Hypercalcaemia and acute renal failure after major burns: An under-diagnosed condition.

BACKGROUND: Hypercalcaemia has been shown to occur in about 20% of patients with major burns requiring prolonged intensive care unit (ICU) treatment, and it may be associated with renal failure. Having observed the early onset of hypercalcaemia, the study aimed to determine the frequency and timing of this condition in a European patient cohort. METHODS: A retrospective cohort study on a prospectively collected, computerised database of the 225 burn-injury ICU admissions between 2001 and 2007 was undertaken. The inclusion criteria included: burns >20% of the body surface area (BSA) or in-hospital stay >20 days. Hypercalcaemia was defined as an ionised plasma calcium (Ca(2+)) concentration >1.32 mmol l(-1) (or total corrected calcium=[Ca]c>2.55 mmol l(-1)). Four emblematic cases are reported in this article. RESULTS: A total of 73 patients met the inclusion criteria (age: 13-88 years, burns: 12-85% BSA): of these, 22 (30%) developed hypercalcaemia. The median time to the first hypercalcaemia value was 21 days. Only 11 patients had both high Ca(2+) and elevated [Ca]c (which remained normal in others). The risk factors of the disorder were burned surface (p=0.017) and immobilisation (fluidised bed use: p<0.05, duration: p=0.02) followed by burned BSA. Acute renal failure tended to be more frequent in hypercalcaemic patients (five (23%) vs. three (6%): p=0.11), while mortality was not increased. The disorder resolved with hydration and mobilisation in most cases: pamidronate was successful in three cases that were most severe. CONCLUSION: Hypercalcaemia and associated acute renal failure occur more frequently and earlier than previously reported. Determining the ionised Ca rather than the total Ca with albumin correction enables earlier detection of hypercalcaemia. Bisphosphonates are an effective treatment option in controlling severe hypercalcaemia and preventing bone loss.

The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn's disease after failure of two other anti-TNF antibodies.

BACKGROUND: Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn's disease (CD) patients previously treated with infliximab (IFX). AIM: To assess the efficacy and tolerability of a third anti-TNF in CD after failure of and/or intolerance to two different anti-TNF antibodies. METHODS: Crohn's disease patients who received ADA or CZP after loss of response and/or intolerance to two anti-TNF agent were included in this retrospective study. Data were collected using a standardized questionnaire. Clinical response, duration, safety and reasons for discontinuation were assessed. RESULTS: Sixty-seven patients treated with CZP (n = 40) or ADA (n = 27) were included. A clinical response was observed in 41 (61%) at week 6 and 34 patients (51%) at week 20. The probability of remaining under treatment at 3 months, 6 months and 9 months was 68%, 60% and 45%, respectively. At the end of follow-up, the third anti-TNF had been stopped in 36 patients for intolerance (n = 13), or failure (n = 23). Two deaths were observed. CONCLUSIONS: The treatment with a third anti-TNF (CZP or ADA) agent of CD patients, who have experienced loss of response and/or intolerance to two anti-TNF antibodies, has favourable short-term and long-term efficacy. It is an option to be considered in patients with no other therapeutic options.

Association of ECG abnormalities and incident heart failure events

Background: With the aging of the population, the heart failure (HF) incidence and prevalence trends are expected to significantly worsen unless concentrated prevention efforts are undertaken. ECG abnormalities are common in the elderly but data are limited for their association with HF risk. Objective: To assess whether baseline ECG abnormalities or dynamic changes are associated with an increased risk of HF. Method: A prospective cohort study of 2915 participants aged 70 to 79 years without a preexisting HF followed for a median period of 11.4 (IQR 7.0-11.7) years from the Health Aging and Body Composition study. The Minnesota Code was used to define major and minor ECG abnormalities at baseline and at 4-year. Main outcome measure was adjudicated incident HF events. Using Cox models, the (1) the association between ECG abnormalities and incident HF and (2) incremental value of adding ECG to the Health ABC HF Risk Score, was assessed. Results: At baseline, 380 participants (13.0%) had minor and 620 (21.3%) had major ECG abnormalities. During follow-up, 485 (16.6%) participants developed incident HF. After adjusting for the eight clinical variables in the Health ABC HF Risk Score, the hazard ratio (HR) was 1.27 (95% confidence interval [CI] 0.96-1.68) for minor and 1.99 (CI 1.61-2.44) for major ECG abnormalities (P for trend <0.001) compared to no ECG abnormalities. The association did not change according to presence of baseline CHD. At 4-year, 263 participants developed new and 549 had persistent abnormalities and both were associated with increased HF risk (HR = 1.94, CI 1.38-2.72 for new and HR=2.35, CI 1.82-3.02 for persistent compared to no ECG abnormalities). Baseline ECG correctly reclassified 10.6% of overall participants across the categories of the Health ABC HF Risk Score. Conclusion: Among older adults, baseline ECG abnormalities and changes in them over time are common; both are associated with an increased risk of HF. Whether ECG should be incorporated in routine screening of older adults should be evaluated in randomized controlled trials.

Serum resistin concentrations and risk of new onset heart failure in older persons: the health, aging, and body composition (Health ABC) study.

OBJECTIVE: Resistin is associated with inflammation and insulin resistance and exerts direct effects on myocardial cells including hypertrophy and altered contraction. We investigated the association of serum resistin concentrations with risk for incident heart failure (HF) in humans. METHODS AND RESULTS: We studied 2902 older persons without prevalent HF (age, 73.6+/-2.9 years; 48.1% men; 58.8% white) enrolled in the Health, Aging, and Body Composition (Health ABC) Study. Correlation between baseline serum resistin concentrations (20.3+/-10.0 ng/mL) and clinical variables, biochemistry panel, markers of inflammation and insulin resistance, adipocytokines, and measures of adiposity was weak (all rho <0.25). During a median follow-up of 9.4 years, 341 participants (11.8%) developed HF. Resistin was strongly associated with risk for incident HF in Cox proportional hazards models controlling for clinical variables, biomarkers, and measures of adiposity (HR, 1.15 per 10.0 ng/mL in adjusted model; 95% CI, 1.05 to 1.27; P=0.003). Results were comparable across sex, race, diabetes mellitus, and prevalent and incident coronary heart disease subgroups. In participants with available left ventricular ejection fraction at HF diagnosis (265 of 341; 77.7%), association of resistin with HF risk was comparable for cases with reduced versus preserved ejection fraction. CONCLUSIONS: Serum resistin concentrations are independently associated with risk for incident HF in older persons.

Patterns of Adherence to Raltegravir-Based Regimens and the Risk of Virological Failure Among HIV-Infected Patients: The RALTECAPS Cohort Study.

ABSTRACT:: Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

Determinants of methicillin-susceptible Staphylococcus aureus native bone and joint infection treatment failure: a retrospective cohort study.

BACKGROUND: Although methicillin-susceptible Staphylococcus aureus (MSSA) native bone and joint infection (BJI) constitutes the more frequent clinical entity of BJI, prognostic studies mostly focused on methicillin-resistant S. aureus prosthetic joint infection. We aimed to assess the determinants of native MSSA BJI outcomes. METHODS: Retrospective cohort study (2001-2011) of patients admitted in a reference hospital centre for native MSSA BJI. Treatment failure determinants were assessed using Kaplan-Meier curves and binary logistic regression. RESULTS: Sixty-six patients (42 males [63.6%]; median age 61.2 years; interquartile range [IQR] 45.9-71.9) presented an acute (n = 38; 57.6%) or chronic (n = 28; 42.4%) native MSSA arthritis (n = 15; 22.7%), osteomyelitis (n = 19; 28.8%) or spondylodiscitis (n = 32; 48.5%), considered as "difficult-to-treat" in 61 cases (92.4%). All received a prolonged (27.1 weeks; IQR, 16.9-36.1) combined antimicrobial therapy, after surgical management in 37 cases (56.1%). Sixteen treatment failures (24.2%) were observed during a median follow-up period of 63.3 weeks (IQR, 44.7-103.1), including 13 persisting infections, 1 relapse after treatment disruption, and 2 super-infections. Independent determinants of treatment failure were the existence of a sinus tract (odds ratio [OR], 5.300; 95% confidence interval [CI], 1.166-24.103) and a prolonged delay to infectious disease specialist referral (OR, 1.134; 95% CI 1.013-1.271). CONCLUSIONS: The important treatment failure rate pinpointed the difficulty of cure encountered in complicated native MSSA BJI. An early infectious disease specialist referral is essential, especially in debilitated patients or in presence of sinus tract.

Kinetics of atrial repolarization alternans in a free-behaving ovine model.

Kinetics of Atrial Repolarization Alternans. INTRODUCTION: Repolarization alternans (Re-ALT), a beat-to-beat alternation in action potential repolarization, promotes dispersion of repolarization, wavebreaks, and reentry. Recently, Re-ALT has been shown to play an important role in the transition from rapid pacing to atrial fibrillation (AF) in humans. The detailed kinetics of atrial Re-ALT, however, has not been reported so far. We developed a chronic free-behaving ovine pacing model to study the kinetics of atrial Re-ALT as a function of pacing rate. METHODS: Thirteen sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms and delivery of rapid pacing protocols. Beat-to-beat differences in the atrial T-wave apex amplitude as a measure of Re-ALT and activation time were analyzed at incremental pacing rates until the effective refractory period (ERP) defined as stable 2:1 capture. RESULTS: Atrial Re-ALT appeared intermittently but without periodicity, and increased in amplitude as a function of pacing rate until ERP. Intermittent 2:1 atrial capture was observed at pacing cycle lengths 40 ms above ERP, and increased in duration as a function of pacing rate. Episodes of rapid pacing-induced AF were rare, and were preceded by Re-ALT or complex oscillations of atrial repolarization, but without intermittent capture. CONCLUSION: We show in vivo that atrial Re-ALT developed and increased in magnitude with rate until stable 2:1 capture. In rare instances where capture failure did not occur, Re-ALT and complex oscillations of repolarization surged and preceded AF initiation. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1003-1012, September 2012).

Comparison of the power spectral changes of the voluntary surface electromyogram and M wave during intermittent maximal voluntary contractions.

INTRODUCTION: To compare the power spectral changes of the voluntary surface electromyogram (sEMG) and of the compound action potential (M wave) in the vastus medialis and vastus lateralis muscles during fatiguing contractions. METHODS: Interference sEMG and force were recorded during 48 intermittent 3-s isometric maximal voluntary contractions (MVC) from 13 young, healthy subjects. M waves and twitches were evoked using supramaximal femoral nerve stimulation between the successive MVCs. Mean frequency (F mean), and median frequency were calculated from the sEMG and M waves. Muscle fiber conduction velocity (MFCV) was computed by cross-correlation. RESULTS: The power spectral shift to lower frequencies was significantly greater for the voluntary sEMG than for the M waves (P < 0.05). Over the fatiguing protocol, the overall average decrease in MFCV (~25 %) was comparable to that of sEMG F mean (~22 %), but significantly greater than that of M-wave F mean (~9 %) (P < 0.001). The mean decline in MFCV was highly correlated with the mean decreases in both sEMG and M-wave F mean. CONCLUSIONS: The present findings indicated that, as fatigue progressed, central mechanisms could enhance the relative weight of the low-frequency components of the voluntary sEMG power spectrum, and/or the end-of-fiber (non-propagating) components could reduce the sensitivity of the M-wave spectrum to changes in conduction velocity.

Identification of ectodysplasin target genes reveals the involvement of chemokines in hair development.

Ectodysplasin (Eda), a member of the tumor necrosis factor (Tnf) family, regulates skin appendage morphogenesis via its receptor Edar and transcription factor NF-κB. In humans, inactivating mutations in the Eda pathway components lead to hypohidrotic ectodermal dysplasia (HED), a syndrome characterized by sparse hair, tooth abnormalities, and defects in several cutaneous glands. A corresponding phenotype is observed in Eda-null mice, where failure in the initiation of the first wave of hair follicle development is a hallmark of HED pathogenesis. In an attempt to discover immediate target genes of the Eda/NF-κB pathway, we performed microarray profiling of genes differentially expressed in embryonic skin explants after a short exposure to recombinant Fc-Eda protein. Upregulated genes included components of the Wnt, fibroblast growth factor, transforming growth factor-β, Tnf, and epidermal growth factor families, indicating that Eda modulates multiple signaling pathways implicated in skin appendage development. Surprisingly, we identified two ligands of the chemokine receptor cxcR3, cxcl10 and cxcl11, as new hair-specific transcriptional targets of Eda. Deficiency in cxcR3 resulted in decreased primary hair follicle density but otherwise normal hair development, indicating that chemokine signaling influences the patterning of primary hair placodes only.

Relapsing acute respiratory failure induced by minocycline.

The antibiotic minocycline, which is used in the treatment of acne, has been associated with various pulmonary complications such as pulmonary lupus and hypersensitivity pneumonitis. We now report a particularly severe case of minocycline-related pulmonary toxicity that was characterized by a relapsing form of hypersensitivity eosinophilic pneumonia complicated by acute respiratory failure.

Learning from failure - rationale and design for a study about discontinuation of randomized trials (DISCO study).

BACKGROUND: Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. METHODS/DESIGN: Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. DISCUSSION: Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Autotransplant for Hodgkin lymphoma after failure of upfront BEACOPP escalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone).

BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) escalated is the preferred upfront Hodgkin lymphoma (HL) treatment in a number of countries. Upon failure, high-dose chemotherapy with autologous stem cell support (HDT/ASCT) is performed, but its effectiveness has not been verified in this setting. We analyzed all Swiss cases of chemosensitive HL autografted after failure of BEACOPP escalated (n = 22) and compared outcomes with 22 cases of HDT/ASCT following frontline ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) failure. Five-year progression-free survival (PFS) was 76% for ABVD and 42% for BEACOPP escalated (p = 0.029). Two- and 5-year overall survival (OS) was 90% and 71% for ABVD and 72% and 65% for BEACOPP escalated, respectively (p = not significant). Three patients in the ABVD and four in the BEACOPP escalated groups underwent allotransplant for relapse after HDT/ASCT. Grade 3-4 toxicities were comparable in both groups. Three cases of therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML) were recorded in the BEACOPP escalated group. The acceptable PFS and OS of chemosensitive patients with HL autografted after failure of upfront BEACOPP escalated seem to justify this approach.