bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of electrocardiographic markers of acute and long‐term hemodynamic improvement in patients with pulmonary hypertension
Authors: Piłka Michał , Darocha Szymon , Banaszkiewicz Marta , Wieteska‐Miłek Maria , Mańczak Małgorzata , Mańczak Rafał , Kędzierski Piotr , Florczyk Michał , Dobosiewicz Anna , Torbicki Adam , Kurzyna Marcin 
Published: April 2020

AbstractBackgroundThe remodeling of the right heart in patients with chronic pulmonary hypertension (cPH) is associated with the appearance of electrocardiographic (ECG) abnormalities. We investigated the resolution of ECG markers of right ventricular hypertrophy (RVH) caused by acute and long‐term hemodynamic improvement.MethodsTwenty‐nine (29) patients with chronic thromboembolic pulmonary hypertension (CTEPH) and seven patients with pulmonary arterial hypertension (PAH) were included in the analysis. Patients with CTEPH achieved a significant long‐term hemodynamic improvement following the treatment with balloon pulmonary angioplasty (BPA); all the patients with PAH reported significant acute hemodynamic relief after a single inhalation of iloprost, fulfilling the criteria of responder. Standard 12‐lead ECG was performed before and after intervention.ResultsThe interval between baseline and control ECG in CTEPH and PAH groups was 28 (IQR: 17–36) months and 15 min (IQR: 11–17), respectively. Despite similar hemodynamic improvement in both groups, only the CTEPH group presented significant changes in most analyzed ECG parameters: T‐wave axis (p = .002), QRS‐wave axis (p = .012), P‐wave amplitude (p < .001) and duration in II (p = .049), R‐wave amplitude in V1 (p = .017), R:S ratio in V1 (p = .046), S‐wave amplitude in V5 (p = .004), R‐wave amplitude in V5 (p = .044), R:S ratio in V5 (p = .004), S‐wave amplitude in V6 (p = .026), R‐wave amplitude in V6 (p = .01), and R‐wave amplitude in aVR (p = .031). In patients with PAH, significant differences were found only for P wave in II (duration: p = .035; amplitude: p = .043) and QRS axis (p = .018).ConclusionsThe effective treatment of cPH ensures improvement in ECG parameters of RVH, but it requires extended time.
The Bezold–Jarisch reflex in a patient with coronary spastic angina
Authors: Sakai Chieko , Kawasaki Tatsuya , Sugihara Hiroki , Matoba Satoaki 
Published: April 2020

AbstractAcute inferior myocardial damage can induce transient bradycardia and hypotension—the Bezold–Jarisch reflex, which is explained by the preferential distribution of vagal nerves in the inferior wall of the left ventricle. We report a 76‐year‐old man who showed a perfusion defect in the inferior wall with redistribution on exercise scintigraphy with thallium‐201. Of note, during exercise at an intensity of 100 watts, the patient's heart rate transiently decreased from 122 to 95 bpm in sinus rhythm, accompanied by ST‐segment depression. A diagnosis of coronary spastic angina was made since no stenotic lesions were observed on conventional coronary angiography.
Evaluation of ocular symptoms and tropism of SARS‐CoV‐2 in patients confirmed with COVID‐19
Authors: Hong Nan , Yu Wangshu , Xia Jianhua , Shen Ye , Yap Maurice , Han Wei 
Published: April 2020

AbstractPurposeThe SARS‐CoV‐2 RNA has been detected in tears and conjunctival samples from infected individuals. Conjunctivitis is also reported in a small number of cases. We evaluated ocular symptoms and ocular tropism of SARS‐CoV‐2 in a group of patients with COVID‐19.MethodFifty‐six patients infected with SARS‐CoV‐2 were recruited as subjects. Relevant medical histories were obtained from the electronic medical record system. Ocular history and ocular symptoms data were obtained by communicating directly with the subjects. The Ocular Surface Disease Index (OSDI) and Salisbury Eye Evaluation Questionnaire (SEEQ) were used to assess the anterior ocular surface condition before and after the onset of disease.ResultsPatients classified as severe COVID‐19 cases were more likely to have hypertension compared to mild cases (p = 0.035). Of the 56 subjects, thirteen patients (23%) were infected in Wuhan, 32 patients (57%) were community‐infected, 10 patients (18%) were unknown origin, 1 (2%) was a physician likely infected by a confirmed patient. Three patients wore face mask with precaution when contacting the confirmed patients. Fifteen (27%) had aggravated ocular symptoms, of which 6 (11%) had prodromal ocular symptoms before disease onset. The differences in mean scores of OSDI questionnaire and SEEQ between before and after onset of COVID‐19 were all significant (p < 0.05 for both).ConclusionsOcular symptoms are relatively common in COVID‐19 disease and may appear just before the onset of respiratory symptoms. Our data provided the anecdotal evidences of transmission of SARS‐CoV‐2 via ocular surface.
Atypical general movements in the general population: Prevalence over the last 15 years and associated factors
Authors: Wu Ying‐Chin , Bouwstra Hylco , Heineman Kirsten R. , Hadders‐Algra Mijna 
Published: April 2020

AbstractAimTo determine the prevalence of atypical general movements (GMs) in the general population, to examine its time trend and associated factors.MethodsParticipants consisted of 300 infants born in 2016‐2018 (current cohort; gestational age 39.4 weeks (27‐42); 162 boys), representative of the Dutch population. GMs were assessed at 2‐4 months corrected age in terms of GM‐complexity (definitely abnormal (DA) or not) and fidgety movements (present or absent). GM‐complexity data from a cohort of 455 Dutch infants born in 2001‐2002 were used to investigate the time trend.ResultsIn the current cohort, 10 infants (3%) showed DA GM‐complexity and 8 (3%) absent fidgety movements. Only one infant had both GM‐impairments (0.3%). The prevalence of DA GM‐complexity did not differ from that in the 2001‐2002 cohort (adjusted odds ratio (OR) = 1.47 [0.53, 4.06]). DA GM‐complexity was associated with maternal smoking (adjusted OR = 3.59 [1.56, 8.28]) and marginally with prematurity (adjusted OR = 2.78 [1.00, 7.74]); absence of fidgety movements was curvilinearly associated with assessment age only (OR = 1.06 [1.01, 1.12]).ConclusionIn the general population, the prevalence of DA GM‐complexity and absent fidgety movements is 3%. The finding that they rarely co‐occur and are associated with different factors indicates that GM‐assessment needs to address both aspects.
Nitrergic perivascular innervation in health and diseases: Focus on vascular tone regulation
Authors: Xavier Fabiano E. 
Published: April 2020

AbstractFor a long time, the vascular tone was considered to be regulated exclusively by tonic innervation of vasoconstrictor adrenergic nerves. However, accumulating experimental evidence has revealed the existence of nerves mediating vasodilatation, including perivascular nitrergic nerves (PNN), in a wide variety of mammalian species. Functioning of nitrergic vasodilator nerves is evidenced in several territories, including cerebral, mesenteric, pulmonary, renal, penile, uterine and cutaneous arteries. Nitric oxide (NO) is the main neurogenic vasodilator in cerebral arteries and acts as a counter‐regulatory mechanism for adrenergic vasoconstriction in other vascular territories. In the penis, NO relaxes the vascular and cavernous smooth muscles leading to penile erection. Furthermore, when interacting with other perivascular nerves, NO can act as a neuromodulator. PNN dysfunction is involved in the genesis and maintenance of vascular disorders associated with arterial and portal hypertension, diabetes, ageing, obesity, cirrhosis and hormonal changes. For example defective nitrergic function contributes to enhanced sympathetic neurotransmission, vasoconstriction and blood pressure in some animal models of hypertension. In diabetic animals and humans, dysfunctional nitrergic neurotransmission in the corpus cavernosum is associated with erectile dysfunction. However, in some vascular beds of hypertensive and diabetic animals, an increased PNN function has been described as a compensatory mechanism to the increased vascular resistance. The present review summarizes current understanding on the role of PNN in control of vascular tone, its alterations under different conditions and the associated mechanisms. The knowledge of these changes can serve to better understand the mechanisms involved in these disorders and help in planning new treatments.
Working in Bed—A Commentary on “Automation, Algorithms, and Beyond: Why Work Design Matters More than Ever in a Digital World” by Parker and Grote
Authors: Wiklund Johan 
Published: April 2020

AbstractTechnology influences work in important ways deserving scholarly attention. These include: that humans have the moral obligation to design humane work conditions for artificial intelligence; that connectedness and social media lead to burnout and unhappiness; that artificial intelligence may generate competitive advantages for the neurodiverse; and that gig work potentially creates opportunities for the disabled.
Vitamin D deficiency in long‐term hospitalization psychiatric wards in an equatorial nation
Authors: Suri Tarun , Suri Sandeep , Poremski Daniel , Fang Tina , Su Alex 
Published: April 2020

AbstractIntroductionVitamin D deficiency and insufficiency have been shown to be prevalent in several populations, including in people who have a mental illness. Deficiency has been linked to specific mental health sequelae. Furthermore, deficiency may be perpetuated by medications routinely prescribed to people with severe mental illness. Therefore, symptoms of mental illness may be exacerbated by deficient levels of vitamin D, and treatments for mental illness may exacerbate deficiency. This study sought to determine the vitamin D levels of people hospitalized for a period longer than a year in an equatorial nation, Singapore. The inpatient population was then categorized according to levels to determine the need for supplementation.MethodsTotal 25‐hydroxy vitamin D in serum and plasma levels were tested in 403 individuals in long‐term psychiatric wards. Blood serum and plasma levels were classified into three groups. Regression models were constructed to test the associations between levels and clinical covariates.ResultsForty (9.9%) people had vitamin D levels that were sufficient. A link was found between vitamin D levels and medications given for gastrointestinal illnesses (β −2.48, p = .014, 95%CI ‐4.46 to‐0.51) and between vitamin D levels and length of stay (β −0.13, p = .027, 95%CI ‐0.24 to‐0.01). No other relationships were statistically significant.DiscussionDespite its geographic location and opportunities for regular outdoor activity, vitamin D deficiency, and insufficiency are prevalent among people hospitalized for long periods of time in an equatorial nation. The level of deficiency is comparable to those observed in other settings.
Assessing the impact of cystic fibrosis on the antipyretic response of ibuprofen in children: Physiologically‐based modeling as a candle in the dark
Authors: Cicali Brian , Long Tao , Kim Sarah , Cristofoletti Rodrigo 
Published: April 2020

AimThe goal of this study is to present the utility of quantitative modelling for extrapolation of drug safety and efficacy to underrepresented populations in controlled clinical trials. To illustrate this, the stepwise development of an integrated disease/pharmacokinetics/pharmacodynamics model of antipyretic efficacy of ibuprofen in children with cystic fibrosis (CF) is presented along with therapy optimization suggestions.MethodPublished clinical trials, in vitro data, and drug physiochemical properties were used to develop an ibuprofen‐mediated antipyresis model for febrile children also having CF. Workflow included first developing a mechanistic absorption model using in vitro‐in vivo extrapolation followed by physiologically‐based pharmacokinetic (PBPK) modelling. The verified PBPK model was then scaled to paediatric patients with CF. Once verified, the PBPK model was linked to an indirect response model of antipyresis for simulation of the overall antipyretic efficacy of ibuprofen in CF children.ResultsModel simulations showed therapeutic inequivalence between healthy children and paediatric patients with CF; Cmax and AUC decreased by 39% (32–46%) and 44% (36–52%), respectively, in patients. Further, and in agreement with literature reports, predicted pharmacodynamics time courses suggest a slower onset and faster offset of action in patients compared to healthy children, 30 and 60 minutes, respectively. Exploratory simulations suggest an increase in dosing frequency for CF children as a better therapeutic strategy.ConclusionModel‐informed approaches to leveraging knowledge obtained throughout the life cycle of drug development may play a key role in extrapolating drug efficacy and safety to underrepresented populations.
Supratheraputic rivaroxaban levels: A persistent drug‐drug interaction after discontinuation of amiodarone
Authors: Skov Kenneth , Falskov Britt , Jensen Esther Agnete , Dorff Mikkel Helleberg 
Published: April 2020

AbstractWe report the case of an 88‐year old woman referred for evaluation of increased INR. Surprisingly supratherapeutic levels of rivaroxaban was detected. Upon scrutiny of the patient's medical history, a drug‐drug interaction between amiodarone and rivaroxaban persisting 3 weeks after cessation of amiodaron remains the prime suspect causing the clinical picture. Both INR and rivaroxaban levels returned to normal within 3 days of cessation of rivaroxaban. The case highlights that rivaroxaban, although highly variably, does affect INR. Furthermore, it highlights that the potential for DDIs involving amiodarone may persists for weeks or months after discontinuation. Amiodarone is predicted to increase rivaroxaban exposure, through inhibition of rivaroxaban elimination via CYP3A4 and P‐gp. Elderly patients and patients with declining renal function are especially at risk of increased rivaroxaban exposure when a DDI with amiodarone occurs.
Primary urethral cancer: treatment patterns and associated outcomes
Authors: Mano Roy , Vertosick Emily A. , Sarcona Joseph , Sjoberg Daniel D. , Benfante Nicole E. , Donahue Timothy F. , Herr Harry W. , Donat S. Machele , Bochner Bernard H. , Dalbagni Guido , Goh Alvin C. 
Published: April 2020

ObjectivesTo evaluate treatment patterns and associated outcomes of patients with urethral cancer.Patients and MethodsAfter obtaining institutional review board approval we identified 165 patients treated for primary urethral cancer between 1956 and 2017. Treatment included monotherapy (surgery or radiation), dual therapy (surgery+radiation, surgery+chemotherapy, or chemotherapy+radiation) or triple therapy (surgery+radiation+chemotherapy). Rates of different treatments were described by treatment year. The association between treatment type and outcomes was evaluated with multivariable Cox regression models, adjusting for disease characteristics.ResultsThe study cohort included 74 men and 91 women, with a median age of 61 years. Common histologies were squamous cell (36%), urothelial (27%) and adenocarcinoma (25%). At presentation, 72% of patients had invasive disease, 24% had nodal involvement, and 5% had metastases. Treatment included monotherapy (57%), dual therapy (21%), and triple therapy (10%). The use of monotherapy decreased over time, while rates of dual therapy remained consistent, and rates of triple therapy increased. The median follow‐up was 4.7 years. Estimated 5‐year local recurrence‐free, disease‐specific and overall survival were 51%, 48% and 41%, respectively. Monotherapy was associated with decreased local recurrence‐free survival after adjusting for stage, histology, sex and year of treatment (P = 0.017). There was no evidence that treatment type was associated with distant recurrence, cancer‐specific or overall survival.ConclusionsWe found preliminary evidence that multimodal therapy, more commonly used in recent years, was of benefit in patients with primary urethral cancer. This finding should be confirmed in further studies involving multiple centres because of the low incidence of the disease.
A randomised Phase II trial of carboplatin and gemcitabine ± vandetanib in first‐line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin
Authors: Jones Robert , Crabb Simon , Chester John , Elliott Tony , Huddart Robert , Birtle Alison , Evans Linda , Lester Jason , Jagdev Satinder , Casbard Angela , Huang Chao , Madden Tracie‐Ann , Griffiths Gareth 
Published: April 2020

ObjectivesTo assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first‐line treatment of patients with advanced transitional cell carcinoma urothelial cancer (UC) who were unsuitable for cisplatin.Patients and methodsFrom 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double‐blind, placebo‐controlled randomised Phase II trial, receiving six 21‐day cycles of intravenous carboplatin (target area under the concentration versus time curve 4.5, day 1) and gemcitabine (1000 mg/m2 days 1 and 8) combined with either oral vandetanib 100 mg or placebo (once daily). Progression‐free survival (PFS; primary endpoint), adverse events, tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention‐to‐treat and per‐protocol analyses were used to analyse the primary endpoint.ResultsThe 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8 months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65–1.76; P = 0.71); the median OS was 10.8 vs 13.8 months (HR 1.41, 95% CI 0.79–2.52; P = 0.88); and radiological response rates were 50% and 55%.ConclusionThere is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first‐line treatment in patients with UC who were unfit for cisplatin.
Oxysterols: From physiological tuners to pharmacological opportunities
Authors: Brown Andrew J. , Sharpe Laura J. , Rogers Michael J. 
Published: April 2020

Oxysterols are oxygenated forms of cholesterol generated via autooxidation by free radicals and ROS, or formed enzymically by a variety of enzymes such as those involved in the synthesis of bile acids. Although found at very low concentrations in vivo, these metabolites play key roles in health and disease, particularly in development and regulating immune cell responses, by binding to effector proteins such as LXRα, RORγ and Insig and directly or indirectly regulating transcriptional programmes that affect cell metabolism and function. In this review, we summarise the routes by which oxysterols can be generated and subsequently modified to other oxysterol metabolites and highlight their diverse and profound biological functions and opportunities to alter their levels using pharmacological approaches.LINKED ARTICLESThis article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc
B1 and B2 kinin receptor blockade improves psoriasis‐like disease
Authors: Soley Bruna da Silva , Silva Leonardo Martins , Mendes Daniel Augusto Gasparin Bueno , Báfica André , Pesquero João Bosco , Bader Michael , Witherden Deborah A. , Havran Wendy L. , Calixto João B. , Otuki Michel Fleith , Cabrini Daniela Almeida 
Published: April 2020

Background and PurposeThe entire kallikrein–kinin system is present in the skin, and it is thought to exert a relevant role in cutaneous diseases, including psoriasis. The present study was designed to evaluate the relevance of kinin receptors in the development and progression of a model of psoriasis in mice.Experimental ApproachThe effects of kinin B1 and B2 receptor knockout and of kinin receptor antagonists (SSR240612C or FR173657) were assessed in a model of psoriasis induced by imiquimod in C57BL/6 mice. Severity of psoriasis was assessed by histological and immunohistochemical assays of skin, along with objective scores based on the clinical psoriasis area and severity index.Key ResultsBoth kinin receptors were up‐regulated following 6 days of imiquimod treatment. Kinin B1 and B2 receptor deficiency and the use of selective antagonists show morphological and histological improvement of the psoriasis hallmarks. This protective effect was associated with a decrease in undifferentiated and proliferating keratinocytes, decreased cellularity (neutrophils, macrophages, and CD4+ T lymphocytes), reduced γδ T cells, and lower accumulation of IL‐17. The lack of B2 receptors resulted in reduced CD8+ T cells in the psoriatic skin. Relevantly, blocking kinin receptors reflected the improvement of psoriasis disease in the well‐being behaviour of the mice.Conclusions and ImplicationsKinins exerted critical roles in imiquimod‐induced psoriasis. Both B1 and B2 kinin receptors exacerbated the disease, influencing keratinocyte proliferation and immunopathology. Antagonists of one or even both kinin receptors might constitute a new strategy for the clinical treatment of psoriasis.
Cloning and characterization of the rat Slo3 (KCa5.1) channel: From biophysics to pharmacology
Authors: Wang Guang‐Ming , Zhong Zhi‐Gang , Du Xiang‐Rong , Zhang Fei‐Fei , Guo Qing , Liu Ye , Tang Qiong‐Yao , Zhang Zhe 
Published: April 2020

Background and PurposeThe Slo3 potassium (KCa5.1) channel, which is specifically expressed in the testis and sperm, is essential for mammalian male fertilization. The sequence divergence of the bovine, mouse and human Slo3 α‐subunit revealed a rapid evolution rate across different species. The rat Slo3 (rSlo3) channel has not been cloned and characterized previously.Experimental ApproachWe used molecular cloning, electrophysiology (inside‐out patches and outside‐out patches) and mutagenesis to investigate the biophysical properties and pharmacological characteristics of the rSlo3 channel.Key ResultsThe rat Slo3 channel (rSlo3) is gated by voltage and cytosolic pH rather than intracellular calcium. The characteristics of voltage‐dependent, pH‐sensitivity and activation kinetics of the rSlo3 channel differ from the characteristics of other Slo3 orthologues. In terms of pharmacology, the 4‐AP blockade of the rSlo3 channel also shows properties distinct from its blockade of the mSlo3 channel. Iberiotoxin and progesterone weakly inhibit the rSlo3 channel. Finally, we found that propofol, one of the widely used general anaesthetics, blocks the rSlo3 channel from both intracellular and extracellular sides, whereas ketamine only blocks the rSlo3 channel at the extracellular side.Conclusion and ImplicationsOur findings suggest that the rSlo3 channel possesses unique biophysical and pharmacological properties. Our results provide new insights into the diversities of the Slo3 family of channels, which are valuable for estimating the effects of the use of these drugs to improve sperm quality.