bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and nature of adverse drug events in paediatric intensive care units: A prospective multicentre study
Authors: Alghamdi Anwar A. , Keers Richard N. , Sutherland Adam , Hann Mark , Gray Jennifer , Mason Graham , Isaac Rhian E. , Ashcroft Darren M. 
Published: December 2021

AimsThe aim of this study was to assess the incidence, nature, preventability and severity of adverse drug events (ADEs) across three paediatric intensive care units (PICUs) in England.MethodsA prospective observational cohort study was conducted across three PICUs over a three‐month period during 2019. Included patients were aged ≤18 years and stayed in PICU for a minimum of 24 hours. Identification of suspected ADEs was performed by trained PICU pharmacists. A multidisciplinary expert panel assessed causality, preventability and severity of events.ResultsA total of 302 patients were included and 62 ADEs were confirmed (definite/probable causality). One in six patients experienced one or more ADEs. The estimated incidence of ADEs were 20.5 per 100 patients (95% CI 15.3–27.5) and 16.7 per 1000 patient‐days (95% CI 9.3–29.9). The majority of ADEs were judged preventable by the expert panel (36/62, 58.1%). ADEs were commonly involved with medicines prescribing (29/62, 46.8%) and caused temporary patient harm (42/62, 67.7%). Medications for the central nervous system (14/62, 22.6%), infections (13/62, 20.9%) and cardiovascular system (12/62, 19.4%) were commonly implicated with ADEs. Multivariable analysis revealed that patients who stayed in PICU for ≥7 days (OR 6.29, 95% CI 2.42–16.32) were more likely to experience an ADE compared to patients with a stay of 1–6 days.ConclusionADEs are common in English PICUs and most of them may be preventable. There is a strong association between ADE occurrence and duration of PICU stay, which represents a target for remedial interventions. Exploring contributory factors of preventable ADEs is now necessary to inform preventive policies.
Semiparametric Additive Time-Varying Coefficients Model for Longitudinal Data with Censored Time Origin
Authors: Sun Yanqing , Shou Qiong , Gilbert Peter B. , Heng Fei , Qian Xiyuan 
Published: December 2021

Abstract
Statistical analysis of longitudinal data often involves modeling treatment effects on clinically relevant longitudinal biomarkers since an initial event (the time origin). In some studies including preventive HIV vaccine efficacy trials, some participants have biomarkers measured starting at the time origin, whereas others have biomarkers measured starting later with the time origin unknown. The semiparametric additive time-varying coefficient model is investigated where the effects of some covariates vary nonparametrically with time while the effects of others remain constant. Weighted profile least squares estimators coupled with kernel smoothing are developed. The method uses the expectation maximization approach to deal with the censored time origin. The Kaplan–Meier estimator and other failure time regression models such as the Cox model can be utilized to estimate the distribution and the conditional distribution of left censored event time related to the censored time origin. Asymptotic properties of the parametric and nonparametric estimators and consistent asymptotic variance estimators are derived. A two-stage estimation procedure for choosing weight is proposed to improve estimation efficiency. Numerical simulations are conducted to examine finite sample properties of the proposed estimators. The simulation results show that the theory and methods work well. The efficiency gain of the two-stage estimation procedure depends on the distribution of the longitudinal error processes. The method is applied to analyze data from the Merck 023/HVTN 502 Step HIV vaccine study.
Mineralocorticoid pathway in retinal health and diseases
Authors: Behar‐Cohen Francine , Zhao Min 
Published: December 2021

In the retina, the mineralocorticoid receptor is expressed in retinal and choroidal vessels and in cells from neural and glial origins. Like in the brain, the major ligand of the mineralocorticoid receptor is cortisol, and the mineralocorticoid/glucocorticoid receptor balance regulates the activation of the MR pathway. Experimental mineralocorticoid receptor pathway activation using either pharmacological agents or transgenic manipulation favours retinal and choroidal pathology. In various models of retinal diseases, such as glaucomatous neuropathy, retinopathy of prematurity, ischaemic retinopathies, diabetic retinopathy and choroidal neovascularization, mineralocorticoid receptor antagonism exerts beneficial effects, demonstrating its potential in the treatment of major blinding retinal diseases. But specific formulations are required to optimize the bioavailability of mineralocorticoid receptor antagonists in various compartments of the eye, and molecular biomarkers of mineralocorticoid receptor pathway activation remain to be identified in humans to select patients amenable to clinical trials.LINKED ARTICLESThis article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc
Alternative pain management via endocannabinoids in the time of the opioid epidemic: Peripheral neuromodulation and pharmacological interventions
Authors: Lee Ming Tatt , Mackie Ken , Chiou Lih‐Chu 
Published: December 2021

The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the endocannabinoid system in the CNS, via activation of CB1 receptors in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB1 receptors in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB1 receptor agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered positive allosteric modulators of CB1 receptors. On the other hand, as non‐pharmacological pain relief is advocated by the US‐NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation‐induced analgesia is also discussed.LINKED ARTICLESThis article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc
Effect of cenobamate on the single‐dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects
Authors: Greene Stephen A. , Kwak Charles , Kamin Marc , Vernillet Laurent , Glenn Kelli J. , Gabriel Lana , Kim Hong Wook 
Published: December 2021

AbstractThis study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no‐effect interval (0.80–1.25). When co‐administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC0–last) GMR (90% CIs) for midazolam was 0.734 (0.647–0.832). When co‐administered with cenobamate 200 mg/day, AUC0–last GMRs (90% CI) for midazolam, bupropion, S‐warfarin, and omeprazole were 0.277 (0.238–0.323), 0.615 (0.522–0.724), 1.14 (1.10–1.18), and 2.07 (1.44–2.98), respectively. Co‐administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co‐administration of cenobamate led to omeprazole values which were outside and above the no‐effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co‐administration of cenobamate with these probes drugs was well‐tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose‐dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.
Malignancy‐associated acquired vulvar lymphangioma circumscriptum: A clinicopathologic study of 71 cases
Authors: Luu Yen T. , Kimmis Brooks D. , Bodine Jared S. , Gloyeske Nika C. , Dai Hongyan 
Published: December 2021

AbstractBackgroundAcquired lymphangioma circumscriptum of the vulva is rare and can occur subsequent to malignancies of the anogenital and pelvic region. We sought to investigate the clinicopathologic characteristics of malignancy‐associated acquired vulvar lymphangioma circumscriptum (AVLC).MethodsWe identified all cases of AVLC within our institution with history of prior malignancy between 2005 and 2021. A similar search was performed in the PubMed database to identify published cases to date. The clinical and histopathologic information was recorded.ResultsA total of 71 cases were identified. The most common preceding malignancy was cervical carcinoma (71.8%, 51/71). Radiation therapy was given to 91.4% (64/70) of the patients and lymph node dissection was made on 70.2% (40/57). Median interval between the diagnosis of malignancy and the AVLC was 10 years (range 0‐32 years). AVLC frequently presented as vesicular (31.6%, 18/57) or verrucous (28.1%, 16/57) lesions clinically. Common treatments for AVLC included excision (53.1%, 26/49) and laser therapy (16.3%, 8/49), with an overall recurrence rate of 42.9% (24/56) at a median follow‐up interval of 1.8 years (range 0.04‐32.3 years).ConclusionAVLC is a rare, late complication of anogenital and pelvic malignancies causing debilitating physical symptoms and psychological stress. Further studies are warranted to determine the most effective treatment modalities to mitigate recurrence.
Evidence for the presence of a human saprophytic oral bacterium, Mycoplasma faucium, in the skin lesions of a psoriatic patient
Authors: Arabatzis Michael , Velegraki Aristea 
Published: December 2021

AbstractPsoriasis is currently regarded a mixed autoimmune and autoinflammatory disease. This report describes for the first time the detection of a saprophytic, human oral Tenericutes species, Mycoplasma faucium, in the skin lesions of a patient presenting initially guttate and later plaque psoriasis. An unusual finding in standard histopathology investigation consisted of round and oval thinly stained or unstained, possibly intracellular structures, apparently directly pressing on keratinocyte nuclei of the psoriatic stratum spinosum. In ultrastructural study, wall‐less bacteria were present intracellularly in the keratinocytes, mainly of the psoriatic stratum spinosum, and extracellularly in the upper dermis of the psoriatic lesions. M. faucium was consistently detected and identified in the psoriatic skin by general Tenericutes polymerase chain reaction and sequencing in two biopsies performed 31 months apart. This case raises new questions concerning the pathogenesis of psoriasis and its accepted autoimmune/autoinflammatory nature.
Joint impact of BMI, physical activity and diet on type 2 diabetes: Findings from two population‐based cohorts in China
Authors: Shen Qiu‐Ming , Li Hong‐Lan , Li Zhuo‐Ying , Jiang Yu‐Fei , Ji Xiao‐Wei , Tan Yu‐Ting , Xiang Yong‐Bing 
Published: December 2021

AbstractAimsLimited epidemiological data on the combined impact of several lifestyle factors on type 2 diabetes (T2D) incidence was reported in Chinese population. This study aimed to examine how combinations of BMI, physical activity and diet relate to T2D incidence and estimate corresponding population attributable risk in the general population.MethodsA total of 56,691 male and 70,849 female participants aged 40–74 years old in two population‐based cohorts from the Shanghai Men's and Women's Health Studies were used for analysis. The Cox regression model was used to estimate the association between lifestyle factors collected at baseline and T2D incidence. Multivariable‐adjusted population attributable risks were calculated for specific combinations of lifestyle factors.ResultsThere were 3315 male and 5925 female incident T2D, with corresponding density incidence rates of 6.39 and 6.04 per 1000 person‐years. If the healthiest group of healthy lifestyle index (HLI) was used as a reference, the hazard ratios (95% confidence intervals) of T2D increased monotonically in men [2.04 (1.75, 2.38); 2.94 (2.53, 3.42); 4.31 (3.66, 5.07)] and women [1.85 (1.64, 2.08); 2.79 (2.49, 3.13); 4.14 (3.66, 4.67)]. One point increase of HLI was related to 35% and 35% lower risk in men and women. About 52.7% and 58.4% cases in men and women could have been avoided if participants had been adherent to a healthy lifestyle of maintaining healthy body weight, eating a healthy diet and keeping physically active.ConclusionsAn increased number of healthy lifestyle factors were associated with a decreased risk of T2D in the Chinese population. Future interventions targeted at combined healthy lifestyle factors are needed to reduce the burden of T2D.
Complete blood count and cell population data parameters from the Abbott Alinity hq analyzer are useful in differentiating myelodysplastic syndromes from other forms of cytopenia
Authors: Hwang Sang Mee , Nam Youngwon 
Published: December 2021

AbstractIntroductionMyelodysplastic syndromes (MDS) are characterized by morphologic dysplasia and cytopenia and have a propensity for acute leukemic transformation. However, dysplasia is diagnosed by morphology, thus having cell population data (CPD) that can differentiate cytopenic patients with MDS from other conditions may facilitate accurate diagnosis. We assessed the utility of complete blood count (CBC) parameters and CPD derived from an Abbott Alinity hq analyzer to discriminate MDS‐related cytopenia.MethodsThe patient cohort (n = 345) included 64 samples from patients with MDS, 162 from patients with other cytopenia, and 119 from healthy controls. The hematological parameters and research use‐only parameters of the Abbott Alinity hq analyzer were compared between the cytopenic groups. The effectiveness of the individual standard and research CBC parameters to differentiate MDS from other forms of cytopenia was assessed through a receiver operating characteristics (ROC) analysis.ResultsThe percentage of MAC (Macrocytic RBCs) and hemoglobin distribution width (HDW) were higher in the MDS group than in the other cytopenia group and showed the greatest difference between both groups, with an area under the curve (AUC) of 0.766 (0.678–0.855) and 0.786 (0.702–0.870), respectively. The platelet distribution width was higher in the MDS group than in the other cytopenia group, with an AUC of 0.697 (0.623–0.770). WBC CPD extracted from histograms, especially Atyp‐PMN‐loc and Neu‐ALL‐M, showed high AUCs of 0.815 (0.750–0.879) and 0.778 (0.711–0.845), respectively.ConclusionOur findings demonstrate the clinical utility of CPD and hematology parameters of the Abbott Alinity hq analyzer in the differential diagnosis of MDS.
Analysing neutron radiation damage in YBa2Cu3O7–x high‐temperature superconductor tapes
Authors: Linden Y. , Iliffe W.R. , He G. , Danaie M. , Fischer D.X. , Eisterer M. , Speller S.C. , Grovenor C.R.M. 
Published: December 2021

AbstractSuperconducting windings will be necessary in future fusion reactors to generate the strong magnetic fields needed to confine the plasma, and these superconducting materials will inevitably be exposed to neutron damage. It is known that this exposure results in the creation of isolated damage cascades, but the presence of these defects alone is not sufficient to explain the degradation of macroscopic superconducting properties and a quantitative method is needed to assess the subtle lattice damage in between the clusters.We have studied REBCO‐coated conductors irradiated with neutrons to a cumulative dose of 3.3 × 1022 n/m2 that show a degradation of both Tc and Jc values, and use HRTEM analysis to show that this irradiation introduces ∼10 nm amorphous collision cascades. In addition, we introduce a new method for the analysis of these images to quantify the degree of lattice disorder in the apparently perfect matrix between these cascades. This method utilises Fast Fourier and Discrete Cosine Transformations of a statistically relevant number of HRTEM images of pristine, neutron‐irradiated and amorphous samples and extracts the degree of randomness in terms of entropy values. Our results show that these entropy values in both mid‐frequency band FFT and DCT domains correlate with the expected level of lattice damage, with the pristine samples having the lowest and the fully amorphous regions the highest entropy values. Our methodology allows us to quantify ‘invisible’ lattice damage to and correlate these values to the degradation of superconducting properties, and also has relevance for a wider range of applications in the field of electron microscopy where small changes in lattice perfection need to be measured.
Relevant prognostic factors in patients with stage IV small intestine neuroendocrine neoplasms
Authors: Maurer Elisabeth , Heinzel‐Gutenbrunner Monika , Rinke Anja , Rütz Johannes , Holzer Katharina , Figiel Jens , Luster Markus , Bartsch Detlef Klaus 
Published: December 2021

AbstractThere are few, but controversial data on the prognostic role of upfront primary tumour resection and mesenteric lymph node dissection (PTR) in patients with diffuse metastatic small intestinal neuroendocrine neoplasia (SI‐NEN). Therefore, the prognostic role of PTR and other factors was determined in this setting. This retrospective cohort study included patients with stage IV SI‐NETs with unresectable distant metastases without clinical and radiological signs of acute bowel obstruction or ischaemia. Patients diagnosed from January 2002 to May 2020 were retrieved from a prospective SI‐NEN database. Disease specific overall survival (OS) was analysed with regard to upfront PTR and a variety of other clinical (e.g., gender, age, Hedinger disease, carcinoid syndrome, diarrhoea, laboratory parameters, metastatic liver burden, extrahepatic and extra‐abdominal metastasis) and pathological (e.g., grading, mesenteric gathering) parameters by uni‐ and multivariate analysis. A total of 138 patients (60 females, 43.5%) with a median age of 60 years, of whom 101 (73%) underwent PTR and 37 (27%) did not, were included in the analysis. Median OS was 106 (95% CI: 72.52–139.48) months in the PTR group and 52 (95% CI: 30.55–73.46) in the non‐PTR group (p = 0.024), but the non‐PTR group had more advanced metastatic disease (metastatic liver burden ≥50% 32.4% vs. 13.9%). There was no significant difference between groups regarding the rate of surgery for bowel complications during a median follow‐up of 51 months (PTR group 10.9% and non‐PTR group 16.2%, p = 0.403). Multivariate analysis revealed age < 60 years, normal C‐reactive protein (CRP) at baseline, absence of diarrhoea, less than 50% of metastatic liver burden, and treatment with PRRT as independent positive prognostic factors, whereas PTR showed a strong tendency towards better OS, but level of significance was missed (p = 0.067). However, patients who underwent both, PTR and peptide radioreceptor therapy (PRRT) had the best survival compared to the rest (137 vs. 73 months, p = 0.013). PTR in combination with PRRT significantly prolongs survival in patients with stage IV SI‐NEN. Prophylactic PTR does also not result in a lower reoperation rate compared to the non‐PTR approach regarding bowel complications.
Evolutionary dynamics of piRNA clusters in Drosophila
Authors: Wierzbicki Filip , Kofler Robert , Signor Sarah 
Published: December 2021

AbstractSmall RNAs produced from transposable element (TE)‐rich sections of the genome, termed piRNA clusters, are a crucial component in the genomic defence against selfish DNA. In animals, it is thought the invasion of a TE is stopped when a copy of the TE inserts into a piRNA cluster, triggering the production of cognate small RNAs that silence the TE. Despite this importance for TE control, little is known about the evolutionary dynamics of piRNA clusters, mostly because these repeat‐rich regions are difficult to assemble and compare. Here, we establish a framework for studying the evolution of piRNA clusters quantitatively. Previously introduced quality metrics and a newly developed software for multiple alignments of repeat annotations (Manna) allow us to estimate the level of polymorphism segregating in piRNA clusters and the divergence among homologous piRNA clusters. By studying 20 conserved piRNA clusters in multiple assemblies of four Drosophila species, we show that piRNA clusters are evolving rapidly. While 70%–80% of the clusters are conserved within species, the clusters share almost no similarity between species as closely related as D. melanogaster and D. simulans. Furthermore, abundant insertions and deletions are segregating within the Drosophila species. We show that the evolution of clusters is mainly driven by large insertions of recently active TEs and smaller deletions mostly in older TEs. The effect of these forces is so rapid that homologous clusters often do not contain insertions from the same TE families.
The natural, the fundamental, and the perfectly similar: Unraveling a metaphysical braid
Authors: Funkhouser Eric 
Published: December 2021

AbstractSome of our most prominent metaphysicians have argued for a notion of naturalness that combines the roles of joint‐carving, fundamentality, and perfect similarity. This paper argues that it is a mistake to think that there are select properties fulfilling all these roles. Toward this end, epistemologically tractable diagnostic markers for naturalness are presented. From these it follows that there can be perfect naturalness and similarity at nonfundamental levels; and the fundamental need not be perfectly natural or yield perfect similarities. Metaphysicians of naturalness are encouraged to attend to insights from metaphysical property theory and the interdisciplinary study of patterns and complexity, both of which support these conclusions. Distinct metaphysical projects are distinguished.