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Objective: To assess the benefits and harms of targeting intensive versus conventional glycaemic control in patients with type 1 diabetes mellitus. Design: A systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. Data sources: The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded and LILACS to January 2013. Study selection: Randomised clinical trials that prespecified different targets of glycaemic control in participants at any age with type 1 diabetes mellitus were included. Data extraction: Two authors independently assessed studies for inclusion and extracted data. Results: 18 randomised clinical trials included 2254 participants with type 1 diabetes mellitus. All trials had high risk of bias. There was no statistically significant effect of targeting intensive glycaemic control on all-cause mortality (risk ratio 1.16, 95% CI 0.65 to 2.08) or cardiovascular mortality (0.49, 0.19 to 1.24). Targeting intensive glycaemic control reduced the relative risks for the composite macrovascular outcome (0.63, 0.41 to 0.96; p=0.03), and nephropathy (0.37, 0.27 to 0.50; p<0.00001. The effect estimates of retinopathy, ketoacidosis and retinal photocoagulation were not consistently statistically significant between random and fixed effects models. The risk of severe hypoglycaemia was significantly increased with intensive glycaemic targets (1.40, 1.01 to 1.94). Trial sequential analyses showed that the amount of data needed to demonstrate a relative risk reduction of 10% were, in general, inadequate. Conclusions: There was no significant effect towards improved all-cause mortality when targeting intensive glycaemic control compared with conventional glycaemic control. However, there may be beneficial effects of targeting intensive glycaemic control on the composite macrovascular outcome and on nephropathy, and detrimental effects on severe hypoglycaemia. Notably, the data for retinopathy and ketoacidosis were inconsistent. There was a severe lack of reporting on patient relevant outcomes, and all trials had poor bias control. [ABSTRACT FROM AUTHOR]

Background: Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant. Methods: Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1. From one of the clade A Envs both the monomeric and trimeric Env were produced for comparison. Rabbits were immunized with soluble gp120 or trimeric gp140 proteins in combination with the adjuvant dimethyl dioctadecyl ammonium/trehalose dibehenate (CAF01). Env binding in rabbit immune serum was determined using ELISAs based on gp120-IIIB protein. Neutralizing activity of IgG purified from rabbit immune sera was measured with the pseudovirus-TZMbl assay and a PBMC-based neutralization assay for selected experiments. Results: It was initially established that gp140 trimers induce better antibody responses over gp120 monomers and that the adjuvant CAF01 was necessary for such strong responses. Gp140 trimers, based on HIV-1 variants from patients with bNAbs, were able to elicit both gp120IIIB specific IgG and NAbs to Tier 1 viruses of different subtypes. Potency of NAbs closely correlated with titers, and an gp120-binding IgG titer above a threshold of 100,000 was predictive of neutralization capability. Finally, peptide inhibition experiments showed that a large fraction of the neutralizing IgG was directed against the gp120 V3 region. Conclusions: Our results indicate that the strategy of reverse immunology based on selected Env sequences is promising when immunogens are delivered as stabilized trimers in CAF01 adjuvant and that the rabbit is a valuable model for HIV vaccine studies. [ABSTRACT FROM AUTHOR]

Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutralizing activity against homologous and heterologous viruses. In the present study, we generated a recombinant trimeric soluble gp140, derived from a previously identified Ugandan A-clade HIV field isolate (gp14094UG018). Antibodies elicited in immunized rabbits show a broad binding pattern to HIV envelopes of different clades. An epitope mapping analysis reveals that, on average, the binding is mostly focused on the C1, C2, V3, V5 and C5 regions. Immune sera show neutralization activity to Tier 1 isolates of different clades, demonstrating cross clade neutralizing activity which needs to be further broadened by possible structural modifications of the clade A gp14094UG018. Our results provide a rationale for the design and evaluation of immunogens and the clade A gp14094UG018 shows promising characteristics for potential involvement in an effective HIV vaccine with broad activity. [ABSTRACT FROM AUTHOR]

Background: Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2.Methods/design: SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the 'burden of hypoxia and hyperoxia' expressed in '%hours'. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events.Discussion: Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia.Trial Registration: ClinicalTrial.gov, NCT01590316. [ABSTRACT FROM AUTHOR]

Abstract: The New Zealand white rabbit model (Oryctolagus cuniculus) is widely used to test whether HIV vaccine candidates elicit systemic antibody responses; however, its use in mucosal immunology has not been fully exploited due to the difficulty in collecting mucosal specimens longitudinally and reproducibly. Here we describe feasible and non-feasible methods to collect vaginal and nasal specimens from nulliparous rabbits. Non-feasible methods were those resulting in poor reproducibility and considerable animal twitching during sampling, whereas feasible methods resulted in no animal twitching and potential for sampling reproducibility. Standard operating procedures (SOPs) were implemented to collect vaginal swabs yielding total IgA titres ranging from 12,500 to 312,500. Intranasal immunisation with a naked DNA vaccine encoding HIV gp140 elicited HIV envelope-specific IgA detectable in nasal but not in vaginal secretions. Our methods provide an alternative to reliably assess pre- and post-vaccination mucosal antibody titres longitudinally in rabbits as part of mucosal HIV vaccine immunogenicity studies. [ABSTRACT FROM AUTHOR]

Objective: To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry., Design: Phase II randomised, single blinded, parallel clinical trial., Setting: Eight tertiary neonatal intensive care units in eight European countries., Participants: 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support., Interventions: Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control)., Main Outcome Measures: The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography., Randomisation: Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥ 26 weeks)., Blinding: Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation., Results: The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device., Conclusions: Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring.Trial registration ClinicalTrial.gov NCT01590316., (© Hyttel-Sorensen et al 2015.)

Background: Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C virus worldwide is about 150 million people. Every year, another three to four million people acquire the infection. Chronic hepatitis C is a leading cause of liver-related mortality and morbidity. It is estimated that around 5% to 20% of people with the infection will develop liver cirrhosis, which increases the risk of hepatocellular carcinoma and liver failure. Until 2011, the combination therapy of pegylated interferon-alpha (peginterferon) and ribavirin was the approved standard treatment for chronic hepatitis C. In 2011, first-generation direct-acting antivirals have been licensed, for use in combination with peginterferon and ribavirin for treating hepatitis C virus genotype 1 infection. Nitazoxanide is another antiviral drug with broad antiviral activity and may have potential as an effective alternative, or an addition to standard treatment for the treatment of the hepatitis C virus., Objectives: To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection., Search Methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (last searched April 2013), The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 3), MEDLINE (Ovid SP, 1948 to April 2013), EMBASE (Ovid SP, 1980 to April 2013), LILACS (1983 to April 2013), and Science Citation Index EXPANDED (ISI Web of Knowledge, 1900 to April 2013), using the search strategies and the expected time spans. We also scanned reference lists of identified studies.We also searched ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform search portal for registered trials, either completed or ongoing (April 2013)., Selection Criteria: We included randomised clinical trials that examined the effects of nitazoxanide versus placebo, no intervention, or any other intervention in patients with chronic hepatitis C. We considered any co-intervention, including standard treatment, if delivered to all intervention groups of the randomised trial concerned., Data Collection and Analysis: Two review authors extracted data independently. We assessed the risk of systematic errors ('bias') by evaluation of bias risk domains. We used Review Manager 5.2 for the statistical analyses of dichotomous outcome data with risk ratio (RR) and of continuous outcome data with mean difference (MD). For meta-analyses, we used a fixed-effect model and a random-effects model, along with an assessment of heterogeneity. We assessed risk of random errors ('play of chance') using trial sequential analysis. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to present review results in 'Summary of findings' tables., Main Results: We included seven randomised clinical trials with a total of 538 participants with chronic hepatitis C. Participants were 18 years of age or older, all diagnosed with chronic hepatitis C genotype 1 or 4. All of the trials had a high risk of bias. All of the trials compared nitazoxanide with placebo or no intervention, and six out of seven of the trials included different antiviral co-interventions administered equally to all intervention groups. Only one trial, comparing nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin, provided information that there were no deaths due to any cause or due to chronic hepatitis C (100 participants, very low quality evidence). The relative effect of nitazoxanide versus placebo or no intervention on adverse events was uncertain (37 out of 179 (21%) versus 30 out of 152 (20%); RR 1.10; 95% CI 0.71 to 1.71; I(2) = 65%; four trials; very low quality evidence). Nitazoxanide decreased the risk of failure to achieve sustained virological response when compared with placebo or no intervention (159 out of 290 (55%) versus 133 out of 208 (64%); RR 0.85; 95% CI 0.75 to 0.97; I(2) = 0%; seven trials; low quality evidence) and also the risk of failure to achieve virological end-of-treatment response (125 out of 290 (43%) versus 110 out of 208 (53%); RR 0.81; 95% CI 0.69 to 0.96; I(2) = 46%; seven trials; low quality evidence). Trial sequential analysis supported the meta-analysis result for sustained virological response, but not the meta-analysis for virological end-of-treatment response. Meta-analysis also showed that nitazoxanide did not decrease the number of participants who showed no improvement in alanine aminotransferase and aspartate aminotransferase serum levels when compared with placebo or no intervention (52 out of 97 (54%) versus 47 out of 95 (49%); RR 1.09; 95% CI 0.84 to 1.42; I(2) = 0%; three trials; very low quality evidence). None of the included trials assessed the effects of nitazoxanide on morbidity or on quality of life. Histological changes were only reported on a subset of three participants out of thirteen participants included in a long term-follow-up trial., Authors' Conclusions: We found very low quality, or no, evidence on nitazoxanide for clinically- or patient-relevant outcomes, such as all-cause mortality, chronic hepatitis C-related mortality, morbidity, and adverse events in participants with chronic hepatitis C genotype 1 or 4 infection. Our results of no improvement in alanine aminotransferase and aspartate aminotransferase serum levels were also uncertain. No conclusion could be drawn about liver histology because of a lack of data. Our results indicate that nitazoxanide might have an effect on sustained virological response and virological end-of-treatment response. However, both results could be influenced by systematic errors because all the trials included in the review had a high risk of bias. Furthermore, only the beneficial effect on number of participants achieving sustained virological response was supported when we applied trial sequential analysis. The results on virological end-of-treatment response might, therefore, be caused by a random error. We totally lack information on the effects of nitazoxanide in participants with chronic hepatitis C genotypes 2 or 3 infection. More randomised clinical trials with a low risk of bias are needed to assess the effects of nitazoxanide for chronic hepatitis C.

HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques.

Background: The acquisition of immunoglobulin (Ig) G to variant surface antigens (VSAs) seems important for the development of protective immunity against malaria. Unlike VSAs expressed by parasite isolates associated with uncomplicated malaria, VSAs expressed by parasite isolates associated with severe malaria (VSA(SM)) are frequently recognized by IgG., Methods: We analyzed levels of anti-VSA IgG in 57 individuals in Daraweesh, Sudan, before and after the transmission season. IgG responses to 79 Plasmodium falciparum isolates from children with defined malaria syndromes and exposed to high transmission in a different part of Africa were also analyzed., Results: After the transmission season, individuals with malaria had an increase in IgG recognition to 25.8% (95% confidence interval [CI], 19.9%-31.7%) and a decrease in IgG recognition to 7.6% (95% CI, 4.4%-10.8%) of 79 parasite isolates, and individuals without malaria had an increase in IgG recognition to 8.1% (95% CI, 6.0%-10.2%) and a decrease in IgG recognition to 11.9% (95% CI, 7.0%-16.8%) of 79 parasite isolates. Most newly acquired IgG responses were against parasite isolates expressing VSAs(SM) that are frequently recognized by IgG., Conclusions: Anti-VSA IgG levels decrease in the absence of infection, and an episode of clinical malaria induces IgG against a range of VSAs, particularly VSAs(SM).

The slow acquisition of protection against Plasmodium falciparum malaria probably reflects the extensive diversity of important antigens. The variant surface antigens (VSA) that mediate parasite adhesion to a range of host molecules are regarded as important targets of acquired protective immunity, but their diversity makes them questionable vaccine candidates. We determined levels of VSA-specific immunoglobulin G (IgG) in human plasma collected at four geographically distant and epidemiologically distinct localities with specificity for VSA expressed by P. falciparum isolates from three African countries. Plasma levels of VSA-specific IgG recognizing individual parasite isolates depended on the transmission intensity at the site of plasma collection but were largely independent of the geographical origin of the parasites. The total repertoire of immunologically distinct VSA thus appears to be finite and geographically conserved, most likely due to functional constraints. Furthermore, plasma samples frequently had high IgG reactivity to VSA expressed by parasites isolated more than 10 years later, showing that the repertoire is also temporally stable. Parasites from patients with severe malaria expressed VSA (VSASM) that were better recognized by plasma IgG than VSA expressed by other parasites, but importantly, VSASM-type antigens also appeared to show substantial antigenic homogeneity. Our finding that the repertoire of immunologically distinct VSA in general, and in particular that of VSASM, is geographically and temporally conserved raises hopes for the feasibility of developing VSA-based vaccines specifically designed to accelerate naturally acquired immunity, thereby enhancing protection against severe and life-threatening P. falciparum malaria.