Geographic Equity and Environmental Sustainability of Conference Models: Results of a Comparative Analysis.

We conducted a comparative analysis of in-person, virtual, and hybrid conferences on tuberculosis hosted by Keystone Symposia and examined the number of participants, their country of residence, carbon dioxide equivalents (CO2e) produced, and participant impressions regarding scientific quality. Data were available from three in-person meetings, one virtual meeting, and one hybrid. The virtual conference hosted 2.5-fold more participants compared with the in-person conferences (842 versus an average of 328) from more than double the number of countries (68 versus an average of 33). The virtual conference attracted 4.5-fold more participants from countries with a high burden of tuberculosis, compared with the average in-person conference (209 versus an average of 46). For in-person meetings, an average of 79% of participants were based in high-income countries. For the virtual meeting, 53% of participants were from high-income countries, and 47% from low- and middle-income countries. For the hybrid conference, there were 465 participants from 43 countries, of which 289 attended in person from a total of 20 countries, and 176 participated virtually from 34 countries. Of those who took part in person, 91% were from high-income countries. The average CO2e emissions from an in-person conference was 696 tons of CO2e, with 96.0% from air travel. The virtual meeting produced 0.48 ton of CO2e from electricity usage, a 1,450-fold decrease compared with in-person events. Virtual conferences scored a content quality rating of 87.3% to 90.8% compared with a range of 86.4% to 92.2% for in-person conferences.

Reimagining scientific conferences-a Keystone Symposia report.

Scientific conferences play an important role in advancing research, scholarship, and the careers of emerging scientists. The COVID-19 pandemic offered meeting organizers and researchers alike an opportunity to reimagine what scientific conferences could look like. Virtual conferences can increase inclusivity and accessibility while decreasing costs and carbon emissions. However, it is generally perceived that the digital world fails to adequately recapitulate many of the benefits of in-person face-to-face interactions; these include socializing, and collaborative environments that can forge new research directions and provide critical career development opportunities. On November 15 and 16, 2022, researchers, representatives from diverse scientific conference organizations, leaders in virtual platform technologies, and innovators in conference design gathered online for the Open Access Keystone eSymposium "Reimagining Scientific Conferences." The meeting focused on how conference organizers can leverage lessons from the pandemic and emerging virtual platforms to engage new audiences, rethink strategies for scientific exchange, and decrease the carbon footprint of in-person events.

Why Climate Action Is Global Health Action.

The impacts of climate change on global health and populations are far-reaching, yet they disproportionately affect vulnerable groups, thereby exacerbating disparities. As humanity reckons with the emergency of climate change, our global health community needs to contend with our own contributions to greenhouse gas emissions. We know that transformation is possible and that climate action is the antidote to the existential challenge. As a global health community, we have an immense opportunity, responsibility, and commitment to lead, support, inspire, and empower climate action, research, and innovation that align deeply with our mission and core values.

Environmentally sustainable practices in global health research and higher education institutions: Lessons from consultation with the TropEd Global Health institutions.

OBJECTIVE: To examine how global health institutions are reducing the greenhouse gas emissions from their own operations and analyse the facilitators and barriers to achieving decarbonisation goals. METHODS: We reviewed the sustainability goals and implementation plans of 10 global health universities from the 'TropEd' network. We systematically collected information from institutional websites and annual reports. Through online interviews, 11 key informants validated the information from 9 of the institutions and shared their opinions regarding what factors are helping their institutions decarbonise and what factors are hindering progress. RESULTS: 4/10 institutions sampled have a sustainability strategy and implementation plan, only 3/10 have specific decarbonisation goals, and 3/10 are reporting on progress. 5/10 institutions reported that they are in the process of determining emission reduction targets. CONCLUSION: This paper identifies common success factors that facilitate decarbonisation as well as common challenges and how they are being tackled, and makes recommendations on sustainability efforts in academic institutions.

The role of governance in implementing sustainable global health interventions: review of health system integration for integrated community case management (iCCM) of childhood illnesses.

Improving health outcomes in countries with the greatest burden of under-5 child mortality requires implementing innovative approaches like integrated community case management (iCCM) to improve coverage and access for hard-to-reach populations. ICCM improves access for hard-to-reach populations by deploying community health workers to manage malaria, diarrhoea and pneumonia. Despite documented impact, challenges remain in programme implementation and sustainability. An analytical review was conducted using evidence from published and grey literature from 2010 to 2019. The goal was to understand the link between governance, policy development and programme sustainability for iCCM. A Governance Analytical Framework revealed thematic challenges and successes for iCCM adaptation to national health systems. Governance in iCCM included the collective problems, actors in coordination and policy-setting, contextual norms and programmatic interactions. Key challenges were country leadership, contextual evidence and information-sharing, dependence on external funding, and disease-specific stovepipes that impede funding and coordination. Countries that tailor and adapt programmes to suit their governance processes and meet their specific needs and capacities are better able to achieve sustainability and impact in iCCM.

Reducing the Carbon Footprint of Academic Conferences: The Example of the American Society of Tropical Medicine and Hygiene.

We calculated carbon emissions associated with air travel of 4,834 participants at the 2019 annual conference of the American Society of Tropical Medicine and Hygiene (ASTMH). Together, participants traveled a total of 27.7 million miles or 44.6 million kilometers. This equates to 58 return trips to the moon. Estimated carbon dioxide equivalent (CO2e) emissions were 8,646 metric tons or the total weekly carbon footprint of approximately 9,366 average American households. These emissions contribute to climate change and thus may exacerbate many of the global diseases that conference attendees seek to combat. Options to reduce conference travel-associated emissions include 1) alternating in-person and online conferences, 2) offering a hybrid in-person/online conference, and 3) decentralizing the conference with multiple conference venues. Decentralized ASTMH conferences may allow for up to 64% reduction in travel distance and 58% reduction in CO2e emissions. Given the urgency of the climate crisis and the clear association between global warming and global health, ways to reduce carbon emissions should be considered.

Exploration of Crime-Scene Characteristics in Juvenile Homicide in the French-Speaking Part of Belgium.

This study explores modeling crime-scene characteristics of juvenile homicide in the French-speaking part of Belgium. Multidimensional scaling analysis was carried out on crime-scene characteristics derived from the court files of 67 individuals under 22 years old, who had been charged with murder or attempted murder (1995-2009). Three thematic regions (Expressive: multiple offenders; Instrumental: theft; Instrumental: sex/forensic awareness) distinguished types of aggression displayed during the offense. These themes reaffirm that the expressive-instrumental differentiation found in general homicide studies is valuable when attempting to discriminate juvenile homicides. The proposed framework was found useful to classify the offenses, as 84% of homicides were assigned to a dominant theme. Additionally, associations between crime-scene characteristics and offenders' characteristics were analyzed, but no associations were found, therefore failing to provide empirical support for the homology assumption. Cultural comparisons, as well as the influence of age on the thematic structure are discussed.

malERA: An updated research agenda for malaria elimination and eradication.

Achieving a malaria-free world presents exciting scientific challenges as well as overwhelming health, equity, and economic benefits. WHO and countries are setting ambitious goals for reducing the burden and eliminating malaria through the "Global Technical Strategy" and 21 countries are aiming to eliminate malaria by 2020. The commitment to achieve these targets should be celebrated. However, the need for innovation to achieve these goals, sustain elimination, and free the world of malaria is greater than ever. Over 180 experts across multiple disciplines are engaged in the Malaria Eradication Research Agenda (malERA) Refresh process to address problems that need to be solved. The result is a research and development agenda to accelerate malaria elimination and, in the longer term, transform the malaria community's ability to eradicate it globally.

Gender Comparison of Young People Charged With Murder in England and Wales.

This study investigated gender differences regarding young people charged with murder in England and Wales. A sample of 318 cases was collected from the Home Office's Homicide Index and analysed. Of these cases, 93% of the offenders were male and 7% female. The analyses explored gender differences in terms of the offender's race, offender's age, victim's age, victim's gender, weapon used, offender-victim relationship, and circumstances of the offence. The study found that a female offender was significantly more likely to murder a family member than a male offender, and a male offender was significantly more likely to murder a stranger than a female offender. In addition, a female offender was significantly more likely to murder a victim below the age of 5 than a male offender. Implications for interventions with young people who are charged with murder are discussed.

Vitamin D supplementation for prevention of cancer in adults.

BACKGROUND: The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded, and the Conference Proceedings Citation Index-Science to February 2014. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. SELECTION CRITERIA: We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults who were healthy or were recruited among the general population, or diagnosed with a specific disease. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We conducted random-effects and fixed-effect model meta-analyses. For dichotomous outcomes, we calculated the risk ratios (RRs). We considered risk of bias in order to assess the risk of systematic errors. We conducted trial sequential analyses to assess the risk of random errors. MAIN RESULTS: Eighteen randomised trials with 50,623 participants provided data for the analyses. All trials came from high-income countries. Most of the trials had a high risk of bias, mainly for-profit bias. Most trials included elderly community-dwelling women (aged 47 to 97 years). Vitamin D was administered for a weighted mean of six years. Fourteen trials tested vitamin D3, one trial tested vitamin D2, and three trials tested calcitriol supplementation. Cancer occurrence was observed in 1927/25,275 (7.6%) recipients of vitamin D versus 1943/25,348 (7.7%) recipients of control interventions (RR 1.00 (95% confidence interval (CI) 0.94 to 1.06); P = 0.88; I² = 0%; 18 trials; 50,623 participants; moderate quality evidence according to the GRADE instrument). Trial sequential analysis (TSA) of the 18 vitamin D trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. We did not observe substantial differences in the effect of vitamin D on cancer in subgroup analyses of trials at low risk of bias compared to trials at high risk of bias; of trials with no risk of for-profit bias compared to trials with risk of for-profit bias; of trials assessing primary prevention compared to trials assessing secondary prevention; of trials including participants with vitamin D levels below 20 ng/mL at entry compared to trials including participants with vitamin D levels of 20 ng/mL or more at entry; or of trials using concomitant calcium supplementation compared to trials without calcium. Vitamin D decreased all-cause mortality (1854/24,846 (7.5%) versus 2007/25,020 (8.0%); RR 0.93 (95% CI 0.88 to 0.98); P = 0.009; I² = 0%; 15 trials; 49,866 participants; moderate quality evidence), but TSA indicates that this finding could be due to random errors. Cancer occurrence was observed in 1918/24,908 (7.7%) recipients of vitamin D3 versus 1933/24,983 (7.7%) in recipients of control interventions (RR 1.00 (95% CI 0.94 to 1.06); P = 0.88; I² = 0%; 14 trials; 49,891 participants; moderate quality evidence). TSA of the vitamin D3 trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. Vitamin D3 decreased cancer mortality (558/22,286 (2.5%) versus 634/22,206 (2.8%); RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I² = 0%; 4 trials; 44,492 participants; low quality evidence), but TSA indicates that this finding could be due to random errors. Vitamin D3 combined with calcium increased nephrolithiasis (RR 1.17 (95% CI 1.03 to 1.34); P = 0.02; I² = 0%; 3 trials; 42,753 participants; moderate quality evidence). TSA, however, indicates that this finding could be due to random errors. We did not find any data on health-related quality of life or health economics in the randomised trials included in this review. AUTHORS' CONCLUSIONS: There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women. Vitamin D3 supplementation decreased cancer mortality and vitamin D supplementation decreased all-cause mortality, but these estimates are at risk of type I errors due to the fact that too few participants were examined, and to risks of attrition bias originating from substantial dropout of participants. Combined vitamin D3 and calcium supplements increased nephrolithiasis, whereas it remains unclear from the included trials whether vitamin D3, calcium, or both were responsible for this effect. We need more trials on vitamin D supplementation, assessing the benefits and harms among younger participants, men, and people with low vitamin D status, and assessing longer duration of treatments as well as higher dosages of vitamin D. Follow-up of all participants is necessary to reduce attrition bias.

Vitamin D supplementation for prevention of mortality in adults.

BACKGROUND: Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials. SELECTION CRITERIA: Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses. MAIN RESULTS: We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I(2) = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I(2) = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I(2) = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I(2) = 17%; 710 participants; 3 trials). AUTHORS' CONCLUSIONS: Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.

Typical investigational medicinal products follow relatively uniform regulations in 10 European Clinical Research Infrastructures Network (ECRIN) countries.

BACKGROUND: In order to facilitate multinational clinical research, regulatory requirements need to become international and harmonised. The EU introduced the Directive 2001/20/EC in 2004, regulating investigational medicinal products in Europe. METHODS: We conducted a survey in order to identify the national regulatory requirements for major categories of clinical research in ten European Clinical Research Infrastructures Network (ECRIN) countries-Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom-covering approximately 70% of the EU population. Here we describe the results for regulatory requirements for typical investigational medicinal products, in the ten countries. RESULTS: Our results show that the ten countries have fairly harmonised definitions of typical investigational medicinal products. Clinical trials assessing typical investigational medicinal products require authorisation from a national competent authority in each of the countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines, i.e., no more than 60 days, in all ten countries. The authority to which the application has to be sent to in the different countries is not fully harmonised. CONCLUSION: The Directive 2001/20/EC defined the term 'investigational medicinal product' and all regulatory requirements described therein are applicable to investigational medicinal products. Our survey showed, however, that those requirements had been adopted in ten European countries, not for investigational medicinal products overall, but rather a narrower category which we term 'typical' investigational medicinal products. The result is partial EU harmonisation of requirements and a relatively navigable landscape for the sponsor regarding typical investigational medicinal products.

Vitamin D supplementation for prevention of mortality in adults.

BACKGROUND: The available evidence on vitamin D and mortality is inconclusive. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D for prevention of mortality in adults. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science (to January 2011). We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. SELECTION CRITERIA: We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention. Vitamin D could have been administered as supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: Six authors extracted data independently. Random-effects and fixed-effect model meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RR). To account for trials with zero events, meta-analyses of dichotomous data were repeated using risk differences (RD) and empirical continuity corrections. Risk of bias was considered in order to minimise risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. MAIN RESULTS: Fifty randomised trials with 94,148 participants provided data for the mortality analyses. Most trials included elderly women (older than 70 years). Vitamin D was administered for a median of two years. More than one half of the trials had a low risk of bias. Overall, vitamin D decreased mortality (RR 0.97, 95% confidence interval (CI) 0.94 to 1.00, I(2) = 0%). When the different forms of vitamin D were assessed separately, only vitamin D(3) decreased mortality significantly (RR 0.94, 95% CI 0.91 to 0.98, I(2) = 0%; 74,789 participants, 32 trials) whereas vitamin D(2), alfacalcidol, or calcitriol did not. Trial sequential analysis supported our finding regarding vitamin D(3), corresponding to 161 individuals treated to prevent one additional death. Vitamin D(3) combined with calcium increased the risk of nephrolithiasis (RR 1.17, 95% CI 1.02 to 1.34, I(2) = 0%). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18, 95% CI 1.17 to 8.68, I(2) = 17%). Data on health-related quality of life and health economics were inconclusive. AUTHORS' CONCLUSIONS: Vitamin D in the form of vitamin D(3) seems to decrease mortality in predominantly elderly women who are mainly in institutions and dependent care. Vitamin D(2), alfacalcidol, and calcitriol had no statistically significant effect on mortality. Vitamin D(3) combined with calcium significantly increased nephrolithiasis. Both alfacalcidol and calcitriol significantly increased hypercalcaemia.

Compassionate use of interventions: results of a European Clinical Research Infrastructures Network (ECRIN) survey of ten European countries.

BACKGROUND: 'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries. METHODS: The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK). RESULTS: European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount. CONCLUSIONS: 'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes.

Pentoxifylline for alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a life-threatening disease, with an average mortality of approximately 40%. There is no widely accepted, effective treatment for alcoholic hepatitis. Pentoxifylline is used to treat alcoholic hepatitis, but there has been no systematic review to assess its effects. OBJECTIVES: To assess the benefits and harms of pentoxifylline in alcoholic hepatitis. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, and full text searches were conducted until August 2009. Manufacturers and authors were contacted. SELECTION CRITERIA: All randomised clinical trials of pentoxifylline in participants with alcoholic hepatitis compared to control were selected for inclusion. DATA COLLECTION AND ANALYSIS: Two authors extracted data and evaluated the risk of bias. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Trial sequential analysis (TSA) was also used for statistical analysis of dichotomous and continuous data in order to control for random error. Where data were only available from one trial, we used Fisher's exact test or Student's t-test. MAIN RESULTS: Five trials, with a total of 336 randomised participants, were included. A total of 105 participants (31%) died. Of the five included trials, four (80%) had a high risk of bias. Meta-analysis using all five trials showed that pentoxifylline reduced mortality compared with control (RR 0.64; 95% CI 0.46 to 0.89). However, this result was not supported by trial sequential analysis, which adjusts for multiple testing on accumulating data. Furthermore, four of the five trials were judged to have a high risk of bias, thus risking an overestimated intervention effect. Meta-analysis showed that pentoxifylline reduced the hepatic-related mortality due to hepatorenal syndrome (RR 0.40; 95% CI 0.22 to 0.71), but trial sequential analysis did not support this result. Data from one trial suggests that pentoxifylline may increase the occurrence of serious and non-serious adverse events compared to control. AUTHORS' CONCLUSIONS: The current available data may indicate a possible positive intervention effect of pentoxifylline on all-cause mortality and mortality due to hepatorenal syndrome, and conversely, an increase in serious and non-serious adverse events. However, the evidence is not firm; no conclusions can be drawn regarding whether pentoxifylline has a positive, negative, or neutral effect on participants with alcoholic hepatitis.

Common definition for categories of clinical research: a prerequisite for a survey on regulatory requirements by the European Clinical Research Infrastructures Network (ECRIN).

BACKGROUND: Thorough knowledge of the regulatory requirements is a challenging prerequisite for conducting multinational clinical studies in Europe given their complexity and heterogeneity in regulation and perception across the EU member states. METHODS: In order to summarise the current situation in relation to the wide spectrum of clinical research, the European Clinical Research Infrastructures Network (ECRIN) developed a multinational survey in ten European countries. However a lack of common classification framework for major categories of clinical research was identified, and therefore reaching an agreement on a common classification was the initial step in the development of the survey. RESULTS: The ECRIN transnational working group on regulation, composed of experts in the field of clinical research from ten European countries, defined seven major categories of clinical research that seem relevant from both the regulatory and the scientific points of view, and correspond to congruent definitions in all countries: clinical trials on medicinal products; clinical trials on medical devices; other therapeutic trials (including surgery trials, transplantation trials, transfusion trials, trials with cell therapy, etc.); diagnostic studies; clinical research on nutrition; other interventional clinical research (including trials in complementary and alternative medicine, trials with collection of blood or tissue samples, physiology studies, etc.); and epidemiology studies. Our classification was essential to develop a survey focused on protocol submission to ethics committees and competent authorities, procedures for amendments, requirements for sponsor and insurance, and adverse event reporting following five main phases: drafting, consensus, data collection, validation, and finalising. CONCLUSION: The list of clinical research categories as used for the survey could serve as a contribution to the, much needed, task of harmonisation and simplification of the regulatory requirements for clinical research in Europe.

Sialic acid transport in Haemophilus influenzae is essential for lipopolysaccharide sialylation and serum resistance and is dependent on a novel tripartite ATP-independent periplasmic transporter.

Sialylation of the lipopolysaccharide (LPS) is an important mechanism used by the human pathogen Haemophilus influenzae to evade the innate immune response of the host. We have demonstrated that N-acetylneuraminic acid (Neu5Ac or sialic acid) uptake in H. influenzae is essential for the subsequent modification of the LPS and that this uptake is mediated through a single transport system which is a member of the tripartite ATP-independent periplasmic (TRAP) transporter family. Disruption of either the siaP (HI0146) or siaQM (HI0147) genes, that encode the two subunits of this transporter, results in a complete loss of uptake of [14C]-Neu5Ac. Mutant strains lack sialylated glycoforms in their LPS and are more sensitive to killing by human serum than the parent strain. The SiaP protein has been purified and demonstrated to bind a stoichiometric amount of Neu5Ac by electrospray mass spectrometry. This binding was of high affinity with a Kd of approximately 0.1 microM as determined by protein fluorescence. The inactivation of the SiaPQM TRAP transporter also results in decreased growth of H. influenzae in a chemically defined medium containing Neu5Ac, supporting an additional nutritional role of sialic acid in H. influenzae physiology.