bluuebunny/crossref_metadata_2025 huggingface dataset:
Methotrexate-induced iatrogenic immunodeficiency-associated lymphoproliferative disorder causing hypercalcaemia
Authors: Lee Monica , Nguyen Khoa Anh , Kaplan Robert
Published: June 2019

Hypercalcaemia is a rare but potentially life-threatening consequence of malignancies. Solid cancers, such as lymphomas, increase serum calcium primarily through parathyroid hormone-related protein or ectopic production of 1alpha-hydroxylase. We present a case of 56-year-old woman with Sjogren’s syndrome and psoriasis in the setting of chronic methotrexate (MTX) use who developed worsening hypercalcaemia and symptoms suggestive of lymphoma. Pathology results diagnosed her with MTX-induced iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD). This case reminds clinicians that chronic MTX use is associated with LPDs and can ultimately lead to hypercalcaemia. The patient’s MTX and other immunosuppressive medications were stopped, and her calcium corrected with fluids and calcitonin. At her 8-month follow-up postdischarge, the patient was asymptomatic with normal laboratory results and in partial clinical remission.
Oral malignant melanoma of alveolar ridge
Authors: Astekar Madhusudan , Choubey Rajkumar R , Manjunatha Bhari Sharanesha , Gupta Santosh
Published: June 2019

Malignancy of melanocytes, a pigment-producing cell, is referred as malignant melanoma (MM) which occur basically on skin and oral mucous membrane, but as well found in ears, eyes, gastrointestinal tract and genital mucosa. Oral melanomas has propensity to metastasise and invade more voluntarily than other malignant counterparts. Here we present a case of 52-year-old male patient with a chief symptom of blackening of gums in the upper front tooth region. In dental history, the patient revealed history of faulty artificial prosthesis fixed in the same region since 6 months. On the basis of a through clinical assessment, a provisional opinion of oral malignant melanoma, was prepared. On histopathological and immunohistochemical analysis with S-100 and homatropine methylbromide 45 the diagnosis of MM was confirmed.
Cerebral aspergillosis within new tumour site presents as incidental new brain lesion in patient receiving temozolomide for glioblastoma multiforme
Authors: Liu Shiyuan Anabeth , Sullivan Timothy , Bryce Clare , Chan Amy M , Cilmi Salvatore
Published: June 2019

Glioblastoma multiforme (GBM) is an aggressive tumour that can lead to lymphopaenia. Its standard treatment involves temozolomide (TMZ) chemotherapy with radiation, often with addition of corticosteroids for symptomatic management. Although TMZ is also immunosuppressive, patients receiving TMZ rarely develop disseminated opportunistic infections. Here, we report the case of a patient with GBM receiving TMZ, radiotherapy and corticosteroids, who develops an incidental new brain lesion that is found to be disseminatedAspergilluswithin a new GBM tumour site. The patient received successful early treatment of her central nervous system aspergillosis. This case illustrates the profound immunosuppressive potential of GBM in conjunction with TMZ and corticosteroids, which can lead to high-morbidity opportunistic infections concurrently with tumour progression. Future research is needed to elucidate GBM, TMZ and corticosteroids’ compound immune effects and guide management that strikes a balance between treating high-morbidity infections and continuing with immunosuppressive chemotherapy.
Observing Ramadan and sleep-wake patterns in athletes: a systematic review, meta-analysis and meta-regression
Authors: Trabelsi Khaled , Bragazzi Nicola , Zlitni Sahar , Khacharem Aimen , Boukhris Omar , El-Abed Kais , Ammar Achraf , Khanfir Saber , Shephard Roy J , Hakim Ahmed , Moalla Wassim , Chtourou Hamdi
Published: June 2019

Objective

To evaluate the effect of observing Ramadan on athletes’ sleep patterns.

Design

Systematic review and meta-analysis.

Data sources

The entire content of PubMed/MEDLINE and Web of Science.

Eligibility criteria for selecting studies

Single-group, prepost and cross-over design studies conducted in athletes aged ≥18 years, training at least twice a week and published in English before 12 July 2018 were included. Studies assessing sleep quantity, quality, daytime sleepiness and/or daily naps based on objective or subjective methods were deemed eligible.

Study appraisal

The methodological quality was assessed using ‘QualSyst’.

Results

Of 13 selected articles, 7 were of strong quality, 3 were moderate and 3 were weak. 11 studies evaluated total sleep time (TST); this decreased during Ramadan in 4 studies, increased in 1 and remained unchanged in 6. Pooled TST findings indicated a moderate effect size (− 0.97, SE=0.37, 95% CI −1.69 to −0.25, t=−2.64, p=0.01) with significant heterogeneity but no publication bias. Meta-regressions showed no effects of study year, age, sample size, type of sport or competition level, but there were effects of country (with France and Tunisia being the most affected countries and Turkey the least affected, Q=32.14, p<0.0001) and study design (Q=7.74, p=0.02). Four studies measured self-reported sleep quality and it decreased in three studies. One study of sleep architecture reported more frequent waking and more light sleep during Ramadan. Daily nap duration was increased in two studies, but daytime sleepiness remained unchanged in four studies.

Conclusion

When athletes continue to train at least two times/week while observing Ramadan, TST is decreased compared with athletes’ baseline levels.
Pre-post changes in main outcomes of medical rehabilitation in Germany: protocol of a systematic review and meta-analysis of individual participant and aggregated data
Authors: Schuler Michael , Murauer Kathrin , Stangl Stephanie , Grau Anna , Gabriel Katharina , Podger Lauren , Heuschmann Peter U , Faller Hermann
Published: June 2019

Introduction

Multidisciplinary, complex rehabilitation interventions are an important part of the treatment of chronic diseases. However, little is known about the effectiveness of routine rehabilitation interventions within the German healthcare system. Due to the nature of the social insurance system in Germany, randomised controlled trials examining the effects of rehabilitation interventions are challenging to implement and scarcely accessible. Consequently, alternative pre-post designs can be employed to assess pre-post effects of medical rehabilitation programmes. We present a protocol of systematic review and meta-analysis methods to assess the pre-post effects of rehabilitation interventions in Germany.

Methods and analysis

The respective study will be conducted within the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A systematic literature review will be conducted to identify studies reporting the pre-post effects (start of intervention vs end of intervention or later) in German healthcare. Studies investigating the following disease groups will be included: orthopaedics, rheumatology, oncology, pulmonology, cardiology, endocrinology, gastroenterology and psychosomatics. The primary outcomes of interest are physical/mental quality of life, physical functioning and social participation for all disease groups as well as pain (orthopaedic and rheumatologic patients only), blood pressure (cardiac patients only), asthma control (patients with asthma only), dyspnoea (patients with chronic obstructive pulmonary disease only) and depression/anxiety (psychosomatic patients only). We will invite the principal investigators of the identified studies to provide additional individual patient data. We aim to perform the meta-analyses using individual patient data as well as aggregate data. We will examine the effects of both study-level and patient-level moderators by using a meta-regression method.

Ethics and dissemination

Only studies that have received institutional approval from an ethics committee and present anonymised individual patient data will be included in the meta-analysis. The results will be presented in a peer-reviewed publication and at research conferences. A declaration of no objection by the ethics committee of the University of Würzburg is available (number 20180411 01).

Trial registration number

CRD42018080316.
GASS Trial study protocol: a multicentre, single-blind, randomised clinical trial comparing general anaesthesia and sedation during intra-arterial treatment for stroke
Authors: Maurice Axelle , Ferré Jean-Christophe , Ronzière Thomas , Devys Jean-Michel , Subileau Aurelie , Laffon Marc , Laviolle Bruno , Beloeil Helene
Published: June 2019

Introduction

Treatment of acute stroke has drastically changed in the last 10 years. Endovascular therapy is now the standard of care for patients with a stroke caused by a large vessel occlusion in the anterior circulation. The impact of the type of anaesthesia (general anaesthesia or conscious sedation) during endovascular therapy on the outcome of the patients is still a matter of debate. Previous studies are mostly retrospective and/or focused on the early postprocedure outcome and/or without blood pressure goals and/or single-centre small size studies. We therefore designed a multicentre study hypothesising that conscious sedation is associated with a better functional outcome 3 months after endovascular therapy for the treatment of stroke compared with general anaesthesia.

Methods/analysis

The General Anesthesia vs Sedation for Stroke (GASS) Trial is a randomised, parallel, single-blind, multicentre study of 350 patients undergoing endovascular therapy for the treatment of stroke. Patients will be randomly allocated to receive either a general anaesthesia or a conscious sedation. The primary outcome measure is the modified Rankin score assessed 3 months after the treatment. Data will be analysed on the intention-to-treat principle.

Ethics/dissemination

The GASS Trial has been approved by an independent ethics committee for all study centres. Participant recruitment begins in September 2016. Results will be published in international peer-reviewed medical journals.

Trial registration number

NCT02822144.
The feasibility and potential use of case-tracked client journeys in primary healthcare: a pilot study
Authors: Barton Elsa , Freeman Toby , Baum Fran , Javanparast Sara , Lawless Angela
Published: June 2019

Objectives

To determine the feasibility of case-tracking methods in documenting client journeys at primary healthcare (PHC) services in order to investigate the comprehensiveness of service responses and the experiences of clients.

Design

Prospective pilot study. Quantitative and qualitative case management data were collected from staff via questionnaire or interview.

Setting

Five Australian multidisciplinary PHC services were involved including four South Australian state-managed and one Northern Territory Aboriginal community-controlled PHC service.

Participants

Clients using services for depression (95) or diabetes (185) at the PHC services were case tracked over a 12-month period to allow construction of client journeys for these two conditions. Clients being tracked were invited to participate in two semi-structured interviews (21) and complete a health log.

Results

Though a number of challenges were encountered, the case-tracking methods were useful in documenting the complex nature of client journeys for those with depression or diabetes accessing PHC services and the need to respond to the social determinants of health. A flexible research design was crucial to respond to the needs of staff and changing organisational environments.

Conclusions

The client journeys provided important information about the services’ responses to depression and diabetes, and about aspects unique to comprehensive PHC such as advocacy and work that takes into account the social determinants of health.
Survey on female genital mutilation/cutting in Jeddah, Saudi Arabia
Authors: Rouzi Abdulrahim A , Berg Rigmor C , Alamoudi Rana , Alzaban Faten , Sehlo Mohammad
Published: June 2019

Objectives

The objective of this study was to determine whether female genital mutilation/cutting (FGM/C) exists in Jeddah, Saudi Arabia.

Design

A cross-sectional study.

Setting

King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

Participants

Between December 2016 and August 2017, women attending the obstetrics and gynaecology clinics were asked to participate in a cross-sectional survey. This included questions on demographics, FGM/C status and type and attitudes towards the practice.

Results

In a convenience sample of 963 women aged 18 to 75 years, 175 (18.2%) had undergone FGM/C. Compared with women without FGM/C, women with FGM/C were older, married, non-Saudi and had a lower monthly income. Thirty-seven (21.1%) women had had FGM/C with some cutting of body parts (type I or II), 11 (6.3%) with suturing (type III), 46 (26.3%) with no cutting of body parts (type IV) and 81 (46.3%) did not know their type of FGM/C. There was also a significant association between nationality and age at which FGM/C was performed, with Saudi women undergoing the procedure earlier than Egyptian, Somali, Yemeni and Sudanese women.

Conclusions

FGM/C is prevalent in Jeddah, Saudi Arabia, among immigrant women from other countries, and it is practised among Saudi women. Further research is needed to determine its prevalence.
Social support network typologies and their association with dementia and depression among older adults in Singapore: a cross-sectional analysis
Authors: Lau Ying Wen , Vaingankar Janhavi Ajit , Abdin Edimansyah , Shafie Saleha , Jeyagurunathan Anitha , Zhang Yunjue , Magadi Harish , Ng Li Ling , Chong Siow Ann , Subramaniam Mythily
Published: June 2019

Objectives

To examine the social support network type and its associations with depression and dementia among older adults in Singapore.

Design

This study is a cross-sectional analysis of data from the Well-being of the Singapore Elderly study. The Practitioner Assessment of Network Type was used to identify five social support network types. Odds Ratios (OR) of dementia and depression were estimated with logistic regression and multinomial logistic regression, respectively, adjusted for sociodemographic variables.

Setting

Singapore.

Outcome measures

10/66 criteria and Automated Geriatric Examination for Computer Assisted Taxonomy computer algorithm.

Participants

2421 older adults aged 60 years and above, and their informants.

Results

Logistic regression revealed that as compared with participants in the family dependent social support network type, those in the locally integrated social support network type were negatively associated with dementia. It was observed that it is the older adults’ perception of the quality of social interaction that influences the likelihood of depression.

Conclusion

The social support network typology presents knowledge about the older adults’ social network profile and their cognitive functioning-ability which would help stakeholders better identify older adults who might be at risk of cognitive decline or experiencing delay in diagnosis of dementia.
Supervision training interventions in the health and human services: realist synthesis protocol
Authors: Lee Sarah , Denniston Charlotte , Edouard Vicki , Palermo Claire , Pope Kirsty , Sutton Keith , Waller Susan , Ward Bernadette , Rees Charlotte
Published: June 2019

Introduction

Supervision training aims to develop workplace supervisory competencies. Despite extensive supervision literature, including literature reviews, the processes through which supervision training interventions produce their effects, for whom and under what circumstances is not clearly delineated. The purpose of this study is to explain the effect of contextual factors on the underpinning mechanisms of supervision training outcomes.

Methods and analysis

We propose to examine supervision training interventions across the health and human services workforce using realist methods. Pawson’s five stages for undertaking a realist synthesis will be followed: (1) clarifying the scope of the review; (2) determining the search strategy; (3) study selection; (4) extracting data and (5) synthesising the evidence and drawing conclusions. Extracted data will include study characteristics, characteristics of participant cohort, intervention type, contextual factors, underlying mechanisms and supervision training outcomes. Patterns in context–mechanism–outcome configurations will be identified. Initial programme theories will be developed based on a comprehensive search of the literature, which will include key terms relating to supervision and training. The search strategy will involve: (1) electronic database searching using Medline, Cumulative Index to Nursing and Allied Health Literature, Social Services Abstracts, Educational Resources Information Center, PsycINFO and Australian Public Affairs Information Service and (2) hand and citation searching. We will also contact authors where necessary and discuss identified literature among the project team with extensive expertise in supervision training.

Ethics and dissemination

The realist synthesis will propose an evidence-informed theory of supervision training interventions (ie, what interventions work for whom and why). The findings will be disseminated in peer-reviewed journals and presentations and through discussions with relevant organisations and stakeholders. The research will be used by educators to develop evidenced-based supervision training interventions. It will also help workplace supervisors to better understand what types of supervision training might work most optimally for them and their colleagues. Other researchers could use the synthesis findings to guide future supervision research.

PROSPERO registration number

CRD42018094186
Diagnostic strategies in general practice and the emergency department: a comparative qualitative analysis
Authors: Bösner Stefan , Abushi Jamal , Feufel Markus , Donner-Banzhoff Norbert
Published: June 2019

Objective

We sought to explore differences and commonalities between diagnostic strategies used by clinicians in general practice and the emergency department.

Design

Qualitative study.

Settings

We videotaped 282 consultations of 12 general practitioners (GPs) in Germany, irrespective of presenting complaint or final diagnosis. Reflective interviews were performed after each consultation. In addition, 171 consultations of 16 emergency physicians (EPs) based at two tertiary care hospitals in the Midwest of the USA were observed, and their conversations recorded. Recordings of consultations and GP interviews were transcribed verbatim and analysed using a coding system that was based on published literature and systematically checked for reliability.

Results

EPs more often considered acute and severe conditions, even if pretest probabilities were low. In contrast, GPs more often involved their patients in the decision-making process and provided assurance concerning their complaints. To focus their workup, EPs used a more directive style of interviewing including a high proportion of routine questions and rarely used open questions or active listening.

Conclusions

Strategies used by physicians in both settings seem to be well adapted to their respective environments. Whereas the physician-led diagnostic process in the emergency department is well suited to rule out life-threating disease, diagnosis and appropriate treatment of everyday problems may require a more patient-centred style.
Cluster randomised controlled trial of an m-health intervention in centre-based childcare services to reduce the packing of discretionary foods in children’s lunchboxes: study protocol for the ’SWAP IT Childcare' trial
Authors: Pond Nicole , Finch Meghan , Sutherland Rachel , Wolfenden Luke , Nathan Nicole , Kingsland Melanie , Grady Alice , Gillham Karen , Herrmann Vanessa , Yoong Sze Lin
Published: June 2019

Introduction

In many developed nations, including Australia, a substantial number of children aged under 5 years attend centre-based childcare services that require parents to pack food in lunchboxes. These lunchboxes often contain excessive amounts of unhealthy (‘discretionary’) foods. This study aims to assess the impact of a mobile health (m-health) intervention on reducing the packing of discretionary foods in children’s childcare lunchboxes.

Methods and analysis

A cluster randomised controlled trial will be undertaken with parents from 18 centre-based childcare services in the Hunter New England region of New South Wales, Australia. Services will be randomised to receive either a 4-month m-health intervention called ‘SWAP IT Childcare’ or usual care. The development of the intervention was informed by the Behaviour Change Wheel model and will consist primarily of the provision of targeted information, lunchbox food guidelines and website links addressing parent barriers to packing healthy lunchboxes delivered through push notifications via an existing app used by childcare services to communicate with parents and carers. The primary outcomes of the trial will be energy (kilojoules) from discretionary foods packed in lunchboxes and the total energy (kilojoules), saturated fat (grams), total and added sugars (grams) and sodium (milligrams) from all foods packed in lunchboxes. Outcomes will be assessed by weighing and photographing all lunchbox food items at baseline and at the end of the intervention.

Ethics and dissemination

The study was approved by the Hunter New England Local Health District Human Ethics Committee (06/07/26/4.04) and ratified by the University of Newcastle, Human Research Ethics Committee (H-2008–0343). Evaluation and process data collected as part of the study will be disseminated in peer-reviewed publications and local, national and international presentations and will form part of PhD student theses.

Trial registration number

ACTRN12618000133235; Pre-results.
Replacing meat with alternative plant-based products (RE-MAPs): protocol for a randomised controlled trial of a behavioural intervention to reduce meat consumption
Authors: Bianchi Filippo , Aveyard Paul , Astbury Nerys M , Cook Brian , Cartwright Emma , Jebb Susan A
Published: June 2019

Introduction

Reducing meat consumption could contribute towards preventing some chronic conditions and protecting the natural environment. This study will examine the effectiveness of a behavioural intervention to reduce meat consumption.

Methods and analyses

Replacing meat with alternative plant-based product is a randomised controlled trial comparing a behavioural intervention to reduce meat consumption with a no intervention control condition. Eligible volunteers will be recruited from the general public through advertisement and randomised in a 1:1 ratio to receive no intervention or a 4-week intervention comprising the provision of free plant-based meat alternatives, written information on the health and environmental benefits of eating less meat, success stories of people who reduced their meat consumption and recipes. The primary outcome is the change in meat consumption at 4 weeks (T1) from baseline. Secondary and exploratory outcomes include changes in meat consumption at 8 weeks (T2) from baseline and changes from the baseline to both follow-up in other aspects of participants diet, putative psychosocial determinants of eating a low meat diet and of using meat substitutes and biomarkers of health risk, including blood lipid profiles, blood pressure, weight and body composition. Linear models will be employed to explore whether the changes in each of the aforementioned outcomes differ significantly between the control and intervention group. Qualitative interviews on a subsample of participants receiving the intervention will evaluate their experiences of the intervention and help to identify the mechanisms through which the intervention reduced meat consumption or the barriers preventing the intervention to aid this dietary transition.

Ethics and dissemination

The trial has been granted ethical approval by the Medical Sciences Interdivisional Research Ethics Committee (IDREC) of the University of Oxford (Ref: R54329/RE001). All results originating from this study will be submitted for publication in scientific journals and presented at meetings and through the media.

Trial registration number

ISRCTN13180635;Pre-recruitment.
Hope for the best …but expect the worst: a qualitative study to explore how women with recurrent miscarriage experience the early waiting period of a new pregnancy
Authors: Bailey Sarah Louise , Boivin Jacky , Cheong Ying C , Kitson-Reynolds Ellen , Bailey Christopher , Macklon Nick
Published: June 2019

Objective

To investigate how women experience the initial period of a new pregnancy after suffering recurrent miscarriage (RM).

Design

A qualitative study, nested within a randomised controlled feasibility study of a coping intervention for RM, used semi-structured face-to-face interviews. Interviews were audio-recorded, transcribed verbatim and analysed using a thematic network approach.

Setting

Participants were recruited from the Recurrent Miscarriage Clinic and Early Pregnancy Unit in two tertiary referral hospitals in the UK.

Participants

14 women with RMs and who had previously participated in the randomised controlled trial (RCT) feasibility component of the study were recruited.

Results

Seven organising themes emerged from the data: (1) turmoil of emotions, (2) preparing for the worst, (3) setting of personal milestones, (4) hypervigilance, (5) social isolation, (6) adoption of pragmatic approaches, (7) need for professional affirmation.

Conclusions

The study established that for women with a history of RM, the waiting period of a new pregnancy is a traumatic time of great uncertainty and emotional turmoil and one in which they express a need for emotional support. Consideration should be given to the manner in which supportive care is best delivered within the constraints of current health service provision.

Trial registration number

ISRCTN43571276
Improving oral health through dental fluoride varnish application in a primary care paediatric practice
Authors: Sudhanthar Sathyanarayan , Lapinski Jillian , Turner Jane , Gold Jonathan , Sigal Yakov , Thakur Kripa , Napolova Olga , Stiffler Michael
Published: June 2019

Dental caries affect 97% of people during their lifetime. A total of 59% of children aged 12–19 will have at least one documented cavity. The American Academy of Pediatrics recommends fluoridated toothpaste to all children starting at tooth eruption, regardless of caries risk. Besides, fluoride varnish is recommended for all children every 3–6 months from tooth emergence until they have a permanent dental home. This project aimed to increase oral fluoride varnish application for children starting at 6 months or the time of tooth eruption up to 3 years of age by at least 50% over 18 months.

The stakeholders identified were physicians, nurses, medical assistants and the health information team. We obtained baseline data about oral health screening and fluoride varnish from both the clinic sites. The quality improvement (QI) project was based on Plan-Do-Study-Act (PDSA) cycles with a 6-month gap in-between the three cycles. For the first cycle, all medical staff members participated in 2-hour knowledge and skills training on dental caries and current recommendations on fluoride varnish. PDSA cycle 2 involved having automatic reminders for providers in electronic medical records. PDSA cycle 3 planned to have automatic fluoride orders for the recommended age groups. The QI team analysed the results after every 6 months, and improvements were made based on the input from data and medical staff.

The number of patients who had fluoride varnish applied increased from 14% (n=50) to 55% at the end of PDSA cycle 3. Administration of the varnish did not affect the flow of the patients in busy primary care practice. The rate of improvement was across all the age groups, providers and in both clinical sites. It is possible to adhere to the oral fluoride varnish guidelines in a busy primary care practice, which may help benefit young children who are at risk for caries.
Sexual and reproductive healthcare providers’ opinions on expansion of pharmacy-led provision of contraception
Authors: Boog Katie , Chen Zhong Eric , Cameron Sharon
Published: June 2019

Introduction

Reduced funding to contraceptive services in the UK is resulting in restricted access for women. Pharmacists are already embedded in sexual and reproductive health (SRH) care in the UK and could provide an alternative way for women to access contraception. The aim of this study was to determine the views of UK contraception providers about community pharmacist-led contraception provision.

Methods

An anonymous questionnaire was distributed to healthcare professionals at two UK SRH events, asking respondents about: (1) the use of patient group directions (PGDs) for pharmacist provision of oral contraception (OC); (2) the sale of OC as a pharmacy medicine or general sales list medicine; (3) the perceived impact of pharmacy provision of OC on broader SRH outcomes; and (4) if other contraceptive methods should be provided in pharmacies.

Results

Of 240 questionnaires distributed, 174 (72.5%) were returned. Respondents largely supported pharmacy-led provision of all non-uterine methods of contraception, excluding the contraceptive implant. Provision of the progestogen-only pill by PGD was most strongly supported (78% supported initiation). Respondents felt that the use of bridging (temporary) contraception would improve (103/144, 71.5%), use of effective contraception would increase (81/141, 57.4%), and unintended pregnancies would decline (71/130, 54.6%); but that use of long-acting reversible contraception would decrease (86/143, 60.1%). Perceived barriers included pharmacists’ capacity and competency to provide a full contraception consultation, safeguarding concerns, and women having to pay for contraception.

Conclusions

UK SRH providers were largely supportive of community pharmacy-led provision of contraception, with training and referral pathways being required to support contraception delivery by pharmacists.
British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis
Authors: Chapman Michael Huw , Thorburn Douglas , Hirschfield Gideon M , Webster George G J , Rushbrook Simon M , Alexander Graeme , Collier Jane , Dyson Jessica K , Jones David EJ , Patanwala Imran , Thain Collette , Walmsley Martine , Pereira Stephen P
Published: June 2019

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
KrasandLkb1mutations synergistically induce intraductal papillary mucinous neoplasm derived from pancreatic duct cells
Authors: Collet Louis , Ghurburrun Elsa , Meyers Nora , Assi Mohamad , Pirlot Boris , Leclercq Isabelle A , Couvelard Anne , Komuta Mina , Cros Jérôme , Demetter Pieter , Lemaigre Frédéric P , Borbath Ivan , Jacquemin Patrick
Published: June 2019

Objective

Pancreatic cancer can arise from precursor lesions called intraductal papillary mucinous neoplasms (IPMN), which are characterised by cysts containing papillae and mucus-producing cells. The high frequency ofKRASmutations in IPMN and histological analyses suggest that oncogenic KRAS drives IPMN development from pancreatic duct cells. However, induction ofKrasmutation in ductal cells is not sufficient to generate IPMN, and formal proof of a ductal origin of IPMN is still missing. Here we explore whether combining oncogenicKrasG12Dmutation with an additional gene mutation known to occur in human IPMN can induce IPMN from pancreatic duct cells.

Design

We created and phenotyped mouse models in which mutations inKrasand in the tumour suppressor gene liver kinase B1 (Lkb1/Stk11) are conditionally induced in pancreatic ducts using Cre-mediated gene recombination. We also tested the effect of β-catenin inhibition during formation of the lesions.

Results

ActivatingKrasG12Dmutation andLkb1inactivation synergised to induce IPMN, mainly of gastric type and with malignant potential. The mouse lesions shared several features with human IPMN. Time course analysis suggested that IPMN developed from intraductal papillae and glandular neoplasms, which both derived from the epithelium lining large pancreatic ducts. β-catenin was required for the development of glandular neoplasms and subsequent development of the mucinous cells in IPMN. Instead, the lack of β-catenin did not impede formation of intraductal papillae and their progression to papillary lesions in IPMN.

Conclusion

Our work demonstrates that IPMN can result from synergy betweenKrasG12Dmutation and inactivation of a tumour suppressor gene. The ductal epithelium can give rise to glandular neoplasms and papillary lesions, which probably both contribute to IPMN formation.
Higher left ventricular mass–wall stress–heart rate product and outcome in aortic valve stenosis
Authors: Gerdts Eva , Saeed Sahrai , Midtbø Helga , Rossebø Anne , Chambers John Boyd , Einarsen Eigir , Bahlmann Edda , Devereux Richard
Published: June 2019

Objective

Whether increased myocardial oxygen demand could help explain the association of left ventricular (LV) hypertrophy with higher adverse event rate in patients with aortic valve stenosis (AS) is unknown.

Methods

Data from 1522 patients with asymptomatic mostly moderate AS participating in the Simvastatin-Ezetimibe in AS study followed for a median of 4.3 years was used. High LV mass–wall stress–heart rate product was identified as >upper 95% CI limit in normal subjects. The association of higher LV mass–wall stress–heart rate product with major cardiovascular (CV) events, combined CV death and hospitalised heart failure and all-cause mortality was tested in Cox regression analyses, and reported as HR and 95% CI.

Results

High LV mass–wall stress–heart rate product was found in 19% at baseline, and associated with male sex, higher body mass index, hypertension, LV hypertrophy, more severe AS and lower LV ejection fraction (all p<0.01). Adjusting for these confounders in time-varying Cox regression analysis, 1 SD higher LV mass–wall stress–heart rate product was associated with higher HR of major CV events (HR 1.16(95% CI 1.06 to 1.29)), combined CV death and hospitalised heart failure (HR 1.29(95% CI 1.09 to 1.54)) and all-cause mortality (HR 1.34(95% CI 1.13 to 1.58), all p<0.01).

Conclusion

In patients with initially mild–moderate AS, higher LV mass–wall stress–heart rate product was associated with higher mortality and heart failure hospitalisation. Our results suggest that higher myocardial oxygen demand is contributing to the higher adverse event rate reported in AS patients with LV hypertrophy.

Trial registration number

NCT000092677;Post-results.
UK resilience to a chemical incident
Authors: Clarke Samuel Alexander , Weir A G A
Published: June 2019

Following the deliberate chemical attacks in Salisbury last year, a review of UK resilience to chemical incidence was undertaken. The scope was not limited to deliberate attacks, related to terrorism, but was to include non-deliberate and accidental events. Chemical incidents have wide-reaching consequences irrespective of whether they are deliberate or not. The effects of these incidents manifest themselves in terms of immediate health consequences and will also include economic, political and public health effects that may have a much longer impact than the initial disruption. The economic consequences of the Novichok attack were devastating to the local population and businesses in both the short term and the long term, being felt over a year later. This review discusses the effects of these incidents on infrastructure, healthcare provision, law and order, economics and government at a local, regional and national level. The NHS Emergency Preparedness, Resilience and Response Framework was reviewed, and this provides a basic outline of advice for local government to follow in the case of chemical incidents. However, the wider issues of interdepartmental co-operation and how to maintain a response in the long term require further thought. Moreover, the methods by which interagency and regional resilience is maintained in preparing for such an event require a clearer guideline.
Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
Authors: Karki Shakun , Farb Melissa G. , Sharma Vishva M. , Jash Sukanta , Zizza Elaina J. , Hess Donald T. , Carmine Brian , Carter Cullen O. , Pernar Luise I. , Apovian Caroline M. , Puri Vishwajeet , Gokce Noyan
Published: June 2019

Background

Pathophysiological mechanisms that connect obesity to cardiovascular disease are incompletely understood. FSP27 (Fat‐specific protein 27) is a lipid droplet‐associated protein that regulates lipolysis and insulin sensitivity in adipocytes. We unexpectedly discovered extensive
FSP
27 expression in human endothelial cells that is downregulated in association with visceral obesity. We sought to examine the functional role of
FSP
27 in the control of vascular phenotype.

Methods and Results

We biopsied paired subcutaneous and visceral fat depots from 61 obese individuals (body mass index 44±8 kg/m
2
, age 48±4 years) during planned bariatric surgery. We characterized depot‐specific
FSP
27 expression in relation to adipose tissue microvascular insulin resistance, endothelial function and angiogenesis, and examined differential effects of
FSP
27 modification on vascular function. We observed markedly reduced vasodilator and angiogenic capacity of microvessels isolated from the visceral compared with subcutaneous adipose depots. Recombinant
FSP
27 and/or adenoviral
FSP
27 overexpression in human tissue increased endothelial nitric oxide synthase phosphorylation and nitric oxide production, and rescued vasomotor and angiogenic dysfunction (
P
<0.05), while si
RNA
‐mediated
FSP
27 knockdown had opposite effects. Mechanistically, we observed that
FSP
27 interacts with vascular endothelial growth factor‐A and exerts robust regulatory control over its expression. Lastly, in a subset of subjects followed longitudinally for 12±3 months after their bariatric surgery, 30% weight loss improved metabolic parameters and increased angiogenic capacity that correlated positively with increased
FSP
27 expression (
r
=0.79,
P
<0.05).

Conclusions

Our data strongly support a key role and functional significance of
FSP
27 as a critical endogenous modulator of human microvascular function that has not been previously described.
FSP
27 may serve as a previously unrecognized regulator of arteriolar vasomotor capacity and angiogenesis which are pivotal in the pathogenesis of cardiometabolic diseases linked to obesity.
Therapeutic Effect of Targeting Branched‐Chain Amino Acid Catabolic Flux in Pressure‐Overload Induced Heart Failure
Authors: Chen Mengping , Gao Chen , Yu Jiayu , Ren Shuxun , Wang Menglong , Wynn R. Max , Chuang David T. , Wang Yibin , Sun Haipeng
Published: June 2019

Background

Branched‐chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied.

Methods and Results

BT2 (3,6‐dichlorobenzo[b]thiophene‐2‐carboxylic acid), a small‐molecule inhibitor of branched‐chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle‐treated mice, whereas the BT2‐treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity.

Conclusions

Our data provide the first proof‐of‐concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure.
Dietary Pattern Specific Protein Biomarkers for Cardiovascular Disease: A Cross‐Sectional Study in 2 Independent Cohorts
Authors: Warensjö Lemming Eva , Byberg Liisa , Stattin Karl , Ahmad Shafqat , Lind Lars , Elmståhl Sölve , Larsson Susanna C. , Wolk Alicja , Michaëlsson Karl
Published: June 2019

Background

Mechanisms related to the influence of diet on the development of cardiovascular disease are not entirely understood, and protein biomarkers may help to understand these pathways. Studies of biomarkers identified with multiplex proteomic methods and dietary patterns are largely lacking.

Methods and Results

Dietary patterns were generated through principal component analysis in 2 population‐based Swedish cohorts, the EpiHealth (EpiHealth study; n=20 817 men and women) and the SMCC (Swedish Mammography Cohort Clinical [n=4650 women]). A set of 184 protein cardiovascular disease biomarkers were measured with 2 high‐throughput, multiplex immunoassays. Discovery and replication multivariable linear regression analyses were used to investigate the associations between the principal component analysis–generated dietary patterns and the cardiovascular disease–associated protein biomarkers, first in the EpiHealth (n=2240) and then in the Swedish Mammography Cohort Clinical. Four main dietary patterns were identified in the EpiHealth, and 3 patterns were identified in the Swedish Mammography Cohort Clinical. The
healthy
and the
Western/traditional
patterns were found in both cohorts. In the EpiHealth, 57 protein biomarkers were associated with 3 of the dietary patterns, and 41 of these associations were replicated in the Swedish Mammography Cohort Clinical, with effect estimates ranging from 0.057 to 0.083 (
P
‐value range, 5.0×10
−2
–1.4×10
−9
) for each SD increase in the relative protein concentration. Independent associations were established between dietary patterns and the 21 protein biomarkers. Two proteins, myeloperoxidase and resistin, were associated with both the
healthy
and the
light meal
pattern but in opposite directions.

Conclusions

We have discovered and replicated independent associations between dietary patterns and 21 biomarkers linked to cardiovascular disease, which have a role in the pathways related to inflammation, endothelial and immune function, cell adhesion, and metabolism.
Early Rapid Decline in Kidney Function in Medically Managed Patients With Atherosclerotic Renal Artery Stenosis
Authors: Cooper Emily L. , Xie Yanmei , Nguyen Hanh , Brewster Pamela S. , Sholl Haden , Sharrett Megan , Ren Kaili , Chen Tian , Tuttle Katherine R. , Haller Steven T. , Jamerson Kenneth , Murphy Timothy P. , D'Agostino Ralph B. , Massaro Joseph M. , Henrich William , Cooper Christopher J. , Cutlip Donald E. , Dworkin Lance D. , Shapiro Joseph I.
Published: June 2019

Background

Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well understood.

Methods and Results

Patients enrolled in the medical therapy–only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (
RD
) in estimated glomerular filtration rate (
eGFR
), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy–only cohort,
eGFR
was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early
RD
. Baseline log cystatin C (odds ratio, 1.78 [1.11–2.85];
P
=0.02), age (odds ratio, 1.04 [1.00–1.07];
P
<0.05), and Chronic Kidney Disease Epidemiology Collaboration creatinine
eGFR
(odds ratio, 1.86 [1.15–3.0];
P
=0.01) were associated with an early
RD
. Despite continued medical therapy only, the
RD
group had an improvement in
eGFR
at 1 year (6.9%;
P
=0.04). The
RD
and nondecline groups were not significantly different for clinical events and all‐cause mortality (
P
=0.78 and
P
=0.76, respectively). Similarly, renal replacement therapy occurred in 1 of 66 (1.5%) of the
RD
patients and in 6 of 294 (2%) of the nondecline patients. The regression to the mean of improvement in
eGFR
at 1 year in the
RD
group was estimated at 5.8±7.1%.

Conclusions

Early rapid declines in kidney function may occur in patients with renal artery stenosis when medical therapy is initiated, and their clinical outcomes are comparable to those without such a decline, when medical therapy only is continued.
Senescent Kidney Cells in Hypertensive Patients Release Urinary Extracellular Vesicles
Authors: Santelli Adrian , Sun In O. , Eirin Alfonso , Abumoawad Abdelrhman M. , Woollard John R. , Lerman Amir , Textor Stephen C. , Puranik Amrutesh S. , Lerman Lilach O.
Published: June 2019

Background

Hypertension may be associated with renal cellular injury. Cells in distress release extracellular vesicles (
EV
s), and their numbers in urine may reflect renal injury. Cellular senescence, an irreversible growth arrest in response to a noxious milieu, is characterized by release of proinflammatory cytokines. We hypothesized that
EV
s released by senescent nephron cells can be identified in urine of patients with hypertension.

Methods and Results

We recruited patients with essential hypertension (
EH
) or renovascular hypertension and healthy volunteers (n=14 each). Renal oxygenation was assessed using magnetic resonance imaging and blood samples collected from both renal veins for cytokine‐level measurements.
EV
s isolated from urine samples were characterized by imaging flow cytometry based on specific markers, including p16 (senescence marker), calyxin (podocytes), urate transporter 1 (proximal tubules), uromodulin (ascending limb of Henle's loop), and prominin‐2 (distal tubules). Overall percentage of urinary p16+
EV
s was elevated in
EH
and renovascular hypertension patients compared with healthy volunteers and correlated inversely with renal function and directly with renal vein cytokine levels. Urinary levels of p16
+
/urate transporter 1
+
were elevated in all hypertensive subjects compared with healthy volunteers, whereas p16
+
/prominin‐2
+
levels were elevated only in
EH
versus healthy volunteers and p16
+
/uromodulin
+
in renovascular hypertension versus
EH
.

Conclusions

Levels of p16
+
EV
s are elevated in urine of hypertensive patients and may reflect increased proximal tubular cellular senescence. In
EH
,
EV
s originate also from distal tubules and in renovascular hypertension from Henle's loop. Hence, urinary
EV
s levels may be useful to identify intrarenal sites of cellular senescence.
A Novel Proangiogenic Function of Fsp27 in Endothelium: You Only Live Thrice?
Authors: Mineo Chieko
Published: June 2019

See Article
Karki et al