bluuebunny/crossref_metadata_2025 huggingface dataset:
Down‐regulation of interleukin‐33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression
Authors: Sung Hsin‐Yu , Chen Wei‐Yu , Huang Hui‐Ting , Wang Chih‐Yen , Chang Song‐Bin , Tzeng Shun‐Fen
Published: June 2019

Interleukin‐33 (IL‐33), a member of the IL1 family, has been found to be expressed in oligodendrocytes (OLGs) and released as an alarmin from injured OLGs to work on other glial cell‐types in the central nervous system. However, its functional role in OLGs remains unclear. Herein, we present that IL‐33 was mainly expressed in the nucleus of CC1+‐oligodendrocytes (OLGs) in mouse and rat corpus callosum, as well as NG2+‐oligodendrocyte precursor cells (OPCs). The in vitro study indicated that the amount of IL‐33 expressing in OPCs was higher when compared to that detected in OLGs. Results from the experiments using lentivirus‐mediated shRNA delivery against IL‐33 expression (IL33‐KD) in OPCs showed that IL33‐KD reduced the differentiation of OLGs into mature OLGs along with the down‐regulation of OLG differentiation‐related genes and mature OLG marker proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Alternatively, we observed reduced differentiation of OLGs that were prepared from the brains of IL‐33 gene knockout (IL33‐KO) mice with anxiolytic‐like behavior. Observations were correlated with the results showing lower levels of MBP and PLP in IL33‐KO cultures than those detected in the control cultures prepared from wildtype (WT) mice. Transmission Electron Microscopy (TEM) analysis revealed that the myelin structures in the corpus callosum of the IL33‐KO mice were impaired compared to those observed in the WT mice. Overall, this study provides important evidence that declined expression of IL‐33 in OPCs suppresses the maturation of OLGs. Moreover, gene deficiency of IL‐33 can disrupt OLG maturation and interfere with myelin compaction.

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Cover Image for this issue: doi: 10.1111/jnc.14522
Natural history of prediabetes in older adults from a population‐based longitudinal study
Authors: Shang Y. , Marseglia A. , Fratiglioni L. , Welmer A.‐K. , Wang R. , Wang H.‐X. , Xu W.
Published: June 2019

Background

The natural history of prediabetes in older adults remains unknown.

Objectives

To assess the rate at which prediabetes progresses to diabetes, leads to death or reverts to normoglycaemia in older adults and to identify prognostic factors related to different outcomes of prediabetes.

Methods

In the Swedish National Study on Aging and Care‐Kungsholmen, 2575 diabetes‐free participants aged ≥60 years were examined at baseline and followed for up to 12 years. At each wave, diabetes was diagnosed via medical examination, antidiabetic drug use, medical records or glycated haemoglobin (HbA1c) ≥6.5%. Prediabetes was defined as HbA1c ≥5.7% and normoglycaemia as HbA1c <5.7% in diabetes‐free participants. Data were analysed with multinomial logistic regression.

Results

At baseline, 918 (36%) individuals had prediabetes. Of them, 204 (22%) reverted to normoglycaemia (3.4/100 person‐years, 95% CI 5.6–12.3), 119 (13%) developed diabetes (2.0/100 person‐years, 95% CI 1.7–2.4) and 215 (23%) died (13.0/100 person‐years, 95% CI 11.4–14.9) during the 12‐year follow‐up. The rates of reversion, progression and mortality were higher in the first 6‐year than in the second 6‐year follow‐up, albeit not statistically significant. Lower systolic blood pressure (SBP), absence of heart diseases and weight loss promoted the reversion from prediabetes to normoglycaemia, whilst obesity accelerated its progression to diabetes.

Conclusions

During a 12‐year follow‐up, most of older adults with prediabetes remained stable or reverted to normoglycaemia, whereas only one‐third developed diabetes or died. Lower SBP, no heart diseases and weight management may promote reversion to normoglycaemia, suggesting possible strategies for achieving normoglycaemia in older adults with prediabetes.
Genetic diversity of hop stunt viroid from symptomatic and asymptomatic citrus trees in Iran
Authors: Vamenani Ramtin , Rahimian Heshmatollah , Alavi Seyyed Mohammad , Pakdin Parizi Ali , Mirza Razzaz Tarlan
Published: June 2019

Hop stunt viroid as the causal agent of cachexia disease has detected from citrus trees in different areas in Iran. Although cachexia has not been reported as a decline disease for citrus trees, it can impair crop quality and reduce plant yields. This study was undertaken to molecularly detect HSVd among different commercial citrus cultivars and determine genetic diversity of this viroid in Mazandaran province of Iran. Sampling was performed from symptomatic and symptomless citrus cultivars in Mazandaran province. HSVd specific primers were used for molecular detection. SSCP and sequencing were applied to assay HSVd genetic diversity. Results showed the detection of HSVd in all symptomatic Satsuma (25 out of 25), Clementine (25 out of 25), sweet lime (20 out of 20) and sweet orange cv. Valencia (7 out of 7), as well as, 31% (14 out of 22), 100% (12 out of 12) and 33% (5 out of 15) of page mandarin, lemon and grapefruit trees, respectively. 10 different HSVd genomes were identified by sequencing the SSCP profiles among which HSVd‐IR1 had the most frequency.
Parallel signaling pathways of pituitary adenylate cyclase activating polypeptide (PACAP) regulate several intrinsic ion channels
Authors: Johnson Gregory C. , May Victor , Parsons Rodney L. , Hammack Sayamwong E.
Published: June 2019

Pituitary adenylate cyclase activating polypeptide (PACAP), acting through its cognate receptors PAC1, VPAC1, and VPAC2, is a pleiotropic signaling neuropeptide of the vasoactive intestinal peptide/secretin/glucagon family. PACAP has known functions in neuronal growth, development, and repair, and central PACAP signaling has acute behavioral consequences. One of the ways in which PACAP may affect neuronal function is through the modulation of intrinsic membrane currents to control neuronal excitability. Here, we review the evidence of PACAP‐dependent modulation of calcium‐ and voltage‐gated potassium currents, hyperpolarization‐activated cation currents, calcium currents, and voltage‐gated sodium currents. Interestingly, PACAP signaling pathways diverge into parallel pathways to target different ionic currents for modulation, though single pathways are not limited to modulating just one target ionic current. Despite the various targets of modulation, the weight of the evidence suggests that PACAP signaling most commonly leads to a net increase in neuronal excitability. We discuss possible mechanisms by which PACAP signaling leads to the modulation of intrinsic membrane currents that may contribute to changes in behavior.
An Unusual Delayed Onset of Systemic Toxicity After Fluoroscopy‐Guided Cervical Epidural Steroid Injection With Levobupivacaine: A Case Report
Authors: Kang Hee Yong , Kim Jeong Eun , Kim Yun Jong , Park Sung Wook , Kim Youngsoon
Published: June 2019

Background

Cervical epidural steroid injection (CESI) with local anesthetics is commonly used to treat neck pain and radicular pain of the upper extremity. Local anesthetic systemic toxicity (LAST) occurs shortly after injection as a complication; however, delayed onset is a very rare event, especially in central nervous system (CNS) block.

Case report

We present a case in which delayed onset of LAST occurred in a patient who received CESI for cervical and arm radiating pain due to a cervical disc protrusion. We performed the interlaminar approach for CESI using fluoroscopic guidance. After confirming the location of the epidural space using the loss of resistance technique and spreading of contrast agent (Telebrix®30), a mixture of 0.25% levobupivacaine 12.5 mg (5 mL in volume), hyaluronidase 1,500 IU (1 mL), dexamethasone 5 mg (1 mL), and normal saline 3 mL was administrated. After 50 minutes of injection, the patient showed CNS toxicity (unconsciousness, seizure) with normal blood pressure and tachycardia; therefore, she was immediately sedated with intravenous midazolam (3 mg), and 15 L/min of oxygen was administered. The patient fully recovered after 30 minutes of sedation without any sequelae.

Conclusion

Delayed onset of LAST is a rare complication of a common procedure in CESI, so it is important to be aware of this complication and the presentation of toxicity.
The Dynamics of Self‐Governance Capacity: The Dutch Rural Civic Initiative ‘Project Ulrum 2034’
Authors: Ubels Hiska , Bock Bettina B. , Haartsen Tialda
Published: June 2019

In this article, we use Kooiman’s theory of governance in combination with key‐conditions of community self‐steering identified in recent studies to examine how the self‐steering capacity developed of a community initiative aiming at improving the liveability of a small Dutch village. Using non‐participatory observations and qualitative analysis, we obtained in‐depth insights into how this initiative, ‘Project Ulrum 2034’ managed to build local autonomy from 2010 to 2018. We found that government support was crucial for many of its successes. Also, tensions came to light between 1. local autonomy, and its dependence on professional support, and; 2. broader community engagement, and accountability related to the public funding obtained leading to the formalisation of its organisation and the centralisation of tasks. We discovered that self‐steering capacities fluctuate in time, are dynamic and develop in a non‐linear way. The voluntary engagement was above all temporary, except for some activities when of direct interest to those involved. The continuity of community self‐governance was fragile, due to its dependency on external funding and voluntary engagement.
Comparing the Effects of Single‐ and Multiple‐Component Therapies for Insomnia on Sleep Outcomes
Authors: Sidani Souraya , Epstein Dana R. , Fox Mary , Collins Laura
Published: June 2019

Background

Single‐ and multiple‐component therapies are recommended in professional guidelines for managing chronic insomnia. Systematic reviews point to insufficient evidence of the comparative effectiveness of these therapies, which is required for treatment decision making.

Purpose

To compare the effectiveness of three single‐component and one multiple‐component therapies on short‐term sleep outcomes.

Methods

The data were obtained from 517 persons with chronic insomnia, enrolled in a partially randomized preference trial. They were allocated to the single‐component therapies: sleep education and hygiene (SEH), stimulus control therapy (SCT), and sleep restriction therapy (SRT), or the multiple‐component therapy (MCT). The outcomes, perceived insomnia severity and sleep parameters, were assessed with established measures at pre and posttest. Repeated measure analysis of variance was used to compare the outcomes across therapy groups over time. The clinical relevance of the therapies’ effects was evaluated by examining the effect size and remission rate.

Results

The four therapies differed in their effectiveness in reducing perceived insomnia severity and improving sleep outcomes. SEH was least effective. SCT, SRT, and MCT were moderately effective. SCT and SRT demonstrated slightly higher remission rates than MCT for perceived insomnia severity and some sleep parameters.

Linking Evidence to Action

SCT and SRT are viable single‐component therapies that produce clinical benefits. Single‐component insomnia treatment may be more convenient to implement in the primary care setting due to the reduced number of treatment recommendations compared to MCT.
Fructose co‐ingestion to increase carbohydrate availability in athletes
Authors: Fuchs Cas J. , Gonzalez Javier T. , van Loon Luc J. C.
Published: June 2019

Carbohydrate availability is important to maximize endurance performance during prolonged bouts of moderate‐ to high‐intensity exercise as well as for acute post‐exercise recovery. The primary form of carbohydrates that are typically ingested during and after exercise are glucose (polymers). However, intestinal glucose absorption can be limited by the capacity of the intestinal glucose transport system (SGLT1). Intestinal fructose uptake is not regulated by the same transport system, as it largely depends on GLUT5 as opposed to SGLT1 transporters. Combining the intake of glucose plus fructose can further increase total exogenous carbohydrate availability and, as such, allow higher exogenous carbohydrate oxidation rates. Ingesting a mixture of both glucose and fructose can improve endurance exercise performance compared to equivalent amounts of glucose (polymers) only. Fructose co‐ingestion can also accelerate post‐exercise (liver) glycogen repletion rates, which may be relevant when rapid (<24 h) recovery is required. Furthermore, fructose co‐ingestion can lower gastrointestinal distress when relatively large amounts of carbohydrate (>1.2 g/kg/h) are ingested during post‐exercise recovery. In conclusion, combined ingestion of fructose with glucose may be preferred over the ingestion of glucose (polymers) only to help trained athletes maximize endurance performance during prolonged moderate‐ to high‐intensity exercise sessions and accelerate post‐exercise (liver) glycogen repletion.

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Rotor–Stator Interactions in a 2.5-Stage Axial Compressor—Part II: Impact of Aerodynamic Modeling on Forced Response
Authors: Sanders Christoph , Terstegen Marius , Jeschke Peter , Schoenenborn Harald , Heners Jan Philipp
Published: June 2019

The main objective of this study is the validation of numerical forced response predictions through experimental blade vibration measurements for higher order modes of a blade-integrated disk (blisk). To this end, a linearized and a nonlinear frequency domain CFD methods are used, as well as a tip timing measurement system. The focus is on the blade excitation by downstream vanes, in particular, because this study shows that the correct prediction of acoustic modes is of key importance in this case. The analysis of these modes is presented, both experimentally and numerically, in Part I of this publication. The grid independence study for the aerodynamic work on the blade surface conducted in this part shows a possible prediction uncertainty of more than 100% when a coarse grid is chosen. For the validation of the numerical setup, a study was performed using different turbulence and transition models. The results are compared to the measured performance map, to a 2D field traverse conducted with a pneumatic probe, and to data gained by unsteady pressure sensors mounted in the casing of the compressor. Flow features relevant for the prediction of blade stresses are best represented using the SST turbulence model in combination with the γ–ReΘ transition model. Nonlinear simulations with this setup are able to predict the blade stresses due to downstream excitation with an average difference of 23% compared to tip timing measurements. Single row linearized CFD methods have shown to be incapable of making a correct stress prediction when acoustic modes form a major part of the exciting mechanisms. In summary, this two-part publication proves the importance of acoustic rotor–stator interactions for blade vibrational stresses excited by downstream vanes in a state-of-the-art high-pressure compressor.
Effect of Sink Temperature on the Stability of the Pressure-Controlled Loop Heat Pipe
Authors: Joung Wukchul , Lee Joohyun
Published: June 2019

Recently, a novel temperature control technique utilizing the unique thermohydraulic operating principles of the pressure-controlled loop heat pipes (PCLHPs) was proposed and proved its effectiveness, by which a faster and more stable temperature control was possible by means of the pressure control. However, due to its recent emergence, the proposed hydraulic temperature control technique has not been fully characterized in terms of the various operating parameters including the sink temperature. In this work, the effect of the sink temperature on the loop heat pipe (LHP)-based hydraulic temperature control was investigated to improve the stability of the proposed technique. Start-up characteristics and transient responses of the operating temperatures to different pressure steps and sink temperatures were examined. From the test results, it was found that there was a minimum sink temperature, which ensured a steady-state operation after the start-up and a stable hydraulic temperature control with the increasing pressure steps, due to the unstable balance between the heat leak and the liquid subcooling in the compensation chamber at low sink temperatures. In addition, the range of the stable hydraulic temperature control was extended with the increasing coolant temperature due to the decreased heat leak, which resulted in the increased pressure difference between the evaporator and the compensation chamber. Therefore, it was found and suggested that for a stable hydraulic temperature control in an extended range, it was necessary to operate the PCLHP at higher sink temperatures than the low limit.
Atomic layer deposition of BN as a novel capping barrier for B2O3
Authors: Pilli Aparna , Jones Jessica , Chugh Natasha , Kelber Jeffry , Pasquale Frank , LaVoie Adrien
Published: June 2019

The deposition of boron oxide (B2O3) films on Si and SiO2 substrates by atomic layer deposition (ALD) is of growing interest in microelectronics for shallow doping of high aspect ratio transistor structures. B2O3, however, forms volatile boric acid (H3BO3) upon ambient exposure, requiring a passivation barrier, for which BN was investigated as a possible candidate. Here, the authors demonstrate in situ deposition of BN by sequential BCl3/NH3 reactions at 600 K on two different oxidized boron substrates: (a) B2O3 deposited using BCl3/H2O ALD on Si at 300 K (“B2O3/Si”) and (b) a boron-silicon oxide formed by sequential BCl3/O2 reactions at 650 K on SiO2 followed by annealing to 1000 K (“B-Si-oxide”). X-ray photoelectron spectroscopy (XPS) data demonstrate layer-by-layer growth of BN on B2O3/Si with an average growth rate of ∼1.4 Å/cycle, accompanied by some B2O3 removal during the first BN cycle. In contrast, continuous BN growth was observed on B-Si-oxide without any reaction with the substrate. XPS data also indicate that the oxide/nitride heterostructures are stable upon annealing in ultrahigh vacuum to >1000 K. XPS data, after the exposure of these heterostructures to ambient, indicate a small amount of BN oxidation at the surface NHx species, with no observable hydroxylation of the underlying oxide films. These results demonstrate that BN films, as thin as 13 Å, are potential candidates for passivating boron oxide films prepared for shallow doping applications.
Time domain room acoustic simulations using the spectral element method
Authors: Pind Finnur , Engsig-Karup Allan P. , Jeong Cheol-Ho , Hesthaven Jan S. , Mejling Mikael S. , Strømann-Andersen Jakob
Published: June 2019

This paper presents a wave-based numerical scheme based on a spectral element method, coupled with an implicit-explicit Runge-Kutta time stepping method, for simulating room acoustics in the time domain. The scheme has certain features which make it highly attractive for room acoustic simulations, namely (a) its low dispersion and dissipation properties due to a high-order spatio-temporal discretization; (b) a high degree of geometric flexibility, where adaptive, unstructured meshes with curvilinear mesh elements are supported; and (c) its suitability for parallel implementation on modern many-core computer hardware. A method for modelling locally reacting, frequency dependent impedance boundary conditions within the scheme is developed, in which the boundary impedance is mapped to a multipole rational function and formulated in differential form. Various numerical experiments are presented, which reveal the accuracy and cost-efficiency of the proposed numerical scheme.
Whistles emitted by Indo-Pacific humpback dolphins (Sousa chinensis) in Zhanjiang waters, China
Authors: Dong Lijun , Caruso Francesco , Lin Mingli , Liu Mingming , Gong Zining , Dong Jianchen , Cang Siyuan , Li Songhai
Published: June 2019

Whistles emitted by Indo-Pacific humpback dolphins in Zhanjiang waters, China, were collected by using autonomous acoustic recorders. A total of 529 whistles with clear contours and signal-to-noise ratio higher than 10 dB were extracted for analysis. The fundamental frequencies and durations of analyzed whistles were in ranges of 1785–21 675 Hz and 30–1973 ms, respectively. Six tonal types were identified: constant, downsweep, upsweep, concave, convex, and sine whistles. Constant type was the most dominant tonal type, accounting for 32.51% of all whistles, followed by sine type, accounting for 19.66% of all whistles. This paper examined 17 whistle parameters, which showed significant differences among the six tonal types. Whistles without inflections, gaps, and stairs accounted for 62.6%, 80.6%, and 68.6% of all whistles, respectively. Significant intraspecific differences in all duration and frequency parameters of dolphin whistles were found between this study and the study in Malaysia. Except for start frequency, maximum frequency and the number of harmonics, all whistle parameters showed significant differences between this study and the study conducted in Sanniang Bay, China. The intraspecific differences in vocalizations for this species may be related to macro-geographic and/or environmental variations among waters, suggesting a potential geographic isolation among populations of Indo-Pacific humpback dolphins.
Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance
Authors: Ferré Elise M. N. , Break Timothy J. , Burbelo Peter D. , Allgäuer Michael , Kleiner David E. , Jin Dakai , Xu Ziyue , Folio Les R. , Mollura Daniel J. , Swamydas Muthulekha , Gu Wenjuan , Hunsberger Sally , Lee Chyi-Chia R. , Bondici Anamaria , Hoffman Kevin W. , Lim Jean K. , Dobbs Kerry , Niemela Julie E. , Fleisher Thomas A. , Hsu Amy P. , Snow Laquita N. , Darnell Dirk N. , Ojaimi Samar , Cooper Megan A. , Bozzola Martin , Kleiner Gary I. , Martinez Juan C. , Deterding Robin R. , Kuhns Douglas B. , Heller Theo , Winer Karen K. , Rajan Arun , Holland Steven M. , Notarangelo Luigi D. , Fennelly Kevin P. , Olivier Kenneth N. , Lionakis Michail S.
Published: June 2019

AIRE deficiency causes a characteristic pattern of pulmonary immunopathology that is responsive to T and B lymphocyte–directed immunomodulation.
Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration
Authors: McDermott Anna M. , Herberg Samuel , Mason Devon E. , Collins Joseph M. , Pearson Hope B. , Dawahare James H. , Tang Rui , Patwa Amit N. , Grinstaff Mark W. , Kelly Daniel J. , Alsberg Eben , Boerckel Joel D.
Published: June 2019

Mechanical loading regulates mesenchymal condensation–mediated endochondral bone regeneration.
Supercharging adoptive T cell therapy to overcome solid tumor–induced immunosuppression
Authors: Mardiana Sherly , Solomon Benjamin J. , Darcy Phillip K. , Beavis Paul A.
Published: June 2019

Immune checkpoints can be targeted using exogenous reagents or via genetic modification to enhance the efficacy of adoptive T cell therapy.
Recurrent episodes of falls and amnestic confusional states as diagnostic challenge in the elderly
Authors: Novitskaya Yulia , Götz-Trabert Katrin , Schulze-Bonhage Andreas
Published: June 2019

New-onset paroxysmal events in patients over 60 years of age are often diagnostically challenging owing to atypical presentation. Recurrent falls and transient states of confusion are especially common in the elderly population, yet their causes often remain undiagnosed due to concomitant cognitive deficits and motor impairments. We present an elderly patient with newly occurring ‘blackouts’ without obvious triggers and transient states of confusion for which he was amnestic. All neurological exams including brain MRI scan and routine electroencephalography (EEG) were normal. Long-term ECG monitoring using an event recorder captured an asystole during a habitual episode, leading to the diagnosis of syncope and pacemaker implantation. A subsequent video EEG monitoring performed due to ongoing unexplained confusional states revealed both bradycardia and long-lasting confusional states to be caused by unrecognised temporal lobe seizures. Ictal video EEG monitoring may play a crucial role in establishing a diagnosis of atypical temporal lobe seizures in the elderly.
Petrified pinna and pericarditis in autoimmune polyendocrine syndrome
Authors: Sedhai Yub Raj , Basnyat Soney
Published: June 2019

Petrified pinna refers to the calcification or ossification of the external auricular cartilage. It is an uncommon clinical entity and is most often associated with local trauma, frostbite or inflammation. Auricular calcification may be the exclusive cutaneous marker of underlying endocrinopathy. It has been most commonly associated with adrenal insufficiency and other endocrine conditions like diabetes mellitus, hypothyroidism and acromegaly. We present a 47-year-old Caucasian man who presented with acute pericarditis with tamponade physiology, who was found to have petrified pinnae as a telltale sign of the underlying autoimmune polyendocrine syndrome type 2.
Maternal Immunization and Antenatal Care Situation Analysis (MIACSA) study protocol: a multiregional, cross-sectional analysis of maternal immunization delivery strategies to reduce maternal and neonatal morbidity and mortality
Authors: Roos Nathalie , Lambach Philipp , Mantel Carsten , Mason Elizabeth , Muñoz Flor M , Giles Michelle , Moran Allisyn , Hombach Joachim , Diaz Theresa
Published: June 2019

Introduction

Maternal immunization (MI) with tetanus toxoid containing vaccine, is a safe and cost-effective way of preventing neonatal tetanus. Given the prospect of introducing new maternal vaccines in the near future, it is essential to identify and understand current policies, practices and unmet needs for introducing and/or scaling up MI in low-income and middle-income countries (LMICs).

Methods and analysis

The Maternal Immunization and Antenatal Care Situation Analysis (MIACSA) is a mixed methods, cross-sectional study that will collect data in four phases: (1) a review of global databases for selected health indicators in 136 LMICs; (2) a structured online survey directed at Maternal, Newborn and Child Health and Expanded Programme on Immunization focal points in all 136 LMICs; (3) semistructured telephone interviews of 30 selected LMICs and (4) 10 week-long country visits, including key informant interviews, health facility visits and focus group discussions. The principal analyses will assess correlations between the various aspects of MI delivery strategies and proxy measures of health systems performance related to vaccine-preventable disease control. The primary outcome will be a typology of existing MI delivery models, and secondary outcomes will include country profiles of child and maternal health indicators, and a MI gaps and needs analysis.

Ethics and dissemination

The protocol was approved by the WHO Ethics Review Committee (ERC.0002908). The results will be made available in a project report and submitted for publication in peer-reviewed journals that will be shared broadly among global health decision-makers, researchers, product developers and country-level stakeholders.
Introducing a sector-wide pooled fund in a fragile context: mixed-methods evaluation of the health transition fund in Zimbabwe
Authors: D’Aquino Luigi , Pyone Thidar , Nigussie Assaye , Salama Peter , Gwinji Gerald , van den Broek Nynke
Published: June 2019

Introduction

Aid effectiveness and improving its impact is a central policy matter for donors and international organisations. Pooled funding is a mechanism, whereby donors provide financial contributions towards a common set of broad objectives by channelling finance through one instrument. The results of pooled funds as an aid mechanism are mixed, and there is limited data on both methodology for, and results of, assessment of effectiveness of pooled funding.

Methods

This study adapted a conceptual framework incorporating the Paris Principles of Aid Effectiveness and qualitative methods to assess the performance of the Health Transition Fund (HTF) Zimbabwe. 30 key informant interviews, and 20 focus group discussions were conducted with informants drawn from village to national level. Descriptive secondary data analysis of Demographic Health Surveys, Health Management Information Systems (HMIS) and policy reports complemented the study.

Results

The HTF combined the most optimal option to channel external aid to the health sector in Zimbabwe during a period of socioeconomic and political crisis. It produced results quickly and at scale and enhanced coordination and ownership at the national and subnational level. Flexibility in using the funds was a strong feature of the HTF. However, the initiative compromised on the investment in local capacity and systems, since the primary focus was on restoring essential services within a nearly collapsed healthcare system, rather than building long-term capacity. Significant changes in maternal and newborn health outcomes were observed during the HTF implementation in Zimbabwe.

Conclusion

A framework which can be used to assess pooled funds was adapted and applied. Future assessments could use this or another framework to provide new evidence regarding effectiveness of pool donor funds although the frameworks should be properly tested and adapted in different contexts.
Unintended discontinuation of medication following hospitalisation: a retrospective cohort study
Authors: Redmond Patrick , McDowell Ronald , Grimes Tamasine C , Boland Fiona , McDonnell Ronan , Hughes Carmel , Fahey Tom
Published: June 2019

Objectives

Whether unintended discontinuation of common, evidence-based, long-term medication occurs after hospitalisation; what factors are associated with unintended discontinuation; and whether the presence of documentation of medication at hospital discharge is associated with continuity of medication in general practice.

Design

Retrospective cohort study between 2012 and 2015.

Setting

Electronic records and hospital supplied discharge notifications in 44 Irish general practices.

Participants

20 488 patients aged 65 years or more prescribed long-term medication for chronic conditions.

Primary and secondary outcomes

Discontinuity of four evidence-based medication drug classes: antithrombotic, lipid-lowering, thyroid replacement drugs and respiratory inhalers in hospitalised versus non-hospitalised patients; patient and health system factors associated with discontinuity; impact of the presence of medication in the hospital discharge summary on continuity of medication in a patient’s general practitioner (GP) prescribing record at 6 months follow-up.

Results

In patients admitted to hospital, medication discontinuity ranged from 6%–11% in the 6 months posthospitalisation. Discontinuity of medication is significantly lower for hospitalised patients taking respiratory inhalers (adjusted OR (AOR) 0.63, 95% CI (0.49 to 0.80), p<0.001) and thyroid medications (AOR 0.62, 95% CI (0.40 to 0.96), p=0.03). There is no association between discontinuity of medication and hospitalisation for antithrombotics (AOR 0.95, 95% CI (0.81 to 1.11), p=0.49) or lipid lowering medications (AOR 0.92, 95% CI (0.78 to 1.08), p=0.29). Older patients and those who paid to see their GP were more likely to experience increased odds of discontinuity in all four medicine groups. Less than half (39% to 47.4%) of patients had medication listed on their hospital discharge summary. Presence of medication on hospital discharge summary is significantly associated with continuity of medication in the GP prescribing record for lipid lowering medications (AOR 1.64, 95% CI (1.15 to 2.36), p=0.01) and respiratory inhalers (AOR 2.97, 95% CI (1.68 to 5.25), p<0.01).

Conclusion

Discontinuity of evidence-based long-term medication is common. Increasing age and private medical care are independently associated with a higher risk of medication discontinuity. Hospitalisation is not associated with discontinuity but less than half of hospitalised patients have medication recorded on their hospital discharge summary.
Evaluation protocol of the implementation of a learning healthcare system in clinical practice: the Connected Health Cities programme in the north of England
Authors: Steels Stephanie , van Staa Tjeerd
Published: June 2019

Introduction

The ‘learning healthcare system’ (LHS) has been proposed to deliver better outcomes for patients and communities by analysing routinely captured health information and feeding back results to clinical staff. This approach is being piloted in the Connected Health Cities (CHC) programme in four regions in the north of England. This article describes the protocol of the evaluation of this programme.

Methods and analysis

In designing this evaluation, we had to take a pragmatic approach to ensure the feasibility of completing the work within 1 year. Furthermore, we have designed the evaluation in such a way as to be able to capture differences in how each of the CHC regions uses a variety of methods to create their own LHS. A mixed methods approach has been adopted for this evaluation due the scale and complexities of the pilot study. A documentary review will identify how CHC pilot study deliverables were operationalised. To gain a broad understanding of CHC staff experiences, an online survey will be offered to all staff to complete. Semi-structured interviews with key programme staff will be used to gain a deeper understanding of key achievements, as well as how challenges have been overcome or managed. Our data analysis will triangulate the documentary review, survey and interview data. A thematic analysis using our logic model as a framework will also be used to assess progress against the CHC programme deliverables and to identify recommendations to support future programme decision-making.

Ethics and dissemination

Ethical approval was granted by The University of Manchester Ethics Committee on 24 May 2018. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media, the internet and various stakeholder/patient and public engagement activities.
Magnitude and modifiers of the weekend effect in hospital admissions: a systematic review and meta-analysis
Authors: Chen Yen-Fu , Armoiry Xavier , Higenbottam Caroline , Cowley Nicholas , Basra Ranjna , Watson Samuel Ian , Tarrant Carolyn , Boyal Amunpreet , Sutton Elizabeth , Wu Chia-Wei , Aldridge Cassie P , Gosling Amy , Lilford Richard , Bion Julian
Published: June 2019

Objective

To examine the magnitude of the weekend effect, defined as differences in patient outcomes between weekend and weekday hospital admissions, and factors influencing it.

Design

A systematic review incorporating Bayesian meta-analyses and meta-regression.

Data sources

We searched seven databases including MEDLINE and EMBASE from January 2000 to April 2015, and updated the MEDLINE search up to November 2017. Eligibility criteria: primary research studies published in peer-reviewed journals of unselected admissions (not focusing on specific conditions) investigating the weekend effect on mortality, adverse events, length of hospital stay (LoS) or patient satisfaction.

Results

For the systematic review, we included 68 studies (70 articles) covering over 640 million admissions. Of these, two-thirds were conducted in the UK (n=24) or USA (n=22). The pooled odds ratio (OR) for weekend mortality effect across admission types was 1.16 (95% credible interval 1.10 to 1.23). The weekend effect appeared greater for elective (1.70, 1.08 to 2.52) than emergency (1.11, 1.06 to 1.16) or maternity (1.06, 0.89 to 1.29) admissions. Further examination of the literature shows that these estimates are influenced by methodological, clinical and service factors: at weekends, fewer patients are admitted to hospital, those who are admitted are more severely ill and there are differences in care pathways before and after admission. Evidence regarding the weekend effect on adverse events and LoS is weak and inconsistent, and that on patient satisfaction is sparse. The overall quality of evidence for inferring weekend/weekday difference in hospital care quality from the observed weekend effect was rated as ‘very low’ based on the Grading of Recommendations, Assessment, Development and Evaluations framework.

Conclusions

The weekend effect is unlikely to have a single cause, or to be a reliable indicator of care quality at weekends. Further work should focus on underlying mechanisms and examine care processes in both hospital and community.

Prospero registration number

CRD42016036487
Staying Quit After Release (SQuARe) trial protocol: a randomised controlled trial of a multicomponent intervention to maintain smoking abstinence after release from smoke-free prisons in Victoria, Australia
Authors: Young Jesse T , Puljević Cheneal , Love Alexander D , Janca Emilia K , Segan Catherine J , Baird Donita , Whiffen Rachel , Pappos Stan , Bell Emma , Kinner Stuart A
Published: June 2019

Introduction

Smoke-free policies have been introduced in prisons internationally. However, high rates of relapse to smoking after release from prison indicate that these policies typically result in short-term smoking cessation only. These high rates of relapse, combined with a lack of investment in relapse prevention, highlight a missed opportunity to improve the health of a population who smoke tobacco at two to six times the rate of the general population. This paper describes the rationale and design of a randomised controlled trial, testing the effectiveness of a caseworker-delivered intervention promoting smoking cessation among former smokers released from smoke-free prisons in Victoria, Australia.

Methods and analysis

The multicomponent, brief intervention consists of behavioural counselling, provision of nicotine spray and referral to Quitline and primary care to promote use of government-subsidised smoking cessation pharmacotherapy. The intervention is embedded in routine service delivery and is administered at three time points: one prerelease and two postrelease from prison. Control group participants will receive usual care. Smoking abstinence will be assessed at 1 and 3 months postrelease, and confirmed with carbon monoxide breath testing. Linkage of participant records to survey and routinely collected administrative data will provide further information on postrelease use of health services and prescribed medication.

Ethics and dissemination

Ethical approval has been obtained from the Corrections Victoria Research Committee, the Victorian Department of Justice Human Research Ethics Committee, the Department of Human Services External Request Evaluation Committee and the University of Melbourne Human Research Ethics Committee. Results will be submitted to major international health-focused journals. In case of success, findings will assist policymakers to implement urgently needed interventions promoting the maintenance of prison-initiated smoking abstinence after release, to reduce the health disparities experienced by this marginalised population.

Trial registration number

ACTRN12618000072213; Pre-results.
Defining certainty of net benefit: a GRADE concept paper
Authors: Alper Brian S , Oettgen Peter , Kunnamo Ilkka , Iorio Alfonso , Ansari Mohammed Toseef , Murad M Hassan , Meerpohl Joerg J , Qaseem Amir , Hultcrantz Monica , Schünemann Holger J , Guyatt Gordon
Published: June 2019

Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology is used to assess and report certainty of evidence and strength of recommendations. This GRADE concept article is not GRADE guidance but introduces certainty of net benefit, defined as the certainty that the balance between desirable and undesirable health effects is favourable. Determining certainty of net benefit requires considering certainty of effect estimates, the expected importance of outcomes and variability in importance, and the interaction of these concepts. Certainty of net harm is the certainty that the net effect is unfavourable. Guideline panels using or testing this approach might limit strong recommendations to actions with a high certainty of net benefit or against actions with a moderate or high certainty of net harm. Recommendations may differ in direction or strength from that suggested by the certainty of net benefit or harm when influenced by cost, equity, acceptability or feasibility.
Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for a multicentre, randomised, placebo-controlled study
Authors: Hendricks Oliver , Andersen Tonny Elmose , Christiansen Afshin Ashouri , Primdahl Jette , Hauge Ellen Margrethe , Ellingsen Torkell , Horsted Tina Ingrid , Bachmann Anja Godske , Loft Anne Gitte , Bojesen Anders Bo , Østergaard Mikkel , Lund Hetland Merete , Krogh Niels Steen , Roessler Kirsten Kaya , Petersen Kim Hørslev
Published: June 2019

Introduction

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, systemic, inflammatory diseases, primarily in the musculoskeletal system. Pain and fatigue are key symptoms of RA and AS. Treatment presents a clinical challenge for several reasons, including the progressive nature of the diseases and the involvement of multiple pain mechanisms. Moreover, side effects of pain treatment pose an implicit risk. Currently, no well-controlled studies have investigated how medical cannabis affects pain and cognitive functions in RA and AS. The present study aims to evaluate the efficacy and safety of medical cannabis in the treatment of persistent pain in patients with RA and AS with low disease activity.

Methods and analysis

A double-blinded, randomised, placebo-controlled study of cannabidiol (CBD), followed by an open label add-on of tetrahydrocannabinol (THC) with collection of clinical data and biological materials in RA and AS patients treated in routine care. The oral treatment with CBD in the experimental group is compared with placebo in a control group for 12 weeks, followed by an observational 12-week period with an open label add-on of THC in the primary CBD non-responders. Disease characteristics, psychological parameters, demographics, comorbidities, lifestyle factors, blood samples and serious adverse events are collected at baseline, after 12 and 24 weeks of treatment, and at a follow-up visit at 36 weeks. Data will be analysed in accordance with a predefined statistical analysis plan.

Ethics and dissemination

The Danish Ethics Committee (S-20170217), the Danish Medicines Agency (S-2018010018) and the Danish Data Protection Agency approved the protocol. The project is registered in the European Clinical Trials Database (EudraCT 2017-004226-15). All participants will give written informed consent to participate prior to any study-related procedures. The results will be presented at international conferences and published in peer-reviewed journals.
Evaluation of the impact of the NICE head injury guidelines on inpatient mortality from traumatic brain injury: an interrupted time series analysis
Authors: Marincowitz Carl , Lecky Fiona , Allgar Victoria , Sheldon Trevor
Published: June 2019

Objective

To evaluate the impact of National Institute for Health and Care Excellence (NICE) head injury guidelines on deaths and hospital admissions caused by traumatic brain injury (TBI).

Setting

All hospitals in England between 1998 and 2017.

Participants

Patients admitted to hospital or who died up to 30 days following hospital admission with International Classification of Diseases (ICD) coding indicating the reason for admission or death was TBI.

Intervention

An interrupted time series analysis was conducted with intervention points when each of the three guidelines was introduced. Analysis was stratified by guideline recommendation specific age groups (0–15, 16–64 and 65+).

Outcome measures

The monthly population mortality and admission rates for TBI.

Study design

An interrupted time series analysis using complete Office of National Statistics cause of death data linked to hospital episode statistics for inpatient admissions in England.

Results

The monthly TBI mortality and admission rates in the 65+ age group increased from 0.5 to 1.5 and 10 to 30 per 100 000 population, respectively. The increasing mortality rate was unaffected by the introduction of any of the guidelines.

The introduction of the second NICE head injury guideline was associated with a significant reduction in the monthly TBI mortality rate in the 16–64 age group (-0.005; 95% CI: −0.002 to −0.007).

In the 0–15 age group the TBI mortality rate fell from around 0.05 to 0.01 per 100 000 population and this trend was unaffected by any guideline.

Conclusion

The introduction of NICE head injury guidelines was associated with a reduced admitted TBI mortality rate after specialist care was recommended for severe TBI. The improvement was solely observed in patients aged 16–64 years.

The cause of the observed increased admission and mortality rates in those 65+ and potential treatments for TBI in this age group require further investigation.
Improving the effectiveness of cancer multidisciplinary team meetings: analysis of a national survey of MDT members’ opinions about streamlining patient discussions
Authors: Hoinville Linda , Taylor Cath , Zasada Magda , Warner Ross , Pottle Emma , Green James
Published: June 2019

Background

Cancer is diagnosed and managed by multidisciplinary teams (MDTs) in the UK and worldwide, these teams meet regularly in MDT meetings (MDMs) to discuss individual patient treatment options. Rising cancer incidence and increasing case complexity have increased pressure on MDMs. Streamlining discussions has been suggested as a way to enhance efficiency and to ensure high-quality discussion of complex cases.

Methods

Secondary analysis of quantitative and qualitative data from a national survey of 1220 MDT members regarding their views about streamlining MDM discussions.

Results

The majority of participants agreed that streamlining discussions may be beneficial although variable interpretations of ‘streamlining’ were apparent. Agreement levels varied significantly by tumour type and occupational group. The main reason for opposing streamlining were concerns about the possible impact on the quality and safety of patient care. Participants suggested a range of alternative approaches for improving efficiency in MDMs in addition to the use of treatment protocols and pre-MDT meetings.

Conclusions

This work complements previous analyses in supporting the development of tumour-specific guidance for streamlining MDM discussions considering a range of approaches. The information provided about the variation in opinions between MDT for different tumour types will inform the development of these guidelines. The evidence for variation in opinions between those in different occupational groups and the reasons underlying these opinions will facilitate their implementation. The impact of any changes in MDM practices on the quality and safety of patient care requires evaluation.
Curriculum review: serrated lesions of the colorectum
Authors: Dhillon Angad Singh , Ibraheim Hajir , Green Susi , Suzuki Noriko , Thomas-Gibson Siwan , Wilson Ana
Published: June 2019

Colorectal cancer (CRC) is the second leading cause of death from cancer in the UK. Sporadic CRC evolves by the cumulative effect of genetic and epigenetic alterations. Typically, over the course of several years, this leads to the transformation of normal colonic epithelium to benign adenomatous polyp, low-grade to high-grade dysplasia and finally cancer—the adenoma-carcinoma sequence. Over the last decade, the serrated neoplasia pathway which progresses by methylation of tumour suppressing genes has been increasingly recognised as an important alternative pathway accounting for up to 30% of CRC cases. Endoscopists should be aware of the unique features of serrated lesions so that their early detection, appropriate resection and surveillance interval can be optimised.