bluuebunny/crossref_metadata_2025 huggingface dataset:
Root causes and outcomes of postoperative pulmonary complications after abdominal surgery: a retrospective observational cohort study
Authors: Fernandes Antero , Rodrigues Jéssica , Lages Patrícia , Lança Sara , Mendes Paula , Antunes Luís , Santos Carla Salomé , Castro Clara , Costa Rafael S. , Lopes Carlos Silva , da Costa Paulo Matos , Santos Lúcio Lara
Published: December 2019

Background

Postoperative pulmonary complications (PPCs) contribute significantly to overall postoperative morbidity and mortality. In abdominal surgery, PPCs remain frequent. The study aimed to analyze the profile and outcomes of PPCs in patients submitted to abdominal surgery and admitted in a Portuguese polyvalent intensive care unit.

Methods

From January to December 2017 in the polyvalent intensive care unit of Hospital Garcia de Orta, Almada, Portugal, we conducted a retrospective, observational study of inpatients submitted to urgent or elective abdominal surgery who had severe PPCs. We evaluated the perioperative risk factors and associated mortality. Logistic regression was performed to find which perioperative risk factors were most important in the occurrence of PPCs.

Results

Sixty patients (75% male) with a median age of 64.5 [47–81] years who were submitted to urgent or elective abdominal surgery were included in the analysis. Thirty-six patients (60%) developed PPCs within 48 h and twenty-four developed PPCs after 48 h. Pneumonia was the most frequent PPC in this sample. In this cohort, 48 patients developed acute respiratory failure and needed mechanical ventilation. In the emergency setting, peritonitis had the highest rate of PPCs. Electively operated patients who developed PPCs were mostly carriers of digestive malignancies. Thirty-day mortality was 21.7%. The risk of PPCs development in the first 48 h was related to the need for neuromuscular blocking drugs several times during surgery and preoperative abnormal arterial blood gases. Median abdominal surgical incision, long surgery duration, and high body mass index were associated with PPCs that occurred more than 48 h after surgery. The American Society of Anesthesiologists physical status score 4 and COPD/Asthma determined less mechanical ventilation needs since they were preoperatively optimized. Malnutrition (low albumin) before surgery was associated with 30-day mortality.

Conclusion

PPCs after abdominal surgery are still a major problem since they have profound effects on outcomes. Our results suggest that programs before surgery, involve preoperative lifestyle changes, such as nutritional supplementation, exercise, stress reduction, and smoking cessation, were an effective strategy in mitigating postoperative complications by decreasing mortality.
Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report
Authors: Spagnoli Carlotta , Rizzi Susanna , Salerno Grazia Gabriella , Frattini Daniele , Fusco Carlo
Published: December 2019

Background

Pathogenic variants in KIF1A (kinesin family member 1A) gene have been associated with hereditary spastic paraplegia (HSP) type 30 (SPG30), encopassing autosomal dominant and recessive, pure and complicated forms.

Case presentation

We report the long-term follow-up of a 19 years-old boy first evaluated at 18 months of age because of toe walking and unstable gait with frequent falls. He developed speech delay, mild intellectual disability, a slowly progressive pyramidal syndrome, microcephaly, bilateral optic subatrophy and a sensory axonal polyneuropathy. Brain MRI showed cerebellar atrophy, stable along serial evaluations (last performed at 18 years of age). Targeted NGS sequencing disclosed the de novo c.914C > T missense, likely pathogenic variant on KIF1A gene.

Conclusions

We report on a previously unpublished de novo heterozygous likely pathogenic KIF1A variant associated with slowly progressive complicated SPG30 and stable cerebellar atrophy on long-term follow-up, adding to current knowledge on this HSP subtype.
Temporal trends in the use of targeted temperature management after cardiac arrest and association with outcome: insights from the Paris Sudden Death Expertise Centre
Authors:   on behalf of the SDEC, Lascarrou Jean-Baptiste , Dumas Florence , Bougouin Wulfran , Chocron Richard , Beganton Frankie , Legriel Stephane , Aissaoui Nadia , Deye Nicolas , Lamhaut Lionel , Jost Daniel , Vieillard-Baron Antoine , Marijon Eloi , Jouven Xavier , Cariou Alain
Published: December 2019

Purpose

Recent doubts regarding the efficacy may have resulted in a loss of interest for targeted temperature management (TTM) in comatose cardiac arrest (CA) patients, with uncertain consequences on outcome. We aimed to identify a change in TTM use and to assess the relationship between this change and neurological outcome.

Methods

We used Utstein data prospectively collected in the Sudden Death Expertise Center (SDEC) registry (capturing CA data from all secondary and tertiary hospitals located in the Great Paris area, France) between May 2011 and December 2017. All cases of non-traumatic OHCA patients with stable return of spontaneous circulation (ROSC) were included. After adjustment for potential confounders, we assessed the relationship between changes over time in the use of TTM and neurological recovery at discharge using the Cerebral Performance Categories (CPC) scale.

Results

Between May 2011 and December 2017, 3925 patients were retained in the analysis, of whom 1847 (47%) received TTM. The rate of good neurological outcome at discharge (CPC 1 or 2) was higher in TTM patients as compared with no TTM (33% vs 15%, P < 0.001). Gender, age, and location of CA did not change over the years. Bystander CPR increased from 55% in 2011 to 73% in 2017 (P < 0.001) and patients with a no-flow time longer than 3 min decreased from 53 to 38% (P < 0.001). The use of TTM decreased from 55% in 2011 to 37% in 2017 (P < 0.001). Meanwhile, the rate of patients with good neurological recovery remained stable (19 to 23%, P = 0.76). After adjustment, year of CA occurrence was not associated with outcome.

Conclusions

We report a progressive decrease in the use of TTM in post-cardiac arrest patients over the recent years. During this period, neurological outcome remained stable, despite an increase in bystander-initiated resuscitation and a decrease in “no flow” duration.
Text-mining clinically relevant cancer biomarkers for curation into the CIViC database
Authors: Lever Jake , Jones Martin R. , Danos Arpad M. , Krysiak Kilannin , Bonakdar Melika , Grewal Jasleen K. , Culibrk Luka , Griffith Obi L. , Griffith Malachi , Jones Steven J. M.
Published: December 2019

Background

Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic, prognostic, predisposing, and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include the open-access Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase. These databases rely on time-consuming manual curation from skilled experts who read and interpret the relevant biomedical literature.

Methods

To aid in this curation and provide the greatest coverage for these databases, particularly CIViC, we propose the use of text mining approaches to extract these clinically relevant biomarkers from all available published literature. To this end, a group of cancer genomics experts annotated sentences that discussed biomarkers with their clinical associations and achieved good inter-annotator agreement. We then used a supervised learning approach to construct the CIViCmine knowledgebase.

Results

We extracted 121,589 relevant sentences from PubMed abstracts and PubMed Central Open Access full-text papers. CIViCmine contains over 87,412 biomarkers associated with 8035 genes, 337 drugs, and 572 cancer types, representing 25,818 abstracts and 39,795 full-text publications.

Conclusions

Through integration with CIVIC, we provide a prioritized list of curatable clinically relevant cancer biomarkers as well as a resource that is valuable to other knowledgebases and precision cancer analysts in general. All data is publically available and distributed with a Creative Commons Zero license. The CIViCmine knowledgebase is available athttp://bionlp.bcgsc.ca/civicmine/.
Acetylsalicylic acid rescues the immunomodulation of inflamed gingiva-derived mesenchymal stem cells via upregulating FasL in mice
Authors: Yu Tingting , Yan Boxi , Li Jing , Zhang Ting , Yang Ruili , Wang Xuedong , Liu Yan , Liu Dawei
Published: December 2019

Background

Gingiva-derived mesenchymal stem cells (GMSCs) obtained multipotent differentiation and immunomodulatory properties. However, collecting healthy gingival tissues may be challenging in the clinical situation. Thus, in our present study, we aim to evaluate whether the immunomodulatory capacity of gingiva-derived mesenchymal stem cells from inflamed gingival tissues (iGMSCs) is impaired and find a way to rescue their deficient properties.

Methods

We compared the immunomodulation capacity of GMSCs and iGMSCs using an in vitro co-culture system and a mouse colitis model. T cell apoptosis, T helper 17 (Th17), and regulatory T (Treg) cell differentiation were detected by flow cytometry analysis.

Results

We demonstrated that iGMSCs obtained a decreased immunomodulatory capacity compared with GMSCs. Acetylsalicylic acid (ASA) pretreatment was able to rescue iGMSCs’ impaired immunomodulatory properties. Mechanistically, ASA was capable of upregulating the expression of Fas ligand (FasL) in iGMSCs, leading to an improvement in iGMSC-mediated T cell apoptosis and therapeutic efficacy in the treatment in colitis mice.

Conclusions

This study indicates that the deficient immunomodulatory function of iGMSCs could be rescued by ASA pretreatment via upregulating of FasL in mice. This strategy might serve as a practical approach to rescue deficient MSC function for further therapeutic application.
Anti-HIV, antitumor and immunomodulatory activities of paclitaxel from fermentation broth using molecular imprinting technique
Authors: Ryang Junhyok , Yan Yan , Song Yangyang , Liu Fang , Ng Tzi Bun
Published: December 2019

In this study, a single component paclitaxel was obtained from fermentation broth by molecular imprinting technique, and its antiviral, antitumor and immunomodulatory activities were studied. The results showed that paclitaxel had a good inhibitory activity on human breast cancer MCF-7 cells and showed a concentration- dependent relationship with an IC50 of about 15 μg/mL in the sulforhodamine B assay. At the same time, paclitaxel exerted a weak inhibitory activity on cervical cancer Hela cells. In addition, paclitaxel not only inhibited the invasion of HIV-1 pseudovirus into cells, but also exhibited inhibitory activity to a certain extent after viral invasion of the cells. At a paclitaxel concentration of 20 μg/mL, the inhibition of HIV-1 pseudovirus reached about 66%. The inhibition of HIV-1 protease activity was concentration-dependent. At a concentration of 20 μg/mL, the inhibitory effect of paclitaxel on HIV-1 protease was similar to that of the positive control pepstatin A, being 15.8%. The HIV-1 integrase inhibiting activity of paclitaxel was relatively weak. Paclitaxel significantly up-regulated the expression of interleukin-6.
Evaluation of antiviral activity of Bacillus licheniformis-fermented products against porcine epidemic diarrhea virus
Authors: Peng Ju-Yi , Horng Yi-Bing , Wu Ching-Ho , Chang Chia-Yu , Chang Yen-Chen , Tsai Pei-Shiue , Jeng Chian-Ren , Cheng Yeong-Hsiang , Chang Hui-Wen
Published: December 2019

Bacillus licheniformis (B. licheniformis) is commonly used as probiotic and its secondary metabolites are attractive anti-microbial candidate. In the present study, we aimed to evaluate the antiviral activity of crude extracts from B. licheniformis against porcine epidemic diarrhea virus (PEDV), a highly contagious enveloped porcine virus that has caused great economic loss in pigs. In vivo, PEDV-infected piglets supplemented with air-dried solid state fermentative cultivate containing B. licheniformis-fermented products (BLFP) showed milder clinical symptoms and decreased viral shedding. Importantly, no significant systemic pathological lesions and no reduction in average daily gain were noted in pigs supplemented with the BLFP, which suggests that it is safe for use in pigs. In vitro experiments revealed that while B. licheniformis crude extracts exhibited no toxicity in Vero cells, co-cultivation of B. licheniformis crude extracts with PEDV significantly reduced viral infection and replication. Summarized current results suggest that the B. licheniformis-fermented products could be a novel candidate food additive for reducing the impact of PED on the swine industry.
The occurrence of the multidrug resistance (MDR) and the prevalence of virulence genes and QACs resistance genes in E. coli isolated from environmental and avian sources
Authors: Enany Mohamed E. , Algammal Abdelazeem M. , Nasef Soad A. , Abo-Eillil Sara A. M. , Bin-Jumah May , Taha Ayman E. , Allam Ahmed A.
Published: December 2019

Colibacillosis is a major disease affecting poultry leads to high morbidity and mortality which causing tremendous economic losses worldwide. These economic disparities are amplified among low and middle-income where sanitation and hygiene are challenged by the increasing demand for quality sources of animal protein. With a view to investigating the prevalence of virulence genes and QACs resistance genes as well as monitoring the antibiogram of E. coli strains, a total of 368 specimens were collected from diseased broiler chickens (n = 226) and environmental sources (n = 142) at large-scale poultry farms in Ismailia Governorate, Egypt. The bacteriological examination proved that E. coli prevalence was 26.76% and 50.44% in the farm environment and diseased broilers, respectively. In tandem, the isolated E. coli strains were serogrouped, determining the most common serotypes were O78, O1:H7, O91:H21 and O126. Isolates were tested for antimicrobial susceptibility against 12 antibiotics, screened for 4 virulence genes (iss, papC, eaeA, and cfaI), and screened for 3 QACs resistance genes (qacEΔ1, qacA/B, and qacC/D). All the tested strains were positive for iss and papC genes, only 20.3% of the tested strains were positive for eaeA gene, moreover, the examined strains were negative to CFAI gene. Furthermore, all the tested strains were positive for qacEΔ1, qacA/B, and qacC/D genes. In conclusion; virulence genes (iss, papC) as well as QACs resistance genes are common in avian Pathogenic E. coli and environmental strains and are mainly associated with multi-drug resistance phenomena.
Existence of traveling wave solutions with critical speed in a delayed diffusive epidemic model
Authors: Cheng Yueling , Lu Dianchen , Zhou Jiangbo , Wei Jingdong
Published: December 2019

In this paper, we prove the existence of a critical traveling wave solution for a delayed diffusive SIR epidemic model with saturated incidence. Moreover, we establish the nonexistence of traveling wave solutions with nonpositive wave speed for this model. Our results solve some open problems left in the recent paper (Z. Xu in Nonlinear Anal. 111:66–81, 2014).
Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer’s disease and not in other tauopathies
Authors: Pires Geoffrey , McElligott Sacha , Drusinsky Shiron , Halliday Glenda , Potier Marie-Claude , Wisniewski Thomas , Drummond Eleanor
Published: December 2019

We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer’s disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT,n = 21; Moderate NFT,n = 22; Low/No NFT,n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis – Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick’s disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.
A metastable subproteome underlies inclusion formation in muscle proteinopathies
Authors: Ciryam Prajwal , Antalek Matthew , Cid Fernando , Tartaglia Gian Gaetano , Dobson Christopher M. , Guettsches Anne-Katrin , Eggers Britta , Vorgerd Matthias , Marcus Katrin , Kley Rudolf A. , Morimoto Richard I. , Vendruscolo Michele , Weihl Conrad C.
Published: December 2019

Protein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders. To respond to this question, we analyzed proteomic datasets from biopsies of patients with genetic and acquired protein aggregate myopathy (PAM) by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that a metastable subproteome is present in skeletal muscle from healthy patients. The expression of this subproteome escalate as proteomic samples are taken more proximal to the pathologic inclusion, eventually exceeding its solubility limits and aggregating. While most supersaturated proteins decrease or maintain steady abundance across healthy fibers and inclusion-containing fibers, proteins within the metastable subproteome rise in abundance, suggesting that they escape regulation. Taken together, our results show in the context of a human conformational disorder that the supersaturation of a metastable subproteome underlies widespread aggregation and correlates with the histopathological state of the tissue.
Lifelong Machine Learning and root cause analysis for large-scale cancer patient data
Authors: Pal Gautam , Hong Xianbin , Wang Zhuo , Wu Hongyi , Li Gangmin , Atkinson Katie
Published: December 2019

Introduction

This paper presents a lifelong learning framework which constantly adapts with changing data patterns over time through incremental learning approach. In many big data systems, iterative re-training high dimensional data from scratch is computationally infeasible since constant data stream ingestion on top of a historical data pool increases the training time exponentially. Therefore, the need arises on how to retain past learning and fast update the model incrementally based on the new data. Also, the current machine learning approaches do the model prediction without providing a comprehensive root cause analysis. To resolve these limitations, our framework lays foundations on an ensemble process between stream data with historical batch data for an incremental lifelong learning (LML) model.

Case description

A cancer patient’s pathological tests like blood, DNA, urine or tissue analysis provide a unique signature based on the DNA combinations. Our analysis allows personalized and targeted medications and achieves a therapeutic response. Model is evaluated through data from The National Cancer Institute’s Genomic Data Commons unified data repository. The aim is to prescribe personalized medicine based on the thousands of genotype and phenotype parameters for each patient.

Discussion and evaluation

The model uses a dimension reduction method to reduce training time at an online sliding window setting. We identify the Gleason score as a determining factor for cancer possibility and substantiate our claim through Lilliefors and Kolmogorov–Smirnov test. We present clustering and Random Decision Forest results. The model’s prediction accuracy is compared with standard machine learning algorithms for numeric and categorical fields.

Conclusion

We propose an ensemble framework of stream and batch data for incremental lifelong learning. The framework successively applies first streaming clustering technique and then Random Decision Forest Regressor/Classifier to isolate anomalous patient data and provides reasoning through root cause analysis by feature correlations with an aim to improve the overall survival rate. While the stream clustering technique creates groups of patient profiles, RDF further drills down into each group for comparison and reasoning for useful actionable insights. The proposed MALA architecture retains the past learned knowledge and transfer to future learning and iteratively becomes more knowledgeable over time.
Describing a “mass shooting”: the role of databases in understanding burden
Authors: Booty Marisa , O’Dwyer Jayne , Webster Daniel , McCourt Alex , Crifasi Cassandra
Published: December 2019

Background

The mass shooting phenomenon has gained much attention lately as this form of gun violence appears to increase in frequency. Although many organizations collect information on mass shootings (fatal and nonfatal injuries), no federal definition of this phrase exists. The purpose of this study was to highlight the different statistics that result among databases that define and track “mass shootings.” Establishing definitive guidelines for a mass shooting definition could improve research credibility when presenting evidence to policy makers.

Methods

We obtained data for mass shootings that occurred in 2017 from four sources: Gun Violence Archive, Mother Jones Investigation, Everytown for Gun Safety, and FBI’s Supplemental Homicide Report. We also examined FBI’s Active Shooter Report to compare the mass shootings datasets with active shooter situations, which have been federally defined. First, we examined the overlap among databases. Then, we applied the strictest fatal mass shooting definition to the mass shooting datasets to determine whether the differences in databases could be contributing to differences in fatalities and injuries recorded.

Results

Gun Violence Archive recorded the most mass shooting incidents at 346 incidents in 2017, while Mother Jones only recorded 11 cases. Only 2 events were found in all four mass shooting datasets. When the strictest definition – four or more individuals fatally shot – was applied to all datasets, the number of mass shootings in 2017 ranged from 24 (Gun Violence Archive) to 5 (Mother Jones), but incidents collected still varied.

Conclusions

There is much variety in statistics obtained from the different sources that have collected mass shooting information, with little overlap among databases. Researchers should advocate for a standard definition that considers both fatalities and nonfatalities to most appropriately convey the burden of mass shootings on gun violence.
CT-assessed sarcopenia is a predictive factor for both long-term and short-term outcomes in gastrointestinal oncology patients: a systematic review and meta-analysis
Authors: Su Huaiying , Ruan Junxian , Chen Tianfeng , Lin Enyi , Shi Lijing
Published: December 2019

Background

The impact of sarcopenia on the outcome of gastrointestinal (GI) oncological patients is still controversial. We aim to discuss the prevalence of sarcopenia and its relation to the oncological outcome.

Methods

Embase, Medline, PubMed, and the Cochrane library were systematically searched for related keywords. Studies using CT to assess sarcopenia and evaluate its relationship with the outcome of GI oncological patients were included. Long-term outcomes, including overall survival and disease-free survival, were compared by hazard ratios (HRs) with 95% confidence intervals (CIs). Short-term outcomes, including total complications and major complications (Clavien-Dindo ≥IIIa) after curable surgery, were compared by the risk ratio (RR) and 95% CI.

Results

A total of 70 studies including 21,875 patients were included in our study. The median incidence of sarcopenia was 34.7% (range from 2.1 to 83.3%). A total of 88.4% of studies used skeletal muscle index (SMI) in the third lumbar level on CT to define sarcopenia, and a total of 19 cut-offs were used to define sarcopenia. An increasing trend was found in the prevalence of sarcopenia when the cut-off of SMI increased (β = 0.22, 95% CI = 0.12–0.33, p < 0.001). The preoperative incidence of sarcopenia was associated both with an increased risk of overall mortality (HR = 1.602, 95% CI = 1.369–1.873, P < 0.001) and with disease-free mortality (HR = 1.461, 95% CI = 1.297–1.646, P < 0.001). Moreover, preoperative sarcopenia was a risk factor for both total complications (RR = 1.188, 95% CI = 1.083–1.303, P < 0.001) and major complications (RR = 1.228, 95% CI = 1.042–1.448, P = 0.014).

Conclusion

The prevalence of sarcopenia depends mostly on the diagnostic cut-off points of different criteria. Preoperative sarcopenia is a risk factor for both long-term and short-term outcomes.
Advanced Burkitt Lymphoma in Sub-Saharan Africa Pediatric Units: Results of the Third Prospective Multicenter Study of the Groupe Franco-Africain d’Oncologie Pédiatrique
Authors: Bouda Gabrielle C. , Traoré Fousseyni , Couitchere Line , Raquin Marie-Anne , Guedenon Koffi M. , Pondy Angele , Moreira Claude , Rakotomahefa Mbola , Harif Mhamed , Patte Catherine
Published: December 2019

PURPOSE

To evaluate the results of an intensive polychemotherapy regimen for Burkitt lymphoma (BL) in sub-Saharan African pediatric centers.

PATIENTS AND METHODS

Children with advanced-stage BL (stages II bulky, III, and IV) treated with the GFAOP–Lymphomes Malins B (GFALMB) 2009 protocol in 7 centers between April 2009 and September 2015 were prospectively registered. Treatment regimen contained a prephase with cyclophosphamide followed by 2 induction courses (cyclophosphamide, vincristine, prednisone, high-dose methotrexate [HDMTX]), 2 consolidation courses (cytarabine, HDMTX), and a maintenance phase only for stage IV. HDMTX was given at the dose of 3 g/m2.

RESULTS

Four hundred patients were analyzed: 7% had stage II bulky, 76% stage III, and 17% stage IV disease. Median age was 7.3 years, and sex ratio was 1.9:1 (male:female). A total of 221 patients received the whole protocol treatment and 195 achieved complete remission (CR), 11 of them after a second-line treatment. Treatment abandonment rate was 22%. One hundred twenty-five patients died, of whom 49 deaths were related to treatment toxicity. A total of 275 patients are alive, including 25 despite treatment abandonment, but only 110 are known to be in CR with a follow-up > 1 year, indicating a high rate of loss to follow-up. Twelve-month overall survival (OS) was 60% (95% CI, 54% to 66%) and 63%, 60%, and 31%, respectively, for stage II bulky, III, and IV. Patients with stage III disease who started second induction course within 34 days had OS of 76%, versus 57% ( P = .0062) beyond 34 days.

CONCLUSION

The GFA-LMB2009 protocol improved patients’ survival. Early dose intensity of treatment is a strong prognostic factor. Improving supportive care and decreasing loss to follow-up are crucial.
Congenital Muscular Dystrophy and Congenital Myopathy
Authors: Butterfield Russell J.
Published: December 2019

PURPOSE OF REVIEW

Congenital muscular dystrophies and congenital myopathies are a heterogeneous group of disorders resulting in hypotonia, muscle weakness, and dystrophic or myopathic features on muscle biopsy. This article summarizes the clinical and genetic aspects of these disorders.

RECENT FINDINGS

Historically, diagnoses of congenital muscular dystrophy and congenital myopathy have been made by clinical features and histopathology; however, recent advances in genetics have changed diagnostic practice by relying more heavily on genetic findings. This article reviews the clinical and genetic features of the most common congenital muscular dystrophies including laminin subunit alpha 2 (LAMA2)–related (merosin deficient), collagen VI–related, and α-dystroglycan–related congenital muscular dystrophies and reviews the most common congenital myopathies including nemaline rod, core, and centronuclear myopathies. With the increasing accessibility of genetic testing, the number of genes found to be associated with these disorders has increased dramatically. A wide spectrum of severity and onset (from birth to adulthood) exist across all subtypes. Progression and other features are variable depending on the subtype and severity of the specific genetic mutation.

Congenital muscular dystrophy and congenital myopathy are increasingly recognized disorders. A growing appreciation for the breadth of phenotypic variability and overlap between established subtypes has challenged long-standing phenotypic and histopathologic classifications of these disorders but has driven a greater understanding of pathogenesis and opened the door to the development of novel treatments.
Approach to Muscle and Neuromuscular Junction Disorders
Authors: Pasnoor Mamatha , Dimachkie Mazen M.
Published: December 2019

PURPOSE OF REVIEW

Muscle and neuromuscular junction disorders are a diverse group of disorders that can be difficult to diagnose. This article provides a diagnostic approach based on clinical history and neurologic examination leading to a narrow set of diagnostic tests.

RECENT FINDINGS

Numerous discoveries in recent years have facilitated clinician access to more advanced laboratory and genetic testing to pinpoint the exact diagnosis in patients with muscle or neuromuscular junction disorders. Large-scale genetic testing has become much less expensive, and free testing has become available for many of the rare conditions because of increased research and the availability of effective therapies for these rare disorders.

The approach to muscle and neuromuscular junction disorders depends on the clinical pattern of muscle weakness. By classifying patients into one of 10 muscle patterns, diagnostic testing can be targeted and gene testing yield will be optimized. With the increased accessibility and reduced cost of genetic testing (eg, gene panels, whole-exome sequencing, whole-genome sequencing, and chromosomal microarray), this clinical approach to muscle weakness and targeted gene testing will ensure a cost-effective investigational plan. This clinical approach should also assist clinicians in making a timely and accurate diagnosis.
The Limb-Girdle Muscular Dystrophies
Authors: Wicklund Matthew P.
Published: December 2019

purpose of review

As a group, the limb-girdle muscular dystrophies (LGMDs) are the fourth most prevalent genetic muscle disease, yet they are still not well known or understood. This article defines and describes LGMDs, delineates a diagnostic strategy, and discusses treatment of the LGMDs.

recent findings

In 2018, the definition of the LGMDs was further refined, and a new nomenclature was proposed. Diagnosis of the LGMDs was long guided by the distinctive clinical characteristics of each particular subtype but now integrates use of genetics—with next-generation sequencing panels, exomes, and full genome analysis—early in the diagnostic assessment. Appreciation of the phenotypic diversity of each LGMD subtype continues to expand. This emphasizes the need for precision genetic diagnostics to better understand each subtype and formulate appropriate management for individual patients. Of significant relevance, the explosion of research into therapeutic options accentuates the need for accurate diagnosis, comprehensive disease characterization, and description of the natural histories of the LGMDs to move the field forward and to mitigate disease impact on patients with LGMD.

summary

The LGMDs are genetic muscle diseases that superficially appear similar to one another but have important differences in rates of progression and concomitant comorbidities. Definitive diagnoses are crucial to guide management and treatment now and in the future. As targeted treatments emerge, it will be important for clinicians to understand the nomenclature, diagnosis, clinical manifestations, and treatments of the LGMDs.
Combinatorial genetic replenishments in myocardial and outflow tract tissues restore heart function in tnnt2 mutant zebrafish
Authors: Liu Lian , Fei Fei , Zhang Ranran , Wu Fang , Yang Qian , Wang Feng , Sun Shaoyang , Zhao Hui , Li Qiang , Wang Lei , Wang Youhua , Gui Yonghao , Wang Xu
Published: December 2019

Cardiac muscle troponin T (Tnnt2) mediates muscle contraction in response to calcium ion dynamics, and Tnnt2 mutations are associated with multiple types of cardiomyopathy. Here, we employed a zebrafish model to investigate the genetic replenishment strategies of using conditional and inducible promoters to rescue the deficiencies in the heart. tnnt2a mutations were induced in zebrafish via the CRISPR/Cas9 technique, and the mutants displayed heart arrest and dilated cardiomyopathy (DCM)-like phenotypes. We first utilized the classic myocardial promoter of the myl7 and TetOn inducible system to restore tnnt2a expression in myocardial tissue in tnnt2a mutant zebrafish. However, this attempt failed to recover normal heart function and circulation, although heart pumping was partially restored. Further analyses via both RNA-seq and immunofluorescence indicated that Tnnt2a, which was also expressed in a novel group of myl7-negative smooth muscle cells on the outflow tract (OFT), was indispensably responsible for the normal mechanical dynamics of OFT. Lastly, tnnt2 expression induced by OFT cells in addition to the myocardial cells successfully rescued heart function and circulation in tnnt2a mutant zebrafish. Together, our results reveal the significance of OFT expression of Tnnt2 for cardiac function and demonstrate zebrafish larva as a powerful and convenient in vivo platform for studying cardiomyopathy and the relevant therapeutic strategies.
Prolonged survival out of water is linked to a slow pace of life in a selfing amphibious fish
Authors: Turko Andy J. , Doherty Justine E. , Yin-Liao Irene , Levesque Kelly , Kruth Perryn , Holden Joseph M. , Earley Ryan L. , Wright Patricia A.
Published: December 2019

Metabolic rate and life history traits vary widely both among and within species reflecting trade-offs in energy allocation, but the proximate and ultimate causes of variation are not well understood. We tested the hypothesis that these trade-offs are mediated by environmental heterogeneity, using isogenic strains of the amphibious fish Kryptolebias marmoratus that vary in the amount of time each can survive out of water. Consistent with pace of life theory, the strain that survived air exposure the longest generally exhibited a “slow” phenotype including the lowest metabolic rate, largest scope for metabolic depression, slowest consumption of energy stores, and least investment in reproduction under standard conditions. Growth rates were fastest in the otherwise “slow” strain, however. We then tested for fitness trade-offs between “fast” and “slow” strains using microcosms where fish were held with either constant water availability or under fluctuating conditions where water was absent for half of the experiment. Under both conditions the “slow” strain grew larger and was in better condition, and under fluctuating conditions the “slow” strain produced more embryos. However, the “fast” strain had larger adult population sizes under both conditions, indicating that fecundity is not the sole determinant of population size in this species. We conclude that genetically based differences in pace of life of amphibious fish determine survival duration out of water. Relatively “slow” fish tended to perform better under conditions of limited water availability, but there was no detectable cost under control conditions. Thus, pace of life differences may reflect a conditionally neutral instead of antagonistic trade-off.
Tissue specific expression of 11BHSD and its effects on plasma corticosterone during the stress response
Authors: Pérez Jonathan H. , Swanson Ryan E. , Lau Hannah J. , Cheah Jeffrey , Bishop Valerie R. , Snell Katherine R. S. , Reid Angus M. A. , Meddle Simone L. , Wingfield John C. , Krause Jesse S.
Published: December 2019

The hypothalamic-pituitary-adrenal (HPA) axis is under complex regulatory control at multiple levels. Enzymatic regulation plays an important role in both circulating levels and target tissue exposure. Three key enzyme pathways are responsible for the immediate control of glucocorticoids. De novo synthesis of glucocorticoid from cholesterol involves a multistep enzymatic cascade. This cascade terminates with 11β-hydroxylase, responsible for the final conversion of 11 deoxy- precursors into active glucocorticoids. Additionally, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) controls regeneration of glucocorticoids from inactive metabolites, providing a secondary source of active glucocorticoids. Localized inactivation of glucocorticoids is under the control of Type 2 11β-HSD (11β-HSD2). The function of these enzymes is largely unexplored in wild species, particularly songbirds. Here we aim to explore the contribution of both clearance and generation of glucocorticoids to regulation of the hormonal stress response via use of pharmacological antagonists. Additionally, we mapped 11β-HSD gene expression. We found 11β-HSD1 primarily in liver, kidney, and adrenal glands though it was detectable across all tissue types. 11β-HSD2 was predominately expressed in the adrenal glands and kidney with moderate gonadal and liver expression. Inhibition of glucocorticoid generation by metyrapone was found to decrease levels peripherally, while both peripheral and central DETC administration resulted in elevated concentrations of corticosterone. These data suggest that during the stress response, peripheral antagonism of the 11β-HSD system has a greater impact on circulating glucocorticoid levels than central control. Further studies show aim to elucidate the respective roles of the 11β-HSD and 11β-hydroxylase enzymes.
Maternal glucocorticoids promote offspring growth without inducing oxidative stress or shortening telomeres in wild red squirrels
Authors: Dantzer Ben , van Kesteren Freya , Westrick Sarah E. , Boutin Stan , McAdam Andrew G. , Lane Jeffrey E. , Gillespie Robert , Majer Ariana , Haussmann Mark , Monaghan Pat
Published: December 2019

Elevations in glucocorticoid levels (GCs) in breeding females may induce adaptive shifts in offspring life histories. Offspring produced by mothers with elevated GCs may be better prepared to face harsh environments where a faster pace of life is beneficial. We examined how experimentally elevated GCs in pregnant or lactating North American red squirrels (Tamiasciurus hudsonicus) affected offspring postnatal growth, structural size, oxidative stress levels (two antioxidants and oxidative protein damage) in three different tissues (blood, heart, liver), and liver telomere lengths. We predicted that offspring from mothers treated with GCs would grow faster but would also have higher levels of oxidative stress and shorter telomeres, which may predict reduced longevity. Offspring from mothers treated with GCs during pregnancy were 8.3% lighter around birth but grew (in body mass) 17.0% faster than those from controls, whereas offspring from mothers treated with GCs during lactation grew 34.8% slower than those from controls and did not differ in body mass around birth. Treating mothers with GCs during pregnancy or lactation did not alter the oxidative stress levels or telomere lengths of their offspring. Fast-growing offspring from any of the treatment groups did not have higher oxidative stress levels or shorter telomere lengths, indicating that offspring that grew faster early in life did not exhibit oxidative costs after this period of growth. Our results indicate that elevations in maternal GCs may induce plasticity in offspring growth without long-term oxidative costs to the offspring that might result in a shortened lifespan.
Do enlarged hind legs of male thick-legged flower beetles contribute to take-off or mating?
Authors: Burrows M.
Published: December 2019

The volume of the hind femora in adult male flower beetles, Oedemera nobilis, is 38 times greater than in adult females. To determine what advantage limbs with swollen femora might provide, the behaviour of these insects was analysed with high speed videography. First, because large hind legs are often associated with jumping and take-off, the performance of this behaviour by the two sexes was determined. Take-off was generated by a series of small amplitude wing beats followed by larger ones with the hind legs contributing little or no propulsion. The mean acceleration time to take-off was not significantly different in males (46.2 ms) and females (45.5 ms), but the mean take-off velocity of males was 10% higher than in females. Second, to determine if enlarged hind legs were critical in specifically male behaviour, interactions between males and females, and between males were videoed. A male mounted a female and then encircled her abdomen between the enlarged femora and tibiae of both his hind legs. The joint between these leg parts acted like a mole wrench (vise grip) so that when the tibia was fully flexed a triangular space of 0.3 square mm remained in which a female abdomen (cross-sectional area 0.9 square mm) could be compressed and restrained firmly without inflicting damage. The flexor tibiae muscle in a male hind femur was 5.9 times larger than the extensor. In interactions between males, attempts to achieve a similar entrapment were frequently thwarted by the pursued male extending his hind legs vertically.
Reduced telomere length in embryos exposed to predator cues
Authors: Noguera Jose C. , Velando Alberto
Published: December 2019

It is often assumed that embryos are isolated from external influences, but recent studies indicate that environmental stressors during prenatal stages can exert long-term negative effects on fitness. A potential mechanism by which predation risk may lastingly shape life-history traits and phenotypes is via effects on telomeres. However, whether prenatal exposition to environmental stressors, such as cues of predator presence, affects postnatal telomere length has not hitherto been investigated. Using an experimental design in which we modified the exposure of yellow-legged gull (Larus michahellis) embryos to social cues of predator presence (i.e. alarm calls), we show that prenatally exposed chicks had shorter telomeres after hatching. Since young birds with shorter telomere length have reduced fledging success, reproductive success and lifespan, the reduced telomere length in the exposed chicks is likely to have long-term fitness consequences. Moreover, our results provide a mechanistic link through which predators may negatively affect population dynamics.
Establishment of correctly focused eyes may not require visual input in arthropods
Authors: Owens Madeline , Giordullo Isaiah , Buschbeck Elke K.
Published: December 2019

For proper function, vertebrate and invertebrate visual systems must be able to achieve and maintain emmetropia, a state where distant objects are in focus on the retina. In vertebrates, this is accomplished through a combination of genetic control during early development and homeostatic visual input that fine-tunes the optics of the eye. While emmetropization has long been researched in vertebrates, it is largely unknown how emmetropia is established in arthropods. We used a micro-ophthalmoscope to directly measure how the lens projects images onto the retina in the eyes of small, live arthropods, allowing us to compare the refractive states of light-reared and dark-reared arthropods. First, we measured the image-forming larval eyes of diving beetles (Thermonectus marmoratus), which are known to grow rapidly and dramatically between larval instars. Then, we measured the image-forming principal anterior-median eyes of jumping spiders (Phidippus audax) after emergence from their egg cases. Finally, we measured individual ommatidia in the compound eyes of flesh flies (Sarcophaga bullata) that had developed and emerged under either light or dark conditions. Surprisingly, and in sharp contrast to vertebrates, our data for this diverse set of arthropods suggest that visual input is inconsequential in regard to achieving well-focused eyes. Although it remains unclear whether visual input that is received after the initial development further improves focusing, these results suggest that at least the initial coordination between the lens refractive power and eye size in arthropods may be more strongly predetermined by developmental factors than is typically the case in vertebrates.
Renal artery embolization for iatrogenic renal vascular injuries management: 5 years’ experience
Authors: Contegiacomo Andrea , Amodeo Enrico Maria , Cina Alessandro , Di stasi Carmine , Iezzi Roberto , Coppolino Davide , Attempati Nico , Manfredi Riccardo
Published: December 2019

Objective:

Evaluate the efficacy and safety of renal artery embolization (RAE) for iatrogenic renal vascular injuries (IRVI) management at Fondazione Policlinico Universitario "A. Gemelli" IRCCS, in the last 5 years.

Methods:

Retrospective analysis of all RAE procedures performed from January 2013 to December 2017. Patients-related (age, sex, vascular variants, hemoglobin and serum creatinine), IRVI-related (type and vascular level of IRVI, presence and extension of hematoma), management-related (temporal interval between diagnostic imaging and RAE) and procedure-related (embolic materials, technical success, clinical success and complications) parameters were evaluated.

Results:

28 RAE procedures performed on 28 patients (21 males; 7 females) were included. 19/28 patients had pseudoaneurysm, 7/28 active bleeding and 1/28 arteriovenous fistula; 4/28 patients had a combination of 2 IRVI.

The extent of perirenal hematoma showed correlation with the cause of IRVI (p = 0.028).

Technical success was achieved in all patients whereas clinical success in 25/28 (89.3%), with 3 patients requiring re-treatment. Minor complications were observed during 2/28 (7.1%) endovascular procedures. No major complications occurred. A longer procedural time was observed in patients with lower pre-procedural levels of hemoglobin (p = 0.016).

No differences were found in mean serum creatinine (p = 0.23) before and immediately after treatment, while values of creatinine at 1 week from the procedure were significantly lower (p = 0.04).

Conclusion:

RAE is safe and effective for the management of iatrogenic IRVI showing high technical and clinical success rate and low complication rate.

Advances in knowledge:

Low pre-procedural hemoglobin levels increase procedural duration time. Glue alone or in combination with other materials is as safe as coils.