Cerebral tuberculosis in a patient with systemic lupus erythematosus following cyclophosphamide treatment: a case report.

Central nervous system (CNS) tuberculosis (TB) is a rare but catastrophic event in patients with systemic lupus erythematosus (SLE). Here we report a case of cerebral TB in a patient with lupus myocarditis and nephritis, following cyclophosphamide immunosuppression. To our knowledge this is the first reported case of cerebral TB in SLE in a non-endemic country. A 31-year-old female with SLE and a history of regular travel to Kenya presented to our centre with clinical features of acute heart failure. She was diagnosed with severe lupus myocarditis, and a renal biopsy also confirmed lupus nephritis. Prior to admission, she had also had a cough, fever and weight loss and was under investigation for suspected TB infection. She was treated with ivabradine, beta-blockers and diuretics together with methylprednisolone and cyclophosphamide immunosuppression. Subsequent sputum cultures confirmed TB and she was commenced on triple therapy. Despite this, she developed confusion, dizziness, blurred vision and fluctuating consciousness. Magnetic resonance imaging (MRI) and lumbar puncture revealed CNS TB infection resulting in meningitis. This was later complicated by obstructive hydrocephalus due to TB abscesses. A ventriculoperitoneal (VP) shunt was inserted and TB medications were given intravenously (IV) with dexamethasone. Following a prolonged hospital admission, the patient eventually recovered and rituximab treatment was used to control her SLE. TB infection has been associated with SLE flares. It is likely in this case that TB exacerbated a lupus flare and subsequent immunosuppression resulted in mycobacterial dissemination to the CNS. Systemic and CNS features of TB and SLE are difficult to distinguish and their contemporaneous management represents a diagnostic and therapeutic challenge.

Gene expression profiling of endobronchial ultrasound (EBUS)-derived cytological fine needle aspirates from hilar and mediastinal lymph nodes in non-small cell lung cancer.

OBJECTIVE: Endobronchial ultrasound (EBUS) allows minimally invasive sampling of hilar and mediastinal lymph nodes and has an established role in non-small cell lung cancer (NSCLC) diagnosis and staging. Molecular biomarkers are being explored increasingly in lung cancer research. Gene expression profiling (GEP) is a microarray-based technology that comprehensively assesses genome-wide changes in gene expression that can provide tumour-specific molecular signatures with the potential to predict prognosis and treatment responsiveness. We assessed the feasibility of using EBUS-derived aspirates from benign and tumour-infiltrated lymph nodes for GEP. METHODS: RNA was extracted from EBUS-directed transbronchial fine needle aspiration samples in routine clinical practice. GEP was subsequently performed in six patients with NSCLC, three of whom had tumour-infiltrated nodes and three who had benign lymph nodes; the differences in gene expression were then compared. RESULTS: RNA was successfully extracted in 29 of 32 patients, 12 of whom were diagnosed with NSCLC. RNA yield (median, 12.1 µg) and RNA integrity (median, 6.3) were sufficient after amplification for GEP. Benign and malignant nodes in adenocarcinoma were discriminated by principal component analysis and hierarchical clustering with different expression patterns between malignant and benign nodes. CONCLUSION: We have demonstrated the feasibility of RNA extraction and GEP on EBUS-derived transbronchial fine needle aspirates from benign and tumour-infiltrated lymph nodes in patients with known NSCLC in routine clinical practice. Further studies on larger patient cohorts are required to identify expression profiles that robustly differentiate benign from malignant lymph nodes in NSCLC.

ALK rearrangements in EBUS-derived transbronchial needle aspiration cytology in lung cancer.

OBJECTIVES: Patients with non-small cell lung cancer (NSCLC) positive for anaplastic lymphoma kinase (ALK) gene rearrangements may be treated successfully with the ALK inhibitor crizotinib. ALK copy-number abnormalities have also been described. In this study, we evaluated the suitability of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to determine ALK status in endobronchial ultrasound (EBUS)-derived cytology samples. METHODS: Samples were obtained from 55 consecutive patients with NSCLC who had undergone EBUS-transbronchial needle aspiration (TBNA) according to our standard clinical protocols. All tumours had been screened previously for epithelial growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. FISH, using commercially available ALK rearrangement-specific probes, was employed to assess ALK status. IHC using the ALK-1 monoclonal antibody (DAKO) was also performed. RESULTS: FISH analysis was successful in 52 of 55 samples (94.5%); ALK rearrangement was demonstrated in 3 of 52 samples from patients with NSCLC (5.7%). ALK amplification was observed in 3 of 52 patient samples (5.7%) and an increase in ALK copy number was found in 28 of 52 patient samples (53.8%). IHC on cell blocks demonstrated ALK expression in one of three samples with ALK rearrangement. One patient sample had concomitant ALK rearrangement and KRAS mutation. CONCLUSIONS: We found FISH to be superior to IHC using the ALK-1 monoclonal antibody for the detection of ALK rearrangement in EBUS-TBNA cytology specimens in NSCLC, and also that ALK rearrangement can co-exist with KRAS mutation in the same tumour.

Diagnosis and subclassification of thymoma by minimally invasive fine needle aspiration directed by endobronchial ultrasound: a review and discussion of four cases.

Thymomas have been classified by the World Health Organisation (WHO) into six groups, based on the morphology of epithelial cells and the ratio between epithelial cells and lymphocytes within the tumour. Among 1458 consecutive cases of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) performed in a tertiary referral centre between February 2008 and February 2012, we have encountered four cases of thymic neoplasms. We discuss the cytomorphological features of three cases of type B thymoma (one each of B1, B2 and B3 subtypes) and one case of thymic carcinoma diagnosed on EBUS-TBNA using cell blocks, immunocytochemistry and flow cytometry which allowed preoperative chemotherapy to be carried out in two cases, diagnosis to be made after unsatisfactory surgical mediastinoscopy in the third and diagnosis of lymph node metastasis of the thymic carcinoma in the fourth. The differential diagnosis and criteria for subclassification of thymomas are discussed; although subclassification of these cases was possible in these cases, and tumours other than thymoma excluded, additional cases would be necessary to assess the potential accuracy of EBUS-TBNA. These, to the best of our knowledge, represent the first cases of thymoma that were diagnosed and subclassified according to WHO criteria using multimodality evaluation of EBUS-derived cytological aspirates.

The effect of a novel Bayesian penalised likelihood PET reconstruction algorithm on the assessment of malignancy risk in solitary pulmonary nodules according to the British Thoracic Society guidelines.

PURPOSE: British Thoracic Society (BTS) guidelines advocate using FDG PET-CT with the Herder model to estimate malignancy risk in solitary pulmonary nodules (SPNs). Qualitative and semi-quantitative assessment of SPN uptake is based upon analysis of Ordered Subset Expected Maximisation (OSEM) PET images. Our aim was to assess the effect of a Bayesian Penalised Likelihood (BPL) PET reconstruction on the assessment of SPN FDG uptake and estimation of malignancy risk (Herder score). METHODS: Subjects with SPNs who underwent FDG PET-CT between 2014-2017, with histological confirmation of malignancy or histological/imaging follow-up confirmation of benignity were included. Two blinded readers independently classified SPN uptake on both OSEM and BPL (BTS score; 1 = none; 2 = ≤ mediastinal blood pool (MBP); 3 = >MBP but ≤ 2x liver; 4 = >2x liver), with resultant calculation of the Herder score (%) for both reconstructions. RESULTS: 97 subjects with 75 (77%) malignant SPNs were included. BPL increased the BTS score in 25 (26%) SPNs; 9 SPNs (7 malignant) increased from BTS score 2 to 3, 16 (13 malignant) from BTS score 3 to 4, with a mean Herder score increase of 18 ±â€¯22%. The mean Herder score for all SPNs with BPL was higher than OSEM (73 ±â€¯29 vs 68 ±â€¯32%, p = 0.001). There was no difference in Herder model diagnostic performance between BPL and OSEM, with similar areas under the curve (0.84 vs 0.83, p = 0.39). CONCLUSION: BPL increases the Herder score in 26% of SPNs compared to OSEM but does not alter the diagnostic performance of the Herder model.

Clinical application of a rapid lung-orientated immunoassay in individuals with possible tuberculosis.

BACKGROUND: Immunological ex vivo assays to diagnose tuberculosis (TB) have great potential but have largely been blood-based and poorly evaluated in active TB. Lung sampling enables combined microbiological and immunological testing and uses higher frequency antigen-specific responses than in blood. METHODS: A prospective evaluation was undertaken of a flow cytometric assay measuring the percentage of interferon-gamma synthetic CD4+ lymphocytes following stimulation with purified protein derivative of Mycobacterium tuberculosis (PPD) in bronchoalveolar lavage fluid from 250 sputum smear-negative individuals with possible TB. A positive assay was defined as >1.5%. RESULTS: Of those who underwent lavage and were diagnosed with active TB, 95% (106/111) had a positive immunoassay (95% CI 89% to 98%). In 139 individuals deemed not to have active TB, 105 (76%) were immunoassay negative (95% CI 68% to 82%). Of the remaining 24% (34 cases) with a positive immunoassay, a substantial proportion had evidence of untreated TB; in two of these active TB was subsequently diagnosed. Assay performance was unaffected by HIV status, disease site or BCG vaccination. In culture-positive pulmonary cases, response to PPD was more sensitive than nucleic acid amplification testing (94% vs 73%). The use of early secretory antigen target-6 (ESAT-6) responses in 71 subjects was no better than PPD, and 19% of those with culture-confirmed TB and a positive PPD immunoassay had no detectable response to ESAT-6. CONCLUSIONS: These findings suggest that lung-orientated immunological investigation is a potentially powerful tool in diagnosing individuals with sputum smear-negative active TB, regardless of HIV serostatus.

How good are systemic symptoms and blood inflammatory markers at detecting individuals with tuberculosis?

SETTING: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss. OBJECTIVES: To determine how frequently these features and blood test evidence of inflammation were absent in individuals with TB. METHODS: Prospective cohort study of 175 unselected subjects diagnosed with TB at a UK TB service between 2003 and 2006. RESULTS: Eight (5%) subjects identified by screening and 24 (14%) without culture confirmation were excluded. Of the remaining 143, fever, sweats or weight loss were absent in respectively 37%, 39% and 38%. All three symptoms were absent in 25%. In 88 subjects with pulmonary disease, all three symptoms were absent in 20% (10% of smear-positive cases). Overall, C-reactive protein was normal in 15%, erythrocyte sedimentation rate in 21% and lactate dehydrogenase in 55%. In a multivariable model, factors associated with absent symptoms included drug-resistant TB (adjusted odds ratio [aOR] 3.58, P = 0.004) and female sex (aOR 3.15, P = 0.004). CONCLUSIONS: In our population, TB, including pulmonary disease, frequently presented without fever, sweats or weight loss and with normal blood inflammatory markers. This information is of as much relevance to policy makers seeking to improve active case detection as to clinicians and the general public.

The diagnostic utility of pleural fluid adenosine deaminase for tuberculosis in a low prevalence area.

BACKGROUND: Pleural fluid adenosine deaminase (pfADA) is not routinely measured in patients with undiagnosed pleural effusion due to limited evidence of its diagnostic utility in areas of low tuberculosis (TB) prevalence. METHODS: We conducted a retrospective consecutive case series analysis of all patients who underwent pfADA testing from 2009 to 2015 at a tertiary service pleural centre in south London. Using receiver operating characteristic (ROC) curve analysis, we identified the optimal threshold at which maximal sensitivity and specificity were achieved. RESULTS: Of the 132 patients tested for pfADA, 27 had confirmed pleural TB and 105 did not, with median pfADA levels of respectively 63 IU/l (interquartile range [IQR] 47-88) and 12 IU/l (IQR 7.5-22.5). ROC curve analysis determined the optimal pfADA cut-off to be 30 IU/l, which had positive and negative predictive values of respectively 60.5% and 98.9%, 96.3% sensitivity (95%CI 0.892-1.000) and 83.8% specificity (95%CI 0.768-0.909). The calculated area under the ROC curve was 0.934 (95%CI 0.893-0.975). CONCLUSION: A pfADA level <30 IU/l makes a diagnosis of TB highly unlikely in the South London population. Its high sensitivity and negative predictive values make pfADA a valuable screening test for excluding suspected pleural TB.

Longer-term primary prevention for alcohol misuse in young people: a systematic review.

OBJECTIVE: To identify and summarize rigorous evaluations of psychosocial and educational interventions aimed at the primary prevention of alcohol misuse by young people aged up to 25 years, especially over the longer term (>3 years). METHODS: Cochrane Collaboration Systematic Review. DATA SOURCES: A comprehensive search of 22 databases and recursive checking of bibliographies for randomized and non-randomized controlled trials and interrupted time-series studies. MAIN OUTCOME MEASURES: Objective or self-report measures of alcohol use and misuse. RESULTS: Fifty-six studies were selected for inclusion in the systematic review. Twenty of the 56 studies showed evidence of ineffectiveness. No firm conclusions about the effectiveness of prevention interventions in the short- and medium term were possible. Over the longer term (>3 years), the Strengthening Families Programme (SFP) showed promise as an effective prevention intervention. The Number Needed to Treat (NNT) for the SFP over 4 years for three alcohol initiation behaviours (alcohol use, alcohol use without permission and first drunkenness) was 9 (for all three behaviours). One study also highlighted the potential value of culturally focused skills training over the longer-term (NNT = 17 over 3.5 years for 4+ drinks in the last week) CONCLUSIONS: (1) Research into important outcome variables needs to be undertaken; (2) the methodology of evaluations needs to be improved; (3) the SFP needs to be evaluated on a larger scale and in different settings; (4) culturally focused interventions require further development and rigorous evaluation; and (5) an international register of alcohol and drug misuse prevention interventions should be established and criteria agreed for rating prevention interventions in terms of safety, efficacy and effectiveness.

Primary prevention for alcohol misuse in young people.

BACKGROUND: Alcohol misuse is a cause of concern for health services, policy makers, prevention workers, the criminal justice system, youth workers, teachers and parents. OBJECTIVES: 1. To identify and summarize rigorous evaluations of psychosocial and educational interventions aimed at the primary prevention of alcohol misuse by young people. 2. To assess the effectiveness of primary prevention interventions over the longer-term (> 3 years). SEARCH STRATEGY: Databases searched (no time limits): Project CORK, BIDS, PSYCLIT, ERIC, ASSIA, MEDLINE, FAMILY-RESOURCES-DATABASE, HEALTH-PERIODICALS-DATABASE, EMBASE, BIDS, Dissertation-Abstracts, SIGLE, DRUG-INFO, SOMED, Social-Work-Abstracts, National-Clearinghouse-on-Alcohol-and-Drug-Information, Mental-Health-Abstracts, DRUG-database, ETOH (all searched Feb-June 2002). SELECTION CRITERIA: 1. randomised controlled and non-randomised controlled and interrupted time series designs. 2. educational and psychosocial primary prevention interventions for young people up to 25 years old. 3. alcohol-specific or generic (drugs; lifestyle) interventions providing alcohol outcomes reported. 4. alcohol outcomes: alcohol use, age of alcohol initiation, drinking 5+ drinks on any one occasion, drunkeness, alcohol related violence, alcohol related crime, alcohol related risky behaviour. DATA COLLECTION AND ANALYSIS: Stage 1: All papers screened by one reviewer against inclusion criteria. Stage 2: For those papers that passed Stage 1, key information was extracted from each paper by 2-3 reviewers. MAIN RESULTS: 20 of the 56 studies included showed evidence of ineffectiveness. No firm conclusions about the effectiveness of prevention interventions in the short- and medium-term were possible. Over the longer-term, the Strengthening Families Program (SFP) showed promise as an effective prevention intervention. The Number Needed to Treat (NNT) for the SFP over 4 years for three alcohol initiation behaviours (alcohol use, alcohol use without permission and first drunkeness) was 9 (for all three behaviours). One study also highlighted the potential value of culturally focused skills training over the longer-term (NNT=17 over three-and-a-half years for 4+ drinks in the last week). REVIEWER'S CONCLUSIONS: 1. Research into important outcome variables needs to be undertaken. 2. Methodology of evaluations needs to be improved. 3. The Strengthening Families Programme needs to be evaluated on a larger scale and in different settings. 4. Culturally-focused interventions require further development and rigorous evaluation. 5. An international register of alcohol and drug misuse prevention interventions should be established and criteria agreed for rating prevention intervention in terms of safety, efficacy and effectiveness.

Cognitive changes in pathological gamblers following a 28-day inpatient program.

A cognitive explanation for pathological gambling (PG) posits that problem gambling behaviors are maintained by irrational beliefs and attitudes about gambling. However, it has never been shown that beliefs and attitudes about gambling are affected by treatment. This exploratory study examined the effect of a 28-day inpatient treatment program on beliefs and attitudes in pathological gamblers (PGs). The participants were 66 consecutive admissions to a Veterans Affairs inpatient program for PG. Participants completed a self-report measure of gambling-specific attitudes and beliefs at admission and again before discharge. Discharge scores indicated significant change (p < .001). The results of this study are preliminary but suggest that treatment may affect attitudes and beliefs about gambling. Controlled treatment outcome studies should include a measure of gambling attitudes and beliefs.

Solution-focused therapy and inpatient psychiatric nursing.

1. Creative ways must be found to deliver high quality nursing care--with fewer nurse-patient interactions--to patients experiencing more severe problems. 2. Solution-focused therapy underscores the positive attributes of the patient; facilitates the development of a working partnership between the nurse and patient; helps the patient develop future-oriented goals; and identifies actions necessary for reaching those goals. 3. As a result of incorporating solution-focused therapy at the institution highlighted in this article, the quality of patient care, as well as effectiveness and cohesiveness of the nursing staff, improved.

A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol.

INTRODUCTION: Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. METHODS AND ANALYSIS: The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. ETHICS AND DISSEMINATION: This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05956042.