Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Promoting the get healthy information and coaching service (GHS) in Australian-Chinese communities: facilitators and barriers.

Obesity and being overweight are major public health concerns that health coaching can assist people to manage through encouraging self-management and behaviour change. The Get Healthy Information and Coaching Service (GHS) is a telephone health coaching service in Australia that has effectively improved the health of the general population but has had less participation of culturally and linguistically diverse (CALD) populations. The Chinese population is the largest migrant group in Australia with increased risk of diabetes but had reduced access to the GHS program due to communication barriers. The GHS developed a pilot program for Chinese (Mandarin and Cantonese-speaking) communities using bilingual coaches and translated material to address these barriers. Qualitative research was undertaken with Chinese stakeholders (14 interviews) and 11 program participants from the group which had completed the program (2 focus groups in Mandarin and Cantonese) to understand their experiences and the success of promotional activities. This research does not contain the experiences of the people that withdrew from the program. The bilingual program was culturally and linguistically appropriate and addressed risk factors for chronic conditions. Participants formed positive relationships with bilingual coaches who they preferred to interpreters. They felt the program promoted healthy eating, weight and physical activity. Although Chinese stakeholders had concerns about participants' ability to goal set, participants said they met their health goals and were committed to the GHS program. Strategies to enhance the program included promoting the bilingual GHS to the communities and stakeholders. Factors to consider beyond language in adapting the program to the Australian Chinese communities include meeting the heterogenous needs of the older population, ensuring community engagement and addressing cultural beliefs and practices.

Obesity and being overweight are major public health concerns that health coaching can assist people to manage. The Get Healthy Information and Coaching Service (GHS) is a government telephone health coaching service that has improved the health of the general population but has had less participation of culturally and linguistically diverse populations. The Chinese population is the largest migrant group in Australia with increased risk of diabetes but had reduced access to the GHS program due to communication barriers. The GHS developed a pilot program for Chinese (Mandarin and Cantonese-speaking) communities using bilingual coaches and translated material. Findings from 14 interviews with Chinese stakeholders and two focus groups (in Mandarin and Cantonese) with program participants sought to understand their experiences and success of promotional activities. Results demonstrated the bilingual program was culturally and linguistically appropriate. Participants formed positive relationships with coaches and felt the service promoted healthy eating and weight, and physical activity. Although Chinese stakeholders had concerns about participants' cultural familiarity with goal setting and achieving long-term change, participants said that they met their goals and were committed to the program. Strategies to enhance the program will include promoting the bilingual GHS to the communities and stakeholders.

Reduced kidney function at presentation in unselected acute emergency medical admissions: incidence, outcome and associated factors.

We sought to assess the impact of renal impairment on acute medical admissions and to identify potential contributory factors to admissions involving renal impairment at presentation. In a prospective cohort study, 29.5% of all acute medical emergency admissions had an eGFR <60ml/min/1.73m2 at presentation. Of these, 19.9% had definite chronic kidney disease and 8.4% had definite acute kidney injury. Detailed analysis of a random subset of patients with an eGFR <60ml/min/1.73m2 at presentation demonstrated that the major reasons for admission included falls, dehydration and fluid overload. 46% were on diuretics and 53% were on an ACEI or ARB or both. Gastrointestinal disturbance and recent medication changes were common and diuretic use persisted even with diarrhoea or vomiting.

Germline polymorphisms as biomarkers of tumor response in colorectal cancer patients treated with anti-EGFR monoclonal antibodies: a systematic review and meta-analysis.

Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.

Diurnal blood pressure and urine production in acute spinal cord injury compared with controls.

STUDY DESIGN: This is a prospective observational study. OBJECTIVES: The objective of this study was to determine time-dependent changes in diurnal blood pressure (BP) and urine production in acute spinal cord injury (SCI). SETTING: This study was conducted in a specialist, state-based spinal cord service in Victoria, Australia. METHODS: Consenting patients admitted consecutively with acute SCI were compared with patients confined to bed rest while awaiting surgery and with mobilising able-bodied controls. Participants underwent ambulatory BP monitoring (ABPM), measurement of diurnal urine production and rated orthostatic symptoms over 1 year. Participants with night:day systolic BP (SBP) <90% were classified as dippers, 90-100% as non-dippers and >100% as reverse dippers. RESULTS: Participants comprised tetraplegics (n=47, 40.0±17.3 years), paraplegics (n=35, 34.4±13.9 years), immobilised (n=18, 30.9±11.3 years) and mobilising (n=44, 33.1±13.5 years) controls. At baseline, 24-h BP was significantly lower in tetraplegics (111.8±1.9/62.1±1.1 mm Hg) but not in paraplegics (116.7± 1.4/66.0±1.1 mm Hg), compared with controls (117.1 ±1.3/69.1±1.1 mm Hg), adjusting for gender. This difference was not observed at 1 year. The average night:day SBP in mobilising controls was 86.1±0.7%, differing from paraplegics (94.0±1.5%, P<0.001) and tetraplegics (101.5±1.5%, P<0.001). Urine production in tetraplegics and paraplegics did not fall at night compared with the day. Abnormal diurnal BP and orthostatic symptoms in tetraplegics persisted throughout the study. Nocturnal hypertension was observed in 27% (n=9) of tetraplegics, of whom only 2 had day hypertension. All mobilising controls with nocturnal hypertension (n=6, 14%) had day hypertension. CONCLUSION: People with SCI have a high prevalence of isolated nocturnal hypertension, reverse dipping, orthostatic intolerance and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM.

Nurse Triage in an Irish Out-of-hours General Practice Co-Operative.

Specially trained triage nurses play a crucial role in the operation of out-of-hours GP co-operatives. This study aimed to establish the proportion of all patient contacts with the out-of-hours GP co-operative based in the Mid-West of Ireland (Shannondoc), which were managed by triage nurses. A retrospective, descriptive analysis was conducted on the database of contacts to the Shannondoc urgent, out-of-hours primary care co-operative. Of the 110,039 contacts to the service in 2013, 19,147 (17.4%) were classified as being managed by nurses and 14.2% were managed by nurse telephone triage alone. Twenty-four percent of the 19,147 calls managed by nurses involved children under six years. Triage nurses play an important role in administering safe medical advice over the phone. This has implications for the training of triage nurses and the future planning of urgent out-of-hours primary care services.

Significance of baseline and change in quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3.

BACKGROUND: There is insufficient information regarding the prognostic significance of baseline and change in quality of life (QoL) scores on overall survival (OS) in advanced pancreatic cancer. METHODS: QoL was assessed prospectively using the EORTC QLQ-C30 as part of the PA.3 trial of gemcitabine + erlotinib (G + E) vs. gemcitabine + placebo (G + P). Relevant variables and QoL scores at baseline and change at 8 weeks were analyzed by Cox stepwise regression to determine predictors of OS. RESULTS: 222 of 285 patients (pts) treated with G + E and 220 of 284 pts treated with G + P completed baseline QoL assessments. In a multivariable Cox analysis combining all pts, better QoL physical functioning (PF) score independently predicted longer OS (HR 0.86; CI: 0.80-0.93), as did non-white race (HR 0.64; CI: 0.44-0.95), PS 0-1 (HR 0.65; CI: 0.50-0.85), locally advanced disease (HR 0.55; CI: 0.43-0.71) and G + E (HR 0.78; CI: 0.64-0.96). Improvement in physical function at week 8 also predicted for improved survival (HR 0.89; CI: 0.81-0.97 for 10 point increase in score, p = 0.02). CONCLUSION: In addition to clinical variables, patient reported QoL scores at baseline and change from baseline to week 8 added incremental predictive information regarding survival for advanced pancreatic cancer patients.

Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada.

BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.

Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study.

In 2010, a tissue-engineered trachea was transplanted into a 10-year-old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti-HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross-sectional area analysis showed restriction of growth within an area of in-stent stenosis. This report demonstrates the long-term viability of a decellularized tissue-engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs.

A retrospective review of the ambulatory blood pressure patterns and diurnal urine production in subgroups of spinal cord injured patients.

STUDY DESIGN: Retrospective study. OBJECTIVES: To quantify diurnal blood pressure (BP) patterns and nocturnal hypertension and to measure diurnal urine production in spinal cord injury (SCI) patients with clinically significant disorders of BP control. SETTING: A specialist state-based spinal cord service in Victoria, Australia. METHODS: Medical records of patients with traumatic SCI who were referred to a specialist service for management of a BP disorder were examined. Ambulatory BP and nocturnal urine production were compared between groups of patients classified according to level, completeness and chronicity of SCI. Patients with night:day systolic BP <90% were classified as dippers, 90-100% as non-dippers and >100% as reversed dippers. RESULTS: Patients (44 tetraplegic, 10 paraplegic) were predominantly males (92.6%) aged 41±2.5 years (mean±s.e.m.). Referral was for orthostatic intolerance (n=37), autonomic dysreflexia (n=6), nocturnal polyuria (n=4), elevated BP (n=1) and peripheral oedema (n=1). The average BP was 111.1±1.4/65.0±1.2 mm Hg. In 56% of patients (n=30), BP at night was higher than during the day and another 37% (n=20) were non-dippers. Nocturnal hypertension was present in 31% (n=17) of the patients. In the tetraplegic patients, urine flow rate was greater during the night than day (121±9.5 ml h(-1) vs 89±8.2 ml h(-1), P=0.025). CONCLUSION: Ambulatory BP monitoring in patients with SCI and clinically significant BP disorders detected a high incidence of reversed dipping and nocturnal hypertension. We postulate elevated nocturnal BP may contribute to nocturnal diuresis that might cause relative volume depletion and thereby contribute to daytime orthostatic hypotension.

Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer.

BACKGROUND: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. METHODS: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction. RESULTS: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group. CONCLUSION: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.

Innovative estimation of survival using log-normal survival modelling on ACCENT database.

BACKGROUND: The ACCENT database, with individual patient data for 20 898 patients from 18 colon cancer clinical trials, was used to support Food and Drug Administration (FDA) approval of 3-year disease-free survival as a surrogate for 5-year overall survival. We hypothesised substantive differences in survival estimation with log-normal modelling rather than standard Kaplan-Meier or Cox approaches. METHODS: Time to relapse, disease-free survival, and overall survival were estimated using Kaplan-Meier, Cox, and log-normal approaches for male subjects aged 60-65 years, with stage III colon cancer, treated with 5-fluorouracil-based chemotherapy regimens (with 5FU), or with surgery alone (without 5FU). RESULTS: Absolute differences between Cox and log-normal estimates with (without) 5FU varied by end point. The log-normal model had 5.8 (6.3)% higher estimated 3-year time to relapse than the Cox model; 4.8 (5.1)% higher 3-year disease-free survival; and 3.2 (2.2)% higher 5-year overall survival. Model checking indicated greater data support for the log-normal than the Cox model, with Cox and Kaplan-Meier estimates being more similar. All three model types indicate consistent evidence of treatment benefit on both 3-year disease-free survival and 5-year overall survival; patients allocated to 5FU had 5.0-6.7% higher 3-year disease-free survival and 5.3-6.8% higher 5-year overall survival. CONCLUSION: Substantive absolute differences between estimates of 3-year disease-free survival and 5-year overall survival with log-normal and Cox models were large enough to be clinically relevant, and warrant further consideration.

Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17.

BACKGROUND: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. PATIENTS AND METHODS: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. RESULTS: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). CONCLUSIONS: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

Zero the hero: Evidence for involvement of the ventromedial prefrontal cortex in affective bias for free items.

Recent evidence from psycho-economics shows that when the price of an item decreases to the extent that it becomes available for free, one can observe a remarkable increase of subjective utility toward this item. This phenomenon, which is not observed for any other price but zero, has been termed the zero-price effect (ZPE). The ZPE is attributed to an affective heuristic where the positive affect elicited by the free status of an item provides a mental shortcut biasing choice towards that item. Given that the ZPE relies on affective processing, a key role of the ventromedial prefrontal cortex (vmPFC) has been proposed, yet neuroscientific studies of the ZPE remain scarce. This study aimed to explore the role of the vmPFC in the ZPE using a novel, within-subject assessment in participants with either an acquired (lesion patients) or degenerative (behavioural-variant frontotemporal dementia patients) lesion of the vmPFC, and age-matched healthy controls. All participants were asked to make a series of choices between pairs of items that varied in price. One choice trial involved an equal decrease of both item prices, such that one of the items was priced zero. In contrast to controls, patients with both vmPFC-lesion and behavioural-variant frontotemporal dementia showed marked reductions in zero-related changes of preference in pairs of gift-cards, but not for pairs of food items. Our findings suggest that affective evaluations driving the ZPE are altered in patients with focal or degenerative damage to the vmPFC. This supports the notion of a key role of the vmPFC in the ZPE and, more generally, the importance of this region in value-based affective decision-making. Our findings also highlight the potential utility of affective heuristic tasks in future clinical assessments.

Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care.

BACKGROUND: the interplay between comorbidity, age and performance status (PS) as predictors of outcome in advanced colorectal cancer (ACRC) is poorly understood. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC. PATIENTS AND METHODS: comorbidity was independently evaluated using the Charlson Comorbidity Index (CCI), a validated measure of comorbidity based on the presence of medical conditions weighted according to their effect on mortality. CCI score was correlated with clinical and outcome data. RESULTS: five hundred and seventy-two patients were included; 41% were ≥ 65 years and 25% had comorbidities at randomization. In multivariate analysis (MVA) of all covariates, only older age was associated with greater comorbidity (P = 0.008). Overall survival (OS) was significantly better for patients with greater comorbidity in univariate analysis (P = 0.047). Conversely, better PS was associated with better OS in MVA (hazard ratio 1.92 for PS = 2 versus PS = 0, P < 0.0001). Age was not associated with OS (P = 0.13). Elderly patients had significantly less grade ≥ 3 vomiting (P = 0.034) but more dyspnea (P = 0.005). Patients with greater comorbidity had significantly less grade ≥ 3 vomiting (P = 0.002) but more non-neutropenic fever (P = 0.005). CONCLUSION: better PS was associated with improved OS. For patients with good PS, restricting cetuximab use in the setting of significant comorbidity does not appear justified.

Inner dynein arm defects causing primary ciliary dyskinesia: repeat testing required.

Primary ciliary dyskinesia (PCD) results in chronic nasal symptoms and chest disease leading to bronchiectasis. We noted a number of patients referred for diagnostic testing whose initial results suggested PCD due to an inner dynein arm or radial spoke defect but in whom no abnormality was found on retesting. The present study was an audit of all patients referred for PCD diagnostic testing over a 3-yr period whose initial electron microscopy (EM) and beat pattern analysis suggested an inner dynein arm or radial spoke defect. 21 patients referred for diagnostic testing for PCD suspected of an inner dynein arm defect and six suspected of a radial spoke defect on initial EM and beat pattern analysis had repeat testing performed. On repeat testing, five patients initially suspected of an inner dynein arm defect and one with a radial spoke defect had normal EM and beat pattern, leading to the initial diagnosis being questioned. Patients suspected of PCD due to an inner dynein arm defect or radial spoke defect should have the diagnosis reassessed if it has been based on only one diagnostic sample.

Antigen-specific T cell responses to BK polyomavirus antigens identify functional anti-viral immunity and may help to guide immunosuppression following renal transplantation.

Infection with the polyoma virus BK (BKV) is a major cause of morbidity following renal transplantation. Limited understanding of the anti-viral immune response has prevented the design of a strategy that balances treatment with the preservation of graft function. The proven utility of interferon-gamma enzyme-linked immunospot (ELISPOT) assays to measure T cell responses in immunocompetent hosts was the basis for trying to develop a rational approach to the management of BKV following renal transplantation. In a sample of transplant recipients and healthy controls, comparisons were made between T cell responses to the complete panel of BKV antigens, the Epstein-Barr virus (EBV) antigens, BZLF1 and EBNA1, and the mitogen phytohaemagglutinin (PHA). Correlations between responses to individual antigens and immunosuppressive regimens were also analysed. Antigen-specific T cell responses were a specific indicator of recent or ongoing recovery from BKV infection (P < 0·05), with responses to different BKV antigens being highly heterogeneous. Significant BKV immunity was undetectable in transplant patients with persistent viral replication or no history of BKV reactivation. Responses to EBV antigens and mitogen were reduced in patients with BKV reactivation, but these differences were not statistically significant. The T cell response to BKV antigens is a useful and specific guide to recovery from BKV reactivation in renal transplant recipients, provided that the full range of antigenic responses is measured.

Salt supplementation blunts the blood pressure response to telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes.

AIMS/HYPOTHESIS: We assessed the effects of sodium chloride (NaCl) supplementation on the blood pressure response to treatment with telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes and habitually high (HDS, sodium excretion >200 mmol/24 h on two out of three consecutive occasions) or low (LDS, sodium excretion <100 mmol/24 h on two out of three consecutive occasions) salt intake. METHODS: Patients received 4 weeks of telmisartan followed by 4 weeks of telmisartan plus hydrochlorothiazide. In a double-blind randomised fashion, patients received sodium chloride (NaCl, 100 mmol/24 h) or placebo capsules in addition to their habitual salt intake during the last 2 weeks of telmisartan and telmisartan plus hydrochlorothiazide therapy. The protocol was repeated with NaCl and placebo capsules administered in reverse order to allow each participant to act as his or her own control. At 0, 4, 8, 14, 18 and 22 weeks, 24 h ambulatory blood pressure (ABP) and 24 h urine collections were performed. RESULTS: No statistically significant differences were seen in the ABP response in the LDS vs HDS groups to any of the interventions (p = 0.58). NaCl supplementation reduced the effect of telmisartan with or without hydrochlorothiazide on systolic BP by approximately 50% (-5.8 mmHg during NaCl supplementation vs -11.3 mmHg during placebo, mean difference 5.6 mmHg [95% CI 1.7-9.4 mmHg], p = 0.005), irrespective of habitual salt intake. By contrast, addition of hydrochlorothiazide increased the antihypertensive effect of telmisartan on systolic BP by approximately 35% (p = 0.048) in both groups of patients. CONCLUSIONS/INTERPRETATION: NaCl supplementation blunts the effectiveness of telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes, independently of habitual low or high salt intake.

Antagonist HIV-1 Gag peptides induce structural changes in HLA B8.

In the cellular immune response, recognition by CTL-TCRs of viral antigens presented as peptides by HLA class I molecules, triggers destruction of the virally infected cell (Townsend, A.R.M., J. Rothbard, F.M. Gotch, G. Bahadur, D. Wraith, and A.J. McMichael. 1986. Cell. 44:959-968). Altered peptide ligands (APLs) which antagonise CTL recognition of infected cells have been reported (Jameson, S.C., F.R. Carbone, and M.J. Bevan. 1993. J. Exp. Med. 177:1541-1550). In one example, lysis of antigen presenting cells by CTLs in response to recognition of an HLA B8-restricted HIV-1 P17 (aa 24-31) epitope can be inhibited by naturally occurring variants of this peptide, which act as TCR antagonists (Klenerman, P., S. Rowland Jones, S. McAdam, J. Edwards, S. Daenke, D. Lalloo, B. Koppe, W. Rosenberg, D. Boyd, A. Edwards, P. Giangrande, R.E. Phillips, and A. McMichael. 1994. Nature (Lond.). 369:403-407). We have characterised two CTL clones and a CTL line whose interactions with these variants of P17 (aa 24-31) exhibit a variety of responses. We have examined the high resolution crystal structures of four of these APLs in complex with HLA B8 to determine alterations in the shape, chemistry, and local flexibility of the TCR binding surface. The variant peptides cause changes in the recognition surface by three mechanisms: changes contributed directly by the peptide, effects transmitted to the exposed peptide surface, and induced effects on the exposed framework of the peptide binding groove. While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.