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Background Endoscopic ultrasound-guided biliary drainage (EUS-BD) was associated with better clinical success and a lower rate of adverse events (AEs) than fluoroscopy-guided percutaneous transhepatic biliary drainage (PTBD) in recent single center studies with mainly retrospective design and small case numbers (< 50). The aim of this prospective European multicenter study is to compare both drainage procedures using ultrasound-guidance and primary metal stent implantation in patients with malignant distal bile duct obstruction (PUMa Trial). Methods The study is designed as a non-randomized, controlled, parallel group, non-inferiority trial. Each of the 16 study centers performs the procedure with the best local expertise (PTBD or EUS-BD). In PTBD, bile duct access is performed by ultrasound guidance. EUS-BD is performed as an endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS), EUS-guided choledochoduodenostomy (EUS-CDS) or EUS-guided antegrade stenting (EUS-AGS). Insertion of a metal stent is intended in both procedures in the first session. Primary end point is technical success. Secondary end points are clinical success, duration pf procedure, AEs graded by severity, length of hospital stay, re-intervention rate and survival within 6 months. The target case number is 212 patients (12 calculated dropouts included). Discussion This study might help to clarify whether PTBD is non-inferior to EUS-BD concerning technical success, and whether one of both interventions is superior in terms of efficacy and safety in one or more secondary endpoints. Randomization is not provided as both procedures are rarely used after failed endoscopic biliary drainage and study centers usually prefer one of both procedures that they can perform best. Trial registration ClinicalTrials.gov ID: NCT03546049 (22.05.2018).

[Background and purpose] Screening for and treatment of latent tuberculosis (TB) in patients with end-stage kidney disease (ESKD) are recommended. However, there is limited evidence on safety and treatment completion in this population. The objective of the study is to evaluate three short-course rifamycin-based regimens for the treatment of latent TB in ESKD patients., [Methods] Study design and setting. This is a prospective, open label, randomized clinical trial, that will be conducted at seven teaching hospitals in Spain. Study population, randomization, and interventions. Consecutive adult patients with ESKD requiring treatment for a latent TB infection will be randomly allocated (1:1:1) to receive one of the three treatment regimens of the study: three months of daily isoniazid plus rifampicin (3HR); three months of once-weekly isoniazid plus rifapentine (3HP); or four months of daily rifampicin (4R). Participants will be followed regularly through pre-established visits and a blood test schedule from enrolment to a month after finishing the assigned treatment. Outcomes. The primary outcome will be treatment completion, while the secondary outcomes will be discontinuation of the assigned treatment due to adverse events, related or unrelated to the study treatment; definitive discontinuation of the assigned treatment because of adverse events related to the treatment of the study, and death. Sample size. Two hundred and twenty-five subjects (75 per arm) will be enrolled, which will enable the demonstration, if it exists, of an increase of 0.16 in treatment completion rates either in the 3HP or 4R arm with respect to the 3HR arm., [Discussion] Results of this clinical trial will contribute to evidence-based recommendations on the management of latent TB infection in ESKD patients., [Trial registration] ClinicalTrials.gov identifier: NCT05021731., This study is funded by the Instituto de Salud Carlos III through the grant “21/004444” (co-funded by the European Regional Development Fund/European Social Fund, “Investing in Your Future”).

This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA

In a recent paper, Nagpal et al. [1] voiced concerns about the limited or biased use of scientific evidence to support public health interventions to control neglected tropical diseases (NTDs). Visceral leishmaniasis (VL), also known as kala-azar, is one of the major NTDs and does not escape this problem. Transmission is vector-borne and the Indian subcontinent is the region reporting most of the VL cases worldwide. In this region, the main causative species is Leishmania donovani and Phlebotomus argentipes is the vector. Transmission is considered anthroponotic and peridomestic—occurring at night when female sand flies bite people sleeping inside their house. The World Health Organization and the governments of India, Nepal, and Bangladesh set out in 2005 to eliminate VL from the region by 2015 through a combination of early treatment of cases and vector control. However, while recent advances in diagnostic tools and drugs have significantly improved case management strategies, the available vector control tools against P. argentipes remain limited. The elimination initiative promotes the use of indoor residual spraying (IRS) of households and cattle sheds to reduce vector density, but the evidence underpinning the effectiveness of IRS in this region is scanty. Historical observations show that L. donovani transmission declined concomitantly with dichlorodiphenyltrichloroethane (DDT) spraying during the 1950s–60s to eradicate malaria. In the aftermath of this malaria eradication campaign, very few VL cases were observed in endemic regions until the mid-seventies, when there was resurgence of a VL epidemic in India [2]. To date, there are no randomized trials showing the effect of IRS on the incidence of clinical VL [3,4], though some studies showed a reduction in vector density. When the VL elimination initiative was launched in 2005, there were no clear alternatives for IRS as a vector control strategy. Insecticide treated nets (ITNs) were proposed as an alternative or complement to IRS on the basis of analogy arguments regarding their given efficacy against malaria [5] or on data from observational studies suggesting ITNs reduce the risk of VL [2]; but as for IRS, there were no randomized trials evaluating the effect of ITNs on L. donovani transmission. In this context, a number of field studies were conducted in the Indian subcontinent in the past decade to evaluate the effectiveness and impact of ITNs and other vector control tools on VL. Most of these studies have been reviewed in detail in two recent papers [3,4]. The only two studies evaluating the impact of vector control interventions on clinical outcomes found conflicting results. First, the KALANET project, a cluster randomised controlled trial (CRT) in India and Nepal, showed that mass-distribution of ITNs did not reduce the risk of L. donovani infection or clinical VL [6]. Then, an intervention trial in Bangladesh suggested that widespread bed net impregnation with slow-release insecticide may reduce the frequency of VL [7]. Technical (e.g., type of nets and insecticides, lack of replicas and randomisation in Bangladesh) and biological factors (e.g., insecticide susceptibility and sand fly behaviour) may explain the different results observed. This apparent contradiction raises the question about the role that ITN may play in controlling VL in the Indian subcontinent but has also triggered a lot of discussion on methodology and evidence levels required when evaluating vector control tools for VL. In this paper, we would like to summarise the lessons learned from the KALANET CRT in terms of methodology to inform the generation of future evidence and discuss interpretation of findings against this background. The KALANET trial was designed to evaluate the distribution of ITNs as a public health intervention to prevent VL in the Indian subcontinent. The objective was to answer the question: “in the current context in India and Nepal, would free mass distribution of ITN significantly reduce the incidence rate of VL in endemic regions?” This was a question asked not at the individual level, whether sleeping under an ITNs protects an individual against VL compared to an individual not sleeping under an ITN, but a question asked at program level: does such prevention measure reduce VL incidence in communities. Furthermore, the question was about effectiveness in real life conditions and not a question about efficacy of ITNs in “laboratory conditions,” a difference that is clear for public health experts but not necessarily for all readers. The answer to this question may, for instance, be entirely different in a country such as Bangladesh, where no vector control program was operating for many years, no spraying was implemented at the time, and fewer households were using untreated nets, compared to India and Nepal. The first lesson we learned was about the importance of clarifying the research question itself. To answer the above question, we adopted a study design used previously in a successful intervention trial on zoonotic VL transmission [8]. We designed a CRT to demonstrate a 50% reduction on the risk of L. donovani infection associated to the village-wide distribution of ITN [6]. Long-lasting insecticidal nets (LNs) were chosen as intervention as they remain effective for three to four years in the field [2]. Incident L. donovani infection, measured as seroconversion in the Direct Agglutination Test (DAT), was used as the main outcome. Measuring the impact of LN on the risk of clinical VL would have been the preferred primary outcome, but its low incidence and the long incubation period precluded this. Incidence of VL cases was nonetheless measured as secondary outcome. The trial was conducted in 26 high-incidence clusters (16 in India and 10 in Nepal) with over 20,000 inhabitants followed over 24 months. After randomisation, LNs were distributed in all households in the 13 intervention clusters, with the number of LNs proportional to household size, to make sure that all household members could sleep under the nets. Participants in the control clusters were allowed to continue using their untreated nets. The effect of LNs on the incidence rate of seroconversion and VL was compared after 24 months between intervention and control clusters. No LNs were used in the control clusters. The results of the trial, analysed as suggested by Hayes and Moulton [9], showed that the large scale distribution of LN did not reduce the risk of L. donovani infection [6]. These results were consistent across several endpoints measured, as no difference was observed in (1) incidence rate of clinical VL [6], (2) seroconversion in rK39 ELISA (a second serological marker) [10], and (3) mean P. argentipes exposure measured at cluster level by a sand fly saliva antibody detection ELISA [11]. Similarly, the reduction of P. argentipes density indoor in the study clusters was limited (24.9%) [12]. The main conclusion of the trial was that “there is no evidence that using LNs as a public health intervention provides additional protection against VL at community level compared with existing control practices in India and Nepal (e.g., irregular use of untreated nets and IRS). This does not mean that the use of LNs in those VL endemic regions should be dismissed, as they may provide some degree of personal protection against sand flies [13] and have been shown to reduce the risk of malaria [6]. However, the VL elimination initiative in India and Nepal cannot rely on the stand-alone use of LNs to effectively control transmission.” The above message is complex and was disappointing for many, in the first place for the researchers themselves, as the hopes for a user-friendly, household-controlled tool to control VL in the Indian subcontinent were given a serious blow. Moreover, results from a negative trial are hard to communicate. Criticism of peers focused on four main areas: 1. the biological rationale for the intervention, 2. the choice and number of units of analysis, 3. the choice of endpoint and 4. the adherence to the intervention. Stockdale and Newton also identified these methodological issues as key factors to evaluate studies testing preventative methods against human leishmaniasis infection [3].

Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended in HIV-negative women to avert malaria, while this relies on cotrimoxazole prophylaxis (CTXp) in HIV-positive women. Alternative antimalarials are required in areas where parasite resistance to antifolate drugs is high. The cost-effectiveness of IPTp with alternative drugs is needed to inform policy. METHODS: The cost-effectiveness of 2-dose IPTp-mefloquine (MQ) was compared with IPTp-SP in HIV-negative women (Benin, Gabon, Mozambique and Tanzania). In HIV-positive women the cost-effectiveness of 3-dose IPTp-MQ added to CTXp was compared with CTXp alone (Kenya, Mozambique and Tanzania). The outcomes used were maternal clinical malaria, anaemia at delivery and non-obstetric hospital admissions. The poor tolerability to MQ was included as the value of women's loss of working days. Incremental cost-effectiveness ratios (ICERs) were calculated and threshold analysis undertaken. RESULTS: For HIV-negative women, the ICER for IPTp-MQ versus IPTp-SP was 136.30 US$ (2012 US$) (95%CI 131.41; 141.18) per disability-adjusted life-year (DALY) averted, or 237.78 US$ (95%CI 230.99; 244.57), depending on whether estimates from Gabon were included or not. For HIV-positive women, the ICER per DALY averted for IPTp-MQ added to CTXp, versus CTXp alone was 6.96 US$ (95%CI 4.22; 9.70). In HIV-negative women, moderate shifts of variables such as malaria incidence, drug cost, and IPTp efficacy increased the ICERs above the cost-effectiveness threshold. In HIV-positive women the intervention remained cost-effective for a substantial (up to 21 times) increase in cost per tablet. CONCLUSIONS: Addition of IPTp with an effective antimalarial to CTXp was very cost-effective in HIV-positive women. IPTp with an efficacious antimalarial was more cost-effective than IPTp-SP in HIV-negative women. However, the poor tolerability of MQ does not favour its use as IPTp. Regardless of HIV status, prevention of malaria in pregnancy with a highly efficacious, well tolerated antimalarial would be cost-effective despite its high price. TRIALS REGISTRATION: ClinicalTrials.gov NCT 00811421; Pan African Trials Registry PACTR2010020001429343 and PACTR2010020001813440.

OBJECTIVES: To evaluate the prevalence of transmitted drug resistance (TDR) and non-B subtypes in patients with acute/recent HIV-1 infection in Barcelona during the period 1997-2012. METHODS: Patients from the "Hospital Clinic Primary HIV-1 Infection Cohort" with a genotyping test performed within 180 days of infection were included. The 2009 WHO List of Mutations for Surveillance of Transmitted HIV-1 Drug Resistance was used for estimating the prevalence of TDR and phylogenetic analysis for subtype determination. RESULTS: 189 patients with acute/recent HIV-1 infection were analyzed in 4 time periods (1997-2000, n=28; 2001-4, n=42; 2005-8, n=55 and 2009-12, n=64). The proportion of patients with acute/recent HIV-1 infection with respect to the total of newly HIV-diagnosed patients in our center increased over the time and was 2.18%, 3.82%, 4.15% and 4.55% for the 4 periods, respectively (p=0.005). The global prevalence of TDR was 9%, or 17.9%, 9.5%, 3.6% and 9.4% by study period (p=0.2). The increase in the last period was driven by protease-inhibitor and nucleoside-reverse-transcriptase-inhibitor resistance mutations while non-nucleoside-reverse-transcriptase inhibitor TDR and TDR of more than one family decreased. The overall prevalence of non-B subtypes was 11.1%, or 0%, 4.8%, 9.1% and 20.3 by study period (p=0.01). B/F recombinants, B/G recombinants and subtype F emerged in the last period. We also noticed an increase in the number of immigrant patients (p=0.052). The proportion of men-who-have-sex-with-men (MSM) among patients with acute/recent HIV-1 infection increased over the time (p=0.04). CONCLUSIONS: The overall prevalence of TDR in patients with acute/recent HIV-1 infection in Barcelona was 9%, and it has stayed relatively stable in recent years. Non-B subtypes and immigrants proportions progressively increased.

In a randomized controlled trial Tim Davis and colleagues investigate Artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of P. falciparum and P. vivax malaria. Please see later in the article for the Editors' Summary, Background Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y. Methods and Findings An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI −3.0% to 8.4%] versus −5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p, Editors' Summary Background Malaria is a mosquito-borne parasitic disease that kills more than 600,000 people (mainly young children in sub-Saharan Africa) every year. Plasmodium falciparum causes most of these deaths, but P. vivax is the most common and most widely distributed cause of malaria outside sub-Saharan Africa. Infection with malaria parasites causes recurring flu-like symptoms and must be treated promptly with antimalarial drugs to prevent the development of anemia and potentially fatal damage to the brain and other organs. In the past, malaria was treated with “monotherapies” such as chloroquine, but the parasites quickly developed resistance to many of these inexpensive drugs. The World Health Organization now recommends artemisinin combination therapy (ACT) for first-line treatment of malaria in all regions where there is drug-resistant malaria. In ACT, artemisinin derivatives (fast-acting antimalarial drugs that are rapidly cleared from the body) are used in combination with a slower acting, more slowly eliminated partner drug to prevent reemergence of the original infection and to reduce the chances of the malaria parasites becoming resistant to either drug. Why Was This Study Done? Because falciparum and vivax malaria respond differently to antimalarial drugs, wherever there is transmission of both types of malaria but limited facilities for species-specific malaria diagnosis—as in Papua New Guinea—compromises have to be made about which ACT should be used for the treatment of malaria. Thus, Papua New Guinea's national guidelines recommend artemether-lumefantrine, which is effective against the more deadly P. falciparum, for first-line treatment of uncomplicated (mild) malaria even though this ACT is ineffective against the more common P. vivax. In this open-label randomized trial (a study in which participants are randomly assigned to receive different drugs but know which drug they are being given), the researchers ask whether an alternative ACT might be preferable for the treatment of uncomplicated malaria in young children in Papua New Guinea by comparing outcomes after treatment with artemether-lumefantrine versus artemisinin-naphthoquine (an ACT that should be more effective against vivax malaria than artemether-lumefantrine because naphthoquine stays in the body longer than lumefantrine). Specifically, the researchers test the non-inferiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of falciparum malaria (whether artemisinin-naphthoquine is not worse than artemether-lumefantrine) and the superiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of vivax malaria (whether artemisinin-naphthoquine is better than artemether-lumefantrine). What Did the Researchers Do and Find? The researchers assigned nearly 250 children (aged 0.5 to 5 years) with falciparum malaria, vivax malaria, or both types of malaria to receive six doses of artemether-lumefantrine over three days or three daily doses of artemisinin-naphthoquine. They then followed the children to see how many children in each treatment group and with each type of malaria were free of malaria 42 days after treatment (an “adequate clinical and parasitological response”). Among the patients originally infected with P. falciparum, 97.8% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of their original P. falciparum infection (though some had acquired a new P. falciparum infection) 42 days after treatment. By contrast, among the patients infected with P. vivax, 30% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of P. vivax infection 42 days after treatment. Both ACTs were safe and well tolerated. What Do These Findings Mean? These findings indicate that artemisinin-naphthoquine was non-inferior to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria among young children in Papua New Guinea and had greater efficacy than artemether-lumefantrine against vivax malaria. The accuracy of these findings may be limited by several aspects of the study design. For example, not all the artemether-lumefantrine doses were directly observed, so some children may not have received the full treatment course. Moreover, because all the study participants lived in coastal communities in Papua New Guinea where malaria is highly endemic, treatment responses among children living in areas with lower levels of malaria transmission might be different. Nevertheless, these findings suggest that artemisinin-naphthoquine should be considered alongside other ACTs for the treatment of uncomplicated malaria in regions where there is transmission of multiple Plasmodium species and that artemisinin-naphthoquine may be better than artemether-lumefantrine for the treatment of uncomplicated malaria in young children in regions where P. vivax predominates. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001773. Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2013 provides details on the current global malaria situation, including information on malaria in Papua New Guinea; the World Health Organization's Guidelines for the Treatment of Malaria is available The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish), including personal stories about malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria, including information about malaria in Papua New Guinea, malaria in children, and ACTs The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria MedlinePlus provides links to additional information on malaria (in English and Spanish) More information about this trial is available

HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P

OBJECTIVE: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. METHODS: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×10(6) bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. RESULTS: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients. CONCLUSION: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266.

Aim: Lack of knowledge concerning the nature of placebo and why it is necessary may influence the participation of patients in clinical trials. The objective of the present study is to review how placebo is described in written information for participants in clinical trials to be evaluated by a Human Research Ethics Committee. Methods: All research protocols submitted for evaluation in a Spanish hospital during 2007–2013 were reviewed. The main characteristics of the studies using a placebo were collected. Three authors read each of them to determine how the term “placebo” was explained and if there was any comment on its efficacy and safety. Results: Two thousand seven-hundred and forty research protocols were evaluated, of which three hundred and fifty-nine used a placebo. Pharmaceutical companies sponsored most placebo-controlled clinical trials (91.9%), and phase III studies were the commonest (59.9%). Oncology (15.0%), cardiology (14.2%), and neurology (13.1%) made the greatest contributions. A review of the informed consent forms showed that placebo was described in a similar manner in most studies: the explanation was limited to between four and eight words. Very few gave information about the risks of its use or adverse reactions from its administration. None of the studies provided details about the placebo effect. And 23 lacked any information about placebo at all. Conclusions: Explanations about placebo in informed consent forms is often scarce, and information about the placebo effect and associated risks are absent. This situation may influence a full understanding of placebo by participants in clinical trials and might reduce their informed decision to participate. The study was supported in part by a grant from Victor Grifols i Lucas Foundation (2010-2011). Astrid Hernández is the recipient of a predoctoral fellowship from the Spanish Agency for International Development Cooperation. No external funding source had any role in the design or interpretation of the data of the study

BACKGROUND AND AIMS Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population. METHODS In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured. RESULTS Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p

Objective Independently of total caloric intake, a better quality of the diet (for example, conformity to the Mediterranean diet) is associated with lower obesity risk. It is unclear whether a brief dietary assessment tool, instead of full-length comprehensive methods, can also capture this association. In addition to reduced costs, a brief tool has the interesting advantage of allowing immediate feedback to participants in interventional studies. Another relevant question is which individual items of such a brief tool are responsible for this association. We examined these associations using a 14-item tool of adherence to the Mediterranean diet as exposure and body mass index, waist circumference and waist-to-height ratio (WHtR) as outcomes. Design Cross-sectional assessment of all participants in the “PREvención con DIeta MEDiterránea” (PREDIMED) trial. Subjects 7,447 participants (55–80 years, 57% women) free of cardiovascular disease, but with either type 2 diabetes or ≥3 cardiovascular risk factors. Trained dietitians used both a validated 14-item questionnaire and a full-length validated 137-item food frequency questionnaire to assess dietary habits. Trained nurses measured weight, height and waist circumference. Results Strong inverse linear associations between the 14-item tool and all adiposity indexes were found. For a two-point increment in the 14-item score, the multivariable-adjusted differences in WHtR were −0.0066 (95% confidence interval, –0.0088 to −0.0049) for women and –0.0059 (–0.0079 to –0.0038) for men. The multivariable-adjusted odds ratio for a WHtR>0.6 in participants scoring ≥10 points versus ≤7 points was 0.68 (0.57 to 0.80) for women and 0.66 (0.54 to 0.80) for men. High consumption of nuts and low consumption of sweetened/carbonated beverages presented the strongest inverse associations with abdominal obesity. Conclusions A brief 14-item tool was able to capture a strong monotonic inverse association between adherence to a good quality dietary pattern (Mediterranean diet) and obesity indexes in a population of adults at high cardiovascular risk., The Official funding agency for Biomedical Research of the Spanish Government, Instituto de Salud Carlos III (ISCIII), provided the grants for his study: RTIC G03/140, CIBERobn, RD 06/0045, PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407 and PI11/01647. CIBERobn and RTIC RD 06/0045 are initiatives of ISCIII, Spain. RT is supported by a Rio-Hortega post-residency fellowship of the Instituto de Salud Carlos III, Spanish Government.

Background: Although randomized clinical trials (RCTs) are considered the gold standard of evidence, their reporting is often suboptimal. Trial registries have the potential to contribute important methodologic information for critical appraisal of study results. Methods and Findings: The objective of the study was to evaluate the reporting of key methodologic study characteristics in trial registries. We identified a random sample (n = 265) of actively recruiting RCTs using the World Health Organization International Clinical Trials Registry Platform (ICTRP) search portal in 2008. We assessed the reporting of relevant domains from the Cochrane Collaboration’s ‘Risk of bias’ tool and other key methodological aspects. Our primary outcomes were the proportion of registry records with adequate reporting of random sequence generation, allocation concealment, blinding, and trial outcomes. Two reviewers independently assessed each record. Weighted overall proportions in the ICTRP search portal for adequate reporting of sequence generation, allocation concealment, blinding (including and excluding open label RCT) and primary outcomes were 5.7% (95% CI 3.0–8.4%), 1.4% (0–2.8%), 41% (35–47%), 8.4% (4.1–13%), and 66% (60–72%), respectively. The proportion of adequately reported RCTs was higher for registries that used specific methodological fields for describing methods of randomization and allocation concealment compared to registries that did not. Concerning other key methodological aspects, weighted overall proportions of RCTs with adequately reported items were as follows: eligibility criteria (81%), secondary outcomes (46%), harm (5%) follow-up duration (62%), description of the interventions (53%) and sample size calculation (1%). Conclusions: Trial registries currently contain limited methodologic information about registered RCTs. In order to permit adequate critical appraisal of trial results reported in journals and registries, trial registries should consider requesting details on key RCT methods to complement journal publications. Full protocols remain the most comprehensive source of methodologic information and should be made publicly available.

Background Current recommendations to prevent malaria in African pregnant women rely on insecticide treated nets (ITNs) and intermittent preventive treatment (IPTp). However, there is no information on the safety and efficacy of their combined use. Methods 1030 pregnant Mozambican women of all gravidities received a long-lasting ITN during antenatal clinic (ANC) visits and, irrespective of HIV status, were enrolled in a randomised, double blind, placebo-controlled trial, to assess the safety and efficacy of 2-dose sulphadoxine-pyrimethamine (SP). The main outcome was the reduction in low birth weight. Findings Two-dose SP was safe and well tolerated, but was not associated with reductions in anaemia prevalence at delivery (RR, 0.92 [95% CI, 0.79–1.08]), low birth weight (RR, 0.99 [95% CI, 0.70–1.39]), or overall placental infection (p = 0.964). However, the SP group showed a 40% reduction (95% CI, 7.40–61.20]; p = 0.020) in the incidence of clinical malaria during pregnancy, and reductions in the prevalence of peripheral parasitaemia (7.10% vs 15.15%) (p

Early detection of fibrosis progression is of major relevance for the diagnosis and management of patients with liver disease. This study was designed to find non-invasive biomarkers for fibrosis in a clinical context where this process occurs rapidly, HCV-positive patients who underwent liver transplantation (LT). We analyzed 93 LT patients with HCV recurrence, 41 non-LT patients with liver disease showing a fibrosis stage F≥1 and 9 patients without HCV recurrence who received antiviral treatment before LT, as control group. Blood obtained from 16 healthy subjects was also analyzed. Serum samples were fractionated by ion exchange chromatography and their proteomic profile was analyzed by SELDI-TOF-MS. Characterization of the peptide of interest was performed by ion chromatography and electrophoresis, followed by tandem mass spectrometry identification. Marked differences were observed between the serum proteome profile of LT patients with early fibrosis recurrence and non-recurrent LT patients. A robust peak intensity located at 5905 m/z was the distinguishing feature of non-recurrent LT patients. However, the same peak was barely detected in recurrent LT patients. Similar results were found when comparing samples of healthy subjects with those of non-LT fibrotic patients, indicating that our findings were not related to either LT or HCV infection. Using tandem mass-spectrometry, we identified the protein peak as a C-terminal fragment of the fibrinogen α chain. Cell culture experiments demonstrated that TGF-β reduces α-fibrinogen mRNA expression and 5905 m/z peak intensity in HepG2 cells, suggesting that TGF-β activity regulates the circulating levels of this protein fragment. In conclusion, we identified a 5.9 kDa C-terminal fragment of the fibrinogen α chain as an early serum biomarker of fibrogenic processes in patients with liver disease.

Transparency: A Fundamental Social Obligation for Clinical Research .After 60 years devoted to enhancing the methodology and ethics in clinical research, the last decade has been crucial to the scientific community in refining the transparency on conducting clinical trials (CTs), from their inception to the publication of results. A myriad of articles have been published on the design, conduct, conflicts of interest, reporting, and publication of CTs...

Background The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S. Methodology/Principal Findings The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5–56.3; p = 0.029) over the double-blind phase and of 9.0% (−30.6–36.6; p = 0.609) during the single-blind phase. Conclusions/Significance Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia. Trial Registration ClinicalTrials.gov NCT00197041

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (