Feasibility study of a randomised controlled trial to investigate the treatment of sarcoidosis-associated fatigue with methylphenidate (FaST-MP): a study protocol

Introduction: Fatigue is a frequent and troublesome manifestation of chronic sarcoidosis. This symptom can be debilitating and difficult to treat, with poor response to the treatment. Symptomatic management with neurostimulants, such as methylphenidate, is a possible treatment option. The use of such treatment strategies is not without precedent and has been trialled in cancer-related fatigue. Their use in sarcoidosis requires further evaluation before it can be recommended for clinical practice. Methods and analysis: The Fatigue and Sarcoidosis—Treatment with Methylphenidate study is a randomised, controlled, parallel-arm and feasibility trial of methylphenidate for the treatment of sarcoidosis-associated fatigue. Patients are eligible if they have a diagnosis of sarcoidosis, significant fatigue (measured using the Fatigue Assessment Scale) and have stable disease. Up to 30 participants will be randomly assigned to either methylphenidate (20 mg two times per day) or identical placebo in a 3:2 ratio for 24 weeks. The primary objective is to collect data determining the feasibility of a future study powered to determine the clinical efficacy of methylphenidate for sarcoidosis-associated fatigue. The trial is presently open and will continue until July 2018. Ethics and dissemination: Ethical approval for the study was granted by the Cambridge Central Research Ethics Committee on 21 June 2016 (reference 16/EE/0087) and was approved and sponsored by the Norfolk and Norwich University Hospital (reference 190280). Clinical Trial Authorisation (EudraCT number 2016-000342-60) from the Medicines and Healthcare products Regulatory Agency (MHRA) was granted on 19 April 2016. Results will be presented at relevant conferences and submitted to appropriate journals following trial closure and analysis

Feasibility of investigating methylphenidate for the treatment of sarcoidosis-associated fatigue (the FaST-MP study) – a double-blind, parallel-arm randomised feasibility trial

INTRODUCTION: Sarcoidosis-associated fatigue (SAF) is a common clinical problem with limited treatment options. This study was undertaken to determine the feasibility of performing a definitive trial to determine the clinical efficacy methylphenidate in SAF. METHODS: This was a parallel-arm, double-blind, placebo-controlled randomised controlled feasibility trial enrolling sarcoidosis patients reporting significant fatigue. Patients with a Fatigue Assessment Scale score of more than 21 were randomised to receive up to either 10 mg two times per day methylphenidate or identical placebo capsules two times per day, in a dose escalation fashion, for up to 24 weeks. Outcomes included number of participants eligible and willing to participate, withdrawal rates, adherence rates and ability to maintain blinding. RESULTS: Of 385 patients screened, 56 (14.5%) were eligible and 23 (41% of eligible patients) were randomised. No withdrawals occurred. One participant in the methylphenidate arm discontinued study medications due to chest pain. The side effect profile was not different between the groups. Median medication adherence rates were 98% and 99% in the methylphenidate and placebo arms, respectively. A greater proportion of participants receiving methylphenidate predicted their allocated treatment while blinded compared with those receiving placebo (93.3% vs 57.1%). The investigator could not predict the treatment allocation. Both groups showed clinically meaningful improvements in fatigue from baseline, although no between-group difference was seen. CONCLUSIONS: The data support the feasibility of performing a double-blind parallel trial powered to determine the clinical efficacy of methylphenidate for SAF, however, a multicentre study will be required. TRIAL REGISTRATION NUMBER: NCT02643732

Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines

Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015

Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Feasibility of investigating methylphenidate for the treatment of sarcoidosis-associated fatigue (the FaST-MP study): a double-blind, parallel-arm randomised feasibility trial

IntroductionSarcoidosis-associated fatigue (SAF) is a common clinical problem with limited treatment options. This study was undertaken to determine the feasibility of performing a definitive trial to determine the clinical efficacy methylphenidate in SAF.MethodsThis was a parallel-arm, double-blind, placebo-controlled randomised controlled feasibility trial enrolling sarcoidosis patients reporting significant fatigue. Patients with a Fatigue Assessment Scale score of more than 21 were randomised to receive up to either 10 mg two times per day methylphenidate or identical placebo capsules two times per day, in a dose escalation fashion, for up to 24 weeks. Outcomes included number of participants eligible and willing to participate, withdrawal rates, adherence rates and ability to maintain blinding.ResultsOf 385 patients screened, 56 (14.5%) were eligible and 23 (41% of eligible patients) were randomised. No withdrawals occurred. One participant in the methylphenidate arm discontinued study medications due to chest pain. The side effect profile was not different between the groups. Median medication adherence rates were 98% and 99% in the methylphenidate and placebo arms, respectively. A greater proportion of participants receiving methylphenidate predicted their allocated treatment while blinded compared with those receiving placebo (93.3% vs 57.1%). The investigator could not predict the treatment allocation. Both groups showed clinically meaningful improvements in fatigue from baseline, although no between-group difference was seen.ConclusionsThe data support the feasibility of performing a double-blind parallel trial powered to determine the clinical efficacy of methylphenidate for SAF, however, a multicentre study will be required.Trial registration numberNCT02643732.</jats:sec

Atypical Follicular Cells with Equivocal Features of Papillary Thyroid Carcinoma Is Not a Low-Risk Cytologic Diagnosis

&lt;i&gt;Objective:&lt;/i&gt; To determine whether or not significant differences in the risk of malignancy exist between subgroups of atypical follicular cells in The Bethesda System for Reporting Thyroid Cytology (TBSRTC) in patients who underwent surgical resection. &lt;i&gt;Study Design:&lt;/i&gt; Between 2004 and 2009, consecutive thyroid fine-needle aspirates at our institutions with a cytologic diagnosis of ‘atypical follicular cells’ were retrieved and subclassified using the diagnosis and diagnostic comment as: (1) atypical follicular cells with equivocal features of papillary carcinoma [cannot exclude papillary thyroid carcinoma (PTC)] and (2) atypical follicular cells, other patterns. The risks of malignancy for excised nodules were calculated and comparisons were made between these subgroups. Categorical analysis was performed using a 2-tailed Fisher’s exact test, and p &lt; 0.05 was considered statistically significant. &lt;i&gt;Results:&lt;/i&gt; A total of 7,072 thyroid fine-needle aspiration cases were retrieved, with 1,542 (21.8%) having a histologic follow-up. There were 222 (3.1%) cases of ‘atypical follicular cells’, with 127 (57.2%) having a histologic correlation and 33 having confirmed malignancies. Atypical follicular cells, cannot exclude PTC, have a significantly higher risk of malignancy than atypical follicular cells, other patterns (45.8 vs. 13.9%, p &lt; 0.01). &lt;i&gt;Conclusions:&lt;/i&gt; Atypical follicular cells with equivocal features of papillary carcinoma is not a low-risk cytologic diagnosis.</jats:p

Absence or Presence of High-Grade Squamous Intraepithelial Lesion in Cervical Conization Specimens: A Clinicopathologic Study of 540 Cases

OBJECTIVES: To explore the implications of cervical conization specimens lacking the targeted high-grade squamous intraepithelial lesions (negative cone). METHODS: We studied 540 conization procedures: 400 positive cones and 140 negative cones. Clinicopathologic features and 2-year follow-up results were reported. RESULTS: Negative cones comprised 22% of procedures triggered by CIN2 or higher biopsies. Procedures triggered by cytology produced much higher percentages of negative cones (37% high-grade squamous intraepithelial lesion [HSIL], 46% atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion [ASC-H], and 76% low-grade squamous intraepithelial lesion-cannot exclude high-grade squamous intraepithelial lesion [LSIL-H]). Upon reviewing negative excision-triggering biopsy and cytology, we downgraded 24 (24%) CIN2 biopsies, three (14%) HSIL, five (83%) ASC-H, and 12 (92%) LSIL-H. One-third of our negative cones can be attributed to overdiagnosis either on biopsy or cytology. Patients with negative cones were older and had smaller excisions, negative colposcopic findings, and negative/equivocal high-risk human papillomavirus (HR-HPV). Within 2 years, 35 (25%) women with negative cones experienced ASCUS or LSIL. Only one (0.7%) recurred as CIN3, a significantly lower percentage than women with positive cones (13%). CONCLUSIONS: We advocate careful review of all excision-triggering biopsy and cytology, especially in cases of LSIL-H. Patients with negative cones should be surveyed with cytology and HR-HPV testing

Absence or Presence of High-Grade Squamous Intraepithelial Lesion in Cervical Conization Specimens: A Clinicopathologic Study of 540 Cases

OBJECTIVES: To explore the implications of cervical conization specimens lacking the targeted high-grade squamous intraepithelial lesions (negative cone). METHODS: We studied 540 conization procedures: 400 positive cones and 140 negative cones. Clinicopathologic features and 2-year follow-up results were reported. RESULTS: Negative cones comprised 22% of procedures triggered by CIN2 or higher biopsies. Procedures triggered by cytology produced much higher percentages of negative cones (37% high-grade squamous intraepithelial lesion [HSIL], 46% atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion [ASC-H], and 76% low-grade squamous intraepithelial lesion-cannot exclude high-grade squamous intraepithelial lesion [LSIL-H]). Upon reviewing negative excision-triggering biopsy and cytology, we downgraded 24 (24%) CIN2 biopsies, three (14%) HSIL, five (83%) ASC-H, and 12 (92%) LSIL-H. One-third of our negative cones can be attributed to overdiagnosis either on biopsy or cytology. Patients with negative cones were older and had smaller excisions, negative colposcopic findings, and negative/equivocal high-risk human papillomavirus (HR-HPV). Within 2 years, 35 (25%) women with negative cones experienced ASCUS or LSIL. Only one (0.7%) recurred as CIN3, a significantly lower percentage than women with positive cones (13%). CONCLUSIONS: We advocate careful review of all excision-triggering biopsy and cytology, especially in cases of LSIL-H. Patients with negative cones should be surveyed with cytology and HR-HPV testing