TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis.

BACKGROUND: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. METHODS: A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. DISCUSSION: TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. TRIAL REGISTRATION: Trials Registration: ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.

Weight of salivary gland ultrasonography compared to other items of the 2016 ACR/EULAR classification criteria for Primary Sjögren's syndrome.

OBJECTIVE: Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion. METHODS: A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS. RESULTS: A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%. CONCLUSION: SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria.

The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong.

INTRODUCTION: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. METHODS: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. RESULTS: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. CONCLUSION: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Correction to: Raised Serum IL-8 Levels Are Associated with Excessive Fatigue in Female Carriers of X-Linked Chronic Granulomatous Disease in the UK.

The original version of the article, "Raised Serum IL-8 Levels Are Associated with Excessive Fatigue in Female Carriers of X-Linked Chronic Granulomatous Disease in the UK" incorrectly listed the name of the fourth author as Fai W. Ng. The correct spelling of the author's name is WF Ng.

Extrapulmonary involvement associated with Mycoplasma pneumoniae infection.

Mycoplasma pneumoniae infection usually presents with upper and lower respiratory tract infection. Extrapulmonary involvement is not uncommon, however. We report two cases of predominantly extrapulmonary manifestations of Mycoplasma pneumoniae infection without significant pulmonary involvement. Both cases were diagnosed by serology. These cases illustrate the diversity of clinical presentations of Mycoplasma pneumoniae infection. Clinicians should maintain a high index of suspicion.

Cardiovascular risk factors in women with primary Sjögren's syndrome: United Kingdom primary Sjögren's syndrome registry results.

OBJECTIVE: To determine the prevalence of traditional cardiovascular risk factors using established definitions in a large cohort of clinically well-characterized primary Sjögren's syndrome (SS) patients and to compare them to healthy controls. METHODS: Data on cardiovascular risk factors in primary SS patients and controls were collected prospectively using a standardized pro forma. Cardiovascular risk factors were defined according to established definitions. The prevalence of cardiovascular risk factors in the primary SS group was determined and compared to that in the control group. RESULTS: Primary SS patients had a higher prevalence of hypertension (28­50% versus 15.5­25.6%; P < 0.01) and hypertriglyceridemia (21% versus 9.5%; P = 0.002) than age- and sex-matched healthy controls. Furthermore, a significant percentage (56%) of hypertensive patients expected to be on antihypertensive treatment according to best practice was not receiving it. CONCLUSION: Primary SS patients are more than 2 times more likely to experience hypertension and hypertriglyceridemia than age- and sex-matched healthy controls. Additionally, hypertension is underdiagnosed and suboptimally treated in primary SS.

Assessment of blood clot formation and platelet receptor function ex vivo in patients with primary Sjogren's syndrome.

OBJECTIVES: Primary Sjögren's syndrome (pSS) shares clinical features and pathogenetic mechanisms with systemic lupus erythematosus (SLE). SLE is associated with an increased thromboembolic risk; however, it is unclear whether pSS patients are susceptible to thromboembolic diseases. In this study, we examined ex vivo blood clot formation (clot strength, rates of clot formation and lysis) in pSS using thromboelastography (TEG) and platelet aggregation to common agonists using multiple electrode aggregometry (MEA). We also investigated the relationship between TEG/MEA parameters and clinical/laboratory features of pSS. DESIGN: Case control. SETTING: Secondary care, single centre. PARTICIPANTS: 34 pSS patients, 11 SLE patients and 13 healthy volunteers (all women) entered and completed the study. PRIMARY OUTCOMES: TEG and MEA parameters between three subject groups. SECONDARY OUTCOMES: The relationships between TEG/MEA and clinical/laboratory parameters analysed using bivariate correlation analysis with corrections for multiple testing. RESULTS: All TEG and MEA parameters were similar for the three subject groups. After corrections for multiple testing, interleukin (IL)-1α and Macrophage inflammatory proteins (MIP)-1α remain correlated inversely with clot strength (r=-0.686, p=0.024 and r=-0.730, p=0.012, respectively) and overall coagulability (r=-0.640, p=0.048 and r=-0.648, p=0.048). Stepwise regression analysis revealed that several cytokines such as MIP-1α, IL-17a, IL-1α and Interferon (IFN)-γ may be key predictors of clot strength and overall coagulability in pSS. CONCLUSIONS: Clot kinetics and platelet receptor function are normal in pSS. Several cytokines correlate with clot strength and overall coagulability in pSS.

Sjögren's syndrome - an update for dental practitioners.

Sjögren's syndrome (SS), an autoimmune, multi-factorial disorder, affects around 5% of females and 0.5% of males in the general population. The dental practitioner has a key role in recognising the clinical features of this condition, organising referral for specialist care and managing the oral health of these patients. In this article, we summarise the clinical manifestations, diagnosis and management of SS relevant to dental practitioners.

Primary Sjogrens syndrome is associated with impaired autonomic response to orthostasis and sympathetic failure.

BACKGROUND: Symptoms in keeping with autonomic dysfunction are commonly described by primary Sjögrens syndrome patients (pSS); whether objective abnormalities of autonomic function occur is unclear. This study set out to explore dynamic cardiovascular autonomic responses in pSS and their relationship with symptoms and quality of life. METHODS: Twenty-one people from the UK pSS registry, 21 community controls and 21 patients with the autoimmune liver disease primary biliary cirrhosis (PBC) (matched case-wise for age and sex) attended for assessment of autonomic responses to orthostasis and Valsalva manoeuvre (VM). pSS patients also completed EULAR Sjögrens Syndrome patient-reported index (ESSPRI), EULAR Sjögren's syndrome disease activity index (ESSDAI), fatigue impact scale and EURO-QOL 5-dimension (EQ-5D). RESULTS: Compared with controls, pSS patients had significantly lower baseline systolic blood pressure (SBP) (114 ± 13 vs. 127 ± 20; P = 0.02), which dropped to a significantly lower value (98 ± 22 vs. 119 ± 24, P = 0.009). When area under the curve (AUC) was calculated for when the SBP was below baseline this was significantly greater in pSS compared to both control groups (pSS vs. control vs. PBC: 153 ± 236 vs. 92 ± 85 vs. 1.2 ± 0.3, P = 0.005). Peak phase IV SBP during the VM was significantly lower in pSS (P = 0.007) indicating early sympathetic failure. Increased heart rate associated with fatigue (P = 0.02; r(2) = 0.2) and EQ-5D. A shift in sympathetic-vagal balance associated with overall symptom burden (ESSPRI) (P = 0.04, r(2) = 0.3) and EULAR sicca score (P = 0.016; r(2) = 0.3), the latter also correlated with baroreceptor effectiveness (P = 0.03; r(2) = 0.2) and diastolic blood pressure variability (P = 0.003; r(2) = 0.4). CONCLUSION: pSS patients have impaired blood pressure response to standing. Dysautonomia correlates with PSS-associated symptoms and quality of life.

Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA.

AIMS: To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished. METHODS: Tissue sections from the central nervous system of infected cases were examined by light microscopy, immunohistochemistry and in situ hybridization. RESULTS: All 13 cases of EV71 encephalomyelitis collected from Asia and France invariably showed stereotyped distribution of inflammation in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus and, to a lesser extent, cerebral cortex and meninges. Anterior pons, corpus striatum, thalamus, temporal lobe, hippocampus and cerebellar cortex were always uninflamed. In contrast, the eight JE cases studied showed inflammation involving most neuronal areas of the central nervous system, including the areas that were uninflamed in EV71 encephalomyelitis. Lesions in both infections were nonspecific, consisting of perivascular and parenchymal infiltration by inflammatory cells, oedematous/necrolytic areas, microglial nodules and neuronophagia. Viral inclusions were absent. CONCLUSIONS: Immunohistochemistry and in situ hybridization assays were useful to identify the causative virus, localizing viral antigens and RNA, respectively, almost exclusively to neurones. The stereotyped distribution of inflammatory lesions in EV71 encephalomyelitis appears to be very useful to help distinguish it from JE.

Atacicept, a novel B cell-targeting biological therapy for the treatment of rheumatoid arthritis.

BACKGROUND: Recent data suggest a key role for B cells in the pathogenesis of many autoimmune diseases including rheumatoid arthritis (RA), and biological therapies targeting B cells are promising treatments for patients with RA. Atacicept inhibits B cell maturation, differentiation and survival, and immunoglobulin production by depriving B cells of growth and development signals. Therefore, atacicept may represent an effective strategy in RA treatment. OBJECTIVE: To evaluate the potential value of atacicept in RA treatment based on preclinical and clinical studies. METHODS: Preclinical and clinical data on atacicept were identified using PubMed and systematically reviewed. RESULTS/CONCLUSION: Preclinical and clinical studies show that atacicept is well tolerated, with no increased incidence of infections. Atacicept displays non-linear pharmacokinetics, with a more than dose-proportional increase in free drug and less than dose-proportional, saturated increase in atacicept-ligand complex. Overall, the pharmacokinetic profiles of atacicept were consistent, dose-related and predictable. Dose-dependent reductions in immunoglobulins and other biomarkers, including rheumatoid factor, occurred rapidly but returned to baseline after discontinuation. There was a biphasic response in B cell number, but no effect on other leucocytes. Atacicept improved the signs and symptoms of RA, although larger studies are needed to confirm its efficacy and its optimal use.

Magnetic resonance imaging for ureteral fibroepithelial polyp.

Ureteric tumours are rare and most of them are malignant. Of benign tumours, ureteral fibroepithelial polyps are the most common but are still considered clinical rarities. In the past, most benign ureteric tumours were only diagnosed after surgical removal. With technological advance, magnetic resonance imaging has become an effective means of assessing ureteric lesions. Non-contrast enhanced magnetic resonance urography can produce an image comparable to an intravenous urogram without use of intravenous water-soluble contrast. A polyp can be diagnosed on imaging if there is an elongated filling defect inside the ureter. Nevertheless, a definitive diagnosis relies on ureteroscopic examination with biopsy. When a non-obstructive polyp is being managed conservatively, imaging is helpful for monitoring. Equally, the information obtained from imaging can be used to plan operative treatment.

The cell biology of bone metabolism.

Contrary to the commonly held misconception, bone is a relatively dynamic organ that undergoes significant turnover as compared to other organs in the body. This review details how complex intercellular signalling, between the osteoprogenitor cells and mature osteoblasts, osteocytes and osteoclasts, regulates and balances activities of bone cells during remodelling and growth. Both systemic, as well as local autocrine and paracrine factors are discussed. A number of recent important advances in cell biology of bone have led to a new paradigm in understanding of the subject. In this regard, the interaction between the immune system and bone cells is of particular interest, leading to the emergence of a new discipline termed osteoimmunology. The role of lymphocytes and a number of key cytokines in the regulation of osteoclastogenesis and osteoblast function is critically examined. The intracellular signalling regulating key cellular pathways involved in cell differentiation and activity are outlined. The emerging evidence of osteocytes as mechanosensors as well as regulators of mineralisation is discussed.

The placentas of patients with severe acute respiratory syndrome: a pathophysiological evaluation.

AIMS: The pathology of the placentas delivered from pregnant women who had severe acute respiratory syndrome (SARS) in Hong Kong was studied. METHODS: The pathology of the placentas was retrospectively studied in detail and compared with control sets. The clinical data of the women and neonates were also reviewed. RESULTS: A total of seven placentas were studied. The placentas from two women convalescent from SARS in the first trimester were normal. In three placentas delivered in the acute stage of SARS, there were increases in intervillous or subchorionic fibrin which might be related to disturbances in maternal placental blood flow due to the hypoxic respiratory disease. Extensive fetal thrombotic vasculopathy (FTV) with sharply demarcated zones of avascular fibrotic villi was noted in the placentas of two patients convalescent from SARS in the third trimester. Both pregnancies had intrauterine growth retardation, oligohydramnios and newborns small for gestation. The aetiology of the FTV might be related to thrombotic tendency due to SARS or placental hypoxia. CONCLUSIONS: This report highlights placental pathology that was probably the result of pathophysiological alteration of the maternal fetal unit during SARS. Further studies are required to delineate the relationship between severe maternal respiratory disease, placental pathology and pregnancy outcome.