRT before LT who were listed for SLK, RRT >90 days, and age >60 were associated with poor outcome following LTA. This suggests that programs should carefully weigh the decision to proceed with LTA vs waiting for SLK in this patient population. Future access to Safety Net KT will be an important consideration for these patients moving forward.
Paired Associative Stimulation Fails to Induce Plasticity in Freely Behaving Intact Rats
Authors: Ting Windsor Kwan-Chun , Huot-Lavoie Maxime , Ethier Christian
Published: September 2019

Paired Associative Stimulation (PAS) has been explored in humans as a non-invasive tool to drive plasticity and promote recovery after neurological insult. A more thorough understanding of the phenomenon of PAS-induced plasticity is needed to fully harness it as a clinical tool. Here, we tested a PAS model in awake rats in order to study the principles of associative plasticity. Using chronically implanted electrodes in motor cortex and forelimb, we explored PAS parameters to effectively change corticomotor excitability, assessed using closed loop, EMG-controlled cortical stimulation. We tested eleven stimulation intervals, chosen to force the coincidence of neuronal activity in the rats’ motor cortex and spinal cord, with timings relevant to the principles of Hebbian spike-timing-dependent plasticity. However, despite a relatively large number of stimulus pairings (300), none of the tested intervals reliably changed corticospinal excitability relative to control conditions. Our results question PAS effectiveness under these conditions.
Direct and High-Throughput Assays for Human Cell Killing through Trogocytosis byEntamoeba histolytica
Authors: Bettadapur Akhila , Ralston Katherine S.
Published: September 2019

Entamoeba histolyticais a microbial eukaryote and causative agent of the diarrheal disease amoebiasis. Pathogenesis is associated with profound damage to human tissues, and treatment options are limited. We discovered that amoebae attack and kill human cells through a cell-nibbling process that we named trogocytosis (trogo-:nibble). Trogocytosis is likely to underlie tissue damage during infection and it represents a potential target for therapeutic intervention, although the mechanism is still unknown. Assays in current use to analyze trogocytosis by amoebae have not been amenable to studying different types of human cells, or to high-throughput analysis. Here, we developed two complementary assays to measure trogocytosis by quantifying human cell viability, both of which can be used for suspension and adherent cells. The first assay uses CellTiterGlo, a luminescent readout for cellular ATP levels, as a proxy for cell viability. We found that the CellTiterGlo signal is proportional to the quantity of viable cells, and can be used to detect death of human cells after co-incubation with amoebae. We established a second assay that is microscopy-based and uses two fluorescent stains to directly differentiate live and dead human cells. Both assays are simple and inexpensive, can be used with suspension and adherent human cell types, and are amenable to high-throughput approaches. These new assays are tools to improve understanding of amoebiasis pathogenesis.
Deep learning-based auto-segmentation of swallowing and chewing structures
Authors: Iyer Aditi , Thor Maria , Haq Rabia , Deasy Joseph O. , Apte Aditya P.
Published: September 2019

Purpose

Delineating the swallowing and chewing structures in Head and Neck (H&N) CT scans is necessary for radiotherapy treatment (RT) planning to reduce the incidence of radiation-induced dysphagia, trismus, and speech dysfunction. Automating this process would decrease the manual input required and yield reproducible segmentations, but generating accurate segmentations is challenging due to the complex morphology of swallowing and chewing structures and limited soft tissue contrast in CT images.

Methods

We trained deep learning models using 194 H&N CT scans from our institution to segment the masseters (left and right), medial pterygoids (left and right), larynx, and pharyngeal constrictor muscle using DeepLabV3+ with the resnet-101 backbone. Models were trained in a sequential manner to guide the localization of each structure group based on prior segmentations. Additionally, an ensemble of models was developed using contextual information from three different views (axial, coronal, and sagittal), for robustness to occasional failures of the individual models. Output probability maps were averaged, and voxels were assigned labels corresponding to the class with the highest combined probability.

Results

The median dice similarity coefficients (DSC) computed on a hold-out set of 24 CT scans were 0.87±0.02 for the masseters, 0.80±0.03 for the medial pterygoids, 0.81±0.04 for the larynx, and 0.69±0.07for the constrictor muscle. The corresponding 95th percentile Hausdorff distances were 0.32±0.08cm (masseters), 0.42±0.2cm (medial pterygoids), 0.53±0.3cm (larynx), and 0.36±0.15cm (constrictor muscle). Dose-volume histogram (DVH) metrics previously found to correlate with each toxicity were extracted from manual and auto-generated contours and compared between the two sets of contours to assess clinical utility. Differences in DVH metrics were not found to be statistically significant (p>0.05) for any of the structures. Further, inter-observer variability in contouring was studied in 10 CT scans. Automated segmentations were found to agree better with each of the observers as compared to inter-observer agreement, measured in terms of DSC.

Conclusions

We developed deep learning-based auto-segmentation models for swallowing and chewing structures in CT. The resulting segmentations can be included in treatment planning to limit complications following RT for H&N cancer. The segmentation models developed in this work are distributed for research use through the open-source platform CERR, accessible at https://github.com/cerr/CERR.
Personalized Cancer Therapy Prioritization Based on Driver Alteration Co-occurrence Patterns
Authors: Mateo Lidia , Duran-Frigola Miquel , Gris-Oliver Albert , Palafox Marta , Scaltriti Maurizio , Razavi Pedram , Chandarlapaty Sarat , Arribas Joaquin , Bellet Meritxell , Serra Violeta , Aloy Patrick
Published: September 2019

Identification of actionable genomic vulnerabilities is the cornerstone of precision oncology. Based on a large-scale drug screening in patient derived-xenografts, we uncover connections between driver gene alterations, derive Driver Co-Occurrence (DCO) networks, and relate these to drug sensitivity. Our collection of 53 drug response predictors attained an average balanced accuracy of 58% in a cross-validation setting, which rose to a 66% for the subset of high-confidence predictions. Morevover, we experimentally validated 12 out of 14de novopredictions in mice. Finally, we adapted our strategy to obtain drug-response models from patients’ progression free survival data. By revealing unexpected links between oncogenic alterations, our strategy can increase the clinical impact of genomic profiling.
Wood capacitance is related to water content, wood density, and anatomy across 30 temperate tree species
Authors: Ziemińska Kasia , Rosa Emily , Gleason Sean M. , Holbrook N. Michele
Published: September 2019

Water released from wood tissue during transpiration (capacitance) can meaningfully affect daily water use and drought response. To provide context for better understanding of capacitance mechanisms, we investigated links between capacitance and wood anatomy. On twig wood of 30 temperate angiosperm tree species, we measured capacitance, water content, wood density, and anatomical traits, i.e., vessel dimensions, tissue fractions, and vessel-tissue contact fractions (fraction of vessel circumference in contact with other tissues). Across all species, the strongest predictors of capacitance were wood density (WD) and predawn lumen volumetric water content (VWCL-pd,r2adj=0.44,P<0.0001). Vessel-tissue contact fractions explained an additional ∼10% of the variation in capacitance. Regression models were not improved by including predawn relative water content (RWCpd) or tissue lumen fractions. Among diffuse-porous species, VWCL-pdand vessel-ray contact fraction were the best predictors of capacitance, whereas among ring/semi-ring-porous species, VWCL-pd, WD and vessel-fibre contact fraction were the best predictors. Mean RWCpdwas 0.65±0.13 and uncorrelated with WD. VWCL-pdwas weakly negatively correlated with WD. Our findings imply that capacitance depends on the amount of stored water, tissue connectivity and the bulk wood properties arising from WD (e.g., elasticity), rather than the fraction of any particular tissue.
Autoencoder-based cluster ensembles for single-cell RNA-seq data analysis
Authors: Geddes Thomas A , Kim Taiyun , Nan Lihao , Burchfield James G , Yang Jean YH , Tao Dacheng , Yang Pengyi
Published: September 2019

Background

Single-cell RNA-sequencing (scRNA-seq) is a transformative technology, allowing global transcriptomes of individual cells to be profiled with high accuracy. An essential task in scRNA-seq data analysis is the identification of cell types from complex samples or tissues profiled in an experiment. To this end, clustering has become a key computational technique for grouping cells based on their transcriptome profiles, enabling subsequent cell type identification from each cluster of cells. Due to the high feature-dimensionality of the transcriptome (i.e. the large number of measured genes in each cell) and because only a small fraction of genes are cell type-specific and therefore informative for generating cell type-specific clusters, clustering directly on the original feature/gene dimension may lead to uninformative clusters and hinder correct cell type identification.

Results

Here, we propose an autoencoder-based cluster ensemble framework in which we first take random subspace projections from the data, then compress each random projection to a low-dimensional space using an autoencoder artificial neural network, and finally apply ensemble clustering across all encoded datasets for generating clusters of cells. We employ four evaluation metrics to benchmark clustering performance and our experiments demonstrate that the proposed autoencoder-based cluster ensemble can lead to substantially improved cell type-specific clusters when applied with both the standard k-means clustering algorithm and a state-of-the-art kernel-based clustering algorithm (SIMLR) designed specifically for scRNA-seq data. Compared to directly using these clustering algorithms on the original datasets, the performance improvement in some cases is up to 100%, depending on the evaluation metrics used.

Conclusions

Our results suggest that the proposed framework can facilitate more accurate cell type identification as well as other downstream analyses. The code for creating the proposed autoencoder-based cluster ensemble framework is freely available from https://github.com/gedcom/autoencoder_cluster_ensemble
Library of model implementations for sharing deep-learning image segmentation and outcomes models
Authors: Apte Aditya P. , Iyer Aditi , Thor Maria , Pandya Rutu , Haq Rabia , Shukla-Dave Amita , Yu-Chi Hu , Elguindi Sharif , Veeraraghavan Harini , Oh Jung Hun , Jackson Andy , Deasy Joseph O.
Published: September 2019

An open-source library of implementations for deep-learning based image segmentation and outcomes models is presented in this work. As oncology treatment planning becomes increasingly driven by automation, such a library of model implementations is crucial to (i) validate existing models on datasets collected at different institutions, (ii) automate segmentation, (iii) create ensembles for improving performance and (iv) incorporate validated models in the clinical workflow. The library was developed with Computational Environment for Radiological Research (CERR) software platform. CERR is a natural choice to centralize model implementations due to its comprehensiveness, popularity, and ease of use. CERR provides well-validated feature extraction for radiotherapy dosimetry and radiomics with fine control over the calculation settings. This allows users to select the appropriate feature calculation used in the model derivation. Models for automatic image segmentation are distributed via Singularity containers, with seamless i/o to and from CERR. Singularity containers allow for segmentation models to be deployed with a variety of scientific computing architectures. Deployment of models is driven by JSON configuration file, making it convenient to plug-in models. Models from the library can be called programmatically for batch evaluation. The library includes implementations for popular radiotherapy models outlined in the Quantitative Analysis of Normal Tissue Effects in the Clinic effort and recently published literature. Radiomics models include features from Image Biomarker Standardization features found to be important across multiple sites and image modalities. Deep learning-based image segmentation models include state of the art networks such as Deeplab and other problem-specific architectures. The library is distributed as GNU-copyrighted software at https://www.github.com/cerr/CERR.
Astrovirus in Reunion Free-tailed Bat (Mormopterus francoismoutoui)
Authors: Joffrin Léa , Hoarau Axel O. G. , Lagadec Erwan , Köster Marie , Ramanantsalama Riana V. , Mavingui Patrick , Lebarbenchon Camille
Published: September 2019

Astroviruses (AstVs) are RNA viruses infecting of a large diversity of avian and mammalian species, including bats, livestock, and humans. We investigated AstV infection in a free-tailed bat species, Mormopterus francoismoutoui, endemic to Reunion Island. A total of 380 guano samples were collected in a maternity colony during 38 different sampling sessions, from June 21st 2016 to September 4th 2018. Each sample was tested for the presence of the AstV RNA-dependent RNA-polymerase (RdRp) gene using a pan-AstV semi-nested polymerase chain reaction assay. In total, 27 guano samples (7.1%) tested positive, with high genetic diversity of the partial RdRp gene sequences among positive samples. A phylogenetic analysis further revealed that the detected viruses were genetically related to AstVs reported in rats, reptiles, dogs, and pigs, but did not cluster with AstVs commonly found in bats. Although more investigations need to be conducted to assess the prevalence of infected bats in the studied population, our findings show that Reunion free-tailed bats are exposed to AstVs, and suggest that cross-species transmission may occur with other hosts sharing the same habitat.
IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infection
Authors: Zhang Zhan , Zou Jun , Shi Zhenda , Zhang Benyue , Etienne-Mesmin Lucie , Chassaing Benoit , Gewirtz Andrew T.
Published: September 2019

Administration of bacterial flagellin elicits production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede this virus. Although IL-18 and IL-22 induce each other’s expression, we found that IL-18 and IL-22 both impeded RV independently of each other and did so by distinct mechanisms, in both cases via activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced pyroptotic death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in levels of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that IL-18/22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.
The effects of data adequacy and calibration size on the accuracy of presence-only species distribution models
Authors: Santika Truly , Hutchinson Michael F. , Wilson Kerrie A.
Published: September 2019

Presence-only data used to develop species distribution models are often biased towards areas that are frequently surveyed. Furthermore, the size of calibration area with respect to the area covered by the species occurrences has been shown to affect model accuracy. However, existing assessments of the effect of data inadequacy and calibration size on model accuracy have predominately been conducted using empirical studies. These studies can give ambiguous results, since the data used to train and test the model can both be biased.

These limitations were addressed by applying simulated data to assess how inadequate data coverage and the size of calibration area affect the accuracy of species distribution models generated by MaxEnt and BIOCLIM. The validity of four presence-only performance measures, Contrast Validation Index (CVI), Boyce index, AUC and AUCratio, was also assessed.

CVI, AUC and AUCratio ranked the accuracy of univariate models correctly according to the true importance of their defining environmental variable, a desirable property of an accuracy measure. Contrastingly, Boyce index failed to rank the accuracy of univariate models correctly and a high percentage of irrelevant variables produced models with a high Boyce index.

Inadequate data coverage and increased calibration area reduced model accuracy by reducing the correct identification of the dominant environmental determinant. BIOCLIM outperformed MaxEnt models in predicting the true distribution of simulated species with a symmetric dominant response. However, MaxEnt outperformed BIOCLIM in predicting the true distribution of simulated species with skew and linear dominant responses. Despite this, the standard performance measures consistently overestimated the performance of MaxEnt models and showed them as always having higher model accuracy than the BIOCLIM models.

It has been acknowledged that research should be directed towards testing and improving species distribution modelling tools, particularly how to handle the inevitable bias and scarcity of species occurrence data. Simulated data, as demonstrated here, provides a powerful approach to comprehensively test the performance of modelling tools and to disentangle the effects of data properties and modelling options on model accuracy. This may be impossible to achieve using real-world data.
The strand-biased mitochondrial DNA methylome and its regulation by DNMT3A
Authors: Dou Xiaoyang , Boyd-Kirkup Jerome D. , McDermott Joseph , Zhang Xiaoli , Li Fang , Rong Bowen , Zhang Rui , Miao Bisi , Chen Peilin , Cheng Hao , Xue Jianhuang , Bennett David , Wong Jiemin , Lan Fei , Han Jing-Dong J.
Published: September 2019

How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in humans and other animals are strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene–gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene bodies and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand-specific non-CpG methylation, its dynamic regulation, and its impact on the polycistronic mitochondrial transcript processing.
Discovery of high-confidence human protein-coding genes and exons by whole-genome PhyloCSF helps elucidate 118 GWAS loci
Authors: Mudge Jonathan M. , Jungreis Irwin , Hunt Toby , Gonzalez Jose Manuel , Wright James C. , Kay Mike , Davidson Claire , Fitzgerald Stephen , Seal Ruth , Tweedie Susan , He Liang , Waterhouse Robert M. , Li Yue , Bruford Elspeth , Choudhary Jyoti S. , Frankish Adam , Kellis Manolis
Published: September 2019

The most widely appreciated role of DNA is to encode protein, yet the exact portion of the human genome that is translated remains to be ascertained. We previously developed PhyloCSF, a widely used tool to identify evolutionary signatures of protein-coding regions using multispecies genome alignments. Here, we present the first whole-genome PhyloCSF prediction tracks for human, mouse, chicken, fly, worm, and mosquito. We develop a workflow that uses machine learning to predict novel conserved protein-coding regions and efficiently guide their manual curation. We analyze more than 1000 high-scoring human PhyloCSF regions and confidently add 144 conserved protein-coding genes to the GENCODE gene set, as well as additional coding regions within 236 previously annotated protein-coding genes, and 169 pseudogenes, most of them disabled after primates diverged. The majority of these represent new discoveries, including 70 previously undetected protein-coding genes. The novel coding genes are additionally supported by single-nucleotide variant evidence indicative of continued purifying selection in the human lineage, coding-exon splicing evidence from new GENCODE transcripts using next-generation transcriptomic data sets, and mass spectrometry evidence of translation for several new genes. Our discoveries required simultaneous comparative annotation of other vertebrate genomes, which we show is essential to remove spurious ORFs and to distinguish coding from pseudogene regions. Our new coding regions help elucidate disease-associated regions by revealing that 118 GWAS variants previously thought to be noncoding are in fact protein altering. Altogether, our PhyloCSF data sets and algorithms will help researchers seeking to interpret these genomes, while our new annotations present exciting loci for further experimental characterization.