bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrergic perivascular innervation in health and diseases: Focus on vascular tone regulation
Authors: Xavier Fabiano E.
Published: April 2020

For 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

Technology 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

Introduction

Vitamin 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.

Methods

Total 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.

Results

Forty (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.

Discussion

Despite 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.
Do we need other “posts” in migration studies? Polish migration to the UK through a postdependence lens
Authors: Gawlewicz Anna
Published: April 2020

In this paper, I discuss postdependence as a compelling new lens to study Polish migration to the UK and Poland as a migratory context. Revisiting existing critiques, I argue that neither postcolonialism nor postsocialism sufficiently reflects on the complicated geo‐historical situatedness of Poland and its distinctive migratory circumstances. Postdependence, on the other hand, advocated by Central and East European scholars, opens up new avenues for exploring dependence, oppression, and the politics of difference, offering a decolonial perspective on migration from/to/within the area. In the paper, I draw on a study of encounters with difference conducted with Polish nationals in England and Poland. In this study, participants utilised orientalist and essentialist discourses to make sense of sameness and difference, and to reflect on England and Poland. I propose that the employment and circulation of such discourses should be understood and explored against the overarching framework of postdependence. In doing so, I address a wider question of whether new conceptual frameworks (new “posts”) are needed and why. The paper contributes to the fast‐growing body of work on East–West migration in Europe and the emerging scholarship on decolonising migration studies.
“GET SMALLER”? Emerging geographies of micro‐living
Authors: Harris Ella , Nowicki Mel
Published: April 2020

Cities across the world are in the grip of an intensifying housing crisis, in which access to affordable, secure, and appropriate housing is increasingly inaccessible for the majority. There is rising pressure on stakeholders to find solutions but, simultaneously, persistent opposition to housing models that contest the neoliberal logics which prioritise housing's financialisation. In this context, many proposed and developed “solutions” have focused on how housing can – in the words of one entry to an architectural competition – “GET SMALLER.” Termed “micro‐living,” a trend is emerging for housing models that shrink living spaces, either by providing self‐contained units at below minimum space standards or by offering “co‐living” tenancies in small private rooms with access to shared communal spaces. Presented as innovative and aspirational, micro‐living distinguishes itself from unequivocally problematic small housing, such as Hong Kong's “coffin homes” or the UK's “beds‐in‐sheds.” While micro‐living is transforming ways of imagining, producing, and inhabiting cities, it has, as yet, been little explored by geographers. Responding to this gap, this paper traces the emerging geographies of micro‐living in major Western cities and demonstrates the importance of the topic in Geography. As well as detailing micro‐living's typologies, we excavate the lineages of micro‐living and consider the discourses it draws on in self‐presenting as an aspirational form of homemaking. In doing so, we highlight some of the issues that micro‐living responds to, exacerbates, and entrenches, including the stunted opportunities of millennials since the 2008 recession and the precarity of contemporary labour economies.
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

Aim

The 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.

Method

Published 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.

Results

Model 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.

Conclusion

Model‐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

We 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

Objectives

To evaluate treatment patterns and associated outcomes of patients with urethral cancer.

Patients and Methods

After 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.

Results

The 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.

Conclusions

We 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

Objectives

To 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 methods

From 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.

Results

The 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%.

Conclusion

There 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 ARTICLES

This 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
Heat shock protein 90 inhibition and multi‐target approach to maximize cardioprotection in ischaemic injury
Authors: Der Sarkissian Shant , Aceros Henry , Williams Pierre‐Marc , Scalabrini Catherine , Borie Mélanie , Noiseux Nicolas
Published: April 2020

Despite several advances in medicine, ischaemic heart disease remains a major cause of morbidity and mortality. The unravelling of molecular mechanisms underlying disease pathophysiology has revealed targets for pharmacological interventions. However, transfer of these pharmcological possibilities to clinical use has been disappointing. Considering the complexity of ischaemic disease at the cellular and molecular levels, an equally multifaceted treatment approach may be envisioned. The pharmacological principle of ‘one target, one key’ may fall short in such contexts, and optimal treatment may involve one or many agents directed against complementary targets. Here, we introduce a ‘multi‐target approach to cardioprotection’ and propose heat shock protein 90 (HSP90) as a target of interest. We report on a member of a distinct class of HSP90 inhibitor possessing pleiotropic activity, which we found to exhibit potent infarct‐sparing effects.
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 Purpose

The 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 Approach

The 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 Results

Both 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 Implications

Kinins 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 Purpose

The 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 Approach

We 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 Results

The 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 Implications

Our 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.
Restoration of HDAC2 and Nrf2 by andrographolide overcomes corticosteroid resistance in chronic obstructive pulmonary disease
Authors: Liao Wupeng , Lim Albert Y. H. , Tan W. S. Daniel , Abisheganaden John , Wong W. S. Fred
Published: April 2020

Background and Purpose

Corticosteroid resistance poses a major barrier to an effective anti‐inflammatory therapy for chronic obstructive pulmonary disease (COPD). The present study aimed to investigate potential corticosteroid re‐sensitization actions of andrographolide, a bioactive molecule from the herb Andrographis paniculata, in COPD models, particularly in peripheral blood mononuclear cells (PBMCs) from COPD patients.

Experimental Approach

Corticosteroid sensitivity in PBMCs collected from COPD patients, or in human monocytic U937 cells exposed to cigarette smoke extract (CSE), was determined by measuring LPS‐induced IL‐8 production, in the presence and absence of andrographolide. The mechanisms of corticosteroid re‐sensitization action of andrographolide were evaluated in a mouse cigarette smoke (CS)‐induced acute lung injury model.

Key Results

Impaired inhibition of IL‐8 production by dexamethasone was detected in PBMCs from COPD patients and in CSE‐exposed U937 cells, together with reduced levels of nuclear factor erythroid 2‐related factor 2 (Nrf2) and histone deacetylase‐2 (HDAC2). In both PBMCs and CSE‐exposed U937 cells, andrographolide restored dexamethasone inhibition of IL‐8 production, accompanied by the up‐regulation of Nrf2 and HDAC2 levels. In the U937 cells, andrographolide was able to block CSE‐induced Akt and reduce the level of c‐Jun. Besides, andrographolide also augmented dexamethasone actions on lowering total and neutrophil counts, cytokine levels, and oxidative damage markers in bronchoalveolar lavage fluid from CS‐exposed mice.

Conclusion and Implications

We report here for the first time a novel corticosteroid re‐sensitization property of andrographolide in human PBMCs and provide mechanistic evidence to support clinical evaluation of andrographolide in reversing steroid resistance in COPD.
Inhibitory checkpoints in human natural killer cells: IUPHAR Review 28
Authors: Mariotti F.R. , Quatrini L. , Munari E. , Vacca P. , Tumino N. , Pietra G. , Mingari M.C. , Moretta L.
Published: April 2020

Immune checkpoint inhibitors have revolutionized cancer therapy leading to exceptional success. However, there is still the need to improve their efficacy in non‐responder patients. Natural killer (NK) cells represent the first line of defence against tumours, due to their ability to release immunomodulatory cytokines and kill target cells that have undergone malignant transformation. Harnessing NK cell response will open new possibilities to improve control of tumour growth. In this respect inhibitory checkpoints expressed on these innate lymphocytes represents a promising target for next‐generation immunotherapy. In this review, we will summarize recent evidences on the expression of NK cells receptors in cancer, with a focus on the inhibitory checkpoint programmed cell death protein 1 (PD‐1). We will also highlight the strength and limitations of the blockade of PD‐1 inhibitory pathway and suggest new combination strategies that may help to unleash more efficiently NK cell anti‐tumour response.
Central nervous system lupus presenting as rhombencephalitis responding to aggressive immunotherapy: A unique case
Authors: Kaur Harleen , Mittal Gaurav K. , Singhdev Jennifer
Published: April 2020

Background

Systemic lupus erythematosus (SLE) is the prototypic autoimmune connective tissue disorder (CTD) usually affecting young females. Central nervous system lupus is a serious complication encountered in SLE cases. Predominant involvement of rhombencephalon in patients of SLE at the first contact with health care professional has not been seen and described frequently in the literature. It still remains a diagnostic and therapeutic challenge.

Case presentation

This paper describes a case of SLE in an adolescent female who was diagnosed as having rhombencephalitis, which is a rare presentation of SLE.

Conclusions

Central nervous system lupus should be included in the provisional diagnosis of any young female patient presenting with complicated neurologic manifestations over the background of joint pain or fever or headache or confusion or psychosis, to avoid misdiagnosis and aid in timely institution of aggressive immunotherapy.
Enhancing Māori and Pasifika graduate interest in ophthalmology surgical training in New Zealand/Aotearoa: Barriers and opportunities
Authors: Freundlich Simone E. N. , Connell Charlotte J. W. , McGhee Charles N. J. , Cunningham William J. , Bedggood Antony , Poole Phillippa
Published: April 2020

Importance

Improving the representation of indigenous ophthalmologists in New Zealand.

Background

Māori, indigenous to New Zealand/Aotearoa and Pacific Peoples indigenous to Pacific Island Nations living in New Zealand, experience poorer health outcomes across several ophthalmic conditions. The Royal Australian and New Zealand College of Ophthalmologists have identified indigenous workforce development as a priority.

Design

Mixed‐methods study, utilizing retrospective analysis of Medical Schools Outcomes Database and Longitudinal Tracking Project responses, and prospective interviews with Māori/Pasifika medical graduates.

Participants

This study involved 64 medical graduates from the University of Auckland (UoA) and the University of Otago, and six Māori/Pasifika medical postgraduates in New Zealand.

Methods

Retrospective analysis of medical graduate responses who ranked ophthalmology among their top‐three preferred specialties in the Medical Schools Outcomes Database and Longitudinal Tracking Project. Prospective semi‐structured interviews with Māori/Pasifika medical postgraduates.

Main Outcome Measures

Specialty training influencing factors and prevocational ophthalmology experience.

Results

A total of 64 (6.7%) out of 954 medical graduates from the UoA and University of Otago ranked ophthalmology among their top‐three preferred training specialties (2012‐2017). Of the 64 graduates, six (9.3%) identified as Māori/Pasifika. No significant difference in influencing factors between Māori/Pasifika and non‐Māori/Pasifika students was identified. Both groups ranked intellectual content, procedural skills, specialty exposure and mentorship as highly influential. Qualitative interviews with Māori/Pasifika graduates highlighted positive experiences in ophthalmology but limited exposure overall. Negative anecdotes and unclear training pathways discouraged Māori/Pasifika interest in Ophthalmology training.

Conclusions and Relevance

Māori/Pasifika graduate interest in ophthalmology training was relatively low. Valuable insights include enhancing specialty exposure, mentor development, promoting Māori/Pasifika connections and clarifying training pathways for future graduates.
Deletions of specific exons of FHOD3 detected by next‐generation sequencing are associated with hypertrophic cardiomyopathy
Authors: Ochoa Juan P. , Lopes Luis R. , Perez‐Barbeito Marlene , Cazón‐Varela Laura , de la Torre‐Carpente Maria M. , Sonicheva‐Paterson Natalia , De Uña‐Iglesias David , Quinn Ellen , Kuzmina‐Krutetskaya Svetlana , Garrote José A. , Elliott Perry M. , Monserrat Lorenzo
Published: April 2020

Despite new strategies, such as evaluating deep intronic variants and new genes in whole‐genome‐sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease‐causing gene for this phenotype, but the relevance and clinical implication of copy‐number variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth‐of‐coverage strategy by next‐generation sequencing (NGS) in 5493 HCM probands and 2973 disease‐controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease.
Next‐generation sequencing approaches and challenges in the diagnosis of developmental anomalies and intellectual disability
Authors: Bruel Ange‐Line , Vitobello Antonio , Tran Mau‐Them Frédéric , Nambot Sophie , Sorlin Arthur , Denommé‐Pichon Anne‐Sophie , Delanne Julian , Moutton Sébastien , Callier Patrick , Duffourd Yannis , Philippe Christophe , Faivre Laurence , Thauvin‐Robinet Christel
Published: April 2020

Recent advances in next‐generation sequencing (NGS) technologies have revolutionized the field of human genetics. Alongside a broad panel of bioinformatics tools and databases, NGS technologies have unprecedentedly improved the molecular diagnosis rate and the identification of new genes associated with rare disorders. However, about 50% of patients remain without a final diagnosis. Here, we highlight the utility of NGS applications in developmental anomalies and intellectual disability, illustrating their main advantages and pitfalls. Through specific examples, we suggest novel strategies and tools for identifying the molecular bases in the remaining patients, and we outline future challenges.
HNRNPH1‐related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome
Authors: Reichert Sara C. , Li Rachel , A. Turner Scott , van Jaarsveld Richard H. , Massink Maarten P.G. , van den Boogaard Marie‐José H. , del Toro Mireia , Rodríguez‐Palmero Agustí , Fourcade Stéphane , Schlüter Agatha , Planas‐Serra Laura , Pujol Aurora , Iascone Maria , Maitz Silvia , Loong Lucy , Stewart Helen , De Franco Elisa , Ellard Sian , Frank Julie , Lewandowski Raymond
Published: April 2020

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2‐related X‐linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1‐related syndromic intellectual disability.
The Otology Questionnaire Amsterdam: A generic patient‐reported outcome measure about the severity and impact of ear complaints. Validation, reliability and responsiveness
Authors: Kraak Jeroen T. , van Dam Tom F. , van Leeuwen Lisette M. , Kramer Sophia E. , Merkus Paul
Published: April 2020

Objective

To examine the construct validity, reliability and responsiveness of the Otology Questionnaire Amsterdam (OQUA).

Design

Multicentre, longitudinal study in 2 separate cohorts of patients visiting an ENT surgeon via an online survey programme.

Setting

Tertiary ENT clinics.

Participants

Cohort 1 consisted of patients at their first visit at an ENT outpatient clinic with an ear complaint. Cohort 2 consisted of patients who underwent surgery, with a 3‐month follow‐up post‐surgery.

Main outcome measures

Construct validity: Hypothesis testing, internal consistency and inter‐item correlation. Reliability: Test‐retest reliability. The construct approach was used for assessing responsiveness. Hypotheses were formulated based on the association between the OQUA and Glasgow Health Status Inventory (GHSI) or Global Rating Scale (GRS).

Results

Construct validity: The correlation between the individual items in the impact domain ranged from 0.424 to 0.737. Confirmatory factor analysis showed a good fit. As expected, the OQUA impact showed strong relationships with GHSI total and general scale.

Reliability: The test‐retest reliability coefficient ranged from 0.541 to 0.838.

Responsiveness: All hypotheses were conformed. As expected, the change score of the OQUA showed good correlation between OQUA impact and GHSI and moderate correlation between the GRS and OQUA complaints.

Conclusion

The OQUA has 8 complaint domains (earache, pressure sensation, itching, tinnitus, hearing loss, ear discharge, loss of taste and dizziness) and 1 impact domain. Each domain results in one score of 0‐100. The OQUA shows good results for construct validity, (test‐retest) reliability and responsiveness, supporting the potential benefit for the patient with an ear complaint visiting the ENT surgeon. The extensive validation furthermore confirms a certified generic otology PROM with an impact and a complaints' part, to be used in different types of otologic interventions and patient groups.
Clinical management of 52 consecutive retro‐rectal tumours treated at a tertiary referral centre
Authors: Carpelan‐Holmström M. , Koskenvuo L. , Haapamäki C. , Renkonen‐Sinisalo L. , Lepistö A.
Published: April 2020

Aim

The aim of this single‐institution study was to analyse the diagnostic methods, preoperative work‐up and outcomes of 52 retro‐rectal tumours.

Method

All patients treated for retro‐rectal tumours from 2012 to 2017 were included.

Results

Out of 52 patients, 40 (77%) were women. The median age of patients at the time of surgery was 43 (19–76) years, and 30 (58%) were asymptomatic at the time of diagnosis. All tumours were visible on magnetic resonance imaging (MRI) prior to surgery. The sensitivity and specificity for predicting malignancy on preoperative imaging for retro‐rectal tumours were 25% and 98%, respectively. Forty‐four procedures (85%) were performed using the perineal approach. The median hospital stay was 3 (1–18) days. There was no 30‐day postoperative mortality. Eleven (21%) patients developed postoperative complications, mostly surgical site infections. Twenty‐nine tumours (56%) were benign tailgut cysts. Four (8%) tumours were malignant and were considered to be removed with a tumour‐free resection margin. Local recurrent disease was detected on MRI in 14 (27%) patients at a median of 1.05 (range 0.78–1.77) years after primary surgery. Only the multi‐lobular shape of the tumour was found to be an independent risk factor for recurrence (P = 0.030).

Conclusion

A preoperative MRI is mandatory in order to plan the surgical strategy for retro‐rectal tumours. Symptomatic, solid, large tumours should be removed because of the risk of malignancy. Minor cystic lesions with thin walls as well as asymptomatic recurrences of benign tumours are suitable to be followed conservatively.
Robotic vs laparoscopic total mesorectal excision for rectal cancers: has a paradigm change occurred? A systematic review by updated meta‐analysis
Authors: Gavriilidis P. , Wheeler J. , Spinelli A. , de‘Angelis N. , Simopoulos C. , Di Saverio S.
Published: April 2020

Aim

The debate about the oncological adequacy, safety and efficiency of robotic vs laparoscopic total mesorectal excision for rectal cancers continues. Therefore, an updated, traditional and cumulative meta‐analysis was performed with the aim of assessing the new evidence on this topic.

Method

A systematic search of the literature for data pertaining to the last 25 years was performed. Fixed‐ and random‐effects models were used to cumulatively assess the accumulation of evidence over time.

Results

Patients with a significantly higher body mass index (BMI), tumours located approximately 1 cm further distally and more patients undergoing neoadjuvant therapy were included in the robotic total mesorectal excision (RTME) cohort compared with those in the laparoscopic total mesorectal excision (LTME) cohort [RTME, mean difference (MD) = 0.22 (0.07, 0.36), P = 0.005; LTME, MD = −0.97 (−1.57, 0.36), P < 0.002; OR = 1.47 (1.11, 1.93), P = 0.006]. Significantly lower conversion rates to open surgery were observed in the RTME cohort than in the LTME cohort [OR = 0.33 (0.24, 0.46), P < 0.001]. Operative time in the LTME cohort was significantly reduced (by 50 min) compared with the RTME cohort. Subgroup analysis of the three randomized controlled trials (RCTs) challenged all the significant results of the main analysis and demonstrated nonsignificant differences between the RTME cohort and LTME cohort.

Conclusion

Although the RTME cohort included patients with a significantly higher BMI, more distal tumours and more patients undergoing neoadjuvant therapy, this cohort demonstrated lower conversion rates to open surgery when compared with the LTME cohort. However, subgroup analysis of the RCTs demonstrated nonsignificant differences between the two procedures.
Small donor size does not negatively impact outcomes after deceased‐donor renal transplantation
Authors: Giffen Zane C. , Siddique Abu Bakkar , Koizumi Naoru , Ortiz Jorge
Published: April 2020

Higher body mass index (BMI) of deceased‐donors is associated with poorer outcomes in transplant recipients. The effect of low donor BMI on recipient graft function is not clear. Scientific Registry of Transplant Recipients data on recipients of deceased‐donor kidneys from 2000 to 2019 were categorized by donor BMI (donor BMI < 18, 18‐27, and >27). Primary outcome was death‐censored graft survival. The impact of multiple recipient and donor variables, including low donor BMI and the difference between donor and recipient BMI, was evaluated using a multivariate Cox proportional‐hazards model. Low BMI donors (LBD) were more likely to be younger, female, and white (all P < .05). LBD were less likely to be Hispanic, diabetic, or have hypertension (all P < .001). LBD recipients were more likely to be younger and female (both P < .001). Low donor BMI was not significantly associated with recipient graft survival. Donor‐recipient BMI difference did not correlate with an increased risk of graft failure. Similar results were obtained when donors were classified using body surface area (BSA). Small donor size in terms of BMI or BSA or a large discrepancy between donor and recipient size should not necessarily preclude transplantation of an otherwise acceptable kidney.
An unusual case of cutaneous Waldenström macroglobulinemia with the MYD88 L265P mutation
Authors: Minzenmayer Andrew N. , Miranda Roberto N. , Powell Priscilla R. , Parekh Palak K.
Published: April 2020

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow involvement and a monoclonal IgM gammopathy. Infiltration of the skin by neoplastic cells is very rare, and it can be difficult to distinguish from marginal zone lymphoma. The MYD88 L265P mutation is strongly associated with Waldenström macroglobulinemia, and it may be helpful in differentiating the two disorders, although the presence of this mutation is not specific, and other factors must be considered when making the final diagnosis. We present a diagnostically challenging case of cutaneous Waldenström macroglobulinemia in which the MYD88 L265P mutation was identified in the skin but not in the bone marrow, due to a low tumor burden.
In vivo cutaneous antinuclear antibody positivity in palisaded neutrophilic and granulomatous dermatitis
Authors: Dong Jinhong , Zubkov Micaella , Weston Gillian , Storonsky Michael , Murphy Michael
Published: April 2020

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is commonly associated with underlying systemic inflammatory and neoplastic diseases, infections, and drug reactions. In vivo cutaneous antinuclear antibodies (ANA) have been described in skin biopsies from patients with known autoimmune disorders, but not previously reported in the setting of PNGD. We present two patients with systemic lupus erythematosus (SLE) and histopathologically confirmed PNGD. Direct immunofluorescence (DIF) studies revealed in vivo cutaneous ANA positivity in both patients. DIF findings in the skin mirrored serum autoantibody results. ANA positivity in skin specimens is reported as highly predictive of systemic connective tissue diseases (SCTD), although specific testing is not currently recommended as part of the laboratory work‐up or diagnostic criteria for these disorders. In this case report, positive ANA results in skin biopsies of PNGD reflect the serological findings and clinical evidence of SLE in both patients. In vivo cutaneous ANA positivity is an interesting and supportive finding in PNGD in the setting of SCTD.
Differences in cytopathologist thyroid nodule malignancy rate
Authors: Ronen Ohad , Cohen Hector , Sela Eyal , Abu Mor
Published: April 2020

Objectives:

The accuracy of a cytological diagnosis obtained by fine needle aspiration is influenced by several factors including the technique used and the experience of both the aspirator as well as the cytologist. In this project we planned to evaluate the interobserver differences of thyroid nodule cytopathology in our medical centre.

Methods:

The study was conducted using retrospective pathology reports from a single academic centre from August 2013 to September 2017. We compared the sensitivity, specificity, negative and positive predictive values, malignancy rates, and accuracy of two cytopathologists who evaluated thyroid nodules.

Results:

We included 287 fine needle aspirations of thyroid nodules in the study. Approximately one fifth (18.5%) of patients had surgery and the rate of malignancy was 40%. There was a similar frequency of use of all thyroid Bethesda system (TBS) categories with the exception of TBS 3 (8.0% and 21.2%, P = .01). As a consequence, the malignancy rate was different in TBS 3 category (40% vs 17%, P = .545).

Conclusions:

There are interobserver differences in the evaluation of thyroid nodules. Clinicians should be aware of such differences because they affect the malignancy rate in each TBS category.
Gastrointestinal endoscopy in the era of the acute pandemic of coronavirus disease 2019: Recommendations by Japan Gastroenterological Endoscopy Society (Issued on April 9th, 2020)
Authors: Irisawa Atsushi , Furuta Takahisa , Matsumoto Takayuki , Kawai Takashi , Inaba Tomoki , Kanno Atsushi , Katanuma Akio , Kawahara Yoshiro , Matsuda Koji , Mizukami Kazuhiro , Otsuka Takao , Yasuda Ichiro , Tanaka Shinji , Fujimoto Kazuma , Fukuda Shinsaku , Iishi Hiroyasu , Igarashi Yoshinori , Inui Kazuo , Ueki Toshiharu , Ogata Haruhiko , Kato Mototsugu , Shiotani Akiko , Higuchi Kazuhide , Fujita Naotaka , Murakami Kazunari , Yamamoto Hironori , Ito Tohru , Okazaki Kazuichi , Kitagawa Yuko , Mine Tetsuya , Tajiri Hisao , Inoue Haruhiro
Published: April 2020

All gastrointestinal endoscopic procedures have a high risk of aerosol contamination of the coronavirus disease 2019 (COVID‐19) to endoscopists, nurses, and healthcare assistants. Given the current pandemic situation of COVID‐19, the Japan Gastroenterological Endoscopy Society issued the recommendation for gastrointestinal (GI) endoscopy based on the status of COVID‐19 as of April 9, 2020, in Japan: (i) indications for GI endoscopy in the pandemic of COVID‐19; (ii) practical protective equipment for medical personnel depending on the risk for COVID‐19; (iii) preprocedural management, such as pharyngeal local anesthesia using lidocaine spray which has a potential to generate the aerosols; (iv) ideal settings of the endoscopy room including the numbers of the staff and the patients; (v) postprocedural management, such as undressing and follow‐up of the patients, as well as the involved staff, were documented to fit the practical scenarios in GI endoscopy, with the available data in Japan and the world. We believe that certain measures will prevent further spread of COVID‐19.
COVID‐19 and gastrointestinal endoscopy: What should be taken into account?
Authors: Sinonquel Pieter , Roelandt Philip , Demedts Ingrid , Van Gerven Laura , Vandenbriele Christophe , Wilmer Alexander , Van Wijngaerden Eric , Bisschops Raf
Published: April 2020

On March 11, 2020 the World Health Organization declared COVID‐19 pandemic, leading to a subsequent impact on the entire world and health care system. Since the causing Severe Acute Respiratory Syndrome Coronavirus 2 houses in the aerodigestive tract, activities in the gastrointestinal outpatient clinic and endoscopy unit should be limited to emergencies only. Health care professionals are faced with the need to perform endoscopic or endoluminal emergency procedures in patients with a confirmed positive or unknown COVID‐19 status. With this report, we aim to provide recommendations and practical relevant information for gastroenterologists based on the limited amount of available data and local experience, to guarantee a high‐quality patient care and adequate infection prevention in the gastroenterology clinic.