bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Method for Gas Chromatographic–Mass Spectrometric Analysis of 1-13C-labeled Long-Chain Fatty Acids in Plasma Samples
Authors: Hernández-Pérez José M , Cabré Eduard , Fluvià Lourdes , Motos Ágata , Pastor Cruz , Corominas August , Gassull Miquel A
Published: January 2020

Background: Gas chromatographic–mass spectrometric (GC/MS) tracking of stable-isotope-labeled substrates is useful in metabolic studies. However, GC/MS analysis of long-chain fatty acid methyl esters yields results that mostly depend on their concentration in the system. We describe a protocol aimed to obviate this and other drawbacks in plasma [1-13C]palmitic and [1-13C]oleic acid measurements.

Methods: Lipoproteins were separated by sequential ultracentrifugation. Free or esterified heptadecanoic acid was used as internal standard. Fatty acids were derivatized to trimethylsilyl (TMS) esters. GC separation was in isothermal mode at 210 °C for 27 min. For both TMS-palmitate and TMS-oleate, M and [M + 1] signals were simultaneously acquired with a dual acquisition program in single-ion monitoring mode. Calibration mixtures containing increasing amounts of labeled fatty acids were prepared gravimetrically to construct calibration curves for isotopic enrichment. Likewise, five calibration curves (for increasing concentrations) were constructed for each fatty acid; this allowed selection of the most appropriate curve for the concentration in a plasma sample.

Results: Oleic acid-TMS ester was clearly separated from that of its stereoisomer, elaidic acid. Within a 10-fold concentration range, the isotopic ratio was independent on the amount of the analyte in the sample, with a maximum uncertainty of 0.34% in terms of molar percent excess. In addition, the within- and between-day imprecision (CV) of the method was <1%.

Conclusion: Results obtained with this method are independent of concentration and sufficiently precise for tracking 1-13C-labeled palmitic and oleic acids in biological samples
Determination of Sulpiride by Capillary Electrophoresis with End-Column Electrogenerated Chemiluminescence Detection
Authors: Liu Jifeng , Cao Weidong , Qiu Haibo , Sun Xiuhua , Yang Xiurong , Wang Erkang
Published: January 2020

Background: Capillary electrophoresis (CE) with tris(2,2′-bipyridyl)ruthenium(II) [Ru(bpy)32+]-electrogenerated chemiluminescence (ECL) detection is a promising method for clinical analysis. In this study, a method combining CE with Ru(bpy)32+ ECL (CE-ECL) detection that can be applied to amine-containing clinical species was developed, and the performance of CE-ECL as a quantitative method for determination of sulpiride in human plasma or urine was evaluated.

Methods: Sulpiride was separated by capillary zone electrophoresis in uncoated fused-silica capillaries [50 cm × 25 μm (i.d.)] filled with phosphate buffer (pH 8.0) and a driving voltage of +15 kV, with end-column Ru(bpy)32+ ECL detection. A platinum disc electrode was used as working electrode. Sulpiride in human plasma or urine samples (100 μL) was extracted by a double-step liquid-liquid extraction procedure, dried under nitrogen at 35 °C in a water bath, and reconstituted with 100 μL of filtered water. The extraction solvent was ethyl acetate–dichloromethane (5:1 by volume).

Results: Under optimum conditions (pH 8.0 phosphate buffer, injection for 6 s at 10 kV, and +1.2 V as detection potential), separation of sulpiride was accomplished within 4 min. The calibration curve was linear over a concentration range of 0.05–25.0 μmol/L, and the limit of detection was 2.9 × 10−8 mol/L for sulpiride. Intra- and interday CVs for ECL intensities were <6%. Extraction recoveries of sulpiride were 95.6–101% with CVs of 2.9–6.0%. The method was clinically validated for patient plasma and urine samples.

Conclusions: CE combined with Ru(bpy)32+ ECL is reproducible, precise, selective, and enables the analysis of sulpiride in human plasma and urine. It thus is of value for rapid and efficient analysis of amine-containing analytes of clinical interest.
Practice Guidelines for Tumor Marker Use in the Clinic
Authors: Sturgeon Catharine
Published: January 2020

Background: Increasing interest in implementing the practice of evidence-based medicine in oncology has encouraged the development of clinical guidelines, many of which include recommendations about the appropriate use of serum tumor markers.

Methods: Recent national and international guidelines relating to the use of tumor markers in germ cell, colorectal, breast, ovarian, prostate, lung, neuroendocrine, and thyroid cancers were identified from the scientific literature and other sources and tabulated.

Results: Guideline recommendations developed by national and international groups and relating to the use of tumor markers for specific cancers are reviewed and compared, considering the recommendations made for their use in screening, diagnosis, prognosis, and monitoring of therapy. Potential advantages and disadvantages of clinical guidelines, how best to implement them, and means of auditing their effectiveness are also considered.

Conclusions: Excellent clinical guidelines, including recommendations for the most appropriate use of tumor markers, are already available for many cancers. Many questions relating to optimal use of these important tests remain to be answered, but current guidelines already contain much valuable information and advice. Further dissemination and implementation of the guidelines should encourage better use of tumor markers in clinical practice. Careful audit studies are also required to establish the impact of these guidelines on the practice of evidence-based medicine.
Tumor-associated Trypsin Inhibitor
Authors: Stenman Ulf-Håkan
Published: January 2020

Tumor-associated trypsin inhibitor (TATI) is a low-molecular-weight (6 kDa) trypsin inhibitor that has been used as a marker for ovarian cancer. It is also expressed together with tumor-associated trypsin by many other tumors, and increased serum concentrations of TATI occur in connection with these. TATI is a prognostic marker for ovarian, bladder, and kidney cancer, which may be associated with the participation of trypsin in protease cascades contributing to tumor invasiveness.
Presence of Filterable and Nonfilterable mRNA in the Plasma of Cancer Patients and Healthy Individuals
Authors: Ng Enders KO , Tsui Nancy BY , Lam Nicole YL , Chiu Rossa WK , Yu Simon CH , Wong SC Cesar , Lo Elena SF , Rainer Timothy H , Johnson Philip J , Lo YM Dennis
Published: January 2020

Background: As RNA is labile, we investigated whether circulating RNA in human plasma may be present in a particle-associated form.

Methods: Blood was collected from 27 healthy individuals and 16 hepatocellular carcinoma (HCC) patients. The plasma from each individual was processed by two means: filtration through filters with different pore sizes (from 5 μm to 0.22 μm) and ultracentrifugation. We assessed plasma RNA content by a real-time quantitative reverse transcription-PCR assay for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) transcripts and plasma DNA by a real-time quantitative PCR assay for the β-globin gene.

Results: The plasma GAPDH mRNA concentrations in the healthy individuals were significantly different in every pair of these filter sizes (P <0.05 for each pair). Overall, the plasma GAPDH mRNA concentration was higher by a median of 15-fold (interquartile range, 10- to 24-fold) in the paired unfiltered sample than in the sample filtered through a 0.22 μm filter. In contrast, no significant difference was seen in β-globin DNA concentrations among different pore-size-filtered plasma samples (P = 0.455). Similarly, a significant difference was observed for RNA, but not DNA, between unfiltered plasma and ultracentrifuged plasma (P <0.05). No significant difference in GAPDH mRNA concentrations was seen between the 0.22-μm-filtered plasma samples and the ultracentrifuged plasma samples (P >0.05). In HCC patients, filtration with a 0.22 μm filter produced a median 9.3-fold (interquartile range, 6.9- to 311-fold) reduction in GAPDH mRNA concentration in plasma. Plasma GAPDH mRNA concentrations in HCC patients were significantly higher than those in healthy individuals, both with or without filtration (P <0.0 5 for filtered plasma samples; P <0.005 for unfiltered plasma samples).

Conclusions: A substantial proportion of plasma mRNA species is particle-associated. In HCC patients, both circulating particle- and non-particle-associated plasma RNA are increased.
Polymorphisms in the Transcobalamin Gene: Association with Plasma Homocysteine in Healthy Individuals and Vascular Disease Patients
Authors: Lievers Karin JA , Afman Lydia A , Kluijtmans Leo AJ , Boers Godfried HJ , Verhoef Petra , den Heijer Martin , Trijbels Frans JM , Blom Henk J
Published: January 2020

Background: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (CVD). Intracellular vitamin B12 deficiency may lead to increased plasma total homocysteine (tHcy) concentrations and because transcobalamin (TC) is the plasma transporter that delivers vitamin B12 to cells, genetic variation in the TC gene may affect intracellular vitamin B12 availability and, consequently, tHcy concentrations.

Methods: We examined five sequence variants, i.e., I23V, G94S, P259R, S348F, and R399Q, in the TC gene as possible determinants of tHcy and, concordantly, as possible risk factors for CVD in 190 vascular disease patients and 601 controls. We also studied potential effect-modification of vitamin B12 by genotype.

Results: In individuals with high vitamin B12, 259PP individuals had lower tHcy concentrations than 259PR and 259RR individuals. Homozygous 23VV individuals had lower fasting tHcy concentrations than their 23IV and 23II peers. None of the genotypes defined by the three other sequence variants showed an association with tHcy concentrations, nor was any TC genotype associated with an increased CVD risk.

Conclusions: In individuals in the highest quartile of the vitamin B12 distribution (>299 pmol/L), tHcy concentrations are lower in 259PP homozygotes than in 259PR and 259RR individuals. Therefore, 259PP individuals, who represent >25% of the general population, may be more susceptible to reduction of plasma tHcy concentrations by increasing the vitamin B12 status.
Quantitative and Compositional Study of Cardiolipin in Platelets by Electrospray Ionization Mass Spectrometry: Application for the Identification of Barth Syndrome Patients
Authors: Valianpour Fredoen , Wanders Ronald JA , Barth Peter G , Overmars Henk , van Gennip Albert H
Published: January 2020

Background: The concentration of cardiolipin (CL) in cultured skin fibroblasts is a useful indicator of Barth syndrome (BTHS; MIM 302060), but the sampling and culturing of fibroblasts are burdensome and time-consuming procedures. We investigated whether the analysis of CL in platelets might help to identify BTHS in patients suspected of having this condition.

Methods: We used HPLC and online electrospray ionization mass spectrometry (HPLC-ESI-MS) to quantify CL molecular species. The CL content of platelets was studied in blood samples of BTHS and non-BTHS patients. Control blood samples drawn from healthy adults were collected and analyzed within 24 h (n = 10) and 48 h (n = 10) to characterize any effect of sample shipping time on the CL content in platelets. Samples were collected from children 1–10 years of age who were not affected by BTHS (n = 6) and from BTHS patients (n = 4) and analyzed within 24 h. Results for all four groups were compared by a Student t-test for all individual analyses.

Results: We found different CL molecular species, e.g., (C18:2)4-CL. BTHS patients had a specific decrease of tetralinoleyl-CL concentrations in platelets (0.1–0.5 nmol/mg of protein; n = 4) compared with all control groups (2.3–5.5 nmol/mg of protein; n = 26). Only minor differences were observed among the different control groups.

Conclusions: Quantitative and compositional analyses of CL in platelets by the proposed method allow identification of BTHS patients more rapidly than gene analysis or analysis of CL in cultured skin fibroblasts. The abnormality of CL may explain the abnormal mitochondrial function observed in BTHS. The differences between the control groups did not cause any complication.
Flow Cytometric Quantification of Competitive Reverse Transcription-PCR Products
Authors: Wedemeyer Niels , Pötter Thomas , Wetzlich Steffi , Göhde Wolfgang
Published: January 2020

Background: Competitive PCR of reverse transcribed mRNA sequences is used to quantify transcripts, but the usual approaches are labor-intensive and time-consuming. We describe the non-gel-based quantification of competitive reverse transcription (RT)-PCR products with use of microparticles and flow cytometry.

Methods: PCR products of a target sequence and an internal control sequence (competitor) were labeled during PCR using digoxigenin (DIG)- and dinitrophenol (DNP)-labeled primer, respectively, allowing specific binding to microparticles coated with the corresponding antibody. Both amplification products were biotinylated to enable fluorescence labeling with streptavidin-R-phycoerythrin. The mean fluorescence intensity of each microparticle population, corresponding to the amount of bound PCR product, was measured in a flow cytometer. We constructed microparticles coated with antibodies against DIG and DNP to specifically capture PCR products derived from target and competitor sequences, respectively.

Results: As required for a reliable competitive PCR assay, nearly identical kinetics were found for the amplification of target and competitor sequences when using only one competitive primer. The method was applied to examine interleukin-8 expression in human lymphocytes after x-irradiation. One hour after irradiation, the concentration of transcripts decreased by half.

Conclusions: The flow cytometric assay for the quantification of competitive RT-PCR products avoids additional hybridization steps and antibody labeling. The use of paramagnetic microparticles would also enable the complete automation of this method.
Single-Point Cardiac Troponin T at Coronary Care Unit Discharge after Myocardial Infarction Correlates with Infarct Size and Ejection Fraction
Authors: Panteghini Mauro , Cuccia Claudio , Bonetti Graziella , Giubbini Raffaele , Pagani Franca , Bonini Elena
Published: January 2020

Background: One of the major concerns in replacing creatine kinase MB (CK-MB) with cardiac troponins is the lack of evidence of the ability of troponins to estimate the size of acute myocardial infarction (AMI). We investigated the ability of a single measurement of cardiac troponin T (cTnT) at coronary care unit (CCU) discharge to estimate infarct size and assess left ventricular (LV) function in AMI patients.

Methods: We studied 65 AMI patients in whom infarct size was estimated by CK-MB peak concentrations and gated single-photon emission computed tomography (SPECT) myocardial perfusion using technetium-99m sestamibi and LV function by SPECT imaging. Measurements of cTnT and SPECT were performed 72 h (median) after admission (range, 40–160 h). SPECT was also repeated 3 months later.

Results: We found a significant correlation between cTnT and both the peak CK-MB concentrations (r = 0.76; P <0.001) and the perfusion defect size at SPECT (r = 0.62; P <0.001). cTnT was inversely related to LV ejection fraction (LVEF) assessed both early (r = −0.56; P <0.001) and 3 months after AMI (r = −0.70; P <0.001). cTnT >2.98 μg/L predicted a LVEF <40% at 3 months with a sensitivity of 86.7%, specificity of 81.4%, and a likelihood ratio for a positive test of 4.7 (95% confidence interval, 4.0–5.4).

Conclusions: A single cTnT measurement at CCU discharge after AMI is useful as a noninvasive estimate of infarct size and for the assessment of LV function in routine clinical setting.
Serum Reference Intervals and Diagnostic Ranges for Free κ and Free λ Immunoglobulin Light Chains: Relative Sensitivity for Detection of Monoclonal Light Chains
Authors: Katzmann Jerry A , Clark Raynell J , Abraham Roshini S , Bryant Sandra , Lymp James F , Bradwell Arthur R , Kyle Robert A
Published: January 2020

Background: The detection of monoclonal free light chains (FLCs) is an important diagnostic aid for a variety of monoclonal gammopathies and is especially important in light-chain diseases, such as light-chain myeloma, primary systemic amyloidosis, and light-chain-deposition disease. These diseases are more prevalent in the elderly, and assays to detect and quantify abnormal amounts of FLCs require reference intervals that include elderly donors.

Methods: We used an automated immunoassay for FLCs and sera from a population 21–90 years of age. We used the calculated reference and diagnostic intervals to compare FLC results with those obtained by immunofixation (IFE) to detect low concentrations of monoclonal κ and λ FLCs in the sera of patients with monoclonal gammopathies.

Results: Serum κ and λ FLCs increased with population age, with an apparent change for those >80 years. This trend was lost when the FLC concentration was normalized to cystatin C concentration. The ratio of κ FLC to λ FLC (FLC K/L) did not exhibit an age-dependent trend. The diagnostic interval for FLC K/L was 0.26–1.65. The 95% reference interval for κ FLC was 3.3–19.4 mg/L, and that for λ FLC was 5.7–26.3 mg/L. Detection and quantification of monoclonal FLCs by nephelometry were more sensitive than IFE in serum samples from patients with primary systemic amyloidosis and light-chain-deposition disease.

Conclusions: Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal FLCs easier and more sensitive than with current methods. The serum FLC assay complements IFE and allows quantification of FLCs in light-chain-disease patients who have no detectable serum or urine M-spike.
Selection, Preparation, and Characterization of Commutable Frozen Human Serum Pools as Potential Secondary Reference Materials for Lipid and Apolipoprotein Measurements: Study within the Framework of the Dutch Project “Calibration 2000”
Authors: Cobbaert Christa , Weykamp Cas , Baadenhuijsen Henk , Kuypers Aldy , Lindemans Jan , Jansen Rob
Published: January 2020

Background: The Dutch project “Calibration 2000” aims at harmonization of laboratory results via calibration by development of matrix-based secondary reference materials. We considered the selection, preparation, and characterization of 34 potential reference materials (PRMs).

Methods: Sixteen PRMs were prepared either strictly according to the NCCLS C37-A protocol or in a less stringent and more convenient way. In addition, 18 commercial, so-called human serum-based calibrators or controls were purchased and tested. Lipoprotein integrity was evaluated by examining the physicochemical characteristics of the materials. Commutability of the PRMs was assessed in 86 Dutch clinical laboratories, using a multicenter split-patient-sample between-field-method (twin-study) design. Normalized residuals of the PRMs with respect to the patient regression lines were calculated; in addition, the extra contribution of each PRM to the total measurement uncertainty (CVNetto) was calculated. On the basis of these results, the most native PRM was selected to investigate its potential to reduce interlaboratory variation and to improve lipid and apolipoprotein standardization.

Results: In general, only the NCCLS C37-A-type materials displayed normalized residuals below the decision limit for commutability and had small CVNetto values ranging between 0 and 3.8%. This contrasts with the findings in regularly pooled frozen sera and lyophilized cryoprotected PRMs. In two subsequent external quality assessment surveys, the NCCLS type C37-A materials contributed to reducing the intermethod lipid and (apo)lipoprotein variation to ∼2–4%.

Conclusions: NCCLS C37-A materials have a strong potential as secondary reference materials, not only for cholesterol but also for HDL-cholesterol, LDL-cholesterol, triglyceride, and apolipoprotein measurements.
Homogeneous, Nonradioactive, Enzymatic Assay for Plasma Pyridoxal 5-Phosphate
Authors: Han Qinghong , Xu Mingxu , Tang Li , Tan Xuezhong , Tan Xiuying , Tan Yuying , Hoffman Robert M
Published: January 2020

Background: Pyridoxal 5′-phosphate (PLP) is the biologically active form of vitamin B6. Clinical studies suggest that low PLP concentrations are an independent risk factor for cardiovascular and other diseases. However, PLP concentrations are not routinely diagnosed because of the lack of a homogeneous, nonradioactive assay. We describe a homogeneous, nonradioactive, enzymatic PLP assay that uses the apo form of the PLP-dependent recombinant enzyme, homocysteine-α,γ-lyase (rHCYase).

Methods: PLP was removed from holoenzyme rHCYase by incubation with hydroxylamine to obtain apo-rHCYase. The restoration of enzymatic activity by reconstitution of the holoenzyme was linearly related to the amount of PLP bound to the enzyme. The amplification principle of the assay allowed nanomolar concentrations of PLP to be measured by the conversion (by reconstituted holo-rHCYase) of millimolar concentrations of homocysteine to H2S. N,N-Dibutylphenylenediamine (DBPDA) was used for determination of H2S, the combination of which forms a chromophore with high absorbance. The assay was initiated by incubation of 5 μL of plasma with apo-rHCYase in a binding buffer for 60 min at 37 °C. Homocysteine (2.5 mmol/L) was added to the assay buffer and incubated at 37 °C for 20 min. The DBPDA reaction was allowed to progress for 10 min and then read at 675 nm.

Results: The PLP enzymatic assay has a lower limit of detection of 5 nmol/L and is linear to 200 nmol/L. The recovery of PLP was 98%. The mean within- and between-run CVs were 9.6% and 12%, respectively. Correlation of 45 samples in the PLP enzymatic assay and the B63H radioenzymatic assay (American Laboratory Products Co., Ltd.) yielded: y = 0.9367x + 10.569 (R2 = 0.9201).

Conclusions: This new PLP assay is the first homogeneous, nonradioactive, vitamin B6 diagnostic method. The assay is applicable to chemistry automated analyzers and may have wide clinical use.
Unveiling the roles of interspecific competition and local adaptation in phenotypic differentiation of parapatric frogs
Authors: Huang Yan , Wang Xiaoyi , Yang Xin , Jiang Jianping , Hu Junhua
Published: January 2020

Understanding how ecological processes affect phenotypic evolution has been and continues to be an important goal of ecology and evolutionary biology. Interspecific competition for resources can be a selective force driving phenotypic differentiation that reduces competition among sympatric species (character divergence), enabling closely-related species to coexist. However, although patterns of character divergence are well documented in both empirical and theoretical researches, how local adaptation to abiotic environment affects trait evolution in the face of interspecific competition is less known. Here, we investigate how patterns in morphological traits of 2 parapatric frog species, Feirana quadranus and F. taihangnica, vary among allopatric and sympatric regions using range-wide data derived from extensive field surveys. Feirana quadranus was overall larger than F. taihangnica in body size (i.e., snout–vent length [SVL]), and the difference between SVL of both species in sympatry was larger than that in allopatry. From allopatry to sympatry, the 2 species diverged in foot and hand traits, but converged in eye size and interorbital span, even when we controlled for the effects of geographic gradients. Sympatric divergence in SVL, hand and foot traits is likely acting as a case of evolutionary shift caused by interspecific competition. In contrast, sympatric convergence of eye-related traits may derive at least partly from adaptation to local environments. These results imply the relative roles of interspecific competition and local adaptation in shaping phenotypic diversification. Our findings illustrate how traits evolve in parapatric species pair due to sympatric divergent and convergent evolution. It thus provides insights into understanding underlying evolutionary processes of parapatric species, that is, competition and local adaptation.
Do healthy doctors deliver better messages of health promotion to their patients?: Data from the SUN cohort study
Authors: Carlos Silvia , Rico-Campà Anaïs , de la Fuente-Arrillaga Carmen , Echavarri María , Fernandez-Montero Alejandro , Gea Alfredo , Salazar Camino , Martínez-González Miguel Angel
Published: January 2020

Background

Healthy lifestyle adherence is associated with lower chronic disease morbidity/mortality. The role of doctors, as counselors and role models, is essential. Among physicians participating in a prospective cohort, we investigated the behavioral counseling on diet and lifestyle provided to their patients in association with their own personal behaviors.

Methods

We assessed 890 doctors aged ≤65 years participating in the ‘Seguimiento Universidad de Navarra’ (SUN) cohort, who replied to an online questionnaire regarding their practices on behavioral counseling and drug prescription to their patients. Data were combined with previous baseline information on their personal healthy habits.

Results

Among doctors, 31% reported <10 min per visit; 73% counseled 60–100% of their patients on smoking cessation, 58% on physical activity, 54% on weight control, 51% on healthy nutrition, 44% on alcohol avoidance/reduction and 28% recommended alcohol moderate consumption. The percentage of doctors that counseled 100% of their patients about lifestyle was 43% for smoking cessation, 15% for exercise and 13% for weight control and nutrition. Better doctor’s adherence to the Mediterranean dietary pattern was associated with more frequent and longer nutrition counseling. Higher practice of physical activity was associated with longer time on counseling about exercise to their patients. Among doctors both current and former smoking were inversely associated with the frequency and duration of their smoking cessation/avoidance counseling practices.

Conclusions

Personal behavioral changes among doctors and better training of medical doctors on a personal healthy diet and lifestyle are likely to contribute to improve the behavioral counseling given to patients.
Spatial statism: Afterword to the Foreword by Ran Hirschl and Ayelet Shachar
Authors: Doyle Oran
Published: January 2020

“Spatial statism” challenges us to pay greater attention to the spatial dimension of public law and provides a critique of how states dominate that geographic space. In this Afterword, I suggest that the spatial dimension of public law can be helpfully understood as a special case of the geographic dimension of law in general. State domination of geographic space warrants critical attention, particularly in the context of migration regulation. But we must also pay attention to the advantages of states as the primary locus of constitutional authority.
Prescribing Patterns of Psychotropic Drugs and Risk of Violent Behavior: A Prospective, Multicenter Study in Italy
Authors: di Giacomo E , Stefana A , Candini V , Bianconi G , Canal L , Clerici M , Conte G , Ferla M T , Iozzino L , Sbravati G , Tura G , Micciolo R , de Girolamo G ,   VIORMED-2 Group, Bava Mattia , Carrà Giuseppe , Gamba Giulia , Martinazzoli Assunta , Mina Giuliana , Ornaghi Alessandra , Travasso Bruno , Vita Antonio
Published: January 2020

Background

This prospective cohort study aimed at evaluating patterns of polypharmacy and aggressive and violent behavior during a 1-year follow-up in patients with severe mental disorders.

Methods

A total of 340 patients (125 inpatients from residential facilities and 215 outpatients) were evaluated at baseline with the Structured Clinical Interview for DSM-IV Axis I and II, Brief Psychiatric Rating Scale, Specific Levels of Functioning scale, Brown-Goodwin Lifetime History of Aggression, Buss-Durkee Hostility Inventory, Barratt Impulsiveness Scale, and State-Trait Anger Expression Inventory-2. Aggressive behavior was rated every 15 days with the Modified Overt Aggression Scale and treatment compliance with the Medication Adherence Rating Scale.

Results

The whole sample was prescribed mainly antipsychotics with high levels of polypharmacy. Clozapine prescription and higher compliance were associated with lower levels of aggressive and violent behavior. Patients with a history of violence who took clozapine were prescribed the highest number of drugs. The patterns of cumulative Modified Overt Aggression Scale mean scores of patients taking clozapine (n = 46), other antipsychotics (n = 257), and no antipsychotics (n = 37) were significantly different (P = .001). Patients taking clozapine showed a time trend at 1-year follow-up (24 evaluations) indicating a significantly lower level of aggressive behavior. Patient higher compliance was also associated with lower Modified Overt Aggression Scale ratings during the 1-year follow-up.

Conclusion

Both inpatients and outpatients showed high levels of polypharmacy. Clozapine prescription was associated with lower Modified Overt Aggression Scale ratings compared with any other antipsychotics or other psychotropic drugs. Higher compliance was associated with lower levels of aggressive and violent behavior.
A hybrid preventive maintenance model for systems with partially observable degradation
Authors: Finkelstein Maxim , Cha Ji Hwan , Levitin Gregory
Published: January 2020

A new model of hybrid preventive maintenance of systems with partially observable degradation is developed. This model combines condition-based maintenance with age replacement maintenance in the proposed, specific way. A system, subject to a shock process, is replaced on failure or at some time ${T}_S$ if the number of shocks experienced by this time is greater than or equal to m or at time $T>{T}_S$ otherwise, whichever occurs first. Each shock increases the failure rate of the system at the random time of its occurrence, thus forming a corresponding shot-noise process. The real deterioration of the system is partially observed via observation of the shock process at time ${T}_S$. The corresponding optimization problem is solved and a detailed numerical example demonstrates that the long-run cost rate for the proposed optimal hybrid strategy is smaller than that for the standard optimal age replacement policy.
Development of data dictionary for neonatal intensive care unit: advancement towards a better critical care unit
Authors: Singh Harpreet , Kaur Ravneet , Saluja Satish , Cho Su Jin , Kaur Avneet , Pandey Ashish Kumar , Gupta Shubham , Das Ritu , Kumar Praveen , Palma Jonathan , Yadav Gautam , Sun Yao
Published: January 2020

Background

Critical care units (CCUs) with extensive use of various monitoring devices generate massive data. To utilize the valuable information of these devices; data are collected and stored using systems like clinical information system and laboratory information management system. These systems are proprietary, allow limited access to their database and, have the vendor-specific clinical implementation. In this study, we focus on developing an open-source web-based meta-data repository for CCU representing stay of the patient with relevant details.

Methods

After developing the web-based open-source repository named data dictionary (DD), we analyzed prospective data from 2 sites for 4 months for data quality dimensions (completeness, timeliness, validity, accuracy, and consistency), morbidity, and clinical outcomes. We used a regression model to highlight the significance of practice variations linked with various quality indicators.

Results

DD with 1555 fields (89.6% categorical and 11.4% text fields) is presented to cover the clinical workflow of a CCU. The overall quality of 1795 patient days data with respect to standard quality dimensions is 87%. The data exhibit 88% completeness, 97% accuracy, 91% timeliness, and 94% validity in terms of representing CCU processes. The data scores only 67% in terms of consistency. Furthermore, quality indicators and practice variations are strongly correlated (P < 0.05).

Conclusion

This study documents DD for standardized data collection in CCU. DD provides robust data and insights for audit purposes and pathways for CCU to target practice improvements leading to specific quality improvements.
National incidence and initial therapy for thymic carcinoma in Japan: based on analysis of hospital-based cancer registry data, 2009–2015
Authors: Koizumi Tomonobu , Otsuki Kengo , Tanaka Yuriko , Noguchi Takuro , Fukushuima Toshirou , Kobayashi Takashi , Ozawa Takesumi , Sekiguchi Nodoka , Hamanaka Kazutoshi
Published: January 2020

Background

Although thymic carcinoma is a rare epithelial neoplasm that tends to be aggressive and metastasize widely, its incidence in Japan remains unclear. This study was to examine the incidence and initial treatment of thymic carcinoma in the Japanese population using data from a hospital-based cancer registry.

Methods

Using data from the national database of hospital-based cancer registries, we examined the incidence and initial treatment of thymic carcinoma diagnosed and treated in designated and non-designated cancer care hospitals between 2009 and 2015. Based on Japanese population estimates, we calculated the incidence rate of thymic cancer in Japan.

Results

A total of 2587 thymic carcinoma cases were diagnosed between 1 January 2009 and 31 December 2015. These patients consisted of 1705 (66%) men and 882 (34%) women, with a median age of 65.5 years (range, 16–96 years). The number and proportion of thymic carcinoma to all registered cancer cases per year increased each year. The incidence rate was estimated to be 0.29/100000 during the observation period, with an annual onset incidence of 0.38/100000 in 2015. Almost half of all cases of thymic carcinoma were treated surgically, while the others were treated with non-surgical therapy consisting of chemotherapy with or without radiotherapy.

Conclusions

We estimated the incidence rate of thymic carcinoma in Japan based on the designated cancer care hospital-based cancer registry. The half of all patients with thymic carcinoma was unfit for multimodality therapy, including thoracic surgery.
Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy
Authors: Tanaka Keiichi , Matsumoto Yoshitaka , Ishikawa Hitoshi , Fukumitsu Nobuyoshi , Numajiri Haruko , Murofushi Keiko , Oshiro Yoshiko , Okumura Toshiyuki , Satoh Toyomi , Sakurai Hideyuki
Published: January 2020

The Rho-associated coiled-coil-containing protein kinase (ROCK) pathway is known to influence metastasis in several cancers; however, the impact of the pathway on clinical outcomes in patients undergoing radiotherapy remains unknown. In the present study, the expression of RhoA, RhoC, ROCK-1, ROCK-2 and p53 was immunohistochemically evaluated using biopsy specimens obtained from 49 patients with stage II–III cervical squamous cell carcinoma treated with concurrent chemoradiotherapy (CCRT). The relationship between the expression of these proteins and patient outcomes was investigated. RhoA overexpression was associated with significantly impaired disease-free survival and distant metastasis-free survival (P = 0.045 and P = 0.041, respectively) in stage III cancer patients. No differences in survival were observed based on the expression of the other proteins among stage III cancer patients. In stage II cancer patients, no differences in survival were noted based on the expression of any of the proteins. The expression of RhoA was able to successfully differentiate cervical cancer patients with distant metastasis after CCRT. This information may help stratify patients according to the risk of metastasis, thereby leading to the potential to provide individualized treatment.
Potential for global spread of a novel coronavirus from China
Authors: Bogoch Isaac I , Watts Alexander , Thomas-Bachli Andrea , Huber Carmen , Kraemer Moritz U G , Khan Kamran
Published: January 2020

An epidemic of a novel coronavirus emerged from Wuhan, China, in late December 2019 and has since spread to several large Chinese cities. Should a scenario arise where this coronavirus spreads more broadly across China, we evaluate how patterns of international disease transmission could change.
Dynamic evolution of sentiments in Never Let Me Go: Insights from multifractal theory and its implications for literary analysis
Authors: Hu Qiyue , Liu Bin , Thomsen Mads Rosendahl , Gao Jianbo , Nielbo Kristoffer L
Published: January 2020

The moods, feelings, and attitudes represented in a novel will resonate in the reader by activating similar sentiments. It is generally accepted that sentiment analysis can capture aspects of such moods, feelings, and attitudes and can be used to summarize a novel’s plot in a story arc. With the availability of a number of algorithms to automatically extract sentiment-based story arcs, new approaches for their utilization becomes pertinent. We propose to use nonlinear adaptive filtering and fractal analysis in order to analyze the narrative coherence and dynamic evolution of a novel. Using Never Let Me Go by Kazuo Ishiguro, the winner of the 2017 Nobel Prize for Literature as an illustrative example, we show that: (1) nonlinear adaptive filtering can extract a story arc that reflects the tragic trend of the novel; (2) the story arc displays persistent dynamics as measured by the Hurst exponent at short and medium timescales; (3) the plot’s dynamic evolution is reflected in the time-varying Hurst exponent. We argue that these findings are indicative of the potential that multifractal theory has for computational narratology and large-scale literary analysis. Specifically that the global Hurst exponent of a story arc is an index of narrative coherence that can identify bland, incoherent, and coherent narratives on a continuous scale. And, further, that the local time-varying Hurst exponent captures variation of a novel’s plot such that the extrema have specific narratological interpretations.
Clinical relevance of Scedosporium spp. and Exophiala dermatitidis in patients with cystic fibrosis: A nationwide study
Authors: de Jong C C M , Slabbers L , Engel T G P , Yntema J B , van Westreenen M , Croughs P D , Roeleveld N , Brimicombe R , Verweij P E , Meis J F , Merkus P J
Published: January 2020

An increased prevalence of various filamentous fungi in sputum samples of patients with cystic fibrosis (CF) has been reported. The clinical significance, however, is mostly unclear. The aim of this study was to investigate the clinical relevance of Scedosporium spp. and Exophiala dermatitidis from sputum samples of patients with CF in the Netherlands. In this cross-sectional study, all CF patients of the Dutch national CF registry who were treated at five of the seven recognized CF centers during a 3-year period were included. We linked clinical data of the national CF registry with the national Dutch filamentous fungal database. We investigated the association between clinical characteristics and a positive sputum sample for Scedosporium spp. and E. dermatitidis, using logistic regression. Positive cultures for fungi were obtained from 3787 sputum samples from 699 of the 1312 patients with CF. Scedosporium spp. was associated with severe genotype, CF-related diabetes, several microorganisms, and inhaled antibiotics. E. dermatitidis was associated with older age, female sex, and Aspergillus spp. CF patients with and without Scedosporium spp. or E. dermatitidis seemed comparable in body mass index and lung function. This study suggests that Scedosporium spp. and E. dermatitidis are probably no major pathogens in CF patients in the Netherlands. Greater understanding of epidemiologic trends, risk factors, and pathogenicity of filamentous fungi in the respiratory tracts of patients with CF is needed.
Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma
Authors: Shafer Danielle , Tombes Mary Beth , Shrader Ellen , Ryan Alison , Bandyopadhyay Dipankar , Dent Paul , Malkin Mark
Published: January 2020

Background

Dimethyl fumarate (DMF), an oral agent approved for the treatment of relapsing–remitting multiple sclerosis (RRMS), has promising preclinical activity against glioblastoma (GBM). This phase I study sought to determine the recommended phase 2 dose (RP2D) of DMF and evaluate its safety and toxicity when combined with standard concurrent radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ in patients with newly diagnosed GBM.

Methods

Using a standard 3 + 3 dose-escalation design with 3 dose levels, patients received daily DMF with 60 Gy RT and concurrent TMZ 75 mg/m2 daily, followed by maintenance DMF (continuously) and TMZ 150–200 mg/m2 on days 1–5 of each 28-day cycle for up to 6 cycles. The maximum tolerated dose (MTD) was determined by evaluation of dose-limiting toxicity (DLT) during the first 6 weeks of therapy.

Results

Twelve patients were treated at the 3 dose levels, and no DLTs were observed. There were no unexpected toxicities. The most common grade 3/4 treatment related adverse events (AEs) were lymphopenia (58%), decreased CD4 count (17%), and thrombocytopenia (17%). Four patients completed all planned treatment; seven patients had progression on treatment. One patient chose to withdraw from the study during maintenance. The median progression-free survival (PFS) for all patients was 8.7 months with no difference in PFS between those with stable disease or a partial response; median overall survival was 13.8 months.

Conclusions

DMF may be safely combined with RT and TMZ in patients with newly diagnosed GBM. The RP2D for DMF is 240 mg three times daily.
The Future of Phage: Ethical Challenges of Using Phage Therapy to Treat Bacterial Infections
Authors: Anomaly Jonathan
Published: January 2020

For over a century, scientists have run experiments using phage viruses to treat bacterial infections. Until recently, the results were inconclusive because the mechanisms viruses use to attack bacteria were poorly understood. With the development of molecular biology, scientists now have a better sense of how phage work, and how they can be used to target infections. As resistance to traditional antibiotics continues to spread around the world, there is a moral imperative to facilitate research into phage therapy as an alternative treatment. This essay reviews ethical questions raised by phage therapy, and discusses regulatory challenges associated with phage research, and phage treatments.
Stepping After Stroke: Walking Characteristics in People With Chronic Stroke Differ on the Basis of Walking Speed, Walking Endurance, and Daily Steps
Authors: Handlery Reed , Fulk George , Pellegrini Christine , Stewart Jill Campbell , Monroe Courtney , Fritz Stacy
Published: January 2020

Background

What contributes to free-living walking after stroke is poorly understood. Studying the characteristics of walking may provide further details that guide interventions.

Objective

The objectives of this study were to examine how the walking characteristics of bouts per day, median steps per bout, maximum steps per bout, and time spent walking differ in individuals with various walking speeds, walking endurance, and daily steps and to identify cutoffs for differentiating ambulators who were active versus inactive.

Design

This study involved a cross-sectional analysis of data from the Locomotor Experience Applied Post-Stroke trial.

Methods

Participants were categorized by walking speed, walking endurance (via the 6-minute walk test), and daily steps (via 2 consecutive days of objective activity monitoring). Differences in walking characteristics were assessed. Linear regression determined which characteristics predicted daily step counts. Receiver operating characteristic curves and areas under the curve were used to determine which variable was most accurate in classifying individuals who were active (≥5500 daily steps).

Results

This study included 252 participants with chronic stroke. Regardless of categorization by walking speed, walking endurance, or daily steps, household ambulators had significantly fewer bouts per day, steps per bout, and maximum steps per bout and spent less time walking compared with community ambulators. The areas under the curve for maximum steps per bout and bouts per day were 0.91 (95% confidence interval = 0.88 to 0.95) and 0.83 (95% confidence interval = 0.78 to 0.88), respectively, with cutoffs of 648 steps and 53 bouts being used to differentiate active and inactive ambulation.

Limitations

Activity monitoring occurred for only 2 days.

Conclusions

Walking characteristics differed based on walking speed, walking endurance, and daily steps. Differences in daily steps between household and community ambulators were largely due to shorter and fewer walking bouts. Assessing and targeting walking bouts may prove useful for increasing stepping after stroke.
HIGHER CORRELATIONS AND THE ALTERNATIVE HYPOTHESIS
Authors: Lagarias Jeffrey C , Rodgers Brad
Published: January 2020

The Alternative Hypothesis (AH) concerns a hypothetical and unlikely picture of how zeros of the Riemann zeta function are spaced, which one would like to rule out. In the Alternative Hypothesis, the renormalized distance between non-trivial zeros is supposed to always lie at a half integer. It is known that the Alternative Hypothesis is compatible with what is known about the pair correlation function of zeta zeros. We ask whether what is currently known about higher correlation functions of the zeros is sufficient to rule out the Alternative Hypothesis and show by construction of an explicit counterexample point process that it is not. A similar result was recently independently obtained by Tao, using slightly different methods. We also apply the ergodic theorem to this point process to show there exists a deterministic collection of points lying in $\tfrac{1}{2}\mathbb{Z}$, which satisfy the Alternative Hypothesis spacing, but mimic the local statistics that are currently known about zeros of the zeta function.
‘Hokclyff’ and the Will of William Hoton
Authors: Brown Peter
Published: January 2020

There are two surviving copies of La Male Regle by Thomas Hoccleve, a lively account of his dissolute life as a clerk of the Privy Seal. One is part of an autograph manuscript of Hoccleve’s works in the Huntington Library, the other an incomplete version in Canterbury Cathedral Archives. Reference to a third copy survives in the will of William Hoton, proved in 1447. As well as La Male Regle, Hoton bequeathed a letter of Pharaoh, a chronicle and statutes, together with a mazer and pious donations. This information, coupled with records of Hoton’s family members, his burial place and associates, produces a profile of William Hoton linking him with the law and the book trade, and possibly with Neville’s Inn, the London town house used by a noble family to whose members Hoccleve addressed some of his poems. Hoton’s will also leads to a second individual who owned La Male Regle—the person who received it as a bequest, the common attorney and citizen, John Mordon. Neither Hoton nor Mordon has hitherto featured in discussions of the reception of the poem, which enjoyed a wider circulation than previously thought.