bluuebunny/crossref_metadata_2025 huggingface dataset:
Modern Comparative Physiology: Under Krogh’s Umbrella
Authors: Basile Anthony J. , Kirkton Scott D. , Hedrick Michael S. , Sweazea Karen L.
Published: April 2020

August Krogh’s principle, “For such a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied” is credited as the cornerstone of comparative physiology. Today, there appears to be some confusion among physiologists as to what type of research falls under the comparative physiology approach. To identify how comparative physiologists and general physiologists define comparative physiology, 54 physiology organizations were contacted and requested to share a cross‐sectional online survey with their members. In total, 245 participants consented to the study with 87% identifying as comparative physiologists (22% as general physiologists). Participants came from 18 countries and were members of 45 physiology or science societies/organizations. When asked to define comparative physiology, the three most common words in the definitions (n=197) were (in descending order): ‘different’, ‘physiology’, ‘animals’. The three most prevalent themes among responses were: comparing/differences across species (68% of responses), only animal research (42%), and environmental/ecological variable (26%). While Krogh’s principle is central to comparative physiology, only 5% of responses either mentioned or described Krogh’s principle. To further determine the participants’ understanding of comparative physiology, a multiple‐choice question was created which asked “Please identify the Comparative Physiology perspective below. Select all that apply.” The most common selected answer among participants (91%; no significant difference between comparative and general physiologists; Chi‐square test: p=0.088) was the ‘comparative physiology ‐ human focused’ perspective which states “Studying how digestion functions in snakes compared to humans.” Further, 49% of all participants selected all five choices for their answer; however, more comparative physiologists selected all five choices compared with general physiologists (50% versus 8%; Chi‐square test: p=<0.001). In conclusion, it appears that comparative physiology has become an umbrella term for a collection of research approaches including Krogh’s Principle and other research themes, such as, but not limited to: 1) simply comparing across species with or without considering evolution, 2) comparing animal to human physiology, or 3) studying extreme or unique traits. While Krogh emphasized comparing physiological systems across animals to determine generalizations, among surveyed physiologists, Krogh’s Principle per se is not the guiding focus in the field of comparative physiology.
Inhibition of Src, SIRT1 or HDAC6 Reduces Transendothelial Migration of Acute Lymphoblastic Leukemia B cells
Authors: Camacho Karina Elizabeth Jimenez , Martinez Ramon Castellanos , Schnoor Michael
Published: April 2020

B‐cell acute lymphoblastic leukemia (B‐ALL) is the most common leukemia in children. B‐ALL cells have the ability to extravasate and infiltrate bone marrow and organs such as lungs, testis and central nervous system. Dynamic actin cytoskeletal remodeling is needed to accomplish transendothelial migration. Cortactin is an actin‐binding protein which accumulates in lamellipodia and invadopodia and regulates neutrophil transendothelial migration during inflammation. Cortactin is overexpressed in B‐cells of B‐ALL patients, and significantly correlates with bone marrow colonization, organ infiltration, drug resistance and disease relapse. Cortactin is a target of Src kinase, and the deacetylases SIRT1 and HDAC6 and as such is prone for post‐translational modifications that regulate its function and localization. Phosphorylation of cortactin at residue Y421 supports lamellipodia and invadopodia formation, whereas acetylation of cortactin diminishes its affinity for F‐actin and decreases cell migration. However, it remains to be explored whether these modifications are required for the migratory advantage that cortactin overexpression bestows on B‐ALL cells. Thus, in this project, we investigate: first, whether pharmacological inhibition of Src, HDAC6 and SIRT1 in leukemic B‐cells reduce transendothelial migration and bone marrow colonization; and second, whether these effects depend on cortactin overexpression. We found that cortactin is constitutively phosphorylated at Y421 in the pre‐B ALL cell line REH and that this phosphorylation is increased after CXCL12 stimulation over time. Of note, Src kinase inhibition with PP2 in leukemic B cells reduced phospho‐cortactin levels and impaired leukemic cell transmigration across HUVEC monolayers and BM organoid colonization. These data suggest that src‐mediated cortactin phosphorylation is required to trigger transmigration. This idea will be further corroborated using cortactin‐depleted REH cells. Moreover, SIRT1 inhibition with EX‐527 and HDAC6 inhibition with Tubastatin‐A also significantly reduced transendothelial migration and bone marrow organoid colonization suggesting that cortactin activation is also regulated by its acetylation status. Taken together, these findings highlight the importance of post‐translational modifications for the regulation of migratory processes of leukemic B cells. Future analysis of the underlying exact molecular mechanisms will contribute to a better understanding of B‐ALL disease progression.
Prenatal Histological, Cellular and Molecular Anomalies in Down Syndrome Lung
Authors: Danopoulos Soula , Bhattacharya Soumyaroop , Deutsch Gail , Mariani Thomas , Alam Denise Al
Published: April 2020

Rationale

Down Syndrome (DS), from trisomy 21 (T21), is the most common human chromosomal anomaly in the United States. Although DS can affect many organ systems, lung and heart disease are the leading causes of death. An abundance of existing data suggests lung abnormalities originate postnatally in DS. However, a single report of branching insufficiency in DS has inferred a potential prenatal origin.

Methods

Prenatal DS lung histology (n=15) was assessed by H&E. Comprehensive gene expression assessment in prenatal DS lungs (n=19), and age‐matched controls (n=19), was performed using high‐throughput RNA sequencing (RNAseq) and validated by qPCR. Spatial differences in cellular phenotypes were examined using immunohistochemistry (IHC) and in situ hybridization (ISH).

Results

Histopathological abnormalities were observed in approximately half of DS (T21) prenatal lung tissue samples analyzed, and included dilated airway terminal airways/acinar tubules, dilated lymphatics and muscularized arteries. RNAseq identified 316 genes significantly dysregulated in DS lung tissue (FDR <0.05), when adjusted for age. Ontology analysis showed IFN pathway genes were significantly up‐regulated and extracellular matrix pathway genes were significantly down‐regulated. qPCR confirmed increased expression of interferon (IFN) pathway genes (MX1, IFIT27), COL6A1, and FABP4, and lower expression of SOX2 in prenatal DS lungs. ISH indicated increased IFN receptor expression in DS lung tissue. IHC for KI67 revealed significant reductions in epithelial and mesenchymal cell proliferation, predominantly in those tissues displaying pathology. Airway smooth muscle was reduced and discontinuous in the proximal airway. Reduction in SOX2 was confirmed by IHC, suggesting a reduction in prenatal airway progenitor cells.

Conclusions

Our data demonstrate for the first time that specific histological, cellular and molecular abnormalities occur prenatally in the human DS lung.

Support or Funding Information

Funding Source: NIH/NHLBI HL141856 and Program in Pediatric Molecular and Personalized Medicine of University of Rochester.
Characterization of p38 Inflammatory Response in Human Pericytes
Authors: Roos Morgan , Grimsey Neil
Published: April 2020

G protein‐coupled receptor (GPCR) mediated mitogen activated protein kinase (MAPK) p38 activation is a crucial regulator of pro‐inflammation and pro‐angiogenic responses during chronic lung disease. Our studies have revealed an atypical (non‐canonical) pathway for p38 activation that induces auto‐phosphorylation of p38 through the direct binding of transforming growth factor β activated kinase 1 binding protein‐1 (TAB1) in endothelial cells. However, during angiogenesis, endothelial cells are known for their rapid reproduction, migration, and tubule formation. Pericyte cells serve to guide these endothelial cells, providing vascular stability and cytokine signaling. During inflammation, pericytes migrate away from the vasculature leaving endothelial tubules exposed and fragile. Atypical p38 activation has not yet been examined in pericyte cells, but is hypothesized to play a key role in regulating G protein‐coupled receptor‐mediated control of vascular function. Very little is known about the cellular mechanisms that control atypical p38 activation, representing a novel therapeutic target. Our preliminary data shows that thrombin and histamine can activate p38 via the atypical p38 signaling pathway in primary human pericytes. As the role of GPCR induced p38 signaling in pericytes has not been examined, our current studies focus on defining this role, including establishing a co‐cultured model of pericyte and endothelial cells. Using this model, we are the first to define the role of atypical p38 signaling in pericytes, along with their vascular formation and function. These studies represent a novel approach to regulate vascular p38 activity, pro‐inflammatory signaling, and chronic lung disease, and this model will provide us with the tools necessary to identify the role of p38 induced inflammation in the migration of pericyte cells.
Analyzing Murine Microglial Cell Response to Different Types of Particulate Matter
Authors: Merrill Lucas , Buchmann Kelsey , Stadem Nathan , Street Mikayla , Mazzer Paula
Published: April 2020

Alzheimer’s and other neurodegenerative diseases affect nearly 24.3 million individuals globally— a number that will likely increase with the rising world population [1]. Studies conducted in Mexico City, Mexico suggest there may be a link between air pollution and chronic inflammation in the brain [4;5]. Research by Lillian Calderón‐Garcidueñas et al. showed that dogs and humans living in Mexico City, Mexico, a city with high amounts of air pollution, developed higher amounts of inflammation in the brain compared to humans and dogs residing in more rural areas [2;3]. Two hallmarks of Alzheimer’s and other related neurodegenerative diseases are the accumulation of β‐amyloid plaques and oxidative stress resulting in apoptosis. Exposing diesel exhaust particulate (DEP) from an industrial forklift engine (NIST, Boulder, CO) and urban dust (UD) filtered from Washington, D.C. (NIST, Boulder, CO) to cultured murine microglial cells (CRL‐2467; ATCC, Manassas, VA), we measured for the activation, production of reactive oxygen species (ROS), and apoptosis in microglial cells. We measured for caspase‐3 activity using a Caspase‐3/CPP32 Colorimetric Kit (Life Technologies, Fredrick, MD), activation by measuring for TNF‐α using mouse tumor necrosis factor α Elisa Kit (Sigma Aldrich, St. Louis, MO), and measured for ROS using an amplex red assay (ThermoFisher Scientific, Minneapolis, MN). We found a possible increase in TNF‐α production in cells cultured with DEP and no increase in ROS in our cells cultured with neither DEP nor UD.

Support or Funding Information

South Dakota Biomedical Research Infrastructure Network
Development of a dopaminergic neurodegeneration assay using laser cytometry of Caenorhabditis elegans models of Parkinson’s disease
Authors: Akano Emmanuel O. , Casazza Julia A. , Dranchak Patricia , Moritz Amy E. , Free R Benjamin , Inglese James , Sibley David R.
Published: April 2020

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons resulting in bradykinesia, tremor, gait abnormalities, and numerous non‐motor complications. The prevalence and economic burden of PD is increasing due to an aging population. However, there are currently no drugs to halt the progression of this disease. Although loss of dopamine in the basal ganglia is recognized as the hallmark of PD, the molecular mechanisms underlying this loss and subsequent brain dysfunction remain poorly characterized. The majority of PD animal models involve the administration of neurotoxins that target dopaminergic neurons leading to their degeneration, however these models correlate poorly with the disease progression in humans. More accurate models may utilize genetic modulation of PD‐related genes and exhibit progressive neurodegeneration. Here, we report the development of a high‐throughput assay for monitoring dopaminergic neurodegeneration in Caenorhabditis elegans (C. elegans). Two strains of C. elegans containing human PD‐linked genes were used, one expressing mutant (A53T) alpha‐synuclein, and the other expressing mutant (G2019S) leucine‐rich repeat kinase 2 (LRRK2). Both strains express GFP in their dopaminergic neurons and the lines were further crossed into a neuronal RNAi‐sensitive background strain expressing mCherry under a pharyngeal promoter. This allows for the accurate measurement of dopaminergic neurons (via GFP) and a normalization and sorting control of the total number of worms plated (via mCherry). Daily measurements of GFP/mCherry fluorescence intensity were performed using laser cytometry of worms sorted into 384‐well microplates. Robust temporal degeneration of dopaminergic neurons was found to occur within the first eight days of adulthood in the C. elegans models of PD, but not in a wild‐type control strain. The LRRK2 model was particularly severe as total GFP intensity dropped by 75–85% during the time of assay. We determined a signal (cell loss) to baseline ratio of approximately 4‐fold, sufficient for screening applications. Our results indicate that this assay provides a reproducible high‐throughput measurement of dopaminergic neurodegeneration using an in vivo model. Future studies may exploit this model to conduct quantitative high‐throughput screens to identify small molecules capable of inhibiting this neurodegeneration or to use RNAi libraries to identify genes mediating the neurodegenerative response, and hence new drug targets for the treatment of PD.

Support or Funding Information

This study is supported by the intramural program of the NINDS/NIH
Essential role of NFATC4‐S‐palmitoylation to promote IP3R1‐expression required for lysosomal Ca++ homeostasis dysregulated in INCL mice
Authors: Mondal Avisek , Sadhukhan Tamal , Appu Abhilash P. , Bagh Maria B. , Mukherjee Anil B.
Published: April 2020

Infantile Neuronal Ceroid Lipofuscinosis (INCL), commonly known as infantile Batten disease, is a devastating neurodegenerative lysosomal storage disease caused by inactivating mutations in the CLN1 gene. CLN1 encodes palmitoyl‐protein thioesterases‐1 (PPT1), a lysosomal depalmitoylating enzyme essential for degradation of S‐palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Despite this discovery more than two decades ago, the precise molecular mechanism of INCL pathogenesis has remained elusive. Here we report that in the brain of Cln1−/− mice, a reliable animal model of INCL, lysosomal Ca++ levels were significantly lower compared with those of their WT littermates. Moreover, in Cln1−/− mice the levels of inositol 1, 4, 5‐triphosphate receptor type‐1 (IP3R1), which facilitates the transport of Ca++ from the ER to the lysosome, were also substantially lower. We found that NFATC4, the transcription factor that regulates Ip3R1‐expression, requires S‐palmitoylation for its translocation from the cytosol to the nucleus. Notably, we identified ZDHHC2 and ZDHHC4 are the palmitoyl acyl transferases that S‐palmitoylate NFATC4. Moreover, the lower levels of these ZDHHCs, S‐palmitoylation of NFATC4 in Cln1−/− mice was significantly decreased suppressing its translocation from the cytosol to the nucleus. Consequently, low IP3R1 expression in Cln1−/− mouse brain significantly reduced lysosomal Ca++ levels. Notably, the enzymatic activities of Ca++‐dependent lysosomal proteases such as cathepsin D (CD) and tripeptidyl peptidase‐1 (TPP1) were markedly inhibited causing lysosomal accumulation of undegraded substrates. Interestingly, mutations in TPP1 (CLN2) and CD (CLN10), cause late infantile NCL (LINCL) and congenital NCL (CNCL), respectively. Our results reveal a previously unrecognized role of Cln1/Ppt1 in regulating lysosomal Ca++ homeostasis and suggest that dysregulation of lysosomal Ca++ homeostasis may compromise its degradative function and contribute to INCL pathogenesis. Studies to determine whether a brain‐penetrant, PPT1‐mimetic, small molecule, NtBuHA, ameliorates this defect are ongoing.

Support or Funding Information

NIH intramural Fund
Ribosomal DNA Transcription Induced by Acute Resistance Exercise is Dependent on rDNA Gene Dosage but not Promoter Methylation
Authors: von Walden Ferdinand , Figueiredo Vandré , Fernandez-Gonzalo Rodrigo , Murach Kevin , Mobley Brooks , Norrbom Jessica , McCarthy John , Alkner Björn
Published: April 2020

Ribosome biogenesis has been shown to increase following resistance exercise; yet, it is currently unknown how promoter methylation and dosage of rDNA genes influence translational capacity, as well as basal and post‐exercise rDNA transcription rates in skeletal muscle. Moreover, whether ribosome biogenesis is induced in response to acute aerobic exercise is not well characterized in skeletal muscle.

Healthy volunteers (n=30; 18 men and 12 women; 31 ±8 yrs, 25 ±4 kg/m2) were randomized to an acute bout of either aerobic (AE, 45 min biking, 70% VO2max) or resistance exercise (RE, 4 x 7 x 2 exercises), or control (no exercise). Skeletal muscle biopsies were obtained before and at 30 min, 3‐, 8‐and 24 hrs following the exercise session, and RNA/DNA was extracted. Ribosomal DNA transcription and rDNA copy number were assessed using qRT‐PCR. Average methylation of the rDNA promoter (−189 to +47) was investigated using the Agena massARRAY EpiTYPER.

rDNA transcription at baseline was negatively associated with rDNA copy number (r=−0,44, p<0.05) but not with average rDNA promoter methylation. Total RNA was not related to rDNA copy number or degree of methylation of the promoter. RE significantly induced rDNA transcription, whereas AE and control did not. Average methylation of the rDNA promoter (mean: 23%, range: 10–35%) varied among volunteers; however, it was not influenced by exercise at any timepoint. Gene dosage of rDNA strongly correlated to fold‐change in rDNA transcription at the 24h timepoint (r=0.85, p<0.01).

Transcription of the rRNA genes increased following resistance exercise but not following aerobic exercise, indicating specificity of exercise modality in stimulating ribosome biogenesis following exercise. Average rDNA promoter methylation varied between subjects but was not affected by exercise. Dosage of the rRNA genes strongly correlated to resistance exercise induced rDNA transcription suggesting the importance of rDNA copy number for ribosome biogenesis, and likely hypertrophic potential.

Support or Funding Information

Swedish Research Council for Sport Science (FvW); Futurum – the Academy for Health and Care, Region Jönköping County (BA)
Early outcomes of transforaminal percutaneous endoscopic lumbar discectomy for high school athletes with herniated nucleus pulposus of the lumbar spine
Authors: Yamaya Seiji , Okada Yuki , Higashino Kosaku , Sakai Toshinori , Tezuka Fumitake , Yamashita Kazuta , Takata Yoichiro , Nagamachi Akihiro , Chikawa Takashi , Sairyo Koichi
Published: April 2020

There are no reports in the literature on the clinical outcomes of percutaneous endoscopic lumbar discectomy (PELD) for high school athletes suffering from herniated nucleus pulposus (HNP) of the lumbar spine. PELD is a minimally invasive surgical procedure that can be performed under local anesthesia via an 8-mm skin incision. This study examined the outcomes of transforaminal PELD in high school athletes suffering from HNP. Subjects were 18 patients [14 males and four females; mean age 17 (15–18) years] who underwent PELD at our institutions. The events in which the patients competed were baseball (n = 6), softball (n = 2), rugby (n = 2), basketball (n = 2), table tennis (n = 2), American football (n = 1), wrestling (n = 1), track and field (n = 1), and dance (n = 1). All patients underwent PELD under local anesthesia. Back pain was assessed using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) and a visual analog scale (VAS) before and after surgery. Time to return to competitive sport, complications, and rate of recurrence of herniation were examined. All factors assessed by the JOABPEQ were significantly improved after surgery. VAS score was also improved after surgery. Time to return to competitive sport was 7 weeks on average. The rate of return to play was 94.4%. There were no complications, such as dural tear, exiting nerve root injury, or hematoma. One patient had recurrence of HNP. PELD is a promising minimally invasive and effective procedure for high school athletes with HNP.
Evaluation of the functional outcome of a percutaneous technique in correction of excessive anteversion in cerebral palsy
Authors: El Barbary Hassan Magdy , Basha Naguib , Nawwar Ahmed Ibrahim Mohammed , Waly Ehab , Mohamed Mohamed Tageldeen , Badawy Mohamed Youness Ali , Zein Abo Bakr , Hegazy Mohamed , El Barbary Menna , Barakat Ahmed Samir
Published: April 2020

In cerebral palsy, patients’ excessive femoral anteversion is one of the most common skeletal abnormalities. The general agreement is concurrent correction of both soft tissue and bony deformities during the same operative setting by combining open femoral derotation osteotomy (FDO) with soft tissue releases. Fifty-one children (75 lower limbs) with cerebral palsy with a mean age of 10.7 years (range 6–16 years) fulfilling the inclusion criteria who underwent percutaneous FDO and when needed customized soft tissue releases. Derotation was maintained by a pin-in-cast technique. The mean follow-up was 24 m (range 14–36 m) and gross motor function classification system, functional mobility scale (FMS) and anteversion angle using the Staheli rotational profile were evaluated. Femoral anteversion was accurately measured by hip ultrasonography followed by a preoperative three-dimensional gait analysis. Preoperative and postoperative data were statistically analyzed to reveal the validity of this method. Internal and external hip rotation improved significantly (P < 0.001, respectively). Mean cast and Schanz screw application time was 49 days and all patients achieved independent walking for at least 5 m within 7 weeks. FMS, ultrasonography measured hip anteversion and gait kinematics also improved significantly (P < 0.01, respectively). Two patients (3.92%) developed a mild knee flexion contracture which resolved completely with physiotherapy at 12 m. The pins-in-fiberglass cast provides sufficient rigid fixation to constitute a reliable and reproducible method permitting early weight bearing. It is versatile enough to allow concomitant soft tissue procedures and correction of other accompanying bony deformities.
Unplanned ICU Admission From Hospital Wards After Rapid Response Team Review in Australia and New Zealand
Authors: Orosz Judit , Bailey Michael , Udy Andrew , Pilcher David , Bellomo Rinaldo , Jones Daryl
Published: April 2020

Objectives:

To evaluate what proportion of unplanned ICU admissions from hospital wards occurred after rapid response team review and compare baseline characteristics and outcomes of patients admitted after rapid response team review with non-rapid response team-related admissions.

Design:

Multicenter binational retrospective cohort study.

Setting:

One-hundred seventy-eight ICUs across Australia and New Zealand.

Patients:

All adults (≥ 17 yr) in the Australian and New Zealand Intensive Care Society Adult Patient Database between 2012 and 2017.

Interventions:

None.

Measurements and Main Results:

Among 97,181 unplanned ICU admissions from the ward, prior rapid response team review occurred in 55,084 cases (56.7%). Rapid response team patients were slightly older (65.4 [16.9] vs 63.3 [18]), had a higher Acute Physiology and Chronic Health Evaluation III score (64.6 [27.1] vs 54.7 [25.3]) and more frequently had limitations of medical treatment (13.1% vs 8.5%) compared with patients with no rapid response team review. The strongest independent associations with ICU admission following rapid response team review included age, ICU admission diagnosis (especially sepsis-, neurologic-, respiratory-, and cardiovascular-related), tertiary ICU status, and presence of limitations of medical treatment (p < 0.0001 all comparisons). Rapid response team-related ICU admissions had a longer median ICU (2.4 d [1.2–4.6 d] vs 2.1 d [1.0–4.2 d]) and hospital (12.8 d [7.0–23.6 d] vs 10.8 d [5.9–20.3 d]) length of stay, and were more likely to die in the ICU (12.3% vs 7.5%) and in-hospital (20.8% vs 13.5%) (p < 0.0001). After adjusting for illness severity and institution, patients admitted following rapid response team review stayed longer in hospital but were not at increased risk of dying in-hospital (adjusted odds ratio, 1.03; 0.98–1.07).

Conclusions:

In Australia and New Zealand, hospital ward patients admitted to ICU following rapid response team review represent the majority of ward-based ICU admissions, are more chronically and acutely ill, and more frequently have sepsis than those admitted from the ward without rapid response team review. Their unadjusted outcomes are worse, but after adjustment their mortality is similar.
New information flows for cancer registries: testing the use of laboratory data in the province of Reggio Emilia, Italy
Authors: Roncaglia Francesca , Mancuso Pamela , Vicentini Massimo , Vitiello Antonio , Vecchia Luigi , Luminari Stefano , Mangone Lucia , Zorzi Manuel , La Vecchia Carlo , Giorgi Rossi Paolo
Published: April 2020

Introduction

Haematological malignancies often escape the standard information flows of cancer registries because diagnosis is not always based on bone marrow histology but, rather, on other laboratory tests.

Objective

To quantify incident haematological malignancies identified exclusively through the laboratory information system and to measure the impact of that source on the sensitivity and accuracy of registering these malignancies.

Methods

We collected data from the only provincial laboratory of Reggio Emilia on molecular biology, flow cytometry tests and bone marrow smears to detect specific markers of some chronic haematological malignancies. We carried out a record linkage between laboratory reports (period 2013–2017) of patients resident in the province of Reggio Emilia and the Cancer Registry of Reggio Emilia.

Results

Of the 303 patients who underwent at least one of these tests, 85 were not included in our Cancer Registry. Of these 85 patients, 42 had received a diagnosis of cancer: 34 myeloproliferative neoplasms, 3 chronic myeloid leukaemias, 3 myelodysplastic neoplasms, 1 multiple myeloma and 1 chronic lymphocytic leukaemia. We recovered 4.2% of the total number of chronic haemolymphopoietic cancers registered in the study period, accounting for 15% of myeloproliferative neoplasms. For 30% of prelinkage cases, the specificity of the morphological code improved.

Conclusions

Although the laboratory information system’s contribution to the completeness of Cancer Registry incident cases was modest, it is useful to add laboratory data to routine cancer registry information flows due to the increasing use of molecular characterisation and to the phenomenon of dehospitalisation.
SETD2 as a regulator of N6-methyladenosine RNA methylation and modifiers in cancer
Authors: Kumari Subhadra , Muthusamy Srinivasan
Published: April 2020

Cancer is an unpleasant, painful disease. It is one of the most devastating diseases worldwide diminishing many lives. Many genetic and epigenetic changes occur before cancer develops. Mutation in SETD2 gene is one such example. RNA splicing, DNA damage repair, DNA methylation and histone methylation are some of the biological processes mediated by SETD2. SETD2 (histone H3 lysine 36 methyltransferase) is a frequently mutated gene in different types of cancer. Loss of SETD2 is associated with worse prognosis and aggressive phenotypes. Histone modification is one of the epigenetic regulation having a significant effect on gene regulation. N6-methyladenosine (m6A) mRNA modification is a well-known posttranscriptional modification playing a pivotal role in many normal and pathological processes affecting RNA metabolism. SETD2 catalyses H3K36 trimethylation and in turn H3K36me3 guides the deposition of m6A on nascent RNA transcripts. Finally, this review summarizes the deep understanding of the role of SETD2 in RNA methylation/modification and how SETD2 mutation contributes to tumour development.
Role of sex steroid hormones in pelvic organ prolapse
Authors: Reddy Ravali A. , Cortessis Victoria , Dancz Christina , Klutke John , Stanczyk Frank Z.
Published: April 2020

Objective:

Pelvic organ prolapse (POP) affects a significant percentage of women and contributes to major healthcare costs both in the United States and worldwide. This review examines the current understanding of the role of sex steroid hormones (estrogens, androgens, and progesterone) in POP in premenopausal, perimenopausal, and postmenopausal women.

Methods:

We reviewed the relevant studies on POP related to estrogens, androgens, and progesterone in both animal models and humans.

Results:

Estrogen has a profound influence on the synthesis and metabolism of pelvic connective tissues, and may have the ability to both prevent POP and improve prognosis if used therapeutically. There is limited research regarding the role of androgens and progesterone and their receptors in POP and results so far have been contradictory, warranting further study to determine whether changes in androgen and progesterone receptor expression are a cause or effect of POP.

Conclusions:

Because of the role that estrogen plays in maintaining the integrity of pelvic floor connective tissues, we propose that rigorous and well-controlled studies are needed on the role of exogenous estrogen administration as a form of POP prevention.

Video Summary:
http://links.lww.com/MENO/A583.
IBS Patients’ Treatment Expectancy and Motivation Impacts Quality of the Therapeutic Alliance With Provider
Authors: Lackner Jeffrey M. , Quigley Brian M. , Radziwon Christopher D. , Vargovich Alison M.
Published: April 2020

Background:

In the absence of a satisfactory medical or dietary treatment, the quality of the therapeutic alliance between irritable bowel syndrome (IBS) patients and their provider is deemed critical to managing refractory IBS. Surprisingly, little research has been conducted on the nature of the therapeutic alliance, factors that influence it, or practical strategies to improve it. This study sought to identify actionable variables that impact therapeutic alliance in patients with refractory IBS.

Methods:

Subjects included a total of 436 Rome III-diagnosed IBS patients (80% female, mean age=41.39 y) who completed a battery of clinical measures at the beginning of the acute treatment phase of an National Institutes of Health (NIH) behavioral trial. Pretreatment candidate predictor variables were organized into 4 categories: sociodemographic, extraintestinal, interpersonal, clinical (eg, symptom severity, pain intensity), cognitive (eg, treatment motivation, expectancy for improvement). Alliance was assessed by patient and clinician-rated measures of the Working Alliance Inventory after first treatment session.

Results:

Patient reports of alliance were most strongly and consistently predicted by patient access to interpersonal support [β=0.16; 95% confidence interval (CI)=0.07-0.25], motivation for IBS symptom improvement (β=0.12; 95% CI=0.02-0.21), and expectancy of IBS symptom improvement (β=0.35; 95% CI=0.25-0.44). Therapist ratings of alliance also were predicted by patient expectancy of IBS symptom improvement (β=0.16; 95% CI=0.05-0.26).

Conclusion:

When managing IBS, a focus on dynamic factors of treatment motivation, social support, and treatment expectancy may be useful in improving the quality of the therapeutic alliance between patient and clinical gastroenterologist.
The Impact of Donor Asphyxiation or Drowning on Pediatric Lung Transplant Recipients
Authors: Seese Laura , Kilic Arman , Turbendian Harma K. , Sanchez Pablo G. , Diaz-Castrillon Carlos E. , Morell Victor O.
Published: April 2020

Background.

Donors with drowning or asphyxiation (DA) as a mechanism of death (MOD) are considered high risk in pediatric lung transplantation. We sought to evaluate whether recipients of DA donors had negatively impacted outcomes.

Methods.

Pediatric recipients recorded in the United Network for Organ Sharing registry between 2000 and 2019 were included. Primary stratification was donor MOD. Propensity matching with a 1:1 ratio was performed to balance the DA and non-DA MOD donor cohorts. Cox multivariable regression was used to determine the risk-adjusted impact of donor MOD. A subanalysis of the effect of lung allocation score was also evaluated.

Results.

A total of 1016 patients underwent bilateral lung transplantation during the study period, including 888 (85.6%) from non-DA donors and 128 (14.4%) from DA donors. Survival at 90 days, 1 year, and 2 years were similar in the matched and unmatched cohorts regardless of the donor MOD. Moreover, separate risk-adjusted analysis of drowning and asphyxiated donors was similar to other MOD donors at 30 days, 1 year, and 5 years. Similar survival findings persisted regardless of pretransplant lung allocation score. Although the rates of posttransplant stroke (1.0% versus 3.1%, P = 0.04) and the length of hospital stay (19 versus 22 d, P = 0.004) were elevated in the unmatched DA MOD recipients, these differences were mitigated after propensity matching.

Conclusions.

This study evaluated the impact of DA MOD donors in pediatric lung transplant recipients and found similar rates of complications and survival in a propensity-matched cohort. These data collectively support the consideration of DA MOD donors for use in pediatric lung transplantation.
Schizophrenia in a patient with full mutation of Fragile X gene and intellectual disability: a ‘STEP’ towards better understanding
Authors: Das Partha , Johnston Chloe F. , Hossain Serena
Published: April 2020

The Fragile X syndrome is the leading hereditary cause of intellectual disability and Autism Spectrum Disorders. There is paucity of information about psychoses in such patients with little follow up. We report a case of schizophrenia in a male patient diagnosed with Fragile X syndrome. The patient has been followed up for a period of 3 years. The diagnostic and management challenges are discussed. This is a unique case of schizophrenia in Fragile X syndrome. We discuss the common molecular pathways to the expression of both schizophrenia and Fragile X syndrome. This is the first case report of schizophrenia in a patient with diagnosis of Fragile X syndrome in Australia.
A Practical Risk-Score for Early Prediction of Neurological Outcome after Out-of-Hospital Cardiac Arrest –MIRA2CLE2
Authors: Pareek Nilesh , Kordis Peter , Beckley-Hoelscher Nicholas , Pimenta Dominic , Kocjancic Spela Tadel , Jazbec Anja , Nevett Joanne , Fothergill Rachael , Kalra Sundeep , Lockie Tim , Shah Ajay M. , Byrne Jonathan , Noc Marko , MacCarthy Philip
Published: April 2020

Aims

The purpose of this study was to develop a practical risk−score to predict poor neurological outcome after out−of−hospital cardiac arrest (OOHCA) for use on arrival to a Heart Attack Centre.

Methods and Results

Between May 2012 and December 2017, 1055 patients had OOHCA in our region, of whom 373 patients were included in the King's Out of Hospital Cardiac Arrest Registry (KOCAR). We performed prediction modelling with multi-variable logistic regression to identify factors independently predictive of the primary outcome in order to derive a risk score. This was externally validated in two independent cohorts comprising 474 patients. The primary outcome was poor neurological function at 6−month follow−up (Cerebral Performance Category 3-−). Seven independent variables for prediction of outcome were identified: Missed (Unwitnessed) arrest, Initial non-shockable rhythm, non-Reactivity of pupils, Age, Changing intra-arrest rhythms, Low pH<;7.20 and Epinephrine administration. From these variables, the MIRA2CLE2 score was developed which had an AUC of 0.90 in the development and 0.85 and 0.89 in the validation cohorts. 3 risk groups of the MIRA2CLE2 were defined − Low risk (≤2−5.6% risk of poor outcome; Intermediate risk (3−4−55.4% of poor outcome) and high risk (≥5−92.3% risk of poor outcome). The risk-score performance was equivalent in a sub-group of patients referred for early angiography and revascularisation where appropriate.

Conclusions

The MIRA2CLE2 score is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA, which has been developed for simplicity of use on admission to a Heart Attack Centre.
Epidemiological characteristics of an outbreak of Coronavirus Disease 2019 in the Philippines
Authors: Alipio Mark M. , Pregoner Joseph Dave M.
Published: April 2020

The outbreak of Coronavirus disease 2019 (Covid-2019) is a source of great concern in the Philippines. In this paper, we described the epidemiological characteristics of the laboratory-confirmed patients with Covid-2019 in the Philippines as of April 3, 2020 and provided recommendations on how to limit the spread of the disease. Data from the DOH NCOV tracker and University of the Philippines’ Covid-2019 tracker were extracted, from its initiation (January 30, 2020) until the most recent situation report (April 3, 2020). The total number of cases and deaths were stratified by sex, age, and region of the Philippines. Descriptive statistics were used to analyze the demographic profile of the confirmed cases. Case fatality rate, in percent, was calculated by dividing the total number of deaths to the total number of confirmed cases. Results revealed that a total of 3,018 cases of Covid-2019 spread were confirmed across 17 regions in the Philippines. These cases occurred over the course of 73 days through person-to-person transmission, highlighting an extremely high infectivity rate. The 144 deaths accounted for, equate to 4.51 case fatality rate, seemingly lower compared to its predecessors, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), but higher compared to that of United States of America, Germany, mainland China, and neighboring Southeast Asian countries such as Malaysia, Singapore, Brunei, and Thailand. Of the 3,018 confirmed cases, majority were male, elderly, and diagnosed in Metro Manila region. Case fatality rates were higher in male and highest among elderly and Filipinos in the Ilocos region. With the surge on the number of cases, precautionary measures should remain a responsibility, and protocols for prevention need to be set. Adherence to infection control guidelines such as but not limited to frequently handwashing for at least 20 seconds, observing coughing etiquette, wearing of masks, and social distancing should be maintained in order to contain the disease.
Characteristics and outcomes of a cohort of SARS-CoV-2 patients in the Province of Reggio Emilia, Italy
Authors: Rossi Paolo Giorgi , Marino Massimiliano , Formisano Debora , Venturelli Francesco , Vicentini Massimo , Grilli Roberto ,   the Reggio Emilia COVID-19 Working Group
Published: April 2020

Objectives

To describe the age- and sex-specific prevalence of SARS-CoV-2 disease (COVID-19) and its prognostic factors.

Design

Population-based prospective cohort study on archive data.

Setting

Preventive services and hospital care in the province of Reggio Emilia, Northern Italy.

Participants

All 2653 symptomatic patients who tested positive for SARS-CoV-2 from February 27 to April 2, 2020 in the province of Reggio Emilia.

Main outcome measures

Hospitalization and death up to April 2, 2020.

Results

Females had higher prevalence of infection than males below age 50 (2.61 vs. 1.84 ‰), but lower in older ages (16.49 vs. 20.86 ‰ over age 80). Case fatality rate reached 20.7% (22/106) in cases with more than 4 weeks follow up. After adjusting for age and comorbidities, men had a higher risk of hospitalization (hazard ratio (HR) 1.4 95% confidence interval (95% CI) 1.2 to 1.6) and of death (HR 1.6, 95% CI 1.2 to 2.1). Patients over age 80 compared to < age 50 had HR 7.1 (95% CI 5.4 to 9.3) and HR 27.8 (95% CI 12.5 to 61.7) for hospitalization and death, respectively. Immigrants had a higher risk of hospitalization (HR 1.3, 95% CI 0.99 to 1.81) than Italians and a similar risk of death. Risk of hospitalization and of death were higher in patients with heart failure (HR 1.6, 95% CI 1.2 to 2.1and HR 2.3, 95% CI 1.6 to 3.2, respectively), arrhythmia (HR 1.5, 95% CI 1.2 to 1.9 and HR 1.8, 95% CI 1.3 to 2.5, respectively), dementia (HR 1.2, 95% CI 0.9 to 1.8 and HR 1.8, 95% CI 1.1 to 2.8, respectively), ischemic heart disease (HR 1.3, 95% CI 1.0 to 1.7 and HR 1.7, 95% CI 1.2 to 2.5, respectively), diabetes (HR 1.5, 95% CI 1.3 to 1.9 and HR 1.6, 95% CI 1.1 to 2.2, respectively), and hypertensions(HR 1.4, 95% CI 1.2 to 2.6 and HR 1.6, 95% CI 1.2 to 2.1, respectively), while COPD increased the risk of hospitalization (HR 1.9, 95% CI 1.4 to 2.5) but not of death (HR 1.1, 95% CI 0.7 to 1.7). Previous use of ACE inhibitors has no effect on risk of death (HR 0.97, 95% CI 0.69 to 1.34)

Conclusions

The mechanisms underlying these associations are mostly unknown. A deeper understanding of the causal chain from infection, disease onset, and immune response to outcomes may explain how these prognostic factors act.
Smoking is Associated with COVID-19 Progression: A Meta-Analysis
Authors: Patanavanich Roengrudee , Glantz Stanton A.
Published: April 2020

Objective

To determine the association between smoking and progression of COVID-19.

Design

A meta-analysis of 12 published papers.

Data Source

PubMed database was searched on April 6, 2020.

Eligibility criteria and data analysis

We included studies reporting smoking behavior of COVID-19 patients and progression of disease. Search terms included “smoking”, “smoker*”, “characteristics”, “risk factors”, “outcomes”, and “COVID-19”, “COVID”, “coronavirus”, “sar cov-2”, “sar cov 2”. There were no language limitations. One author extracted information for each study, screened the abstract or the full text, with questions resolved through discussion among both authors. A random effects meta-analysis was applied.

Main Outcome Measures

The study outcome was progression of COVID-19 among people who already had the disease.

Results

We identified 12 papers with a total of 9,025 COVID-19 patients, 878 (9.7%) with severe disease and 495 with a history of smoking (5.5%). The meta-analysis showed a significant association between smoking and progression of COVID-19 (OR 2.25, 95% CI 1.49-3.39, p=0.001). Limitations in the 12 papers suggest that the actual risk of smoking may be higher.

Conclusions

Smoking is a risk factor for progression of COVID-19, with smokers having higher odds of COVID-19 progression than never smokers. Physicians and public health professionals should collect data on smoking as part of clinical management and add smoking cessation to the list of practices to blunt the COVID-19 pandemic.

What is already known on this topic

Smoking increases risk and severity of pulmonary infections because of damage to upper airways and a decrease in pulmonary immune function.

What this study adds

Smoking is associated with COVID-19 severity.

Smoking history should be part of clinical management of COVID-19 patients and cessation should be added to the list of practices to blunt the COVID-19 pandemic.
The Conceptualization and Preliminary Evaluation of a Dynamic, Mechanistic Mathematical Model to Assess the Water Footprint of Beef Cattle Production
Authors: Menendez Hector M. , Atzori Alberto S. , Tedeschi Luis O.
Published: April 2020

The water footprint assessment method has helped to bring livestock water use to the forefront of research to address water challenges under the ecological footprint perspective. The current assessment methods of water use make a meaningful assessment of livestock water use difficult as they are mainly static, thus poorly adaptable to understand future scenarios of water use and requirements. They lack the integration of fundamental ruminant nutrition and growth equations within a dynamic context that accounts for short and long-term behavior and time delays associated with economically important beef producing areas. This study utilized the System Dynamics methodology to conceptualize a water footprint for ruminants within a dynamic and mechanistic modeling framework. The problem of beef cattle livestock water footprint assessment was articulated, and a dynamic hypothesis was formed to represent the Texas livestock water use system as the initial step in developing the Texas Beef Water Footprint model (TXWFB). The fulfillment of the dynamic hypothesis required the development of three causal loop diagrams (CLD): cattle population, growth and nutrition, and the livestock water footprint. The CLD provided a framework that captured the daily water footprint of beef (WFB) of the cow-calf, stocker, and feedlot phases and the entire beef supply chain. Preliminary simulations captured the oscillatory behavior of the Texas cattle population and overshoot and collapse behavior, under conditions when regional livestock water resources became scarce. Sensitivity analysis from the hypothesized CLD structures indicated that forage quality was less of an impact on the daily WFBof each cattle phase compared to the use of high concentrate feeds. This study provided a framework concept for the development of a dynamic water footprint model for Texan’s beef cattle production and water sustainability.
Flexible open-source automation for robotic bioengineering
Authors: Chory Emma J , Gretton Dana W , DeBenedictis Erika A , Esvelt Kevin M
Published: April 2020

INTRODUCTION

Liquid handling robots have become a biotechnology staple1,2, allowing laborious or repetitive protocols to be executed in high-throughput. However, software narrowly designed to automate traditional hand-pipetting protocols often struggles to harness the full capabilities of robotic manipulation. Here we present Pyhamilton, an open-source Python package that eliminates these constraints, enabling experiments that could never be done by hand. We used Pyhamilton to double the speed of automated bacterial assays over current software and execute complex pipetting patterns to simulate population dynamics. Next, we incorporated feedback-control to maintain hundreds of remotely monitored bacterial cultures in log-phase growth without user intervention. Finally, we applied these capabilities to comprehensively optimize bioreactor protein production by maintaining and monitoring fluorescent protein expression of nearly 500 different continuous cultures to explore the carbon, nitrogen, and phosphorus fitness landscape. Our results demonstrate Pyhamilton’s empowerment of existing hardware to new applications ranging from biomanufacturing to fundamental biology.