bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences and Temporal Changes in Risk of Invasive Pneumococcal Disease in Adults with Hematological Malignancies: Results from a Nationwide 16-Year Cohort Study
Authors: Andersen Michael Asger , Niemann Carsten Utoft , Rostgaard Klaus , Dalby Tine , Sørrig Rasmus , Weinberger Daniel M , Hjalgrim Henrik , Harboe Zitta Barrella
Published: February 2020

Background

Patients with hematological malignancies (HM) are known to carry an increased risk of invasive pneumococcal disease (IPD). However, temporal variations in IPD risks following a cancer diagnosis remain poorly characterized. To inform vaccine guidelines and patient management, we assessed the IPD incidence among patients with HM and other malignancies.

Methods

The study population included all individuals aged ≥15 years during 2000–2016 in Denmark. Variations in incidences of IPD over time and between different types of hematological malignancies and diagnoses were assessed by Poisson regression.

Results

During 85 002 224 person-years of observation, 13 332 episodes of a first IPD were observed, of which 765 (5.7%) occurred among individuals with HM. Among HM patients, the IPD incidence rate decreased continuously during the study period (rate ratio per year, 0.91; 95% confidence interval, .90–.92). The risk of IPD in patients with HM was up to 39 times higher when compared to the background population and was highest for multiple myeloma, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. Unlike other malignancies, the increased IPD risk did not wane with the time since HM diagnosis. We found a vaccination uptake of only ≤2% in patients with HM and ≤1% for those with other types of malignancies.

Conclusions

Adults with HM in general and patients with lymphoid malignancies in particular have an increased risk for IPD, compared with patients with other types of cancer and with individuals free of cancer. The pneumococcal vaccination uptake is extremely low in this at risk-population. Efforts to prevent IPD in HM patients are continuously warranted.
A 2-Biomarker Model Augments Clinical Prediction of Mortality in Melioidosis
Authors: Wright Shelton W , Kaewarpai Taniya , Lovelace-Macon Lara , Ducken Deirdre , Hantrakun Viriya , Rudd Kristina E , Teparrukkul Prapit , Phunpang Rungnapa , Ekchariyawat Peeraya , Dulsuk Adul , Moonmueangsan Boonhthanom , Morakot Chumpol , Thiansukhon Ekkachai , Limmathurotsakul Direk , Chantratita Narisara , West T Eoin
Published: February 2020

Background

Melioidosis, infection caused by Burkholderia pseudomallei, is a common cause of sepsis with high associated mortality in Southeast Asia. Identification of patients at high likelihood of clinical deterioration is important for guiding decisions about resource allocation and management. We sought to develop a biomarker-based model for 28-day mortality prediction in melioidosis.

Methods

In a derivation set (N = 113) of prospectively enrolled, hospitalized Thai patients with melioidosis, we measured concentrations of interferon-γ, interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-ɑ, granulocyte-colony stimulating factor, and interleukin-17A. We used least absolute shrinkage and selection operator (LASSO) regression to identify a subset of predictive biomarkers and performed logistic regression and receiver operating characteristic curve analysis to evaluate biomarker-based prediction of 28-day mortality compared with clinical variables. We repeated select analyses in an internal validation set (N = 78) and in a prospectively enrolled external validation set (N = 161) of hospitalized adults with melioidosis.

Results

All 8 cytokines were positively associated with 28-day mortality. Of these, interleukin-6 and interleukin-8 were selected by LASSO regression. A model consisting of interleukin-6, interleukin-8, and clinical variables significantly improved 28-day mortality prediction over a model of only clinical variables [AUC (95% confidence interval [CI]): 0.86 (.79–.92) vs 0.78 (.69–.87); P = .01]. In both the internal validation set (0.91 [0.84–0.97]) and the external validation set (0.81 [0.74–0.88]), the combined model including biomarkers significantly improved 28-day mortality prediction over a model limited to clinical variables.

Conclusions

A 2-biomarker model augments clinical prediction of 28-day mortality in melioidosis.
Analytical Bias in a Quality Control Scheme
Authors: Allen John R , Earp Rachel , Farrell E Christis , Grümer H D
Published: February 2020

A quality control program utilizing both "known" and "blind" control specimens was analyzed in the routine clinical chemistry laboratory. The results obtained with the control samples of 18 automated and nonautomated procedures demonstrated the presence of analytical bias. Only through the evaluation of blind control samples tested at random times can a reliable measure of the proficiency of the laboratory be achieved.
A Bubble-gating Flow Cell for Continuous-flow Analysis
Authors: Habig R L , Schlein B W , Walters L , Thiers R E
Published: February 2020

A system is described which permits measurements, such as photometry, to be made on air-segmented streams, as in continuous-flow analysis. Elimination of the "debubbler" step before measurement provides two basic assets: (1) more rapid attainment of steady-state conditions (lower interaction between samples), and (2) maintenance of the integrity of the bubbled analysis stream, permitting subsequent handling and remeasurement. A device has been developed for detecting air bubbles. When placed across the light path of a photometer flow cell it inactivates the readout system when bubbles pass by. The resulting system measures the transmittance of each individual liquid segment of the analysis stream, while maintaining the integrity of the stream. Two examples of possible applications of this system are described. One is a simple total-protein determination with biuret, at three times the conventional sampling rate. The other is a continuous-flow, two-point, reaction-rate method for assay of alkaline phosphatase activity.
A Cleaning Technic for Mercury in the Clinical Laboratory
Authors: Furuno Masaki
Published: February 2020

A simple method is described for cleaning mercury used in gasometric carbon dioxide analysis with the Van Slyke apparatus.
Tick-Borne Diseases in the United States
Authors: Rodino Kyle G , Theel Elitza S , Pritt Bobbi S
Published: February 2020

Background

Tick-borne diseases are an important cause of human morbidity and mortality in the United States. The past several decades have witnessed an increase in both the number of recognized tick-borne pathogens and the number of tick-borne disease cases, whereas tick surveys have revealed substantial geographic expansions of tick populations throughout the country. Multiple laboratory testing options exist for diagnosis of tick-borne diseases, including serology, microscopy, and molecular-based methods. The preferred approach varies by the specific disease, locally available test options, and the stage of illness at patient presentation. Accurate and timely detection of tick-borne illness is of utmost importance, as prompt treatment is strongly linked to better outcomes.

Content

This review covers the clinical manifestations and preferred diagnostic approaches for important bacterial, viral, and parasitic tick-borne diseases in the United States, including Lyme disease, tick-borne relapsing fever, anaplasmosis, ehrlichiosis, spotted fever rickettsioses, and babesiosis. Infection with emerging pathogens such as Borrelia miyamotoi, Powassan virus, Heartland virus, Colorado tick fever virus, and Bourbon virus are also covered.

Our understanding of tick-borne diseases in the United States continues to improve with the detection of novel pathogens and development of new diagnostic modalities. While conventional diagnostic methods, including serology and microscopy, will play an ongoing role in the diagnosis of tick-borne diseases, implementation of advanced molecular diagnostics will further broaden our understanding of these diseases by facilitating detection of emerging pathogens and providing more accurate and timely diagnosis.
Long-term prognostic value of stress myocardial perfusion echocardiography in patients with coronary artery disease: a meta-analysis
Authors: Qian Lijun , Xie Feng , Xu Di , Porter T R
Published: February 2020

Aims 

To evaluate the prognostic value of myocardial perfusion (MP) imaging during contrast stress echocardiography (cSE) in patients with known or suspected coronary artery disease (CAD).

Methods and results 

A search in PubMed, Embase databases, and the Cochrane library was conducted through May 2019. The Cochran Q statistic and the I2 statistic were used to assess heterogeneity, and the results were analysed by RevMan V5.3 and Stata V15.1 software. Twelve studies (seven dipyridamole and five exercise/dobutamine) without evidence of patient overlap (same institution publishing results over a similar time period) enrolling 5953 subjects (47% female, 8–80 months of follow-up) were included in the analysis. In all studies, total adverse cardiovascular events were defined as either cardiac death, non-fatal myocardial infarction (NFMI), or need for urgent revascularization. Hazard ratios (HRs) revealed that a MP abnormality [pooled HR 4.75; 95% confidence interval (CI) 2.47–9.14] was a higher independent predictor of total events than abnormal wall motion (WM, pooled HR 2.39; 95% CI 1.58–3.61) and resting left ventricular ejection fraction (LVEF, pooled HR 1.92; 95% CI 1.44–2.55) with significant subgroup differences (P = 0.002 compared with abnormal WM and 0.01 compared with abnormal LVEF). Abnormal MP was associated with higher risks for death [Risk ratio (RR) 5.24; 95% CI 2.91–9.43], NFMI (RR 3.09; 95% CI 1.84–5.21), and need for coronary revascularization (RR 16.44; 95% CI 6.14–43.99).

Conclusion 

MP analysis during stress echocardiography is an effective prognostic tool in patients with known or suspected CAD and provides incremental value over LVEF and WM in predicting clinical outcomes.
Methanogenic response to long-term permafrost thaw is determined by paleoenvironment
Authors: Holm Stine , Walz Josefine , Horn Fabian , Yang Sizhong , Grigoriev Mikhail N , Wagner Dirk , Knoblauch Christian , Liebner Susanne
Published: February 2020

Methane production in thawing permafrost can be substantial, yet often evolves after long lag phases or is even lacking. A central question is to which extent the production of methane after permafrost thaw is determined by the initial methanogenic community. We quantified the production of methane relative to carbon dioxide (CO2) and enumerated methanogenic (mcrA) gene copies in long-term (2–7 years) anoxic incubations at 4 °C using interglacial and glacial permafrost samples of Holocene and Pleistocene, including Eemian, origin. Changes in archaeal community composition were determined by sequencing of the archaeal 16S rRNA gene. Long-term thaw stimulated methanogenesis where methanogens initially dominated the archaeal community. Deposits of interstadial and interglacial (Eemian) origin, formed under higher temperatures and precipitation, displayed the greatest response to thaw. At the end of the incubations, a substantial shift in methanogenic community composition and a relative increase in hydrogenotrophic methanogens had occurred except for Eemian deposits in which a high abundance of potential acetoclastic methanogens were present. This study shows that only anaerobic CO2 production but not methane production correlates significantly with carbon and nitrogen content and that the methanogenic response to permafrost thaw is mainly constrained by the paleoenvironmental conditions during soil formation.
Low prevalence of mismatch repair deficiency in Chinese colorectal cancers: a multicenter study
Authors: Jiang Wu , Sui Qiao-Qi , Li Wen-Liang , Ke Chuan-Feng , Ling Yi-Hong , Liao Le-En , Zhu Zhu , Cai Mu-Yan , Luo Jun , Mao Lin-Lin , Zhang Hui-Zhong , Wan De-Sen , Pan Zhi-Zhong , Ju Hai-Xing , Ding Pei-Rong
Published: February 2020

Background

Although universal testing for mismatch repair deficiency (dMMR) has been recommended to all colorectal cancer (CRC) patients, related evidence for the Chinese population is lacking. Here, we investigated the prevalence and clinicopathological features of dMMR patients in a large Chinese CRC cohort.

Methods

We included 7,373 CRC patients treated at four Chinese medical centers between August 2010 and September 2016. Patients’ baseline characteristics and pathological features were recorded. The clinicopathological features were compared between patients with MLH1/PMS2 deficiency (dMLH1/PMS2) and MSH2/MSH6 deficiency (dMSH2/MSH6).

Results

Among the investigated patients, 654 (8.9%) were identified with dMMR CRCs and, of them, 401 (61.3%) were males, with a median age of 55 years (range, 22–87 years); 355 (54.3%) had stage II CRC based on American Joint Committee on Cancer 8th edition. The prevalence of the dMLH1/PMS2 group and the dMSH2/MSH6 group were 51.5% (337/654) and 25.1% (164/654), respectively. Compared with dMSH2/MSH6 patients, those with dMLH1/PMS2 were older (57 vs 52 years, P < 0.001), more likely to be female (45.7% vs 31.5%, P = 0.004), prone to having tumors located in the right-hand side of the colon (59.0% vs 47.6%, P = 0.015), and less likely to have a family history of tumors (29.7% vs 43.3%, P = 0.003).

Conclusions

The prevalence of dMMR in Chinese CRC patients was low, especially in the dMLH1/PMS2 group. The clinicopathological features were different between dMMR subgroups.
Participatory approaches, local stakeholders and cultural relevance facilitate an impactful community-based project in Uganda
Authors: O’Donovan James , Thompson Andrew , Stiles Christina , Opintan Japheth A , Kabali Ken , Willis Ian , Mutimba Mwebe Edward , Nalweyiso Elizabeth , Mugabi Henry , Kateete David P , Ameniko Matthew , Govina George , Weberman Rachel , O’Neil Edward , Winters Niall , Mutreja Ankur
Published: February 2020

Sanitation is a major global challenge that is often addressed at national and international levels, while community opinions and beliefs are neglected. To promote water, sanitation and hygiene (WASH) we organized a cross-cultural knowledge exchange workshop to assess participatory methods for engaging local stakeholders. The workshop included 22 participants from all sectors of society. Practical solutions to sanitation challenges were identified and later shared with a local community. Qualitative and quantitative analyses were used to assess impact and showed participatory methods were highly valued to encourage information sharing among widely varied stakeholders, and that video was a particularly successful approach when engaging with local communities. An 8-month follow-up survey of village members revealed excellent information recall, positive behaviour changes and a desire for future visits. Our evidence suggests that community-based participation helped identify solutions to WASH issues affecting rural communities in resource-poor settings. Engaging in a multicultural knowledge-share was particularly valuable as it enabled participants to recognize they have common challenges and allowed them to share low-cost solutions from their different communities. Our use of video was widely viewed as an ideal means of circulating findings, as it communicated information to people with a wide variety of community roles and to all age groups. Its relevance was increased by adopting a culturally appropriate context by involving local communities in workshop activities. We recommend that research in low- and middle-income countries should be mindful of the environmental context in which WASH is implemented, and encourage acceptance by engaging with communities through the use of varied participatory methods.
Induced Ketosis as a Treatment for Neuroprogressive Disorders: Food for Thought?
Authors: Morris Gerwyn , Puri Basant K , Carvalho Andre , Maes Michael , Berk Michael , Ruusunen Anu , Olive Lisa
Published: February 2020

Induced ketosis (or ketone body ingestion) can ameliorate several changes associated with neuroprogressive disorders, including schizophrenia, bipolar disorder, and major depressive disorder. Thus, the effects of glucose hypometabolism can be bypassed through the entry of beta-hydroxybutyrate, providing an alternative source of energy to glucose. The weight of evidence suggests that induced ketosis reduces levels of oxidative stress, mitochondrial dysfunction, and inflammation—core features of the above disorders. There are also data to suggest that induced ketosis may be able to target other molecules and signaling pathways whose levels and/or activity are also known to be abnormal in at least some patients suffering from these illnesses such as peroxisome proliferator-activated receptors, increased activity of the Kelch-like ECH-associated protein/nuclear factor erythroid 2-related factor 2, Sirtuin-1 nuclear factor-κB p65, and nicotinamide adenine dinucleotide (NAD). This review explains the mechanisms by which induced ketosis might reduce mitochondrial dysfunction, inflammation, and oxidative stress in neuropsychiatric disorders and ameliorate abnormal levels of molecules and signaling pathways that also appear to contribute to the pathophysiology of these illnesses. This review also examines safety data relating to induced ketosis over the long term and discusses the design of future studies.
Low Sensitivity of BinaxNOW RSV in Infants
Authors: Zuurbier Roy P , Bont Louis J , Langedijk Annefleur C , Hamer Mirjam , Korsten Koos , Drysdale Simon B , Snape Matthew D , Robinson Hannah , Pollard Andrew J , Martinón-Torres Federico , Rodríguez-Tenreiro Sánchez Carmen , Gómez-Carballa Alberto , Dacosta-Urbieta Ana Isabel , Heikkinen Terho , Cunningham Steve , van Houten Marlies A , Wildenbeest Joanne G ,   RESCEU Investigators, Zuurbier Roy , Bont Louis , Langedijk Annefleur , Hamer Mirjam , Korsten Koos , van Houten Marlies , Wildenbeest Joanne , Drysdale Simon , Snape Matthew , Robinson Hannah , Pollard Andrew , Martinón-Torres Federico , Rodríguez-Tenreiro Sánchez Carmen , Gómez-Carballa Alberto , Dacosta-Urbieta Ana , Heikkinen Terho , Cunningham Steve , Nair Harish , Campbell Harry , Openshaw Peter , Beutels Philippe , Molero Eva , Meijer Adam , Kølsen Fischer Thea , van den Berge Maarten , Giaquinto Carlo , Esser Mark , Knirsch Charles , Leach Amanda , Gallichan Scott , Aerssens Jeroen , Rosen Brian , Zuurbier Roy , Bont Louis , Langedijk Annefleur , Hamer Mirjam , Korsten Koos , van Houten Marlies , Wildenbeest Joanne , Drysdale Simon , Snape Matthew , Robinson Hannah , Pollard Andrew , Martinón-Torres Federico , Rodríguez-Tenreiro Sánchez Carmen , Gómez-Carballa Alberto , Dacosta-Urbieta Ana , Heikkinen Terho , Cunningham Steve , Nair Harish , Campbell Harry , Openshaw Peter , Beutels Philippe , Molero Eva , Meijer Adam , Kølsen Fischer Thea , van den Berge Maarten , Giaquinto Carlo , Esser Mark , Knirsch Charles , Leach Amanda , Gallichan Scott , Aerssens Jeroen , Rosen Brian
Published: February 2020

Background

Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis.

Methods

We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard.

Results

One hundred sixty-two respiratory samples from 148 children from October 2017 to February 2019 were studied. Sixty-six (40.7%) samples tested positive for RSV (30 hospitalizations, 31 medically attended episodes not requiring hospitalization, and 5 nonmedically attended episodes). Five of these samples tested positive with BN, leading to an overall sensitivity of BN of 7.6% (95% confidence interval [CI], 3.3%–16.5%) and a specificity of 100% (95% CI, 96.2%–100%). Sensitivity was low in all subgroups.

Conclusions

We found a low sensitivity of BN for point-of-care detection of RSV infection. BinaxNOW RSV should be used and interpreted with caution.
Circulating Antibody-Secreting Cell Response During Mycoplasma pneumoniae Childhood Pneumonia
Authors: Meyer Sauteur Patrick M , Trück Johannes , van Rossum Annemarie M C , Berger Christoph
Published: February 2020

Background

We recently demonstrated that the measurement of Mycoplasma pneumoniae (Mp)-specific immunoglobulin (Ig)M antibody-secreting cells (ASCs) improved diagnosis of Mp infection. Here, we aimed to describe Mp ASC kinetics and duration in comparison to conventional measures such as pharyngeal Mp deoxyribonucleic acid (DNA) and serum antibodies.

Methods

This is a prospective longitudinal study of 63 community-acquired pneumonia (CAP) patients and 21 healthy controls (HCs), 3–18 years of age, from 2016 to 2017. Mycoplasma pneumoniae ASCs measured by enzyme-linked immunospot assay were assessed alongside Mp DNA and antibodies during 6-month follow-up.

Results

Mycoplasma pneumoniae ASCs of the isotype IgM were found in 29 (46%), IgG were found in 27 (43%), and IgA were found in 27 (43%) CAP patients. Mycoplasma pneumoniae ASCs were detected from 2 days to a maximum of 6 weeks after symptom onset, whereas Mp DNA and antibodies persisted until 4 months (P = .03) and 6 months (P < .01). Mycoplasma pneumoniae ASCs were undetectable in HCs, in contrast to detection of Mp DNA in 10 (48%) or antibodies in 6 (29%) controls for a prolonged time. The Mp ASC response correlated with clinical disease, but it did not differ between patients treated with or without antibiotics against Mp.

Conclusions

Mycoplasma pneumoniae-specific ASCs are short-lived and associated with clinical disease, making it an optimal resource for determining Mp pneumonia etiology.
LC–MS-MS Method for the Determination of Antidepressants and Benzodiazepines in Meconium
Authors: López-Rabuñal A , Lendoiro E , Concheiro M , López-Rivadulla M , Cruz A , de-Castro-Ríos A
Published: February 2020

An LC–MS-MS method for the determination of 14 benzodiazepines (BZDs) (alprazolam, α-hydroxyalprazolam, clonazepam, bromazepam, diazepam, nordiazepam, lorazepam, lormetazepam, oxazepam, flunitrazepam, 7-aminoflunitrazepam, triazolam, midazolam and zolpidem) and 15 antidepressants (ADs) (amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, norclomipramine, fluoxetine, norfluoxetine, sertraline, norsertraline, paroxetine, venlafaxine, desmethylvenlafaxine, citalopram and desmethylcitalopram) in meconium was developed and validated. Meconium samples (0.25 ± 0.02 g) were homogenized in methanol and subjected to mixed-mode cation exchange solid-phase extraction. Chromatographic separation was performed in reversed phase, with a gradient of 0.1% formic acid in 2 mM ammonium formate and acetonitrile. Two different chromatographic gradient methods were employed, one for the separation of ADs and another for BZDs. Analytes were monitored by tandem mass spectrometry employing electrospray positive mode in MRM mode (2 transitions per compound). Method validation included: linearity [n = 5, limit of quantification (LOQ) to 400 ng/g], limits of detection (n = 6, 1–20 ng/g), LOQ (n = 9, 5–20 ng/g), selectivity (no endogenous or exogenous interferences), accuracy (n = 15, 90.6–111.5%), imprecision (n = 15, 0–14.6%), matrix effect (n = 10, −73 to 194.9%), extraction efficiency (n = 6, 35.9–91.2%), process efficiency (n = 6, 20.1–188.2%), stability 72 h in the autosampler (n = 3, −8.5 to 9%) and freeze/thaw stability (n = 3, −1.2 to −47%). The method was applied to four meconium specimens, which were analyzed with and without hydrolysis (enzymatic and alkaline). The authentic meconium samples tested positive for alprazolam, α-hydroxyalprazolam, clonazepam, diazepam, nordiazepam, fluoxetine, norfluoxetine, clomipramine and norclomipramine. Therefore, the present LC–MS-MS method allows a high throughput determination of the most common BZDs and ADs in meconium, which could be useful in clinical and forensic settings.
Quantification of Furanylfentanyl and its Metabolites in Human and Rat Plasma Using LC–MS-MS
Authors: Palmquist Kaitlyn B , Swortwood Madeleine J
Published: February 2020

Fentanyl analogs (novel and traditional) continue to impact the ever-growing opioid epidemic. Furanylfentanyl (FuF) is one analog equipotent to fentanyl that has documented involvement in thousands of intoxication and fatality cases around the world. Due to its prevalence, toxicologists need to improve detection and understanding of this analog. A method for the quantification of FuF and its metabolites (4-ANPP, furanyl norfentanyl (FuNorF)) in a small volume (100 μL) of human plasma by LC–MS-MS was developed and validated according to ANSI/ASB Standard. The method was cross validated in rat plasma for a future pharmacokinetic (PK)/pharmacodynamic (PD) study. In human plasma, calibration ranges were 0.025–25 ng/mL (FuF and 4-ANPP) and 0.5–25 ng/mL (FuNorF). Limits of detection were 0.0125 ng/mL (FuF and 4-ANPP) and 0.25 ng/mL (FuNorF). Lower limits of quantification coincided with lowest calibrator concentrations of 0.025 ng/mL (FuF and 4-ANPP) and 0.5 ng/mL (FuNorF). Precision and bias values were determined to be acceptable for all analytes. Matrix effects were acceptable for all analytes (−8.6–25.0%), except FuNorF with suppression >25%. Extraction recoveries ranged from 84.5 to 98.1%. No carryover or endogenous interferences were observed. Qualitative interferences with 4-ANPP were observed from some n-acyl substituted fentanyl analogs predicted to be low-concentration standard impurities. Analytes were stable under all conditions and dilution integrity was sustained. The method was successfully cross validated in rat plasma with acceptable bias (−7.4–8.4%), precision (within-run < 19%CV and between-run < 12.6%CV), matrix effects (−9.3–17.2%, except FuNorF with >25% suppression), recoveries (79.2–94.5%) and dilution integrity (1/2 and 1/10).
In vitro yeast reconstituted translation system reveals function of eIF5A for synthesis of long polypeptide
Authors: Abe Taisho , Nagai Riku , Shimazaki Shunta , Kondo Shunta , Nishimura Satoshi , Sakaguchi Yuriko , Suzuki Tsutomu , Imataka Hiroaki , Tomita Kozo , Takeuchi-Tomita Nono
Published: February 2020

We have recently developed an in vitro yeast reconstituted translation system, which is capable of synthesizing long polypeptides. Utilizing the system, we examined the role of eIF5A and its hypusine modification in translating polyproline sequence within long open reading frames. We found that polyproline motif inserted at the internal position of the protein arrests translation exclusively at low Mg2+ concentrations, and peptidylpolyproline-tRNA intrinsically destabilizes 80S ribosomes. We demonstrate that unmodified eIF5A essentially resolves such ribosome stalling; however, the hypusine modification drastically stimulates ability of eIF5A to rescue polyproline-mediated ribosome stalling and is particularly important for the efficient translation of the N-terminal or long internal polyproline motifs.
Is there a relationship between femoral neck-shaft angle and ischiofemoral impingement in patients with hip pain?
Authors: Gardner Stephanie S , Dong David , Peterson Leif E , Park Kwan J , Harris Joshua D
Published: February 2020

Ischiofemoral impingement (IFI) is a cause of deep gluteal space syndrome. The prevalence of radiographic findings in patients with hip pain is unknown. To assess if there is a correlation between femoral neck-shaft angle (NSA) and the distance of the ischiofemoral space (IFS) and quadratus femoris space (QFS) and to determine the prevalence of quadratus femoris (QF) edema in patients with hip pain. A retrospective case series was conducted involving 100 consecutive hip or pelvis magnetic resonance imaging scans on patients presenting with hip pain. NSA, IFS and QFS distances were measured and presence of QF edema was noted. Analysis of the groups (QF edema vs no edema) was performed using two-tailed t-test and Pearson correlation. There were 18 hips in the edema group (mean age 51.11 years ± 10.5) and 82 hips in the non-edema group (mean age 40.79 years ± 15.9). Within the edema group, there was a moderate positive correlation between NSA and QFS (r = 0.498, P = 0.036) and a weak positive correlation between NSA and IFI (0.312, P = 0.208). The prevalence of QF edema in this study was 18% with only 28% of those subjects having clinical symptoms of IFI. Patients with QF edema had significantly narrower QFS and IFS distances (P < 0.001). The prevalence of QF edema is 18% in a consecutive sample of adults with hip pain. In patients with QF edema, only 28% have symptoms of IFI. In patients with QF edema, there was a moderate positive correlation between NSA and QFS.
Large-scale single-molecule imaging aided by artificial intelligence
Authors: Hiroshima Michio , Yasui Masato , Ueda Masahiro
Published: February 2020

Single-molecule imaging analysis has been applied to study the dynamics and kinetics of molecular behaviors and interactions in living cells. In spite of its high potential as a technique to investigate the molecular mechanisms of cellular phenomena, single-molecule imaging analysis has not been extended to a large scale of molecules in cells due to the low measurement throughput as well as required expertise. To overcome these problems, we have automated the imaging processes by using computer operations, robotics and artificial intelligence (AI). AI is an ideal substitute for expertise to obtain high-quality images for quantitative analysis. Our automated in-cell single-molecule imaging system, AiSIS, could analyze 1600 cells in 1 day, which corresponds to ∼ 100-fold higher efficiency than manual analysis. The large-scale analysis revealed cell-to-cell heterogeneity in the molecular behavior, which had not been recognized in previous studies. An analysis of the receptor behavior and downstream signaling was accomplished within a significantly reduced time frame and revealed the detailed activation scheme of signal transduction, advancing cell biology research. Furthermore, by combining the high-throughput analysis with our previous finding that a receptor changes its behavioral dynamics depending on the presence of a ligand/agonist or inhibitor/antagonist, we show that AiSIS is applicable to comprehensive pharmacological analysis such as drug screening. This AI-aided automation has wide applications for single-molecule analysis.
Dosimetric evaluation of deep inspiration breath hold for left-sided breast cancer: analysis of patient-specific parameters related to heart dose reduction
Authors: Yamauchi Ryohei , Mizuno Norifumi , Itazawa Tomoko , Saitoh Hidetoshi , Kawamori Jiro
Published: February 2020

Deep inspiration breath hold (DIBH) is a common method used worldwide for reducing the radiation dose to the heart. However, few studies have reported on the relationship between dose reduction and patient-specific parameters. The aim of this study was to compare the reductions of heart dose and volume using DIBH with the dose/volume of free breathing (FB) for patients with left-sided breast cancer and to analyse patient-specific dose reduction parameters. A total of 85 Asian patients who underwent whole-breast radiotherapy after breast-conserving surgery were recruited. Treatment plans for FB and DIBH were retrospectively generated by using an automated breast planning tool with a two-field tangential intensity-modulated radiation therapy technique. The prescribed dose was 50 Gy in 25 fractions. The dosimetric parameters (e.g., mean dose and maximum dose) in heart and lung were extracted from the dose–volume histogram. The relationships between dose–volume data and patient-specific parameters, such as age, body mass index (BMI), and inspiratory volume, were analyzed. The mean heart doses for the FB and DIBH plans were 1.56 Gy and 0.75 Gy, respectively, a relative reduction of 47%. There were significant differences in all heart dosimetric parameters (p < 0.001). For patients with a high heart dose in the FB plan, a relative reduction of the mean heart dose correlated with inspiratory volume (r = 0.646). There was correlation between the relative reduction of mean heart dose and BMI (r = −0.248). We recommend considering the possible feasibility of DIBH in low BMI patients because the degree of benefit from DIBH varied with BMI.
Size distribution of superbubbles
Authors: Nath Biman B , Das Pushpita , Oey M S
Published: February 2020

We consider the size distribution of superbubbles in a star-forming galaxy. Previous studies have tried to explain the distribution by using adiabatic self-similar evolution of wind-driven bubbles, assuming that bubbles stall when pressure equilibrium is reached. We show, with the help of hydrodynamical numerical simulations, that this assumption is not valid. We also include radiative cooling of shells. In order to take into account non-thermal pressure in the ambient medium, we assume an equivalent higher temperature than implied by thermal pressure alone. Assuming that bubbles stall when the outer shock speed becomes comparable to the ambient sound speed (which includes non-thermal components), we recover the size distribution with a slope of ∼−2.7 for typical values of interstellar medium pressure in Milky Way, which is consistent with observations. Our simulations also allow us to follow the evolution of size distribution in the case of different values of non-thermal pressure, and we show that the size distribution steepens with lower pressure, to slopes intermediate between only-growing and only-stalled cases.
Asteroid migration due to the Yarkovsky effect and the distribution of the Eos family
Authors: Xu Yang-Bo , Zhou Li-Yong , Lhotka Christoph , Ip Wing-Huen
Published: February 2020

Based on a linearized model of the Yarkovsky effect, we investigate in this paper the dependence of the semimajor axis drift Δa of a celestial body on its size, spinning obliquity, initial orbit, and thermal parameters on its surface. With appropriate simplification and approximation, we obtain the analytical solutions to the perturbation equations for the motion of asteroids influenced by the Yarkovsky effect, and they are then verified by numerical simulations of the full equations of motion. These solutions present explicitly the dependences of Δa on the thermal and dynamical parameters of the asteroid. With these analytical formulae for Δa, we investigate the combined seasonal and diurnal Yarkovsky effects. The critical points where the migration direction reverses are calculated and the consequent selective effects according to the size and rotation state of asteroids are discussed. Finally, we apply the analytical formulae to calculate the migration of Eos family members. The space distribution of asteroids is well reproduced. Our calculations suggest that statistically the orientations of spin axes of family members satisfy a random-obliquity distribution, and the rotation rate ωrot of an asteroid depends on its size R by ωrot ∝ R−1.
Precision and consistency of astrocombs
Authors: Milaković Dinko , Pasquini Luca , Webb John K , Lo Curto Gaspare
Published: February 2020

Astrocombs are ideal spectrograph calibrators whose limiting precision can be derived using a second, independent, astrocomb system. We therefore analyse data from two astrocombs (one 18 GHz and one 25 GHz) used simultaneously on the HARPS (High Accuracy Radial velocity Planet Searcher) spectrograph at the European Southern Observatory. The first aim of this paper is to quantify the wavelength repeatability achieved by a particular astrocomb. The second aim is to measure wavelength calibration consistency between independent astrocombs, that is to place limits or measure any possible zero-point offsets. We present three main findings, each with important implications for exoplanet detection, varying fundamental constant and redshift drift measurements. First, wavelength calibration procedures are important: using multiple segmented polynomials within one echelle order results in significantly better wavelength calibration compared to using a single higher order polynomial. Segmented polynomials should be used in all applications aimed at precise spectral line position measurements. Secondly, we found that changing astrocombs causes significant zero-point offsets (${\approx}60\, {\rm cm\, s}^{-1}$ in our raw data) which were removed. Thirdly, astrocombs achieve a precision of ${\lesssim }4\, {\rm cm\, s}^{-1}$ in a single exposure (${\approx }10{{\,\rm per\,cent}}$ above the measured photon-limited precision) and 1 cm s−1 when time-averaged over a few hours, confirming previous results. Astrocombs therefore provide the technological requirements necessary for detecting Earth–Sun analogues, measuring variations of fundamental constants and the redshift drift.
The nearby spiral density-wave structure of the Galaxy: line-of-sight velocities of the Gaia DR2 main-sequence A, F, G, and K stars
Authors: Griv Evgeny , Gedalin Michael , Shih I-Chun , Hou Li-Gang , Jiang Ing-Guey
Published: February 2020

Distances and velocities of $\approx \!2400\, 000$ main-sequence A, F, G, and K stars are collected from the second data release of ESA's Gaia astrometric mission. This material is analysed to find evidence of radial and azimuthal systematic non-circular motions of stars in the solar neighbourhood on the assumption that the system is subject to spiral density waves (those produced by a spontaneous disturbance, a central bar, or an external companion), developing in the Galactic disc. Data analysis of line-of-sight velocities of $\approx \!1500\, 000$ stars selected within 2 kpc from the Sun and 500 pc from the Galactic mid-plane with distance accuracies of <10 per cent makes evident that a radial wavelength of the wave pattern is 1.1–1.6 kpc and a phase of the wave at the Sun’s location in the Galaxy is 55°–95°. Respectively, the Sun is situated at the inner edge of the nearest Orion spiral arm segment. Thus, the local Orion arm is a part of a predominant density-wave structure of the system. The spiral structure of the Galaxy has an oscillating nature corresponding to a concept of the Lin–Shu-type moderately growing in amplitude, tightly wound, and rigidly rotating density waves.
Electromagnetic signals from the decay of free neutrons in the first hours of neutron star mergers
Authors: Gottlieb Ore , Loeb Abraham
Published: February 2020

The first hours following a neutron star merger are considered to provide several ultraviolet (UV)/optical/near-infrared signals: β-decay emission from free neutrons, radioactive decay of shocked heavy elements in the cocoon and cocoon’s cooling emission. Here, we consider two additional emission sources: β-decay of free neutrons in the cocoon and synchrotron by the β-decay electrons. We present three-dimensional relativistic hydrodynamic simulations of jets that propagate in a multi-layer ejecta from the merger and calculate semi-analytically the resulting light curves. We find that the free neutrons emission at high latitudes is enhanced by the cocoon by a factor of a few to power a wide (≲60°) and brief (∼1 h) UV signal that can reach an absolute magnitude of ≳−15, comparable with the cooling emission. If the ejected neutron matter mass is $M_{\rm n} \gtrsim 10^{-4}\, {\rm M_{\odot }}$, the synchrotron emission may yield a long (∼8 h) quasi-isotropic UV/optical signal with an absolute magnitude between −12 and −15, depending on the magnetic field. Such a high mass of a mildly relativistic component may partly obscure the cocoon’s shocked r-process elements, thereby attenuating its radioactive decay emission. Future observations on these time-scales, including null detections, may place constraints on the ejected neutron matter mass and shed light on the ejecta and jet-cocoon characteristics.
Extreme and high synchrotron peak blazars beyond 4FGL: The 2BIGB γ-ray catalogue
Authors: Arsioli B , Chang Y-L , Musiimenta B
Published: February 2020

This paper presents the results of a γ-ray likelihood analysis over all the extreme and high synchrotron peak blazars (EHSP and HSP) from the 3HSP catalogue. We investigate 2013 multifrequency positions under the eyes of Fermi Large Area Telescope, considering 11 yr of observations in the energy range between 500 MeV and 500 GeV, which results in 1160 γ-ray signatures detected down to the TS=9 threshold. The detections include 235 additional sources concerning the Fermi Large Area Telescope Fourth Source Catalog (4FGL), all confirmed via high-energy TS (Test Statistic) maps, and represent an improvement of ∼25 per cent for the number of EHSP and HSP currently described in γ-rays. We build the γ-ray spectral energy distribution (SED) for all the 1160 2BIGB sources, plot the corresponding γ-ray logN−logS, and measure their total contribution to the extragalactic gamma-ray background, which reaches up to ∼33 per cent at 100 GeV. Also, we show that the γ-ray detectability improves according to the synchrotron peak flux as represented by the figure of merit parameter, and note that the search for TeV peaked blazars may benefit from considering HSP and EHSP as a whole, instead of EHSPs only. The 2BIGB acronym stands for ‘Second Brazil-ICRANet Gamma-ray Blazars’ catalogue, and all the broad-band models and SED data points will be available on public data repositories (OpenUniverse, GitHub, and Brazilian Science Data Center-BSDC).
Mycobacterial DNA polymerase I: activities and crystal structures of the POL domain as apoenzyme and in complex with a DNA primer-template and of the full-length FEN/EXO–POL enzyme
Authors: Ghosh Shreya , Goldgur Yehuda , Shuman Stewart
Published: February 2020

Mycobacterial Pol1 is a bifunctional enzyme composed of an N-terminal DNA flap endonuclease/5′ exonuclease domain (FEN/EXO) and a C-terminal DNA polymerase domain (POL). Here we document additional functions of Pol1: FEN activity on the flap RNA strand of an RNA:DNA hybrid and reverse transcriptase activity on a DNA-primed RNA template. We report crystal structures of the POL domain, as apoenzyme and as ternary complex with 3′-dideoxy-terminated DNA primer-template and dNTP. The thumb, palm, and fingers subdomains of POL form an extensive interface with the primer-template and the triphosphate of the incoming dNTP. Progression from an open conformation of the apoenzyme to a nearly closed conformation of the ternary complex entails a disordered-to-ordered transition of several segments of the thumb and fingers modules and an inward motion of the fingers subdomain—especially the O helix—to engage the primer-template and dNTP triphosphate. Distinctive structural features of mycobacterial Pol1 POL include a manganese binding site in the vestigial 3′ exonuclease subdomain and a non-catalytic water-bridged magnesium complex at the protein-DNA interface. We report a crystal structure of the bifunctional FEN/EXO–POL apoenzyme that reveals the positions of two active site metals in the FEN/EXO domain.
Broadly applicable oligonucleotide mass spectrometry for the analysis of RNA writers and erasers in vitro
Authors: Hagelskamp Felix , Borland Kayla , Ramos Jillian , Hendrick Alan G , Fu Dragony , Kellner Stefanie
Published: February 2020

RNAs are post-transcriptionally modified by dedicated writer or eraser enzymes that add or remove specific modifications, respectively. Mass spectrometry (MS) of RNA is a useful tool to study the modification state of an oligonucleotide (ON) in a sensitive manner. Here, we developed an ion-pairing reagent free chromatography for positive ion detection of ONs by low- and high-resolution MS, which does not interfere with other types of small compound analyses done on the same instrument. We apply ON-MS to determine the ONs from an RNase T1 digest of in vitro transcribed tRNA, which are purified after ribozyme-fusion transcription by automated size exclusion chromatography. The thus produced tRNAValAAC is substrate of the human tRNA ADAT2/3 enzyme and we confirm the deamination of adenosine to inosine and the formation of tRNAValIACin vitro by ON-MS. Furthermore, low resolution ON-MS is used to monitor the demethylation of ONs containing 1-methyladenosine by bacterial AlkB in vitro. The power of high-resolution ON-MS is demonstrated by the detection and mapping of modified ONs from native total tRNA digested with RNase T1. Overall, we present an oligonucleotide MS method which is broadly applicable to monitor in vitro RNA (de-)modification processes and native RNA.
Dialysis after graft loss: a Swiss experience
Authors: Bonani Marco , Achermann Rita , Seeger Harald , Scharfe Michael , Müller Thomas , Schaub Stefan , Binet Isabelle , Huynh-Do Uyen , Dahdal Suzan , Golshayan Dela , Hadaya Karine , Wüthrich Rudolf P , Fehr Thomas , Segerer Stephan
Published: February 2020

Background

Patients returning to dialysis after graft loss have high early morbidity and mortality.

Methods

We used data from the Swiss Transplant Cohort Study to describe the current practice and outcomes in Switzerland. All patients who received a renal allograft between May 2008 and December 2014 were included. The patients with graft loss were divided into two groups depending on whether the graft loss occurred within 1 year after transplantation (early graft loss group) or later (late graft loss group). Patients with primary non-function who never gained graft function were excluded.

Results

Seventy-seven out of 1502 patients lost their graft during follow-up, 40 within 1 year after transplantation. Eleven patients died within 30 days after allograft loss. Patient survival was 86, 81 and 74% at 30, 90 and 365 days after graft loss, respectively. About 92% started haemodialysis, 62% with definitive vascular access, which was associated with decreased mortality (hazard ratio = 0.28). At the time of graft loss, most patients were on triple immunosuppressive therapy with significant reduction after nephrectomy. One year after graft loss, 77.5% (31 of 40) of patients in the early and 43.2% (16 out of 37) in the late-loss group had undergone nephrectomy. Three years after graft loss, 36% of the patients with early and 12% with late graft loss received another allograft.

Conclusion

In summary, our data illustrate high mortality, and a high number of allograft nephrectomies and re-transplantations. Patients commencing haemodialysis with a catheter had significantly higher mortality than patients with definitive access. The role of immunosuppression reduction and allograft nephrectomy as interdependent factors for mortality and re-transplantation needs further evaluation.
Contract Negotiation for Neurosurgeons: A Practical Guide
Authors: Menger Richard , Esfahani Darian R , Heary Robert , Ziu Mateo , Mazzola Catharine A , LeFever Devon , Origitano Thomas , Barnes Todd , Cozzens Jeffrey , Taylor Sherry
Published: February 2020

Contract negotiation is a reality in the career of any neurosurgeon. However, little formal training exists for physicians – including neurosurgeons – on potential techniques and strategies for conducting meaningful contract negotiation. Increasing numbers of neurosurgeons seek hospital employment for which an employment contract will be provided. During contract negotiation, it is likely that a young neurosurgeon will be in discussion with an experienced negotiator acting on behalf of a hospital, practice, or department. Understanding and adapting to this imbalance in experience and using basic negotiating techniques as a means of approaching and resolving key contract issues is critical for the neurosurgeon to maximize his or her value in the course of contract negotiation. Even without formal training in negotiation in residency, negotiation skills can be taught, practiced, and improved. In affiliation with the Medical Director's Ad-Hoc Representational Section of Council of State Neurosurgical Societies (CSNS) this article is intended to serve as a practical guide for contract negotiation. Contract basics, negotiation terms, strategies, unique neurosurgical issues, and value creation are explored.