How to interprete subclinical thyroid dysfunction in the prevention and management of heart failure events? Individual participant data analysis from six prospective cohorts

Background: Guidelines of the Diagnosis and Management of Heart Failure (HF) recommend investigating exacerbating conditions, such as thyroid dysfunction, but without specifying impact of different TSH levels. Limited prospective data exist regarding the association between subclinical thyroid dysfunction and HF events. Methods: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of HF events. Individual data on 25,390 participants with 216,247 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH 0.45-4.49 mIU/L, subclinical hypothyroidism as TSH 4.5-19.9 mIU/L and subclinical hyperthyroidism as TSH <0.45 mIU/L, both with normal free thyroxine levels. HF events were defined as acute HF events, hospitalization or death related to HF events. Results: Among 25,390 participants, 2068 had subclinical hypothyroidism (8.1%) and 648 subclinical hyperthyroidism (2.6%). In age- and gender-adjusted analyses, risks of HF events were increased with both higher and lower TSH levels (P for quadratic pattern<0.01): hazard ratio (HR) was 1.01 (95% confidence interval [CI] 0.81-1.26) for TSH 4.5-6.9 mIU/L, 1.65 (CI 0.84-3.23) for TSH 7.0-9.9 mIU/L, 1.86 (CI 1.27-2.72) for TSH 10.0-19.9 mIUL/L (P for trend <0.01), and was 1.31 (CI 0.88-1.95) for TSH 0.10-0.44 mIU/L and 1.94 (CI 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. Conclusion: Risks of HF events were increased with both higher and lower TSH levels, particularly for TSH ≥10 mIU/L and for TSH <0.10 mIU/L. Our findings might help to interpret TSH levels in the prevention and investigation of HF.

KIR-associated protection from CMV replication requires pre-existing immunity: a prospective study in solid organ transplant recipients.

Previous studies have associated activating Killer cell Immunoglobulin-like Receptor (KIR) genes with protection from cytomegalovirus (CMV) replication after organ transplantation. Whether KIR-associated protection is operating in the context of primary infection, re-activation, or both, remains unknown. Here we correlated KIR genotype and CMV serostatus at the time of transplantation with rates of CMV viremia in 517 heart (n=57), kidney (n=223), liver (n=165) or lung (n=72) allograft recipients reported to the Swiss Transplant Cohort Study. Across the entire cohort we found B haplotypes-which in contrast to A haplotypes may contain multiple activating KIR genes-to be protective in the most immunosuppressed patients (receiving anti-thymocyte globulin induction and intensive maintenance immunosuppression) (hazard ratio after adjustment for covariates 0.46, 95% confidence interval 0.29-0.75, P=0.002). Notably, a significant protection was detected only in recipients who were CMV-seropositive at the time of transplantation (HR 0.45, 95% CI 0.26-0.77, P=0.004), but not in CMV seronegative recipients (HR 0.59, 95% CI 0.22-1.53, P=0.28). These data indicate a prominent role for KIR-and presumably natural killer (NK) cells-in the control of CMV replication in CMV seropositive organ transplant recipients treated with intense immunosuppression.

Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study.

Patients with chronic obstructive pulmonary disease (COPD) often develop weight loss, which is associated with increased mortality. Recombinant human growth hormone (rhGH) treatment has been proposed to improve nitrogen balance and to increase muscle strength in these patients. The aim of this study was to assess the effects of rhGH administration on the nutritional status, resting metabolism, muscle strength, exercise tolerance, dyspnea, and subjective well-being of underweight patients with stable COPD. Sixteen patients attending a pulmonary rehabilitation program (age: 66 +/- 9 yr; weight: 77 +/- 7% of ideal body weight; FEV1: 39 +/- 13% of predicted) were randomly treated daily with either 0.15 IU/kg rhGH or placebo during 3 wk in a double-blind fashion. Measurements were made at the beginning (DO) and at the end (D21) of treatment and 2 mo later (D81). Body weight was similar in the two groups during the study, but lean body mass was significantly higher in the rhGH group at D21 (p < 0.01) and D81 (p < 0.05). The increase in lean body mass was 2.3 +/- 1.6 kg in the rhGH group and 1.1 +/- 0.9 kg in the control group at D21 and 1.9 +/- 1.6 kg in the rhGH group and 0.7 +/- 2.1 kg in the control group at D81. At D21, the resting energy expenditure was increased in the rhGH group (107.8% of DO, p < 0.001 compared with the control group). At D21 and D81, the changes in maximal respiratory pressures, handgrip strength, maximal exercise capacity, and subjective well-being were similar in the two groups. At D21, the 6-min walking distance decreased in the rhGH group (-13 +/- 31%) and increased in the control group (+10 +/- 14%; p < 0.01). We conclude that the daily administration of 0.15 IU/kg rhGH during 3 wk increases lean body mass but does not improve muscle strength or exercise tolerance in underweight patients with COPD.

Postnatal intracerebroventricular administrations of NGF alter spatial memory in adulthood

The present work assessed the effects of intracerebroventricular injections (2x5 mg/2.5 ml) of recombined human nerve growth factor (rhNGF) at postnatal days 2 and 3 upon the development of spatial learning capacities in rats. The treated rats were trained at the age of 22 days to escape onto an invisible platform at a fixed position in space in a Morris navigation task. For half of the subjects, the training position was also cued, a procedure aimed at facilitating escape and reducing attention to the distant spatial cues. At the age of 2 months all the rats were retrained in the same task. Treatment effects were found in both immature and adult rats. The injection of NGF induced a slight alteration of the immature rats' performance. In contrast, a marked impairment of spatial abilities was shown in the 2-month-old rats. The most consistent effects were a significant increase in the escape latency and a decrease bias towards the training platform area during probe trials. The reduction of spatial memory was particularly marked if the subjects had been trained in a cued condition. Taken together, these experiments reveal that an acute pharmacological treatment that leads to transient modifications during early development might induce a behavioural change long after treatment. Thus, the development and the maintenance of an accurate spatial representation are tightly related to the development of brain structures that could be altered by precocious NGF administrations.

Cerebellar lesions: is there a lateralisation effect on memory deficits?

BACKGROUND: Until recently, neurosurgeons eagerly removed cerebellar lesions without consideration of future cognitive impairment that might be caused by the resection. In children, transient cerebellar mutism after resection has lead to a diminished use of midline approaches and vermis transection, as well as reduced retraction of the cerebellar hemispheres. The role of the cerebellum in higher cognitive functions beyond coordination and motor control has recently attracted significant interest in the scientific community, and might change the neurosurgical approach to these lesions. The aim of this study was to investigate the specific effects of cerebellar lesions on memory, and to assess a possible lateralisation effect. METHODS: We studied 16 patients diagnosed with a cerebellar lesion, from January 1997 to April 2005, in the "Centre Hospitalier Universitaire Vaudois (CHUV)", Lausanne, Switzerland. Different neuropsychological tests assessing short term and anterograde memory, verbal and visuo-spatial modalities were performed pre-operatively. RESULTS: Severe memory deficits in at least one modality were identified in a majority (81%) of patients with cerebellar lesions. Only 1 patient (6%) had no memory deficit. In our series lateralisation of the lesion did not lead to a significant difference in verbal or visuo-spatial memory deficits. FINDINGS: These findings are consistent with findings in the literature concerning memory deficits in isolated cerebellar lesions. These can be explained by anatomical pathways. However, the cross-lateralisation theory cannot be demonstrated in our series. The high percentage of patients with a cerebellar lesion who demonstrate memory deficits should lead us to assess memory in all patients with cerebellar lesions.

Prospective determination of plasma imipenem concentrations in critically ill children.

Plasma imipenem concentrations were measured in 19 critically ill children (median age, 0.8 year; range, 0.02 to 12.9 years). Wide interindividual variations (2 to 4x at peak and >10x at trough concentrations) resulted in unpredictable plasma levels in several children. To avoid subtherapeutic drug levels, we recommend treatment with at least 100 mg/kg of body weight/day of imipenem-cilastatin for critically ill children requiring such therapy.

Visuospatial working memory deficits and visual pursuit impairments are not directly related in schizophrenia.

OBJECTIVE: Patients with schizophrenia show deficits in visuospatial working memory and visual pursuit processes. It is currently unclear, however, whether both impairments are related to a common neuropathological origin. The purpose of the present study was therefore to examine the possible relations between the encoding and the discrimination of dynamic visuospatial stimuli in schizophrenia. METHOD: Sixteen outpatients with schizophrenia and 16 control subjects were asked to encode complex disc displacements presented on a screen. After a delay, participants had to identify the previously presented disc trajectory from a choice of six static linear paths, among which were five incorrect paths. The precision of visual pursuit eye movements during the initial presentation of the dynamic stimulus was assessed. The fixations and scanning time in definite regions of the six paths presented during the discrimination phase were investigated. RESULTS: In comparison with controls, patients showed poorer task performance, reduced pursuit accuracy during incorrect trials and less time scanning the correct stimulus or the incorrect paths approximating its global structure. Patients also spent less time scanning the leftmost portion of the correct path even when making a correct choice. The accuracy of visual pursuit and head movements, however, was not correlated with task performance. CONCLUSIONS: The present study provides direct support for the hypothesis that active integration of visuospatial information within working memory is deficient in schizophrenia. In contrast, a general impairment of oculomotor mechanisms involved in smooth pursuit did not appear to be directly related to lower visuospatial working memory performance in schizophrenia.

A Candidate HIV/AIDS Vaccine (MVA-B) that Enhances the Magnitude and Polyfunctionality of Memory HIV-1-Specific T-Cell Responses

Background: The poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (MVA-B) is currently used as a HIV/AIDS vaccine candidate. A general strategy to try to improve the immunogenicity of poxvirus HIV-1 vaccine candidates is the deletion of known or suggested immunomodulatory vaccinia virus (VACV) genes.Methods: We have generated and characterized the innate immune sensing and the immunogenicity profile of a new HIV-1 vaccine candidate, which contains a deletion in a VACV gene.Results: We show that this VACV protein is expressed early during virus infection and localizes to the cytoplasm of infected cells. Deletion of this VACV gene from the MVA-B had no effect on virus growth kinetics; therefore this VACV protein is not essential for virus replication. The innate immune signals elicited by the MVA-B deletion mutant in human macrophages and monocyte-derived dendritic cells were characterized. In a DNA prime/MVA boost immunization protocol in mice, flow cytometry analysis revealed that the MVA-B deletion mutant enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4 + and CD8 + T-cell memory immune responses, with most of the HIV-1 responses mediated by the CD8 + T-cell compartment with an effector phenotype. Significantly, while MVA-B induced preferentially Env- and Gag-specific CD8 + T-cell responses, the MVA-B deletion mutant induced more GPN-specific CD8 + T-cell responses. Furthermore, the MVA-B deletion mutant enhanced the levels of antibodies against Env in comparison with MVA-B.Conclusion: These findings revealed that this new VACV protein can be considered as an immunomodulator and that deleting this gene in MVA-B confers an immunological benefit by inducing innate immune responses and increasing the magnitude and quality of the T-cell memory immune responses to HIV-1 antigens. Our observations are relevant for the improvement of MVA vectors as HIV-1 vaccines.

Prolonged fluconazole exposure leads to a shift to Candida species with decreased susceptibility in breakthrough candidemia: prospective survey of the Fungal Infection Network of Switzerland

Objectives: To compare the clinical characteristics, species distribution and antifungal susceptibility of Candida bloodstream isolates (BSI) in breakthrough (BTC) vs. non-breakthrough candidemia (NBTC) and to study the effect of prolonged vs. short fluconazole (F) exposure in BTC.Methods: Candida BSI were prospectively collected during 2004- 2006 from 27 hospitals (seven university, 20 affiliated) of the FUNGINOS network. Susceptibility to F, voriconazole (V) and caspofungin (C) was tested in the FUNGINOS mycology reference laboratory by microtitre broth dilution method with the Sensititre YeastOneTM test panel. Clinical data were collected using standardized CRFs. BTC was defined as occurring during antifungal treatment/prophylaxis of at least three days duration prior to the candidemia. Susceptibility of BSI was defined according to 2010/2011 CLSI clinical breakpoints.Results: Out of 567 candidemia episodes, 550 Candida BSI were available. Of these, 43 (7.6%) were from BTC (37/43, 86% were isolated after F exposure). 38 BTC (88.4%) and 315 NBTC (55.6%) occurred in university hospitals (P < 0.001). The majority of patients developing BTC were immunocompromised: higher proportions of haematological malignancies (62.8% in BTC vs. 47.1% in NBTC, P < 0.001), neutropenia (37.2% vs. 11.8%, P < 0.001), acute GvHD (14% vs. 0.2%, P < 0.001), immunosuppressive drugs (74.4% vs. 7.8%, P < 0.001), and mucositis (32.6% vs. 2.3%, P < 0.001) were observed. Other differences between BTC and NBTC were higher proportions of patients with central venous catheters in the 2 weeks preceding candidemia (95.3% vs. 83.4%, P = 0.047) and receiving total parenteral nutrition (62.8% vs. 35.9%, P < 0.001), but a lower proportion of patients treated with gastric proton pump inhibitors (23.3% vs. 72.1%, P < 0.001). Overall mortality of BTC and NBTC was not different (34.9% vs. 31.7%, P = 0.73), while a trend to higher attributable mortality in BTC was found (13.9% vs. 6.9%, P = 0.12). Species identification showed a majority of C. albicans in both groups (51.2% in BTC vs. 62.9% in NBTC, P = 0.26), followed by C. glabrata (18.6% vs. 18.5%), C. tropicalis (2.3% vs. 6.3%) and C. parapsilosis (7.0% vs. 4.7%). Significantly more C. krusei were detected in BTC versus NBTC (11.6% vs. 1.6%, P = 0.002). The geometric mean MIC for F, V and C between BTC and NBTC isolates was not significantly different. However, in BTC there was a significant association between duration of F exposure and the Candida spp.: >10 days of F was associated with a significant shift from susceptible Candida spp. (C. albicans, C. parapsilosis, C. tropicalis, C. famata) to non-susceptible species (C. glabrata, C. krusei, C. norvegensis). Among 21 BTC episodes occurring after £10 days of F, 19% of the isolates were non-susceptible, in contrast to 68.7% in 16 BTC episodes occurring after >10 days of F (P = 0.003).Conclusions: Breakthrough candidemia occurred more often in immunocompromised hosts. Fluconazole administered for >10 days was associated with a shift to non-susceptible Candida spp.. Length of fluconazole exposure should be taken into consideration for the choice of empirical antifungal treatment.

Gadolinium-enhanced pulmonary magnetic resonance angiography in the diagnosis of acute pulmonary embolism: a prospective study on 48 patients.

OBJECTIVE: Gadolinium-enhanced pulmonary magnetic resonance angiography (MRA) can be an option in patients with a history of previous adverse reaction to iodinated contrast material and renal insufficiency. Radiation is also avoided. The aim of this study is to prospectively compare the diagnostic value of MRA with that of a diagnostic strategy, taking into account catheter angiography, computed tomography angiography (CTA), and lung scintigraphy [ventilation-perfusion (VQ)]. MATERIAL AND METHODS: Magnetic resonance angiography was done in 48 patients with clinically suspected pulmonary embolism (PE) using fast gradient echo coronal acquisition with gadolinium. Interpretation was done with native coronal images and multiplanar maximum intensity projection reconstructions. Results were compared to catheter angiography (n=15), CTA (n=34), VQ (n=45), as well as 6-12 months clinical follow-ups, according to a sequenced reference tree. RESULTS: The final diagnosis of PE was retained in 11 patients (23%). There were two false negatives and no false positive results with MRA. Computed tomography angiography resulted in no false negatives or false positives. Magnetic resonance angiography had a sensitivity of 82% and a specificity of 100%. CONCLUSION: In our study, pulmonary MRA had a sensitivity of 82% and a specificity of 100% for the diagnosis of PE, with slightly less sensitivity than CTA. In the diagnostic algorithm of PE, pulmonary MRA should be considered as an alternative to CTA when iodine contrast injection or radiation is a significant matter.

A prospective observational safety study on MF59(®) adjuvanted cell culture-derived vaccine, Celtura(®) during the A/H1N1 (2009) influenza pandemic.

BACKGROUND: The present study was a prospective observational study to evaluate the safety profile of Celtura(®), a monovalent, cell culture-derived, inactivated subunit influenza vaccine prepared from A/California/07/2009(H1N1) with the adjuvant MF59(®). Subjects were enrolled prospectively during the H1N1 2009 influenza pandemic at medical centres in Colombia, Chile, Switzerland, and Germany during the period December 2009 to June 2010. METHODS: Subjects ages 18 and older were followed for the occurrence of adverse events (AEs) for six months after vaccination. Adverse events of special interest (AESIs) were neuritis, convulsion (seizure), anaphylaxis, encephalitis, vasculitis, Guillain-Barre syndrome, demyelinating conditions, Bell's palsy, and laboratory-confirmed vaccination failure. RESULTS: Overall, 7348 AEs were reported in 2296 of 3989 enrolled subjects (57.6%). Only two AEs were considered related to injection site reactions. No laboratory-confirmed cases of influenza were reported. There were 108 medically confirmed serious adverse events (SAEs) reported among 73 subjects with 6 such SAEs described as possibly or probably related to vaccination. Three fatal cases were reported and assessed as not related to vaccination. Two AESIs classified as convulsion were reported and assessed as not related to vaccination. Both AESIs occurred well outside the pre-specified 7 day risk window representing the likely timeframe of the occurrence of seizure following vaccination. CONCLUSIONS: The results of this study support the overall good safety profile of MF59 adjuvanted cell culture-derived influenza vaccine as administered in adults during the 2009-2010 H1N1 influenza pandemic. No concern is raised regarding the occurrence of AESIs.

Auditory stimulation does not induce implicit memory during anaesthesia

Background and aim of the study: Formation of implicit memory during general anaesthesia is still debated. Perceptual learning is the ability to learn to perceive. In this study, an auditory perceptual learning paradigm, using frequency discrimination, was performed to investigate the implicit memory. It was hypothesized that auditory stimulation would successfully induce perceptual learning. Thus, initial thresholds of the frequency discrimination postoperative task should be lower for the stimulated group (group S) compared to the control group (group C). Material and method: Eighty-seven patients ASA I-III undergoing visceral and orthopaedic surgery during general anaesthesia lasting more than 60 minutes were recruited. The anaesthesia procedure was standardized (BISR monitoring included). Group S received auditory stimulation (2000 pure tones applied for 45 minutes) during the surgery. Twenty-four hours after the operation, both groups performed ten blocks of the frequency discrimination task. Mean of the thresholds for the first three blocks (T1) were compared between groups. Results: Mean age and BIS value of group S and group C are respectively 40 } 11 vs 42 } 11 years (p = 0,49) and 42 } 6 vs 41 } 8 (p = 0.87). T1 is respectively 31 } 33 vs 28 } 34 (p = 0.72) in group S and C. Conclusion: In our study, no implicit memory during general anaesthesia was demonstrated. This may be explained by a modulation of the auditory evoked potentials caused by the anaesthesia, or by an insufficient longer time of repetitive stimulation to induce perceptual learning.