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1.  The Ubiquitin Ligase Nedd4-1 Participates in Denervation-Induced Skeletal Muscle Atrophy in Mice 
PLoS ONE  2012;7(10):e46427.
Skeletal muscle atrophy is a consequence of muscle inactivity resulting from denervation, unloading and immobility. It accompanies many chronic disease states and also occurs as a pathophysiologic consequence of normal aging. In all these conditions, ubiquitin-dependent proteolysis is a key regulator of the loss of muscle mass, and ubiquitin ligases confer specificity to this process by interacting with, and linking ubiquitin moieties to target substrates through protein∶protein interaction domains. Our previous work suggested that the ubiquitin-protein ligase Nedd4-1 is a potential mediator of skeletal muscle atrophy associated with inactivity (denervation, unloading and immobility). Here we generated a novel tool, the Nedd4-1 skeletal muscle-specific knockout mouse (myoCre;Nedd4-1flox/flox) and subjected it to a well validated model of denervation induced skeletal muscle atrophy. The absence of Nedd4-1 resulted in increased weights and cross-sectional area of type II fast twitch fibres of denervated gastrocnemius muscle compared with wild type littermates controls, at seven and fourteen days following tibial nerve transection. These effects are not mediated by the Nedd4-1 substrates MTMR4, FGFR1 and Notch-1. These results demonstrate that Nedd4-1 plays an important role in mediating denervation-induced skeletal muscle atrophy in vivo.
PMCID: PMC3482220  PMID: 23110050
2.  An analysis of relative costs and potential benefits of different policies for antenatal screening for beta thalassaemia trait and variant haemoglobins. 
Journal of Clinical Pathology  1999;52(9):697-700.
AIMS: To investigate the costs and potential benefits of different policies for antenatal screening for haemoglobinopathies in two multiethnic London communities. METHODS: 1000 consecutive antenatal patient samples referred to each of two London teaching hospital laboratories for haemoglobinopathy testing were investigated using the standard procedures of the laboratory in question. When the standard procedures did not include high performance liquid chromatography (HPLC), this technique was added, in order to assess its diagnostic value and cost-effectiveness. A comparison was made between the costs and potential benefits of universal testing for variant haemoglobins and beta thalassaemia trait using HPLC and the costs and potential benefits of universal testing for variant haemoglobins and selective testing for beta thalassaemia trait using the mean cell haemoglobin (MCH) as a screening test and less automated techniques than HPLC for definitive diagnosis. RESULTS: The costs of the two policies were found to be comparable, as the higher reagent/instrument costs of HPLC were offset by the lower labour costs. Universal testing of 2000 consecutive samples did not disclose any extra cases of beta thalassaemia trait which would not have been detected by universal screening and selective testing. However, six patients were found to have a haemoglobin A2 variant which can interfere with the diagnosis of beta thalassaemia trait. CONCLUSIONS: The introduction of universal testing by HPLC into British laboratories could be cost neutral and has potential benefits. If a higher cost is accepted then the greater degree of automation could be used to release skilled staff for other tasks within the laboratory.
PMCID: PMC501549  PMID: 10655995
5.  Knowledge and preferences concerning acute HIV testing programs among both Peruvian men who have sex with men and transgender women 
International journal of STD & AIDS  2017;28(10):1010-1017.
Immediate antiretroviral therapy (ART) for acute HIV infection (AHI) may decrease HIV transmission in high-risk populations. This study evaluated knowledge of AHI and AHI testing program preferences in Lima, Peru through four semi-structured focus groups with high-risk men who have sex with men (MSM) (n = 20) and transgender women (TW) (n = 16). Using content analysis, emergent themes included knowledge of AHI symptoms, AHI transmission potential, and the HIV testing window period, and preferences concerning point of care results. Participants demonstrated low familiarity with the term AHI, but many correctly identified AHI symptoms. However, these symptoms may not motivate testing because they overlap with common viral illnesses and AIDS. Some were aware that infectiousness is highest during AHI, and believe this knowledge would facilitate HIV testing. The shortened window period with AHI testing would encourage testing following high-risk sex. Delayed result notification would not decrease AHI testing demand among MSM, although it might for some TW.
PMCID: PMC5526724  PMID: 28056724
Acute HIV infection; HIV testing; Latin America; men who have sex with men; transgender women
6.  Designing a more efficient, effective and safe Medical Emergency Team (MET) service using data analysis 
PLoS ONE  2017;12(12):e0188688.
Hospitals have seen a rise in Medical Emergency Team (MET) reviews. We hypothesised that the commonest MET calls result in similar treatments. Our aim was to design a pre-emptive management algorithm that allowed direct institution of treatment to patients without having to wait for attendance of the MET team and to model its potential impact on MET call incidence and patient outcomes.
Data was extracted for all MET calls from the hospital database. Association rule data mining techniques were used to identify the most common combinations of MET call causes, outcomes and therapies.
There were 13,656 MET calls during the 34-month study period in 7936 patients. The most common MET call was for hypotension [31%, (2459/7936)]. These MET calls were strongly associated with the immediate administration of intra-venous fluid (70% [1714/2459] v 13% [739/5477] p<0.001), unless the patient was located on a respiratory ward (adjusted OR 0.41 [95%CI 0.25–0.67] p<0.001), had a cardiac cause for admission (adjusted OR 0.61 [95%CI 0.50–0.75] p<0.001) or was under the care of the heart failure team (adjusted OR 0.29 [95%CI 0.19–0.42] p<0.001).
Modelling the effect of a pre-emptive management algorithm for immediate fluid administration without MET activation on data from a test period of 24 months following the study period, suggested it would lead to a 68.7% (2541/3697) reduction in MET calls for hypotension and a 19.6% (2541/12938) reduction in total METs without adverse effects on patients.
Routinely collected data and analytic techniques can be used to develop a pre-emptive management algorithm to administer intravenous fluid therapy to a specific group of hypotensive patients without the need to initiate a MET call. This could both lead to earlier treatment for the patient and less total MET calls.
PMCID: PMC5744916  PMID: 29281665
7.  Impact of a Graduated Approach on Opioid Initiation and Loss of Earnings Following Workplace Injury 
The aim of this study was to explore the impact of the Ontario Workplace Safety and Insurance Board's (WSIB's) graduated approach to opioid management on opioid prescribing and disability claim duration.
We studied patterns of opioid use and disability claim duration among Ontarians who received benefits through the WSIB between 2002 and 2013. We used interventional time series analysis to assess the impact of the WSIB graduated formulary on these trends.
After the introduction of the graduated formulary, initiation of short- and long-acting opioids fell significantly (P < 0.0001). We also observed a shift toward the use of short-acting opioids alone (P < 0.0001). Although disability claim duration declined, this could not be ascribed to the intervention (P = 0.18).
A graduated opioid formulary may be an effective tool for providers to promote more appropriate opioid prescribing.
PMCID: PMC5732644  PMID: 29216018
8.  Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition 
Cancer cell  2016;30(6):879-890.
Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, reverse-engineering precision cancer prevention.
Graphical Abstract
PMCID: PMC5161110  PMID: 27960085
9.  Optimizing household survey methods to monitor the Sustainable Development Goals targets 6.1 and 6.2 on drinking water, sanitation and hygiene: A mixed-methods field-test in Belize 
PLoS ONE  2017;12(12):e0189089.
The Sustainable Development Goals (SDGs) require household survey programmes such as the UNICEF-supported Multiple Indicator Cluster Surveys (MICS) to enhance data collection to cover new indicators. This study aims to evaluated methods for assessing water quality, water availability, emptying of sanitation facilities, menstrual hygiene management and the acceptability of water quality testing in households which are key to monitoring SDG targets 6.1 and 6.2 on drinking Water, Sanitation and Hygiene (WASH) and emerging issues.
As part of a MICS field test, we interviewed 429 households and 267 women age 15–49 in Stann Creek, Belize in a split-sample experiment. In a concurrent qualitative component, we conducted focus groups with interviewers and cognitive interviews with respondents during and immediately following questionnaire administration in the field to explore their question comprehension and response processes.
About 88% of respondents agreed to water quality testing but also desired test results, given the potential implications for their own health. Escherichia coli was present in 36% of drinking water collected at the source, and in 47% of samples consumed in the household. Both questions on water availability necessitated probing by interviewers. About one quarter of households reported emptying of pit latrines and septic tanks, though one-quarter could not provide an answer to the question. Asking questions on menstrual hygiene was acceptable to respondents, but required some clarification and probing.
In the context of Belize, this study confirmed the feasibility of collecting information on the availability and quality of drinking water, emptying of sanitation facilities and menstrual hygiene in a multi-purpose household survey, indicating specific areas to improve question formulation and field protocols. Improvements have been incorporated into the latest round of MICS surveys which will be a major source of national data for monitoring of SDG targets for drinking water, sanitation and hygiene and emerging issues for WASH sector programming.
PMCID: PMC5720699  PMID: 29216244
10.  Sleep problems and hypothalamic dopamine D3 receptor availability in Parkinson disease 
Neurology  2016;87(23):2451-2456.
To investigate the relationship between hypothalamic D3 dopamine receptor availability and severity of sleep problems in Parkinson disease (PD).
Twelve patients were assessed with PET and the high-affinity dopamine D3 receptor radioligand [11C]-propyl-hexahydro-naphtho-oxazin ([11C]-PHNO). Severity of sleep problems was rated with appropriate subitems of the Unified Parkinson's Disease Rating Scale part I (patient questionnaire) and the Epworth Sleepiness Scale.
We found that lower dopamine D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of excessive daytime sleepiness but not with problems of falling asleep or insomnia.
In our cohort of patients with PD, the occurrence of excessive daytime sleepiness was linked to reductions in hypothalamic dopamine D3 receptor availability. If these preliminary findings are confirmed in larger cohorts of patients with polysomnographic characterization, selective pharmacologic modulation of the dopaminergic D3 system could be used to increase daytime alertness in patients with PD.
PMCID: PMC5177673  PMID: 27807182
11.  A predominance of hypertensive heart disease among patients with cardiac disease in Buea, a semi-urban setting, South West Region of Cameroon 
BMC Research Notes  2017;10:684.
The pattern of heart disease is diverse within and among world regions. The little data on the spectrum of heart disease in Cameroon has been so far limited to major cities. We sought to describe the pattern of heart disease in Buea, the South West Region of Cameroon, a semi-urban setting. This was a descriptive cross-sectional study. Between June 2016 and April 2017 the echocardiography register of the Buea Regional Hospital was surveyed. We extracted data on the age, sex and echocardiographic diagnosis.
Out of 529 patients who underwent echocardiography, 239 (45.2%) had a definite heart disease. There were 137 (57.3%) females. The mean age was 58 years (range 3–94 years). The most common echocardiographic diagnoses were hypertensive heart disease (43.2%), dilated cardiomyopathies (17.6%), ischemic heart diseases (9.6%), and cor pulmonale (8.8%). Rheumatic heart disease affected 6.7% of the patients. The most common rheumatic heart disease was mitral stenosis followed by mitral regurgitation. Congenital heart disease represented 2.1% and 5 patients (2.1%) had pulmonary hypertension. Hypertensive heart disease is the most common cardiac disease in this semi-urban region in Cameroon. Rheumatic heart disease still affects a sizable proportion of patients. Prevention of cardiac disease in our setting should focus on mass screening, the treatment and control of hypertension.
PMCID: PMC5715493  PMID: 29202813
Cardiac disease; Hypertensive heart disease; Rheumatic heart disease; Cameroon
12.  An Autotaxin-LPA-IL-6 Amplification Loop Drives Scleroderma Fibrosis 
We previously implicated the lipid mediator lysophosphatidic acid (LPA) in dermal fibrosis in systemic sclerosis (SSc). Here we identify the role of the LPA-producing enzyme autotaxin (ATX), and connect the ATX-LPA and IL-6 pathways in SSc.
We evaluated a novel ATX inhibitor, PAT-048, on fibrosis and IL-6 expression in the bleomycin (BLM) mouse model of dermal fibrosis. We utilized SSc patient and control dermal fibroblasts to evaluate LPA induction of IL-6, and IL-6 induction of ATX. We next evaluated whether LPA-induced ATX expression is dependent on IL-6, and whether baseline IL-6 expression in SSc fibroblasts is dependent on ATX. Finally, we compared ATX and IL-6 expression in SSc and healthy subject skin.
PAT-048 markedly attenuated BLM-induced dermal fibrosis when initiated before or after fibrosis development. LPA stimulated human dermal fibroblast IL-6 expression, and IL-6 stimulated fibroblast ATX expression, connecting the ATX-LPA and IL-6 pathways in an amplification loop. IL-6 knockdown abrogated LPA-induced ATX expression in fibroblasts, and ATX inhibition attenuated IL-6 expression in fibroblasts and the skin of BLM-challenged mice. Both ATX and IL-6 expression were increased in SSc skin, and LPA-induced IL-6 levels and IL-6-induced ATX levels were increased in SSc fibroblasts compared to controls.
ATX is required for the development and maintenance of dermal fibrosis in the BLM model and enables two major mediators of SSc fibrogenesis, LPA and IL-6, to amplify each other’s production. Our results suggest that concurrent inhibition of these two pathways may be an effective therapeutic strategy for SSc fibrosis.
PMCID: PMC5125861  PMID: 27390295
systemic sclerosis; fibrosing disorders; dermal fibroblasts
13.  Lactate signalling regulates fungal β-glucan masking and immune evasion 
Nature microbiology  2016;2:16238.
Summary Paragraph
As they proliferate, fungi expose antigens at their cell surface that are potent stimulators of the innate immune response, and yet the commensal fungus Candida albicans is able to colonize immuno-competent individuals. We show that C. albicans may evade immune detection by presenting a moving immunological target. We report that the exposure of β-glucan, a key Pathogen Associated Molecular Pattern (PAMP) located at the cell surface of C. albicans and other pathogenic Candida species, is modulated in response to changes in carbon source. Exposure to lactate induces β-glucan masking in C. albicans via a signaling pathway that has recruited an evolutionarily conserved receptor (Gpr1) and transcriptional factor (Crz1) from other well-characterized pathways. In response to lactate, these regulators control the expression of cell wall related genes that contribute to β-glucan masking. This represents the first description of active PAMP masking by a Candida species, a process that reduces the visibility of the fungus to the immune system.
PMCID: PMC5704895  PMID: 27941860
Candida albicans; lactate sensing; signal transduction; PAMP masking; immune evasion; fungal pathogenicity; RNA sequencing
14.  How effective is community physical activity promotion in areas of deprivation for inactive adults with cardiovascular disease risk and/or mental health concerns? Study protocol for a pragmatic observational evaluation of the ‘Active Herts’ physical activity programme 
BMJ Open  2017;7(11):e017783.
There is a high prevalence of inactive adults in the UK, and many suffer from conditions such as cardiovascular disease (CVD) or poor mental health. These coexist more frequently in areas of higher socioeconomic deprivation. There is a need to test the effectiveness, acceptability and sustainability of physical activity programmes. Active Herts uses novel evidence-based behaviour change techniques to target physical inactivity.
Methods and analysis
Active Herts is a community physical activity programme for inactive adults aged 16+ with one or more risk factors for CVD and/or a mild to moderate mental health condition. This evaluation will follow a mixed-methods longitudinal (baseline, and 3-month, 6-month and 12-month follow-ups) design. Pragmatic considerations mean delivery of the programme differs by locality. In two areas programme users will receive a behaviour change technique booklet, regular consultations, a booster phone call, motivational text messages and signposting to 12 weeks of exercise classes. In another two areas programme users will also receive 12 weeks of free tailored exercise classes, with optional exercise ‘buddies’ available. An outcome evaluation will assess changes in physical activity as the primary outcome, and sporting participation, sitting, well-being, psychological capability and reflective motivation as secondary outcomes. A process evaluation will explore the views of stakeholders, delivery staff and programme leads. Economic evaluation will examine the programme costs against the benefits gained in terms of reduced risk of morbidity.
Ethics and dissemination
This study was been approved by the Faculty of Medicine and Health Sciences Research Ethics Committee at the University of East Anglia. Informed written consent will be obtained from programme users in the evaluation. Results will be published in peer-reviewed journals, presented at conferences, and shared through the study website and local community outlets.
Trial registration number ID number: NCT03153098.
PMCID: PMC5719296  PMID: 29175885
physical activity programme; behaviour change; inactive adults; behaviour change techniques; com-b
15.  Poor glycaemic control is associated with reduced exercise performance and oxygen economy during cardio-pulmonary exercise testing in people with type 1 diabetes 
To explore the impact of glycaemic control (HbA1c) on functional capacity during cardio-pulmonary exercise testing in people with type 1 diabetes.
Sixty-four individuals with type 1 diabetes (age: 34 ± 8 years; 13 females, HbA1c: 7.8 ± 1% (62 ± 13 mmol/mol), duration of diabetes: 17 ± 9 years) performed a cardio-pulmonary cycle ergometer exercise test until volitional exhaustion. Stepwise linear regression was used to explore relationships between HbA1c and cardio-respiratory data with p ≤ 0.05. Furthermore, participants were divided into quartiles based on HbA1c levels and cardio-respiratory data were analysed by one-way ANOVA. Multiple regression analysis was performed to explore the relationships between changes in time to exhaustion and cardio-respiratory data. Data were adjusted for confounder.
HbA1c was related to time to exhaustion and oxygen consumption at the power output elicited at the sub-maximal threshold of the heart rate turn point (r = 0.47, R2 = 0.22, p = 0.03). Significant differences were found at time to exhaustion between QI vs. QIV and at oxygen consumption at the power output elicited at the heart rate turn point between QI vs. QII and QI vs. QIV (p < 0.05). Changes in oxygen uptake, power output and in oxygen consumption at the power output elicited at the heart rate turn point and at maximum power output explained 55% of the variance in time to exhaustion (r = 0.74, R2 = 0.55, p < 0.01).
Poor glycaemic control is related to less economical use of oxygen at sub-maximal work rates and an earlier time to exhaustion during cardio-pulmonary exercise testing. However, exercise training could have the same potential to counteract the influence of poor glycaemic control on functional capacity.
Trial registration NCT01704417. Date of registration: October 11, 2012
PMCID: PMC5697085
Glycaemic control; Exercise performance; Oxygen economy; Type 1 diabetes; Heart rate turn point
16.  Topographic effect on the phenology of Ficus pedunculosa var. mearnsii (Mearns fig) in its northern boundary distribution, Taiwan 
Scientific Reports  2017;7:14699.
Mearns fig grows at the edge of coastal vegetation on uplifted coral reefs, its population and mutualistic-pollinators are susceptible to the influence of extreme weather. To determine the phenology of Mearns fig and the effects of various weather events under small-scale topographic differences, phenology was conducted for 3 years and 7 months. Results showed that Mearns figs had multiple leaf and fig productions year-round. Topographic effects caused population in Frog Rock Trail and Jialeshuei, which are less than 10 km away from each other, to exhibit different phenological patterns after experiencing severe weather events. Northeast monsoons led the Jialeshuei population to show low amounts of leaves and figs in winter and the phenological production was also susceptible to disturbances by typhoons in summer. Fig reproduction in such environment was disadvantageous to maintain pollinators. Besides, topographic complex in microhabitat of Frog Rock Trail protected some individuals from these same events thus safeguard population’s survival. The phenology of Mearns fig would respond to the weather events sensitively, which serve as references for estimating the mutualism system, and as indicators of climate change.
PMCID: PMC5676713  PMID: 29116109
18.  Kienböck Disease and Arthroscopy: Assessment, Classification, and Treatment 
Journal of Wrist Surgery  2016;5(4):255-260.
The assessment and management of Kienböck Disease (KD) has always been a conundrum. The Lichtman classification has traditionally been used to guide treatment based on imaging. Arthroscopy provides a direct visualization of the articular surface, allows probing of the surfaces, and enables minimally invasive techniques to be performed.
The Lichtman-Bain classification is a new classification that takes into account the osseous, vascular, and cartilage aspects of the lunate and the secondary effects on the wrist. It identifies the important prognostic factors including age, the status of the lunate, and the status of the wrist.
With arthroscopy, the articular surfaces of the lunate can be assessed to better understand the status of the lunate. The lunate can be defined as intact, compromised, or not reconstructable. If the lunate is intact then lunate decompression (forage) and arthroscopic assisted bone grafting can be performed. If the lunate facet and capitate are functional, then a proximal carpectomy can be performed. This can be performed as an arthroscopic procedure.
Assessment of the wrist includes assessment of the adjacent articular surfaces of the central column articulations (radiocarpal and midcarpal articulations). Instability of the proximal carpal row can also be assessed. The radioscaphoid articulation is often preserved except in late KD, which allows the scaphocapitate fusion to be a good surgical option. This can now be performed as an arthroscopic procedure. Once the radioscaphoid articulation is degenerate, a salvage procedure is required.
PMCID: PMC5074828  PMID: 27777814
Kienböck disease; avascular necrosis; classification; treatment; wrist
19.  The Etiology and Pathogenesis of Kienböck Disease 
Journal of Wrist Surgery  2016;5(4):248-254.
Kienböck disease is a condition that typically occurs in the “at-risk” patient, in the “at-risk” aspect of the proximal condyle of the “at-risk” lunate. In the active male, repetitive loading causes the stress fracture that commences in the single layer proximal subchondral bone plate. The lunate fracture commences at the point the lunate cantilevers over the edge of the distal radius, and then takes on the shape of the radius. We postulate that the stress fracture violates the parallel veins of the venous subarticular plexus—leading to localized venous hypertension and subsequent ischemia and edema of the fatty marrow. The increased osseous compartment pressure further potentiates the venous obstruction, producing avascular necrosis.
If the fracture remains localized, it can heal or settle into a stable configuration, so that the wrist remains functional. Fractures of the subchondral bone plate produce irregularity of the lunate articular surfaces and secondary “kissing lesions” of the lunate facet and capitate, and subsequent degeneration. The lunate collapses when the fracture is comminuted, or there is disruption of the spanning trabeculae or a coronal fracture.
The secondary effect of the lunate collapse is proximal migration of the capitate between the volar and dorsal fragments, producing collapse of the entire central column. The proximal carpal row is now unstable, and is similar to scapholunate instability, where the capitate migrates between the scaphoid and lunate. The scaphoid is forced into flexion by the trapezium, however, degeneration of the scaphoid and scaphoid facet only occurs in late disease or following failed surgery.
In Kienböck disease, the secondary effects of the collapsing lunate are a “compromised” wrist, including: deformity and collapse of the central column, degeneration of the central column (perilunate) articulations, proximal row instability (i.e., between the central and radial columns), and degeneration of the radial column.
PMCID: PMC5074830  PMID: 27777813
Kienböck disease; lunate; etiology; pathogenesis
20.  Development of a Protocol for SPECT/CT in the Assessment of Wrist Disorders 
Journal of Wrist Surgery  2016;5(4):297-305.
Background Single-photon emission computed tomography and computed tomography (SPECT/CT) is a hybrid diagnostic imaging modality that allows clinicians to integrate their diagnostic evaluations and deliver a definitive diagnosis in musculoskeletal disorders. Specifically, in identification of osseous pathology, the conventional bone scan delivers greater specificity compared with magnetic resonance imaging (MRI). However, use of SPECT/CT enhances the sensitivity and specificity. Use of this modality denotes the possibility to specify the lesion more accurately and precisely while grading the activity according to osseous structural changes.
Purpose This study aimed to evaluate the clinical utility of SPECT/CT in the diagnoses and management of osseous wrist disorders. The objectives were to examine the value of SPECT/CT in the diagnosis of osseous-related wrist pain and whether the findings altered management.
Patients and Methods A retrospective cohort study of 20 patients with such wrist pain was conducted. SPECT/CT was used in the diagnostic process for these patients.
Results Following SPECT/CT imaging, the common final diagnoses were osteoarthritis (10; 50%) and avascular necrosis (5; 25%). Less common diagnoses included ulnar carpal impact syndrome, infection, malunion, complex regional pain syndrome, and carpal boss. Some presented with multiple pathologies. SPECT/CT changed the final diagnosis in 11 cases, resulting in nonoperative treatment (7; 63%) or surgery (4; 37%).
Conclusion Findings from this study and the literature demonstrate the clinical utility of SPECT/CT in the assessment of osseous-related wrist disorders. We present an algorithm for the assessment of wrist pain with osseous pathology. This commences with clinical assessment and plane radiographs (first-line investigation). Some cases will require a second-line investigation (ultrasound, CT, and/or MRI). If the diagnosis remains unclear, SPECT/CT is recommended as a third-line investigation.
PMCID: PMC5074841  PMID: 27777821
SPECT/CT; wrist; osteoarthritis; avascular necrosis; ulnar impingement
21.  Effects of climate change on a mutualistic coastal species: Recovery from typhoon damages and risks of population erosion 
PLoS ONE  2017;12(10):e0186763.
Presently, climate change has increased the frequency of extreme meteorological events such as tropical cyclones. In the western Pacific basin, these cyclones are called typhoons, and in this area, around Taiwan Island, their frequency has almost doubled since 2000. When approaching landmasses, typhoons have devastating effects on coastal vegetation. The increased frequency of these events has challenged the survival of coastal plant species and their posttyphoon recovery. In this study, a population of coastal gynodioecious Ficus pedunculosa var. mearnsii (Mearns fig) was surveyed for two years to investigate its recovery after Typhoon Morakot, which occurred in August 2009. Similar to all the Ficus species, the Mearns fig has an obligate mutualistic association with pollinating fig wasp species, which requires syconia (the closed Ficus inflorescence) to complete its life cycle. Moreover, male gynodioecious fig species produces both pollen and pollen vectors, whereas the female counterpart produces only seeds. The recovery of the Mearns fig was observed to be rapid, with the production of both leaves and syconia. The syconium:leaf ratio was greater for male trees than for female trees, indicating the importance of syconium production for the wasp survival. Pollinating wasps live for approximately 1 day; therefore, receptive syconia are crucial. Every typhoon season, few typhoons pass by the coasts where the Mearns fig grows, destroying all the leaves and syconia. In this paper, we highlight the potential diminution of the fig population that can lead to the extinction of the mutualistic pair of species. The effects of climate change on coastal species warrant wider surveys.
PMCID: PMC5658060  PMID: 29073190
22.  Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study 
Cancer Chemotherapy and Pharmacology  2017;80(6):1209-1217.
Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody–drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM.
M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible.
Among 66 patients, median age was 58 years (range 35–80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%.
Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-017-3451-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5686264  PMID: 29075855
ABT-414; Depatuxizumab mafodotin; EGFR; Antibody–drug conjugate; Recurrent glioblastoma
23.  Effectiveness and meaningful use of paediatric surgical safety checklists and their implementation strategies: a systematic review with narrative synthesis 
BMJ Open  2017;7(10):e016298.
To examine the effectiveness and meaningful use of paediatric surgical safety checklists (SSCs) and their implementation strategies through a systematic review with narrative synthesis.
Summary background data
Since the launch of the WHO SSC, checklists have been integrated into surgical systems worldwide. Information is sparse on how SSCs have been integrated into the paediatric surgical environment.
A broad search strategy was created using Pubmed, Embase, CINAHL, Cochrane Central, Web of Science, Science Citation Index and Conference Proceedings Citation Index. Abstracts and full texts were screened independently, in duplicate for inclusion. Extracted study characteristic and outcomes generated themes explored through subgroup analyses and idea webbing.
1826 of 1921 studies were excluded after title and abstract review (kappa 0.77) and 47 after full-text review (kappa 0.86). 20 studies were of sufficient quality for narrative synthesis. Clinical outcomes were not affected by SSC introduction in studies without implementation strategies. A comprehensive SSC implementation strategy in developing countries demonstrated improved outcomes in high-risk surgeries. Narrative synthesis suggests that meaningful compliance is inconsistently measured and rarely achieved. Strategies involving feedback improved compliance. Stakeholder-developed implementation strategies, including team-based education, achieved greater acceptance. Three studies suggest that parental involvement in the SSC is valued by parents, nurses and physicians and may improve patient safety.
A SSC implementation strategy focused on paediatric patients and their families can achieve high acceptability and good compliance. SSCs’ role in improving measures of paediatric surgical outcome is not well established, but they may be effective when used within a comprehensive implementation strategy especially for high-risk patients in low-resource settings.
PMCID: PMC5652514  PMID: 29042377
checklist; surgery; patient safety; paediatric; implementation science
24.  Vulnerable children, stigmatised smokers: The social construction of target audiences in media debates on policies regulating smoking in vehicles 
Health (London, England : 1997)  2016;21(6):633-649.
Following restrictions on smoking in vehicles carrying children in several countries, legislation to safeguard minors from second-hand smoke exposure in vehicles is under-consideration or has been implemented across the United Kingdom. This article presents the first investigation into social constructions of children, smokers and smoking parents in newsprint media and coverage of debates about protecting children from exposure to second-hand smoke in vehicles. Using Scotland as an example, articles on children’s exposure to second-hand smoke published between 1 January 2004 and 16 February 2014 in three Scottish newspapers were identified using Nexis UK. In all, 131 articles were thematically coded and analysed. Children were portrayed as vulnerable and requiring protection, with few articles highlighting children’s ability to voice concerns about the dangers of smoking. Smokers and smoking parents were mainly portrayed in a factual manner, but also frequently as irresponsible and, in some cases, intentionally imposing harm. Individual smokers were blamed for their recklessness, with only a small number of articles mentioning the need to assist smokers in quitting. Supporters of legislation focused on corresponding discourse, whereas critics directed debates towards established arguments against policy, including individual freedom, privacy and problems of enforcement. Focusing on children’s vulnerability to second-hand smoke might have increased support for legislation but risked a side effect of smokers being stigmatised. The media and supporters of public health policy are encouraged to consider appropriate approaches to raise awareness of the health harms of second-hand smoke to children while avoiding unintended stigmatisation of those in which they want to encourage behaviour change.
PMCID: PMC5639949  PMID: 27457688
children; media analysis; second-hand smoke exposure; smoking in vehicles; stigmatisation
25.  Recommendations for data monitoring committees from the Clinical Trials Transformation Initiative 
Clinical Trials (London, England)  2017;14(4):342-348.
Use of data monitoring committees to oversee clinical trials was first proposed nearly 50 years ago. Since then, data monitoring committee use in clinical trials has increased and evolved. Nonetheless, there are no well-defined criteria for determining the need for a data monitoring committee, and considerable variability exists in data monitoring committee composition and conduct. To understand and describe the role and function of data monitoring committees, and establish best practices for data monitoring committee trial oversight, the Clinical Trials Transformation Initiative—a public–private partnership to improve clinical trials—launched a multi-stakeholder project.
The data monitoring committee project team included 16 individuals charged with (1) clarifying the purpose of data monitoring committees, (2) identifying best practices for independent data monitoring committee conduct, (3) describing effective communication practices, and (4) developing strategies for training data monitoring committee members. Evidence gathering included a survey, a series of focus group discussions, and a 2-day expert meeting aimed at achieving consensus opinions that form the foundation of our data monitoring committee recommendations.
We define the role of the data monitoring committee as an advisor to the research sponsor on whether to continue, modify, or terminate a trial based on periodic assessment of trial data. Data monitoring committees should remain independent from the sponsor and be composed of members with no relevant conflicts of interest. Representation on a data monitoring committee generally should include at least one clinician with expertise in the therapeutic area being studied, a biostatistician, and a designated chairperson who has experience with clinical trials and data monitoring. Data monitoring committee meetings are held periodically to evaluate the unmasked data from ongoing trials, but the content and conduct of meetings may vary depending on specific goals or topics for deliberation. To guide data monitoring committee conduct and communication plans, a charter consistent with the protocol’s research design and statistical analysis plan should be developed and agreed upon by the sponsor and the data monitoring committee prior to patient enrollment. We recommend concise and flexible charters that explain roles, responsibilities, operational issues, and how data monitoring committee recommendations are generated and communicated. The demand for data monitoring committee members appears to exceed the current pool of qualified individuals. To prepare a new generation of trained data monitoring committee members, we encourage a combination of didactic educational programs, practical experience, and skill development through apprenticeships and mentoring by experienced data monitoring committee members.
Our recommendations address data monitoring committee use, conduct, communication practices, and member preparation and training. Furthermore recommendations form the foundation for ongoing efforts to improve clinical trial oversight and enhance the safety and integrity of clinical research. These recommendations serve as a call to action for implementation of best practices that benefit study participants, study sponsors, and society.
PMCID: PMC5639979  PMID: 28503947
Data monitoring committees; clinical trials; data and safety monitoring boards

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