bluuebunny/crossref_metadata_2025_split huggingface dataset:
Face mask sampling reveals antimicrobial resistance genes in exhaled aerosols from patients with chronic obstructive pulmonary disease and healthy volunteers
Authors: Kennedy Matthew , Ramsheh Mohammadali Y , Williams Caroline M L , Auty Joss , Haldar Koirobi , Abdulwhhab Mohamad , Brightling Christopher E , Barer Michael R 
Published: September 2018

IntroductionThe degree to which bacteria in the human respiratory tract are aerosolised by individuals is not established. Building on our experience sampling bacteria exhaled by individuals with pulmonary tuberculosis using face masks, we hypothesised that patients with conditions frequently treated with antimicrobials, such as chronic obstructive pulmonary disease (COPD), might exhale significant numbers of bacteria carrying antimicrobial resistance (AMR) genes and that this may constitute a previously undefined risk for the transmission of AMR.MethodsFifteen-minute mask samples were taken from 13 patients with COPD (five paired with contemporaneous sputum samples) and 10 healthy controls. DNA was extracted from cell pellets derived from gelatine filters mounted within the mask. Quantitative PCR analyses directed to the AMR encoding genes:blaTEM(β-lactamase),ErmB(target methylation),mefA(macrolide efflux pump) andtetM(tetracycline ribosomal protection protein) and six additional targets were investigated. Positive signals above control samples were obtained for all the listed genes; however, background signals from the gelatine precluded analysis of the additional targets.Results9 patients with COPD (69%), aerosolised cells containing, in order of prevalence,mefA,tetM, ErmBandblaTEM, while three healthy controls (30%) gave weak positive signals including all targets exceptblaTEM. Maximum estimated copy numbers of AMR genes aerosolised per minute weremefA: 3010,tetM: 486,ErmB: 92 andblaTEM: 24. The profile of positive signals found in sputum was not concordant with that in aerosol in multiple instances.DiscussionWe identified aerosolised AMR genes in patients repeatedly exposed to antimicrobials and in healthy volunteers at lower frequencies and levels. The discrepancies between paired samples add weight to the view that sputum content does not define aerosol content. Mask sampling is a simple approach yielding samples from all subjects and information distinct from sputum analysis. Our results raise the possibility that patient-generated aerosols may be a significant means of AMR dissemination that should be assessed further and that consideration be given to related control measures.
A synopsis of Late Ordovician brachiopod diversity in the Anti-Atlas, Morocco
Authors: Colmenar J. , Villas E. , Rasmussen C. M. Ø. 
Published: September 2018

Abstract

A detailed overview of the taxonomical composition and diversity of the Late Ordovician brachiopod faunas in Morocco is presented. In addition, based on new brachiopod collections, the lower boundary of the Hirnantian Stage in the Anti-Atlas is constrained. A new, prolonged range of the
Hirnantia
Fauna in the Anti-Atlas region permits comparison between known Late Ordovician climatic excursions and changes in brachiopod diversity. Despite the late Katian Boda warming event, the Moroccan brachiopod associations remained notably endemic with low diversities throughout the studied interval. Contrary to what is seen in other high-latitude peri-Gondwanan terranes, species richness decreased during the Boda Event. This suggests that the Moroccan shelves experienced a more persistent, colder climate, favouring well-adapted, incumbent faunas that did not respond to this climatic optimum. Lastly, the two phases of Hirnantian extinctions, which globally are correlated with the growth and melting of ice caps, are expressed differently from elsewhere: the first pulse only caused minor disruption, followed by a radiation of the
Hirnantia
Fauna, whereas the second pulse, related to the subsequent warming phase in the uppermost Hirnantian, caused severe extinctions in Morocco among the opportunistic
Hirnantia
Fauna.
New Upper Ordovician edrioasteroids from Morocco
Authors: Sumrall Colin D. , Zamora Samuel 
Published: September 2018

Abstract

Edrioasteroids from the Katian, Lower Ktaoua and Upper Tiouririne formations provide new data on several previously described species and two new species of edrioasteroids. Ontogenetic and palaeoecological data are provided for
Moroccopyrgus matacarros
. Well-preserved oral areas and internal views of the oral frame show
Euryeschatia reboulorum
to be an unusual lebetodiscinid rather than an isorophinid. The pyrgocystid
Spinadiscus lefebvrei
n. gen. and sp. and the highly inflated isorophinid
Panidiscus tamiformis
n. gen. and sp. are described. Specimens of
Moroccopyrgus matacarros
and
Euryeschatia reboulorum
are only found attached to echinosphaeritid rhombiferans and conulariids, respectively, suggesting commensal relationships. Other species attach to a variety of different surfaces.
CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis
Authors: Penfold Lucy , Woods Angela , Muckett Phillip , Nikitin Alexander Yu. , Kent Tera R. , Zhang Shuai , Graham Rebecca , Pollard Alice , Carling David 
Published: September 2018

Abstract

New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) β1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer.

Significance:
These findings show that CAMKK2 and its downstream target AMPK have opposing effects on prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK.
Immunotherapy Targeting HPV16/18 Generates Potent Immune Responses in HPV-Associated Head and Neck Cancer
Authors: Aggarwal Charu , Cohen Roger B. , Morrow Matthew P. , Kraynyak Kimberly A. , Sylvester Albert J. , Knoblock Dawson M. , Bauml Joshua M. , Weinstein Gregory S. , Lin Alexander , Boyer Jean , Sakata Lindsay , Tan Sophie , Anton Aubrey , Dickerson Kelsie , Mangrolia Drishty , Vang Russell , Dallas Michael , Oyola Sandra , Duff Susan , Esser Mark , Kumar Rakesh , Weiner David , Csiki Ildiko , Bagarazzi Mark L. 
Published: September 2018

AbstractPurpose:Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition.Patients and Methods:We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457.Results:MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%).Conclusions:These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing
Authors: Lizotte Patrick H. , Hong Ruey-Long , Luster Troy A. , Cavanaugh Megan E. , Taus Luke J. , Wang Stephen , Dhaneshwar Abha , Mayman Naomi , Yang Aaron , Kulkarni Meghana , Badalucco Lauren , Fitzpatrick Erica , Kao Hsiang-Fong , Kuraguchi Mari , Bittinger Mark , Kirschmeier Paul T. , Gray Nathanael S. , Barbie David A. , Jänne Pasi A. 
Published: September 2018

Abstract
We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b–restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell–mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8+ cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell–mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted.
ДОСВІД ЗАПРОВАДЖЕННЯ ТРЕНІНГІВ З ОВОЛОДІННЯ ПРАКТИЧНИМИ НАВИЧКАМИ КОМУНІКАЦІЙ ІЗ ПАЦІЄНТАМИ НА БАЗІ ОКРЕМИХ ЗАКЛАДІВ ОХОРОНИ ЗДОРОВ’Я ІВАНО-ФРАНКІВСЬКОЇ ОБЛАСТІ
Authors: Yavorskyy A. M. 
Published: September 2018

Мета роботи – проаналізувати досвід запровадження тренінгів з оволодіння практичними навичками комунікацій із пацієнтами в окремих закладах охорони здоров’я Івано-Франківської області.Основна частина. На базі стаціонарних закладів охорони Івано-Франківської області провели медико-соціальне дослідження рівня і причин незадоволеності пацієнтів отриманим медичним обслуговуванням. Опитано 553 пацієнтів. Встановлено, що серед понад 50 вивчених різноманітних чинників найбільший вплив на задоволеність пацієнтів медичним обслуговуванням мали інформаційно-деонтологічні чинники, спровоковані неналежним ставленням з боку медичного персоналу, усуненням пацієнтів від процесу прийняття рішення щодо призначених їм методів медичних втручань, недостатнім обговоренням з хворими можливих наслідків захворювання, неналежним інформуванням пацієнтів про їх права і обов’язки тощо. Розроблено і впроваджено на базі двох центральних районних, однієї центральної міської та обласної клінічної лікарень Івано-Франківської області короткотривалі навчальні тренінги для лікарів з оволодіння практичними навичками комунікацій із пацієнтами. До їх проведення залучались юрисконсульти лікарень, психологи та спеціально підготовані тренери з числа заступників керівників закладів охорони здоров’я. Результати повторного опитування 445 пацієнтів у цих закладах охорони здоров’я довели ефективність такої форми навчання і доцільність охоплення нею усіх медичних працівників. Висновок.Оволодіння практичними навичками комунікацій із пацієнтами – важлива і необхідна складова програм інформальної освіти у рамках безперервного професійного розвитку усіх фахівців у сфері охорони здоров’я.
Coupling Between Interleukin-1R1 and Necrosome Complex Involves in Hemin-Induced Neuronal Necroptosis After Intracranial Hemorrhage
Authors: Chu Xiang , Wu Xiaofeng , Feng Hua , Zhao Hengli , Tan Yan , Wang Liting , Ran Haiying , Yi Liang , Peng Yan , Tong Haipeng , Liu Rui , Bai Wei , Shi Huiwen , Li Lei , Huo Danqun 
Published: September 2018

Background and Purpose—
Accumulated evidence suggests that hemin—a breakdown product of hemoglobin—plays a pivotal role in the inflammatory injuries that result after hemorrhagic stroke through the Toll Like Receptor 2-Toll Like Receptor 4 signal pathway. However, the mechanism of how hemin triggers neuronal necroptosis directly after intracranial hemorrhage (ICH) is still an area of active research. As animal model and preclinical studies have shown, the recombinant interleukin-1 receptor antagonist (IL-1RA) improves clinical outcomes after stroke. As such, we have chosen to investigate the mechanism of how IL-1RA exerts protective effect in hemin-induced neuronal necroptosis after ICH.

Methods—

Our ICH model was induced by hemin injection in C57BL/6 mice and IL-1R1
−/−
mice. In addition, we used primary cultured neurons to assess hemin-induced cell death. Co-immunoprecipitation, immunoblot, immunofluorescent staining, neurological deficit scores, and brain water content were used to study the mechanisms of IL-1R1 modulation in neuronal necroptosis both in vitro and in vivo.

Results—
Free hemin could mediate neuronal necroptosis directly by assembling necrosome complex and then to trigger cell death. This phenomenon was driven by IL-1R1 as IL-1R1 can form a complex with necrosome. After treatment with IL-1RA, both the expression and translocation of the necrosome decreased while disruption of the interaction between IL-1R1 and RIP1/RIP3 (receptor interacting protein 1/3) increased neuron survival. In addition, the IL-1R1–deficient mice demonstrated lower levels of necrosome components, including RIP1, RIP3, and MLKL (mixed lineage kinase domain-like protein), compared with control groups after hemin treatment. In addition, the neurological deficit scores, brain water content, and inflammatory response were all also reduced in the IL-1R1–deficient mice.

Conclusions—
Functional inhibition of the interaction between IL-1R1 and the necrosome complex improves neuron survival and promotes the recovery of neurological function in experimental ICH. Targeting IL-1R1/RIP1/RIP3 assembly could be a promising therapeutic strategy for patients with ICH.
Mechanical Thrombectomy in Patients With Milder Strokes and Large Vessel Occlusions
Authors: Nagel Simon , Bouslama Mehdi , Krause Lars U. , Küpper Clemens , Messer Mirko , Petersen Martina , Lowens Stephan , Herzberg Moritz , Ringleb Peter A. , Möhlenbruch Markus A. , Tiedt Steffen , Lima Fabricio O. , Haussen Diogo C. , Smith Wade S. , Lev Michael H. , Nogueira Raul G. 
Published: September 2018

Background and Purpose—
We aimed to describe the safety and efficacy of immediate mechanical thrombectomy (MT) in patients with large vessel occlusions and low National Institutes of Health Stroke Scale (NIHSS) versus best medical management.

Methods—
Patients from prospectively collected databases of 6 international comprehensive stroke centers with large vessel occlusions (distal intracranial internal carotid, middle cerebral artery-M1 and M2 segments, or basilar artery with or without tandem occlusions) and NIHSS 0 to 5 were identified and divided into 2 groups for analysis: immediate MT or initial best medical management which included rescue MT after neurological deterioration (best medical management-MT). Uni- and multivariate analyses and patient-level matching for age, baseline NIHSS, and occlusion site were performed to compare baseline and outcome variables across the 2 groups. The primary outcome was defined as good outcome (modified Rankin Scale score, 0–2) at day 90. Safety outcome was symptomatic intracranial hemorrhage as defined by the ECASS (European Cooperative Acute Stroke Study) II and mortality at day 90.

Results—

Compared with best medical management-MT (n=220), patients with immediate MT (n=80) were younger (65.3±13.5 versus 69.5±14.1;
P
=0.021), had more often atrial fibrillation (44.8% versus 28.2%;
P
=0.012), higher baseline NIHSS (4, 0–5 versus 3, 0–5;
P
=0.005), higher Alberta Stroke Program Early CT Score (10, 7–10 versus 10, 5–10;
P
=0.023), more middle cerebral artery-M1, and less middle cerebral artery-M2 (41.3% versus 21.9% and 28.8% versus 49.3%;
P
=0.016) occlusions. The adjusted odds ratio for good outcome was 3.1 (95% CI, 1.4–6.9) favoring immediate MT. In the matched analysis, there was a 14.4% absolute difference in good outcome (84.4% versus 70.1%;
P
=0.03) at day 90 favoring immediate MT. There were no safety concerns.

Conclusions—
Our retrospective, pilot analysis suggests that immediate thrombectomy in large vessel occlusions patients with low NIHSS on presentation may be safe and has the potential to result in improved outcomes. Randomized clinical trials are warranted to establish the optimal management for this patient population.
Progression From Paroxysmal to Sustained Atrial Fibrillation Is Associated With Increased Adverse Events
Authors: Ogawa Hisashi , An Yoshimori , Ikeda Syuhei , Aono Yuya , Doi Kosuke , Ishii Mitsuru , Iguchi Moritake , Masunaga Nobutoyo , Esato Masahiro , Tsuji Hikari , Wada Hiromichi , Hasegawa Koji , Abe Mitsuru , Lip Gregory Y.H. , Akao Masaharu ,   on behalf of the Fushimi AF Registry Investigators
Published: September 2018

Background and Purpose—
Atrial fibrillation (AF) is a common arrhythmic disorder among the elderly and sometimes progresses from paroxysmal to sustained (persistent or permanent) types. Clinical outcomes of patients with progression of AF were unknown. This study assessed the characteristics of patients with AF progression and the impact of AF progression on various clinical events.

Methods—
The Fushimi AF Registry is a community-based prospective survey of the patients with AF in Fushimi-ku, Kyoto. Analyses were performed on 4045 patients, which included 1974 paroxysmal AF (PAF; 48.8%) and 2071 sustained (persistent or permanent) AF (SAF; 51.2%) at baseline.

Results—

During the median follow-up period of 1105 days, progression of AF occurred in 252 patients with PAF (4.22 per 100 person-years). Multivariate Cox regression analysis demonstrated that progression of AF was significantly associated with an increased risk of ischemic stroke or systemic embolism (adjusted hazard ratio [HR], 4.10; 95% CI, 1.95–8.24;
P
<0.001 [versus PAF without progression]; adjusted HR, 2.20; 95% CI, 1.11–4.00;
P
=0.025 [versus SAF]) during progression period from paroxysmal to sustained forms. The risk after the progression was equivalent to SAF (adjusted HR, 1.54; 95% CI, 0.78–2.75;
P
=0.201 [versus SAF]). AF progression was significantly associated with a higher risk of hospitalization for heart failure (adjusted HR, 2.70; 95% CI, 1.55–4.52;
P
<0.001 [versus PAF without progression]; adjusted HR, 1.81; 95% CI, 1.08–2.88;
P
=0.026 [versus SAF]).

Conclusions—
Progression of AF was associated with increased risk of clinical adverse events during arrhythmia progression period from PAF to SAF among Japanese patients with AF. The risk of adverse events was transiently elevated during progression period from PAF to SAF and declined to the level equivalent to SAF after the progression.

Clinical Trial Registration—

URL:
http://www.umin.ac.jp/ctr/
. Unique identifier: UMIN000005834.
Persistently Elevated Microvascular Resistance Postrecanalization
Authors: Ng Felix C. , Coulton Bronwyn , Chambers Brian , Thijs Vincent 
Published: September 2018

Background and Purpose—
Impaired microvascular reperfusion despite complete recanalization (no-reflow) represents a potential therapeutic target to improve outcomes after recanalization therapies. Although well documented in animal models, this phenomenon has not been demonstrated clinically. We investigated whether transcranial Doppler can detect acute microvascular changes postrecanalization as a biomarker of the no-reflow phenomenon in stroke patients.

Methods—
Consecutive patients with recanalized (Thrombolysis in Cerebral Infarction grade IIb/III) acute middle cerebral artery occlusion by thrombectomy at a Comprehensive Stroke Centre with a high-volume neurovascular laboratory were retrospectively identified. Sonographic measures of middle cerebral artery territory microvascular resistance (pulsatility index and resistive index) on days 1 to 3 follow-up transcranial Doppler were compared between patients and age/gender-matched controls.

Results—

In 53 patients, middle cerebral artery pulsatility index was significantly more likely to be asymmetrically increased on interside comparison (27.9% versus 4.9%;
P
=0.007) and abnormally elevated beyond normal reference ranges (46.7% versus 22.0%;
P
=0.016) in the symptomatic hemisphere. Middle cerebral artery pulsatility index elevation was associated with less hemorrhagic infarction (9.5% versus 45.8%;
P
=0.009) but worse functional outcome irrespective of infarct volume as assessed on 90-day modified Rankin Scale (score of ≤1, 18.2% versus 58.1%;
P
=0.035).

Conclusions—
Elevated microvascular resistance within the ischemic territory is commonly present after successful recanalization as measured by pulsatility index on transcranial Doppler and may be a readily available and clinically relevant biomarker of the no-reflow phenomenon.