The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance.

Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than €660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

Invasive meningococcal disease with fatal outcome in a Swiss student visiting Berlin.

Following the fatal invasive meningococcal disease in a Swiss student who had been visiting Berlin, several public health institutions on local, regional and national level cooperated to ensure that the appropriate measures such as contact tracing and post exposure prophylaxis were taken to prevent further cases. The incidence highlighted the importance of early disease notification and showed that if an infectious disease requiring public health action occurs in an international context, it is vital that relevant information is communicated to all levels of the public health systems of the countries involved.

Uniform risk of clinical progression despite differences in utilization of highly active antiretroviral therapy: Swiss HIV Cohort Study.

OBJECTIVE: To compare the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients according to sex, route of HIV acquisition and education, and to assess the impact of differences in utilization on the probability of progression to AIDS. DESIGN AND SETTING: Swiss HIV Cohort Study, a national prospective multi-centre study. PARTICIPANTS: A total of 3342 patients, including 1007 (30%) women. HIV was acquired through injection drug use in 1155 (35%) cases and through sex between men in 1172 (35%). Twenty-eight per cent (957) of participants had attained only the minimum level of schooling. At baseline, the median CD4 cell count was 269x10(6)/l cells, median HIV-1 RNA was 4.3 log10 copies/ml and 2917 (87%) were free of AIDS. METHODS: Kaplan-Meier life tables and Cox proportional hazards regression. RESULTS: During 7007 person-years of follow-up 2285 (69%) patients started HAART and 318 (10%) developed a new AIDS event. In multivariable analysis controlling for CD4 cell count, viral load and disease stage at baseline, the probability of starting HAART was lower in injection drug users compared with men who have sex with men, hazard ratio 0.63 (95% confidence intervals 0.56-0.70) and in patients with minimum schooling compared with those with vocational training, hazard ratio 0.82 (0.75-0.91). The risk of progression to AIDS was similar among men and women, patients with a history of injecting drug use, and patients with lower educational attainment in both univariable and multivariable analysis. CONCLUSION: HIV-infected injecting drug users and those with lower levels of educational attainment start HAART later than other patient groups. The deferred initiation of therapy in these patients does not, however, appear to translate into an increased risk of clinical disease progression. This observation has important implications for treatment policy and the design of future clinical trials.

Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS.

Because glutathione (GSH) in plasma and lymphocytes of HIV-infected patients is low, adjunct therapy with N-acetylcysteine (NAC) to restore GSH homeostasis has been proposed. To investigate the effect of NAC on the GSH status we treated six patients with AIDS with 1.8 g/day of NAC for 2 weeks. During treatment the plasma concentration of cysteine, a precursor for GSH synthesis, increased significantly. Nevertheless, there was no significant increase in GSH in plasma and peripheral blood mononuclear cells. The failure of sulfhydryl supplementation to increase GSH suggests that the low concentrations of the tripeptide are not the result of an increased consumption secondary to an oxidant stress, but rather the consequence of a decreased rate of synthesis of GSH in HIV infection.

Triennial Growth Symposium--Effects of dietary 25-hydroxycholecalciferol and cholecalciferol on blood vitamin D and mineral status, bone turnover, milk composition, and reproductive performance of sows.

To evaluate the role of vitamin D3 during gestation and lactation of sows, 2 independent experiments were performed with the aim of investigating sow reproductive performance, milk composition (study 1 only), and changes in blood status of 25-hydroxycholecalciferol (25-OH-D3), 1,25-dihydroxycholecalciferol (1,25-(OH)2-D3; study 2 only), minerals, and bone markers of sows during gestation and lactation. Study 1 comprised 39 primi- and multiparous crossbred sows fed 1 of 3 barley meal-based diets fortified with 200 IU/kg vitamin D3 (NRC, 1998; treatment DL), 2,000 IU/kg vitamin D3 (cholecalciferol; treatment DN), or 50 µg 25-OH-D3 (calcidiol; treatment HD)/kg feed. This study was conducted over a 4-parity period under controlled conditions. Study 2, running over 1 parity only, was performed in a commercial farm with 227 primi- and multiparous sows allocated to 2 dietary treatments: control (CON), receiving 2,000 IU vitamin D3/kg (equivalent to 50 µg/kg) feed (114 sows), and test (HYD), supplemented with 50 µg 25-OH-D3/kg feed (113 sows). Blood samples of sows were collected at 84 and 110d postcoitum and 1, 5, and 33 d postpartum (study 1) and at insemination and 28 and 80 d postinsemination as well as d 5 and 28 postpartum (study 2). Colostrum and milk samples in study 1 were obtained at 1, 9, and 33 d of lactation after oxytocin administration. Plasma 25-OH-D3 concentrations were increased (P < 0.05) in sows receiving 25-OH-D3 (HD and HYD) at any time of sampling whereas circulating plasma concentrations of 1,25-(OH)2-D3, Ca, and P were not affected by treatment. Milk concentrations of Ca and P were similar, but 25-OH-D3 content (except in colostrum) was clearly increased (P< 0.05) when 25-OH-D3 was fed. Most characteristics of sow reproductive performance responded similarly to the 2 sources and levels of vitamin D3, but weight gain of piglets between birth and weaning was decreased (P< 0.05) in offspring of DL and HD sows compared with animals of treatment DN (study 1). In study 2 total litter weight and birth weight per piglet were increased (P< 0.05) with 25-OH-D3 supplementation in comparison with the control (CON). Overall, feeding sows with 25-OH-D3 was considered to improve maternal supply with vitamin D3 and thereby maintain Ca homeostasis during gestation and lactation.

Effect of source and quantity of dietary vitamin D in maternal and creep diets on bone metabolism and growth in piglets.

Piglets are born with reduced plasma concentrations of 25-hydroxycholecalciferol (25-OH-D(3)) and are thus highly predisposed to vitamin D deficiency. Furthermore, sow milk contains little vitamin D, and the slow intestinal vitamin D absorption of sows limits the efficacy of dietary vitamin D supplementation. Hence, the neonate depends, to a large extent, on the vitamin D stores built up in fetal tissues from maternal sources. The current study was undertaken to evaluate whether the source and quantity of dietary vitamin D provided to the gestating and lactating sow, and also directly in the form of creep feed to the piglet, would influence the vitamin D status, growth performance, and skeletal development of piglets. A total of 39 primiparous and multiparous sows were randomly assigned to 1 of 3 dietary treatments (13 in each treatment), supplemented with either 5 or 50 µg of the commonly used cholecalciferol (vitamin D(3)) or 50 µg of 25-OH-D(3) per kilogram of feed. By wk 3 of lactation, piglets were offered a creep diet with vitamin D supplementation according to the treatment of the dam, and they were offered the same creep diets after weaning at d 35 of age until they reached a BW of approximately 20 kg. When dietary 25-OH-D(3) was provided, circulating concentrations of 25-OH-D(3) in piglet serum increased (P < 0.05) as early as d 21 and later at d 33 and 77, indicating greater body stores in those animals. Bone-breaking strength and cortical bone mineral content and density at the tibial midshaft of piglets were reduced (P < 0.05) when vitamin D(3) was supplemented at 5 µg/kg compared with the bone traits of other groups, but no differences (P > 0.05) were observed between the 2 other groups. After weaning, ADFI was greater (P < 0.05) and growth performance tended (P = 0.08) to improve when doses of 50 µg/kg were administered, regardless of the vitamin D source. In conclusion, supplementation of the diet with 50 µg/kg of either source of vitamin D was proved to be adequate in meeting the needs of gestating sows and in permitting the accumulation of vitamin D in fetal tissues, as well as for normal skeletal mineralization and growth in the offspring. Furthermore, the markedly improved vitamin D status of piglets whose mothers received 25-OH-D(3) possibly resulted from greater tissue reserves present at birth and a greater availability of vitamin D when released from those stores.

The systemic availability of oral glutathione.

When the plasma glutathione concentration is low, such as in patients with HIV infection, alcoholics, and patients with cirrhosis, increasing the availability of circulating glutathione by oral administration might be of therapeutic benefit. To assess the feasibility of supplementing oral glutathione we have determined the systemic availability of glutathione in 7 healthy volunteers. The basal concentrations of glutathione, cysteine, and glutamate in plasma were 6.2, 8.3, and 54 mumol.l-1 respectively. During the 270 min after the administration of glutathione in a dose of 0.15 mmol.kg-1 the concentrations of glutathione, cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemic availability of glutathione is negligible in man. Because of hydrolysis of glutathione by intestinal and hepatic gamma-glutamyltransferase, dietary glutathione is not a major determinant of circulating glutathione, and it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.

The hazards of scoring the quality of clinical trials for meta-analysis.

CONTEXT: Although it is widely recommended that clinical trials undergo some type of quality review, the number and variety of quality assessment scales that exist make it unclear how to achieve the best assessment. OBJECTIVE: To determine whether the type of quality assessment scale used affects the conclusions of meta-analytic studies. DESIGN AND SETTING: Meta-analysis of 17 trials comparing low-molecular-weight heparin (LMWH) with standard heparin for prevention of postoperative thrombosis using 25 different scales to identify high-quality trials. The association between treatment effect and summary scores and the association with 3 key domains (concealment of treatment allocation, blinding of outcome assessment, and handling of withdrawals) were examined in regression models. MAIN OUTCOME MEASURE: Pooled relative risks of deep vein thrombosis with LMWH vs standard heparin in high-quality vs low-quality trials as determined by 25 quality scales. RESULTS: Pooled relative risks from high-quality trials ranged from 0.63 (95% confidence interval [CI], 0.44-0.90) to 0.90 (95% CI, 0.67-1.21) vs 0.52 (95% CI, 0.24-1.09) to 1.13 (95% CI, 0.70-1.82) for low-quality trials. For 6 scales, relative risks of high-quality trials were close to unity, indicating that LMWH was not significantly superior to standard heparin, whereas low-quality trials showed better protection with LMWH (P<.05). Seven scales showed the opposite: high quality trials showed an effect whereas low quality trials did not. For the remaining 12 scales, effect estimates were similar in the 2 quality strata. In regression analysis, summary quality scores were not significantly associated with treatment effects. There was no significant association of treatment effects with allocation concealment and handling of withdrawals. Open outcome assessment, however, influenced effect size with the effect of LMWH, on average, being exaggerated by 35% (95% CI, 1%-57%; P= .046). CONCLUSIONS: Our data indicate that the use of summary scores to identify trials of high quality is problematic. Relevant methodological aspects should be assessed individually and their influence on effect sizes explored.

Mitochondrial function reflected by the decarboxylation of [13C]ketoisocaproate is impaired in alcoholics.

Mitochondria of patients with alcoholic liver disease exhibit structural abnormalities, and mitochondria isolated from animals exposed to ethanol are functionally deficient when studied in vitro. To assess possible functional consequences of these ethanol-associated alterations in vivo, we measured mitochondrial function in alcoholics noninvasively with a breath test. A mitochondrial function, the decarboxylation of ketoisocaproate (KICA), was assessed by measuring the exhalation of 13CO2 following the administration of 1 mg/kg 2-keto[1-13C]isocaproic acid, the decarboxylation of which occurs in mitochondria. The results of the KICA breath test in 12 alcoholic subjects were compared with the results in healthy controls and patients with nonalcoholic liver disease. The peak exhalation of 13CO2 and the fraction of the administered dose decarboxylated in 120 min were both significantly lower in alcoholics than in healthy controls and patients with nonalcoholic liver disease. In alcoholics, KICA decarboxylation was impaired in the presence of normal quantitative liver function tests such as the aminopyrine breath test and galactose elimination capacity, indicating that KICA decarboxylation does not simply reflect a decreased functional hepatic mass. The enrichment of circulating KICA with [13C]KICA was similar in alcoholics and controls, indicating that a decreased bioavailability or an increased dilution of labeled KICA cannot account for the decreased exhalation of 13CO2. It is concluded that mitochondrial function as reflected by KICA decarboxylation is impaired in chronic alcoholics. The functional impairment is specific for ethanol abuse and not a reflection of decreased global hepatic function. KICA decarboxylation could thus be useful as a marker for excessive ethanol consumption.

Transmission of human herpesvirus 8 infection from renal-transplant donors to recipients.

BACKGROUND: Human herpesvirus 8 (HHV-8) has been detected in all forms of Kaposi's sarcoma, including transplantation-associated Kaposi's sarcoma. To investigate the possibility of transmission of HHV-8 through allografts, we measured the seroprevalence of HHV-8 before and after renal transplantation. METHODS: Using an enzyme-linked immunosorbent assay with the recombinant HHV-8 protein orf 65.2, we analyzed serum samples from 220 renal-transplant recipients for the presence of antibodies to HHV-8 on the day of transplantation and one year later. Positive results were confirmed by an indirect immunofluorescence assay that detects antibodies to latent antigen and by Western blotting. Follow-up lasted at least four years. RESULTS: The seroprevalence of HHV-8 in graft recipients increased from 6.4 percent on the day of transplantation to 17.7 percent one year after transplantation. Seroconversion occurred within the first year after transplantation in 25 patients, and Kaposi's sarcoma developed in 2 of them within 26 months after transplantation. Sequential serum samples were obtained from 10 of the patients with seroconversion, and in 8 of these patients, IgM antibodies to HHV-8 appeared within three months after transplantation. In the case of six patients who seroconverted, serum samples from the donors were available, and five (83 percent) tested positive for HHV-8. In a control group of eight patients who were seronegative at the time of transplantation and who received allografts from HHV-8-negative donors, none seroconverted within the year after transplantation. CONCLUSIONS: HHV-8 is transmitted through renal allografts and is a risk factor for transplantation-associated Kaposi's sarcoma.

Colorectal intussusception: an unusual gastrointestinal complication of hereditary angioedema.

A 21-year-old man with a history of hereditary angioedema presented with protracted abdominal pain which failed to respond to infusion of C1 inhibitor concentrate. Evaluation by CT scan revealed extensive colorectal intussusception requiring surgical intervention. Under replacement therapy with C1 inhibitor concentrate, both the operation under general anesthesia and the postoperative phase were uneventful. The intraoperative examination suggested initiation of intussusception by local mucosal edema in the transverse colon.

Safety of heart-lung machines during prolonged standby.

BACKGROUND: Coronary artery bypass surgery is increasingly performed without an extra-corporeal circuit. A heart-lung machine (HLM) is kept on standby for safety reasons, but rarely used. The tubes of the machines are currently discarded after every operation. Costs and waste would be avoided if HLMs could stay on standby for longer periods of time. We therefore investigated the sterility of intra-tube fluid over time. MATERIALS AND METHODS: Four machines were tested. The tube system was fixed and filled with priming solution. Samples of intra-tube fluid and fluid from the fluid bags were taken after 0, 12, 24, 36, 48 and 72 h. Microbiological cultures were performed by direct inoculation and membrane filtration and incubated up to 14 days. Endotoxin levels were also determined. RESULTS: Bacteria were grown from two samples only and were considered as contaminants. Endotoxin concentrations never exceeded acceptable levels. CONCLUSION: To keep HLMs on standby for 72 h is probably safe. The prolonged use of HLMs will contribute to cost and waste reduction in open heart surgery.