bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative Three-Dimensional Reconstructions of Excitatory Synaptic Boutons in the “Barrel Field” of the Adult “Reeler” Mouse Somatosensory Neocortex: A Comparative Fine-Scale Electron Microscopic Analysis with the Wild Type Mouse
Authors: Prume Miriam , Rollenhagen Astrid , Yakoubi Rachida , Sätzler Kurt , Lübke Joachim Hr
Published: December 2019

Synapses are key structural determinants for information processing and computations in the normal and pathologically altered brain. Here, the quantitative morphology of excitatory synaptic boutons in the “reeler” mutant, a model system for various neurological disorders, was investigated and compared with wild-type (WT) mice using high-resolution, fine-scale electron microscopy (EM) and quantitative three-dimensional (3D) models of synaptic boutons. Beside their overall geometry, the shape and size of presynaptic active zones (PreAZs) and postsynaptic densities (PSDs) forming the active zones and the three pools of synaptic vesicles (SVs), namely the readily releasable pool (RRP), the recycling pool (RP), and the resting pool, were quantified. Although the reeler mouse neocortex is severely disturbed, no significant differences were found in most of the structural parameters investigated: the size of boutons (~3 μm2), size of the PreAZs and PSDs (~0.17 μm2), total number of SVs, and SVs within a perimeter (p) of 10 nm and p20 nm RRP; the p60 nm, p100 nm, and p60–p200 nm RP; and the resting pool, except the synaptic cleft width. Taken together, the synaptic organization and structural composition of synaptic boutons in the reeler neocortex remain comparably “normal” and may thus contribute to a “correct” wiring of neurons within the reeler cortical network.
Mas receptor is translocated to the nucleus upon agonist stimulation in brainstem neurons from spontaneously hypertensive rats but not normotensive rats
Authors: Cerniello Flavia M , Silva Mauro G , Carretero Oscar A , Gironacci Mariela M
Published: December 2019

Aims 

Activation of the angiotensin (Ang)-(1-7)/Mas receptor (R) axis protects from sympathetic overactivity. Endocytic trafficking is an essential process that regulates receptor (R) function and its ultimate cellular responses. We investigated whether the blunted responses to Ang-(1-7) in hypertensive rats are associated to an alteration in MasR trafficking.

Methods and results 

Brainstem neurons from Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHRs) were investigated for (i) Ang-(1-7) levels and binding and MasR expression, (ii) Ang-(1-7) responses (arachidonic acid and nitric oxide release and Akt and ERK1/2 phosphorylation), and (iii) MasR trafficking. Ang-(1-7) was determined by radioimmunoassay. MasR expression and functionality were evaluated by western blot and binding assays. MasR trafficking was evaluated by immunofluorescence. Ang-(1-7) treatment induced an increase in nitric oxide and arachidonic acid release and ERK1/2 and Akt phosphorylation in WKY neurons but did not have an effect in SHR neurons. Although SHR neurons showed greater MasR expression, Ang-(1-7)-elicited responses were substantially diminished presumably due to decreased Ang-(1-7) endogenous levels concomitant with impaired binding to its receptor. Through immunocolocalization studies, we evidenced that upon Ang-(1-7) stimulation MasRs were internalized through clathrin-coated pits and caveolae into early endosomes and slowly recycled back to the plasma membrane. However, the fraction of internalized MasRs into early endosomes was larger and the fraction of MasRs recycled back to the plasma membrane was smaller in SHR than in WKY neurons. Surprisingly, in SHR neurons but not in WKY neurons, Ang-(1-7) induced MasR translocation to the nucleus. Nuclear MasR expression and Ang-(1-7) levels were significantly greater in the nuclei of Ang-(1-7)-stimulated SHR neurons, indicating that the MasR is translocated with its ligand bound to it.

Conclusion 

MasRs display differential trafficking in brainstem neurons from SHRs, which may contribute to the impaired responses to Ang-(1-7).
Pseudo-chromosome–length genome assembly of a double haploid “Bartlett” pear (Pyrus communis L.)
Authors: Linsmith Gareth , Rombauts Stephane , Montanari Sara , Deng Cecilia H , Celton Jean-Marc , Guérif Philippe , Liu Chang , Lohaus Rolf , Zurn Jason D , Cestaro Alessandro , Bassil Nahla V , Bakker Linda V , Schijlen Elio , Gardiner Susan E , Lespinasse Yves , Durel Charles-Eric , Velasco Riccardo , Neale David B , Chagné David , Van de Peer Yves , Troggio Michela , Bianco Luca
Published: December 2019

Background

We report an improved assembly and scaffolding of the European pear (Pyrus communis L.) genome (referred to as BartlettDHv2.0), obtained using a combination of Pacific Biosciences RSII long-read sequencing, Bionano optical mapping, chromatin interaction capture (Hi-C), and genetic mapping. The sample selected for sequencing is a double haploid derived from the same “Bartlett” reference pear that was previously sequenced. Sequencing of di-haploid plants makes assembly more tractable in highly heterozygous species such as P. communis.

Findings

A total of 496.9 Mb corresponding to 97% of the estimated genome size were assembled into 494 scaffolds. Hi-C data and a high-density genetic map allowed us to anchor and orient 87% of the sequence on the 17 pear chromosomes. Approximately 50% (247 Mb) of the genome consists of repetitive sequences. Gene annotation confirmed the presence of 37,445 protein-coding genes, which is 13% fewer than previously predicted.

Conclusions

We showed that the use of a doubled-haploid plant is an effective solution to the problems presented by high levels of heterozygosity and duplication for the generation of high-quality genome assemblies. We present a high-quality chromosome-scale assembly of the European pear Pyrus communis and demostrate its high degree of synteny with the genomes of Malus x Domestica and Pyrus x bretschneideri.
Decolonial Sketches and Intercultural Approaches to Truth: Corporeal Experiences and Testimonies of Indigenous Women in Colombia
Authors: Santamaría Angela , Muelas Dunen , Caceres Paula , Kuetguaje Wendi , Villegas Julian
Published: December 2019

This article explores the corporeal and testimonial memories of a group of female indigenous ex-combatants and victims in the Colombian Caribbean and Amazon. Although these groups have often been analyzed in the transitional justice literature, our primary objective is to analyze two local processes for retrieving indigenous women’s memories and possible feminist participatory action research methodologies in the Colombian postconflict context. We examined empowering intercultural and intersectional methodologies to promote the political participation of indigenous women – both ‘victims’ and ‘perpetrators’ – in the Colombian Truth Commission implemented after the peace agreement was enacted. We explain how participatory action research should be used, including techniques such as indigenous women’s body mapping, creating testimonial spaces and conducting ethnographic observations. The article is based on a transitional justice ‘from below’ perspective as well as local transitional justice practices.
Development and Utility of the Observational Research in Oncology Toolbox: Cancer Medications Enquiry Database-Healthcare Common Procedure Coding System (HCPCS)
Authors: Rivera Donna R , Lam Clara J K , Enewold Lindsey , Petkov Valentina I , Tran Quyen , Brennan Sean , Dickie Lois , McNeel Timothy S , Noone Annie M , Ohm Bradley , White Dolly P , Warren Joan L , Mariotto Angela B , Penberthy Lynne
Published: December 2019

Purpose

Health-care claims are of increasing utility as a rich, real-world data resource for conducting treatment-related cancer research. However, multiple dynamic coding nomenclatures exist, leading to study variability. To promote increased standardization and reproducibility, the National Cancer Institute (NCI) developed the Cancer Medications Enquiry Database (CanMED)-Healthcare Common Procedure Coding System (HCPCS) within the Observational Research in Oncology Toolbox.

Methods

The CanMED-HCPCS includes codes for oncology medications that a) have a US Food and Drug Administration-approved indication for cancer treatment or treatment-related symptom management; b) are present in National Comprehensive Cancer Network guidelines; or c) carry an orphan drug designation for treatment or management of cancer. Included medications and their HCPCS codes were primarily identified based on Center for Medicare and Medicaid Services annual HCPCS Indices (2012–2018). To demonstrate the utility of the CanMED-HCPCS, use of systemic treatment for stage II–IV colorectal cancer patients included in the Surveillance, Epidemiology, and End Results-Medicare data (2007–2013) was assessed.

Results

The CanMED-HCPCS (v2018) includes 332 HCPCS codes for cancer-related medications: chemotherapy (156), immunotherapy (74), hormonal therapy (54), and ancillary therapy (48). Observed treatment trends within the NCI Surveillance, Epidemiology, and End Results-Medicare data were as expected; utilization of each treatment type increased with stage, and immunotherapy was largely confined to use among stage IV patients.

Conclusion

The CanMED-HCPCS provides a comprehensive resource that can be used by the research community to facilitate systematic identification of medications within claims or electronic health data using the HCPCS nomenclature and greater reproducibility of cancer surveillance and health services research.
Prevalence of Chronic Ankle Instability in French Paratroopers
Authors: Schmitt Marion , Marchi Joffrey , Jouvion Arnaud , Trappier Thomas , Reyes-Rivet Lisa , De Brier Gratiane , Thefenne Laurent
Published: December 2019

Introduction

Ankle sprain is the most common musculoskeletal injury in the physically active population (up to 50% of sports injuries) and is common in the general population with about one ankle sprain per 10 000 person-days worldwide. It is an even more frequent pathology in the military population with a prevalence of five to eight times higher than in the civilian population. In the general population, 20 to 74% of sprains are complicated by chronic ankle instability. No studies estimate this prevalence in a French military population. The main objective of our study was, therefore, to estimate the prevalence of chronic ankle instability in French paratroopers.

Materials and Methods

The study was carried out in a French parachute regiment over a period of 1 year during periodic medical examinations. To diagnose chronic ankle instability, we used the criteria defined by the International Ankle Consortium in 2013 and two questionnaires that this consortium recommended (FAAM and IdFAI).

Results

Chronic ankle instability has a prevalence of 43.1% after an ankle sprain with a total of 2.3% among paratroopers, which is comparable to data in the literature. After their first sprain, 23.1% of subjects did not consult a health professional and 47.6% of subjects did not receive physiotherapy.

Conclusions

Physiotherapy is the basis of care, both for prevention and treatment of chronic ankle instability. It is necessary to raise awareness of this injury among the military and to encourage their adherence to treatment in order to preserve the operational capabilities of combat units. Subsequently, further studies are needed to expand the study population to provide a more comprehensive view of the impact of this injury on the military. Studies concerning the management of chronic ankle instability adapted to the military population would also be relevant.
Le dépistage et la prise en charge des nouveau-nés à risque d’hypoglycémie
Authors: Narvey Michael R , Marks Seth D
Published: December 2019

L’hypoglycémie entre les premières heures et les premiers jours suivant la naissance demeure l’une des principales affections qu’observent les praticiens du Canada qui s’occupent de nouveau-nés. Bien des cas vivent une transition physiologique normale à la vie extra-utérine, mais un groupe présente une hypoglycémie pendant une plus longue période. Le présent document de principes expose les principaux enjeux auxquels sont exposés les dispensateurs de soins néonatals, y compris la définition d’hypoglycémie, les facteurs de risque, les protocoles de dépistage, les valeurs de glycémie nécessitant une intervention et la gestion des soins pour cette affection. Les auteurs passent en revue le dépistage, la surveillance et les protocoles d’intervention pour mieux distinguer, prendre en charge et traiter les nouveau-nés à risque d’hypoglycémie persistante, récurrente ou marquée. Ils abordent également le rôle des gels de dextrose pour accroître la glycémie ou prévenir une hypoglycémie plus persistante, de même que les précautions à prendre pour réduire les risques de récurrence après le congé de l’hôpital. Le présent document de principes distingue les approches des soins de l’hypoglycémie pendant la « phase de transition » (les 72 premières heures de vie) de celles de l’hypoglycémie persistante, qui se manifeste ou est constatée pour la première fois après cette période.
Les changements climatiques mondiaux et la santé des enfants canadiens
Authors: Buka Irena , Shea Katherine M
Published: December 2019

Les changements climatiques sont une réalité. De nombreuses autorités insistent sur la nécessité de déployer et d’adapter les efforts environnementaux en vue de protéger la santé des êtres humains. Les changements climatiques s’accélèrent, et les pays situés à des latitudes élevées, comme le Canada, les subissent de manière plus directe. De plus, certains paramètres sont plus spectaculaires que dans les pays situés à des latitudes moyennes ou faibles. Les enfants sont vulnérables aux effets des changements climatiques sur la santé, et les médecins et autres dispensateurs de soins doivent être prêts à en détecter, en gérer et en prévenir les dangers. Le présent point de pratique fait ressortir certaines menaces précises des changements climatiques sur la santé des enfants et des adolescents et fournit des ressources pour les professionnels de la santé. Les défis climatiques et leurs effets sur la santé des enfants sont décrits en tenant compte de rapports canadiens importants et d’information prouvée scientifiquement. S’ils connaissent mieux les effets immédiats et à long terme des changements climatiques sur la santé des enfants, les médecins et les autres dispensateurs de soins pourront conseiller les familles et mener leur pratique avec plus d’efficacité.
Sham, alter ego trusts and public policy in South Africa
Authors: Vorster Henry V
Published: December 2019

This article is based on the paper presented by Prof. Vorster at the TIAETL meeting in Tokyo in May 2019.
Overexpressed CXCR4 and CCR7 on the surface of NK92 cell have improved migration and anti-tumor activity in human colon tumor model
Authors: Yang Lili , Huang Changxin , Wang Congjie , Zhang Siyu , Li Zhaoyang , Zhu Ying , Li Da , Gao Lanlan , Ge Zuanmin , Su Meng , Feng Xi , Li Yongqiang
Published: December 2019

Successive infusion of natural killer cells is increasingly being explored as a treatment for cancer patients. The inadequate homing of natural killer cells into the tumor site resulted in the poor efficacy of natural killer cells on solid tumors. For the adoptive transfer of tumor-directed natural killer cell has been proved effective, it is hypothesized that there must be more association between the tumor-produced chemokines and the natural killer cells-expressed chemokine receptors. Increased CXCL12 and CCL21 could ameliorated colorectal cancer via generating an anti-tumor environment by preferentially attracting natural killer cells which expressed the chemokine receptor CXCR4 and CCR7. This study demonstrated that overexpressed CXCR4 and CCR7 on the surface of NK92 cell enhanced their migration to human colon cells. Moreover, the administration of such natural killer cells resulted in tumor shrinkage and a significantly increased survival of experimental mice when compared to ones undergoing the treatment of xenografts with natural killer cells expressing only the mock control. These suggested that chemokine receptor engineered natural killer cells could be a promising tool to improve adoptive tumor immunotherapy.
CLINICAL CHARACTERISTICS AND OUTCOME OF POSTERIOR CYSTOID MACULAR DEGENERATION IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY
Authors: Mohabati Danial , Hoyng Carel B. , Yzer Suzanne , Boon Camiel J. F.
Published: December 2019

Purpose:

To assess clinical characteristics and visual outcome in chronic central serous chorioretinopathy patients with posterior cystoid retinal degeneration (PCRD).

Methods:

Patients' medical records were reviewed retrospectively in 62 cases (83 eyes, mean age = 59 years, 88% male). Data were collected at central serous chorioretinopathy diagnosis, at PCRD manifestation, and at final visit. All treatment modalities were reviewed. Main outcome measures were treatment efficacy in achieving PCRD resolution, and final best-corrected visual acuity.

Results:

In 63 eyes (76%), subretinal fluid was present at first PCRD manifestation, whereas fluorescein angiography showed active focal or diffuse leakage in 65 eyes (78%). Seventy-six eyes (81%) received treatment, and PCRD had resolved completely in 31 eyes (37%) at the final visit. Photodynamic therapy was most successful in achieving a complete PCRD resolution. Best-corrected visual acuity did not improve, even after complete PCRD resolution (mean baseline best corrected visual acuity = 69 ± 19, and mean final best corrected visual acuity = 67 ± 20 ETDRS letters [20/40 and 20/50 in Snellen equivalent respectively], P = 0.354).

Conclusion:

Posterior cystoid retinal degeneration is a relatively common finding in chronic central serous chorioretinopathy, which is often accompanied by active subretinal fluid leakage. Treatment may be beneficial to stop the subretinal fluid leakage component, but is less likely to result in a complete PCRD resolution and/or a best-corrected visual acuity improvement.
Comparison of Neuroborreliosis Between Children and Adults
Authors: Krawczuk Katarzyna , Czupryna Piotr , Pancewicz Sławomir , Ołdak Elżbieta , Król Monika , Moniuszko-Malinowska Anna
Published: December 2019

Background:

Lyme neuroborreliosis (NB) is a tick-borne infectious disorder of the nervous system caused by Borrelia burgdorferi spirochetes. There are not many data available regarding the differences in the course of NB in children and adults. The aim of our study was to compare the clinical course of NB between children and adults.

Methods:

Retrospective analysis of medical documentation of 181 patients with NB was performed. The patients were divided into 2 groups: Group I: 57 children with NB; Group II: 124 adults with NB. Medical data, such as patients’ age, sex, place of living (residence), time from a tick bite, subjective complaints, general examination results, laboratory parameters and treatment were analyzed.

Results:

In children, the most common symptoms were headache (89.5%), neck stiffness (64.9%) and nausea and vomiting (56.1%). In adults, the most common symptoms were headache (77.4%), facial nerve palsy (59.7%), neck stiffness (59.7%), vertigo (41.9%) and lumbosacral region pain (37.1%). Bannwarth’s syndrome was observed in 10.5% of children and 36.3% of adults. In cerebrospinal fluid (CSF) in children, the pleocytosis at admission was higher than in adults, but protein concentration was significantly lower. There were no differences in percentage of mononuclear cells in CSF smear between the groups. In CSF examination after treatment, a decrease in pleocytosis and protein concentration was observed in both groups. Analysis of effectiveness of treatment mostly with third generation cephalosporins (defined as complete recovery) between the groups, calculated by the Kaplan–Meier method and compared with the use of the log-rank test, showed no significant differences between children and adults (log-rank P = 0.619).

Conclusions:

In children, NB more frequently presented as meningitis, and in adults in the form of Bannwarth’s syndrome. CSF pleocytosis in children with NB was higher than in adults, while the protein concentration in children was lower. Outcomes in children and adults were favorable and did not differ after standard NB treatment.
Increased T-helper Cell 2 Response in Infants With Respiratory Syncytial Virus Bronchiolitis Hospitalized Outside Epidemic Peak
Authors: Nenna Raffaella , Fedele Giorgio , Frassanito Antonella , Petrarca Laura , Di Mattia Greta , Pierangeli Alessandra , Scagnolari Carolina , Papoff Paola , Schiavoni Ilaria , Leone Pasqualina , Moretti Corrado , Midulla Fabio
Published: December 2019

Aim:

To test the hypothesis that the balance of type-1/type-2 immune response differs between infants hospitalized with respiratory syncytial virus (RSV) bronchiolitis during the peak months and those during the nonpeak months.

Methods:

We prospectively enrolled 90 unrelated full-term previously healthy infants hospitalized during the first year of life for RSV sole bronchiolitis over 2 epidemics (November 2016 to April 2017 and October 2017 to April 2018). We stratified infants as follows: hospitalized during the peak months (n: 71) and during the nonpeak months (n: 19). The frequencies of CD4+ producing interferon (IFN)-γ and interleukin (IL)-4 and of CD8+ producing IFN-γ T cells were measured by flow cytometry from infant peripheral whole blood. The T-helper cell (Th2) polarization index was calculated as the ratio between CD4+ T cells producing IL-4 and CD4+ T cells producing IFN-γ.

Results:

Infants hospitalized during nonpeak months were significantly less frequently breast-fed, had a higher eosinophils count, a significantly higher percentage of CD4+ T cells producing IL-4 and higher Th2 polarization index than infants hospitalized during the peak months.

Conclusions:

We elucidated the presence of different endotypes in infants with RSV sole bronchiolitis. Previously healthy full-term infants hospitalized during the nonpeak months seem to be more likely those with a possible predisposition to atopy.
Prophylactic Paracetamol After Meningococcal B Vaccination Reduces Postvaccination Fever and Septic Screens in Hospitalized Preterm Infants
Authors: Dubus Magali , Ladhani Shamez , Vasu Vimal
Published: December 2019

Background:

Following the introduction of the 4CMenB (Bexsero, GlaxoSmithKline, Rixensart, Belgium) vaccine against Meningococcal B into the UK vaccination schedule, Public Health England advised paracetamol to be given prophylactically with the vaccine. This was based on observations of increased postvaccination febrile reactions in term infants. Evidence in preterm infants was lacking. We aimed to evaluate whether (i) 4CmenB is associated with an increase in adverse events (AEs) in the 48 hours after vaccination in preterm infants and (ii) the impact of prophylactic paracetamol on AEs.

Methods:

Retrospective case-note review of preterm infants, within a UK level 3 neonatal unit, receiving first or second 4CMenB vaccination, within 3 periods; (i) period 1 (pre-4CMenB): September 2014–September 2015; (ii) period 2 (4CMenB without prophylactic paracetamol): September 2015–March 2016 and (iii) period 3 (4CMenB with prophylactic paracetamol): June 2016–May 2018. Data were collected on a predefined list of postvaccination AEs within 48 hours of vaccination: (i) number (%) of infants with temperature >37.5°C; (ii) highest temperature (°C); (iii) number (%) of infants receiving evaluation for sepsis and (iv) number (%) of infants receiving intravenous antibiotics.

Results:

Ninety-five vaccination episodes were included. Compared with the pre-4CMenB (period 1), more infants developed temperature >37.5°C, needed partial septic screens and had intravenous antibiotics when 4CMenB was introduced without paracetamol prophylaxis (period 2). Paracetamol prophylaxis (period 3) with 4CMenB resulted in fewer infants experiencing postvaccination fever and antibiotic administration comparable to period 1.

Conclusions:

4CMenB is associated with AEs in hospitalized preterm infants. Prophylactic paracetamol administration attenuates this.
E. coli Monomicrobial Necrotizing Fasciitis in an Iron-Overloaded Adolescent
Authors: Nazir Hanan , Al Yazidi Laila , Mutani Mohammed , Zachariah Mathew
Published: December 2019

Escherichia coli is an extremely unusual cause of monomicrobial necrotizing fasciitis of the extremities in children. We report a transfusion-dependent adolescent boy with iron-overload secondary to congenital dyserythropoietic anemia who developed severe E. coli monomicrobial necrotizing fasciitis of the leg following a minor trauma. Combined surgical, antimicrobial and supportive care resulted in a good outcome.
The efficiency of continuous positive airway pressure therapy in carbon monoxide poisoining in the emergency department
Authors: Bal Uğur , Sönmez Bedriye Müge , Inan Selim , Işcanli Murat Doğan , Yilmaz Fevzi
Published: December 2019

Objective

To determine whether oxygen therapy with continuous positive airway pressure (CPAP) is superior to normobaric oxygen therapy in carbon monoxide poisoning.

Methods

The study participants were 43 patients diagnosed with carbon monoxide poisoning between the dates 15 March and 30 June 2016 at the emergency department of an urban teaching hospital. The control group comprised patients who received normobaric oxygen therapy. The case group consisted of patients who underwent one-hour CPAP therapy. The primary outcome was the determination of the half-life of carboxyhemoglobin (COHb) with CPAP treatment. The CPAP and control groups were compared in terms of the reduction in COHb levels after 60 minutes of therapy.

Results

The COHb level among patients in the CPAP group was lower in the 30th and 60th minutes. The half-life of COHb was apparently decreased in the CPAP group compared with the control group (control and case groups mean plasma half-life of COHb were 80.26 ± 12.70 and 36.20 ± 4.58 minutes, respectively).

Conclusion

The results of the present study demonstrate that CPAP therapy may be an effective option for oxygen therapy among patients with carbon monoxide intoxication; this is achieved by decreasing the half-life of COHb.
Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy
Authors: Elgarten Caitlin W. , Aplenc Richard
Published: December 2019

Purpose of review

Despite advances in therapy over the past decades, overall survival for children with acute myeloid leukemia (AML) has not exceeded 70%. In this review, we highlight recent insights into risk stratification for patients with pediatric AML and discuss data driving current and developing therapeutic approaches.

Recent findings

Advances in cytogenetics and molecular profiling, as well as improvements in detection of minimal residual disease after induction therapy, have informed risk stratification, which now relies heavily on these elements. The treatment of childhood AML continues to be based primarily on intensive, conventional chemotherapy. However, recent trials focus on limiting treatment-related toxicity through the identification of low-risk subsets who can safely receive fewer cycles of chemotherapy, allocation of hematopoietic stem-cell transplant to only high-risk patients and optimization of infectious and cardioprotective supportive care.

Further incorporation of genomic and molecular data in pediatric AML will allow for additional refinements in risk stratification to enable the tailoring of treatment intensity. These data will also dictate the incorporation of molecularly targeted therapeutics into frontline treatment in the hope of improving survival while decreasing treatment-related toxicity.
Rethinking clinical endpoints in kidney transplant trials
Authors: Maggiore Umberto , Leventhal Jeremy , Cravedi Paolo
Published: December 2019

Purpose of review

Clinical trials testing novel kidney transplant therapies are challenged by low rates of long-term clinical outcomes such as death and graft loss. Herein, we critically review traditional and more recent strategies to expedite new therapies by minimizing sample size and follow-up duration using surrogates (alone or in the context of composite endpoints), or using different clinical endpoints.

Recent findings

Multiple surrogate endpoints are increasingly important for organ transplantation trial design: glomerular filtration rate slope, albuminuria, donor-specific alloantibodies, and histological score at graft protocol biopsies. However, surrogate endpoint use is limited by bias when data are missing. Hierarchical multiple primary endpoints – that are successfully used in other settings and frequently utilize surrogate endpoints – have not yet been integrated into kidney transplant studies. New clinical endpoints, focusing on treatment safety and patient quality of life have been recently standardized and should be reported regardless of the primary endpoint of any randomized controlled trial.

Defining surrogates, standards for outcome reporting, and statistical strategies to appropriately analyze them are critical to effectively testing and implementing novel therapeutic strategies to improve long-term clinical outcomes in kidney transplantation.
Metachronous Wilms Tumor, Glioblastoma, and T-cell Leukemia in an Child With Constitutional Mismatch Repair Deficiency syndrome due to Novel Mutation in MSH6 (c.2590G>T)
Authors: Citak Elvan C. , Sagcan Fatih , Gundugan Begumhan D. , Bozdogan Sevcan T. , Yilmaz Eda B. , Avci Emel , Balci Yuksel , Karabulut Yasemin Y.
Published: December 2019

Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer predisposition syndrome results from biallelic germline mutations affecting the key DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2. CMMRD is associated with a high risk of developing early onset of central nervous system tumors, hematologic, and intestinal tract tumors. Clinical manifestations, genetic screening, and cancer prevention strategies are limited. In this report we present a patient with metachronous Wilms tumor, glioblastoma, and acute T-cell lymphoblastic leukemia. He had cutaneous features of neurofibromatosis type 1 (NF1). Molecular testing revealed a novel homozygous mutation in MSH6 (c.2590G>T; p.G864*) that has not been reported previously. CMMRD should be considered in patients with cutaneous features similar to NF1 if tumor is found other than expected tumors in NF, early onset cancer, and strong family history of cancer.
A Retrospective Analysis of Invasive Fungal Diseases (IFD) of the Central Nervous System in Children With Lymphoid Malignancies
Authors: Ramanathan Subramaniam , Kate Shruti , Kembhavi Seema , Cheriyalinkal Parambil Badira , K. C. Anand , Bhat Vasudeva , Prasad Maya , Moiyadi Aliasgar , Biswas Sanjay , Narula Gaurav , Banavali Shripad
Published: December 2019

Background:

Outcomes of childhood hematolymphoid malignancies have improved several fold because of immunosuppressive chemotherapy and broad-spectrum antibiotics for managing febrile neutropenia. An apparent trade-off has been an increase in invasive fungal disease (IFD), affecting multiple organs. We report the diagnostic and therapeutic challenges in 8 children with lymphoid cancers who developed intracranial (IC) fungal abscesses between 2010 and 2017.

Methods:

Children below 15 years of age undergoing treatment for leukemia/lymphoma with clinicoradiologic and microbiologic evidence of IC fungal abscess were included. Demographic details, clinical profile, and management were retrospectively audited. Treatment was guided by European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions for IFD with therapeutic drug monitoring (TDM)-directed azole dosing, and surgical intervention.

Results:

Eight patients (4 B-cell acute lymphoblastic leukemia, 2 relapsed B-cell acute lymphoblastic leukemia, and 2 non-Hodgkin lymphoma) were eligible for analysis. Proven, probable, and possible IFDs were seen in 2 (25%), 4 (50%), and 2 (25%) patients, respectively. Proven IFDs were invasive mucormycosis with remaining having mold infections. Cerebrospinal fluid galactomannan was positive in all 4 patients in whom it was tested. TDM was possible in 5/8 (63%) patients. Antifungal therapy was given for a median period of 4.2 months with 5 (63%) patients having complete resolution. Three (37%) patients expired, of which 2 were attributable to IFDs.

Conclusions:

IC fungal abscesses in children can cause significant morbidity and mortality in children with hematolymphoid cancers. Evaluation of cerebrospinal fluid galactomannan may help in early diagnosis and therapy. Prolonged antifungal therapy steered by TDM can help achieve resolution in some cases.
Nonopioid Modalities for Acute Postoperative Pain in Abdominal Transplant Recipients
Authors: Chadha Ryan , Pai Sher-lu , Aniskevich Stephen , McClain Robert , Egan Brian , Webb Christopher , Sakai Tetsuro
Published: December 2019

The field of abdominal organ transplantation is multifaceted, with the clinician balancing recipient comorbidities, risks of the surgical procedure, and the pathophysiology of immunosuppression to ensure optimal outcomes. An underappreciated element throughout this process is acute pain management related to the surgical procedure. As the opioid epidemic continues to grow with increasing numbers of transplant candidates on opioids as well the increase in the development of enhanced recovery after surgery protocols, there is a need for greater focus on optimal postoperative pain control to minimize opioid use and improve outcomes. This review will summarize the physiology of acute pain in transplant recipients, assess the impact of opioid use on post-transplant outcomes, present evidence supporting nonopioid analgesia in transplant surgery, and briefly address the perioperative approach to the pretransplant recipient on opioids.
New Insights Into the Indications for Intestinal Transplantation: Consensus in the Year 2019
Authors: Kaufman Stuart S. , Avitzur Yaron , Beath Sue V. , Ceulemans Laurens J. , Gondolesi Gabriel E. , Mazariegos George V. , Pironi Loris
Published: December 2019

In 2001, a Statement was published that described indications for intestinal transplantation in patients with intestinal failure expected to require parenteral nutrition indefinitely. Since 2001, advances in the management of intestinal failure including transplantation and patient survival, both on extended parenteral nutrition and after transplantation, have improved, leading to a reduction in the number of intestinal transplants worldwide from a peak of 270 per year in 2008 to 149 per year in 2017. These changes suggest that the original 2001 Statement requires reassessment. All patients with permanent intestinal failure should be managed by dedicated multidisciplinary intestinal rehabilitation teams. Under care of these teams, patients should be considered for intestinal transplantation in the event of progressive intestinal failure–associated liver disease, progressive loss of central vein access, and repeated life-threatening central venous catheter–associated infections requiring critical care. Additional indications for transplantation include large desmoid tumors and other intra-abdominal tumors with reasonable expectation of posttransplant cure, extensive mesenteric vein thrombosis and intestinal infarction, total intestinal aganglionosis, and nonrecoverable congenital secretory diarrhea. Quality of life typically improves after successful intestinal transplantation and may support the decision to proceed with transplantation when other indications are present. However, the requirement for life-long immunosuppression and its associated side effects preclude intestinal transplantation if motivated only by an expectation of improved quality of life. Increasing experience with intestinal transplantation and critical appraisal of transplant outcomes including graft survival and patient quality of life together with potential advances in immunosuppression can be expected to influence transplant practices in the future.
The development of the social brain in baby siblings of children with autism
Authors: Dean Douglas C. , Freeman Abigail , Lainhart Janet
Published: December 2019

Purpose of review

Impairments in social interaction/communication become apparent after 12 months of age in children who develop Autism spectrum disorder (ASD). Studies of baby siblings of children with ASD provide the means to detect changes in the brain that are present before behavioral symptoms appear. In this review, advances from brain imaging studies of infant siblings over the past 18 months are highlighted.

Recent findings

During the first 2 months of life, functional differences in social brain regions and microstructural differences in dorsal language tracks are found in some high-risk baby siblings. At 4–6 months of age, differences in subcortical and cerebellum volumes and atypical cortical responses to social stimuli are evident. At 6 months, extra-axial cerebrospinal fluid is increased, and at 8 months there is evidence of cortical hyper-reactivity. Patterns of functional connectivity are distinct in infant siblings and suggest dysfunctional activation and integration of information across the cortex and neural networks underlying social behaviors.

Further replication in very large independent samples is needed to verify the majority of the findings discussed and understand how they are related within individual infants. Much more research is needed before translation to clinical practice.
PSA and VIM DBS efficiency in essential tremor depends on distance to the dentatorubrothalamic tract
Authors: Dembek Till A. , Petry-Schmelzer Jan Niklas , Reker Paul , Wirths Jochen , Hamacher Stefanie , Steffen Julia , Dafsari Haidar S. , Hövels Mauritius , Fink Gereon R. , Visser-Vandewalle Veerle , Barbe Michael T.
Published: December 2019

Objective

To investigate the relation between deep brain stimulation (DBS) of the posterior-subthalamic-area (PSA) and the ventral-intermediate-nucleus (VIM) and the distance to the dentatorubrothalamic tract (DRTT) in essential tremor (ET).

Methods

Tremor rating scale (TRS) hemi-scores were analyzed in 13 ET patients, stimulated in both the VIM and the PSA in a randomized, crossover trial. Distances of PSA and VIM contacts to population-based DRTTs were calculated. The relationships between distance to DRTT and stimulation amplitude, as well as DBS efficiency (TRS improvement per amplitude) were investigated.

Results

PSA contacts were closer to the DRTT (p=0.019) and led to a greater improvement in TRS hemi-scores (p=0.005) than VIM contacts. Proximity to the DRTT was related to lower amplitudes (p<0.001) and higher DBS efficiency (p=0.017).

Conclusions

Differences in tremor outcome and stimulation parameters between contacts in the PSA and the VIM can be explained by their different distance to the DRTT.
Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit
Authors: Edlow Brian L. , Barra Megan E. , Zhou David W. , Snider Samuel B. , Threlkeld Zachary D. , Kirsch John E. , Chan Suk-tak , Meisler Steven L. , Bleck Thomas P. , Fins Joseph J. , Giacino Joseph T. , Hochberg Leigh R. , Solt Ken , Brown Emery N. , Bodien Yelena G.
Published: December 2019

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). Early recovery of consciousness would benefit patients and families by reducing the likelihood of premature withdrawal of life-sustaining therapy and may decrease ICU complications related to immobility, facilitate self-expression, enable autonomous decision-making, and increase access to rehabilitative care. Here, we present the connectome-based clinical trial platform (CCTP), a new mechanistic paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. The scientific premise of the CCTP is that personalized brain connectome maps can be used to select patients for targeted therapies that promote recovery of consciousness. Structural and functional MRI connectome maps will identify circuits that may be amenable to neuromodulation. Patients will be selected for clinical trials in the CCTP paradigm based on connectomes that are likely to respond to targeted therapies. To demonstrate the utility of this precision approach, we describe STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based clinical trial in which intravenous methylphenidate will be used to promote early recovery of consciousness in the ICU (ClinicalTrials.gov NCT03814356). We propose that the CCTP has the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.
TrpML-mediated astrocyte microdomain Ca2+ transients regulate astrocyte-tracheal interactions
Authors: Ma Zhiguo , Freeman Marc R.
Published: December 2019

Astrocytes exhibit spatially-restricted near-membrane microdomain Ca2+ transients in their fine processes. How these transients are generated and regulate brain function in vivo remains unclear. Here we show that Drosophila astrocytes exhibit spontaneous, activity-independent microdomain Ca2+ transients in their fine processes. Astrocyte microdomain Ca2+ transients are mediated by the TRP channel TrpML, stimulated by reactive oxygen species (ROS), and can be enhanced in frequency by the neurotransmitter tyramine via the TyrRII receptor. Interestingly, many astrocyte microdomain Ca2+ transients are closely associated with tracheal elements, which dynamically extend filopodia throughout the central nervous system (CNS) to deliver O2 and regulate gas exchange. Many astrocyte microdomain Ca2+ transients are spatio-temporally correlated with the initiation of tracheal filopodial retraction. Loss of TrpML leads to increased tracheal filopodial numbers, growth, and increased CNS ROS. We propose that local ROS production can activate astrocyte microdomain Ca2+ transients through TrpML, and that a subset of these microdomain transients promotes tracheal filopodial retraction and in turn modulate CNS gas exchange.
Unraveling a tangled skein: Evolutionary analysis of the bacterial gibberellin biosynthetic operon
Authors: Nett Ryan S. , Nguyen Huy , Nagel Raimund , Marcassa Ariana , Charles Trevor C. , Friedberg Iddo , Peters Reuben J.
Published: December 2019

Gibberellin (GA) phytohormones are ubiquitous regulators of growth and developmental processes in vascular plants. The convergent evolution of GA production by plant-associated bacteria, including both symbiotic, nitrogen-fixing rhizobia and phytopathogens, suggests that manipulation of GA signaling is a powerful mechanism for microbes to gain an advantage in these interactions. Although homologous operons encode GA biosynthetic enzymes in both rhizobia and phytopathogens, notable genetic heterogeneity and scattered operon distribution in these lineages suggests distinct functions for GA in varied plant-microbe interactions. Therefore, deciphering GA operon evolutionary history could provide crucial evidence for understanding the distinct biological roles for bacterial GA production. To further establish the genetic composition of the GA operon, two operon-associated genes that exhibit limited distribution among rhizobia were biochemically characterized, verifying their roles in GA biosynthesis. Additionally, a maximum-parsimony ancestral gene block reconstruction algorithm was employed to characterize loss, gain, and horizontal gene transfer (HGT) of GA operon genes within alphaproteobacteria rhizobia, which exhibit the most heterogeneity among GA operon-containing bacteria. Collectively, this evolutionary analysis reveals a complex history for HGT of both individual genes and the entire GA operon, and ultimately provides a basis for linking genetic content to bacterial GA functions in diverse plant-microbe interactions.
Circuit-specific dendritic development in the piriform cortex
Authors: Moreno-Velasquez Laura , Lo Hung , Lenzi Stephen , Kaehne Malte , Breustedt Jörg , Schmitz Dietmar , Rüdiger Sten , Johenning Friedrich W.
Published: December 2019

Dendritic geometry is largely determined during postnatal development and has a substantial impact on neural function. In sensory processing, postnatal development of the dendritic tree is affected by two dominant circuit motifs, ascending sensory feedforward inputs and descending and local recurrent connections. In the three-layered anterior piriform cortex, neurons in the sublayers 2a and 2b display vertical segregation of these two circuit motifs. Here, we combined electrophysiology, detailed morphometry and Ca2+ imaging in acute mouse brain slices and modeling to study circuit specific aspects of dendritic development. We observed that determination of branching complexity, dendritic length increases and pruning occurred in distinct developmental phases. Layer 2a and layer 2b neurons displayed developmental phase specific differences between their apical and basal dendritic trees related to differences in circuit incorporation. We further identified functional candidate mechanisms for circuit-specific differences in postnatal dendritic growth in sublayers 2a and 2b at the meso- and microscale level. Already in the first postnatal week, functional connectivity of layer 2a and layer 2b neurons during early spontaneous network activity scales with differences in basal dendritic growth. During the early critical period of sensory plasticity in the piriform cortex, our data is consistent with a model that proposes a role for dendritic NMDA-spikes in selecting branches for survival during developmental pruning in apical dendrites. The different stages of the morphological and functional developmental pattern differences between layer 2a and layer 2b neurons demonstrate the complex interplay between dendritic development and circuit specificity.

Significance Statement

Sensory cortices are composed of ascending sensory circuits that relay sensory information from the periphery and recurrent intracortical circuits. Dendritic trees of neurons are shaped during development and determine which circuits contribute to the neuronal input space. To date, circuit-specific aspects of dendritic development and the underlying mechanisms are poorly understood. Here, we investigate dendritic development in layer 2 of the piriform cortex, a three-layered palaeocortex that displays a clear vertical segregation of sensory and recurrent circuits. Our results suggest that dendritic development occurs in distinct developmental phases with different circuit-specific properties. We further identify candidate mechanisms for neuronal activity patterns that could determine differences in circuit-specific dendritic development.