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Chronic obstructive pulmonary disease (COPD) is a leading cause of death and cigarette smoke is the main risk factor. Detecting its earliest stages and preventing a decline in lung function are key goals. The pathogenesis of COPD is complex but has some similarities to cystic fibrosis (CF), a disease caused by mutations in the cftr gene. CF leads to chronic inflammation, abnormal mucus, and cycles of infection. Cigarette smoke exposure also causes CFTR dysfunction, and it is probably not a coincidence that inflammation, mucus obstruction, and infections are also characteristics of COPD, although the exacerbations can be quite different. We review here the acute effects of cigarette smoke on CFTR function and its potential role in COPD. Understanding CFTR regulation by cigarette smoke may identify novel drug targets and facilitate the development of therapeutics that reduce the progression and severity of COPD.

The protein complex of recombinant human insulin-like growth factor-1 and insulin‑like growth factor binding protein‑3 (rhIGF-1/rhIGFBP-3; mecasermin rinfabate), is an investigational product for the prevention of complications of prematurity. Delivery of rhIGF-1/rhIGFBP-3 is by continuous central line intravenous infusion in preterm infants until endogenous IGF-1 production begins. Protein-specific analytical methodologies were developed to evaluate the compatibility of rhIGF- 1/rhIGFBP-3 at low protein concentrations (∼2.5-10 μg/mL) expected when co-administered with other required medications in the NICU. Highly sensitive detection of the biologic potential degradants (fragments) and/or molecular modifications (oxidized species, aggregates) required the use of reversed-phase high-performance liquid chromatography and size-exclusion ultra-performance liquid chromatography coupled with mass spectrometric detection. We report on the quantification of rhIGF-1/rhIGFBP-3, its components and degradants, to a limit of quantitation of 3.1 μg/mL upon mixing with 24 commonly administered neonatal medications. Methods developed for the rhIGF-1/rhIGFBP-3 admixtures, optimized in studies with furosemide, caffeine citrate and ampicillin, demonstrated good reproducibility, linearity, and limit of detection/quantitation. Using these methods, no increase in degradation of rhIGF-1/rhIGFBP-3 components and no increase in oxidation or aggregation level was observed with caffeine citrate, while admixtures of rhIGF-1/rhIGFBP-3 with ampicillin yielded lower mass recovery of rhIGF-1/rhIGFBP-3 components, which likely resulted from adduct formation. Furosemide was found to be physically incompatible with rhIGF-1/rhIGFBP-3. Our findings support the use of these methodologies for detection of protein modifications under various clinical administration conditions, and additionally supplement physical compatibility data studies of ultra-low concentrations of rhIGF-1/rhIGFBP-3 post co-administration to preterm infants with other medications (manuscript in-preparation).

Monitoring patent ductus arteriosus (PDA) in premature infants is currently performed intermittently using echocardiography which requires considerable expertise. The aim of this pilot study was to investigate whether PDA status could be assessed from standard neonatal intensive care monitoring. Electrocardiography (ECG) and blood pressure (BP) waveforms were acquired from extremely preterm infants using standard neonatal monitors. We developed software using MATLAB to analyse ECG and BP waveforms and their interrelationships in terms of pulse transit time (PTT) and pulse wave velocity (PWV). The times from peak systolic BP to diastolic trough (BPFt) and from the diastolic trough to peak systolic BP (BPRt) were also calculated. PTT, BPFt and BPRt were normalised for heart rate (HR) termed NPTT, NBPFt and NBPRt, respectively. ECG, invasive aortic BP monitoring and echocardiography were performed in 14 preterm infants r = 0.69, P = 0.007) as well as NBPFt (r = 0.65, P = 0.012) and NBPRt (r = 0.71, P = 0.005). No relationship was found between PDA diameter and pulse pressure.Conclusions: Interrelationships between ECG and BP traces as well as BP waveform time analysis are straightforward to measure and associated with PDA diameter. The results of this pilot study suggest that this approach may help provide biomarkers for continuous monitoring PDA diameter and function. What is Known:• Patent ductus arteriosus (PDA) in premature infants is associated with increased risk of developing chronic lung disease, necrotising enterocolitis and cerebral injury.• Currently PDA is assessed intermittently using echocardiography which requires considerable expertise and sometimes is not well tolerated by critically ill preterm infants. What is New:• Blood pressure (BP) and ECG waveform interrelation and BP trace time analysis, taking account of heart rate, relate to PDA diameter.• ECG and BP waveform phase difference as well as BP waveform time analysis may be useful in the continuous assessment of PDA function.

There is growing evidence that supplementation with carnosine, or its rate-limiting precursor β-alanine, can ameliorate aspects of metabolic dysregulation that occur in diabetes and its related conditions. The purpose of this systematic review and meta-analysis was to evaluate the effect of carnosine or β-alanine supplementation on markers of glycemic control and insulin resistance in humans and animals. We performed a systematic search of 6 electronic databases up to 31 December 2020. Primary outcomes were changes in 1) fasting glucose, 2) glycated hemoglobin (HbA1c), and 3) 2-h glucose following a glucose-tolerance test. A set of additional outcomes included fasting insulin and homeostatic model assessment of β-cell function (HOMA-β) and insulin resistance (HOMA-IR). We assessed risk of bias using the Cochrane risk of bias (RoB) 2.0 (human studies) and the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) RoB (animal studies) tools; and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess certainty. We used Bayesian hierarchical random-effects models, with informative priors for human data and noninformative priors for animal data. Inferences were made on posterior samples generated by Hamiltonian Markov Chain Monte Carlo using 90% credible intervals (90% CrI) and calculated probabilities. Twenty studies (n = 4 human, n = 16 rodent) were included, providing data for 2 primary outcomes (fasting glucose and HbA1c) and 3 additional outcomes (fasting insulin, HOMA-β, and HOMA-IR). The model provides evidence that supplementation decreases fasting glucose [humans: mean difference (MD)0.5 = –0.95 mmol · L–1 (90% CrI: –2.1, 0.08); rodent: MD0.5 = –2.26 mmol · L–1 (90% CrI: –4.03, –0.44)], HbA1c [humans: MD0.5 = –0.91% (90% CrI: –1.46, –0.39); rodents: MD0.5 = –1.05% (90% CrI: –1.64, –0.52)], HOMA-IR [humans: standardized mean difference (SMD)0.5 = –0.41 (90% CrI: –0.82, –0.07); rodents: SMD0.5 = –0.63 (90% CrI: –1.98, 0.65)], and fasting insulin [humans: SMD0.5 = –0.41 (90% CrI: –0.77, –0.07)]. GRADE assessment showed our certainty in the effect estimate of each outcome to be moderate (human outcomes) or very low (rodent outcomes). Supplementation with carnosine or β-alanine may reduce fasting glucose, HbA1c, and HOMA-IR in humans and rodents, and fasting insulin in humans; both compounds show potential as therapeutics to improve glycemic control and insulin resistance. This review was registered at PROSPERO as CRD42020191588., Statement of Significance: This study includes all available human and animal data to provide the most comprehensive assessment to date of the effects of carnosine and β-alanine supplementation on glycemic control and insulin resistance.

Objective To assess the perspectives of neonatologists, neonatal nurses, and parents on research-related education and communication practices in the neonatal intensive care unit (NICU). Study design Questionnaire circulated through interest groups and administered using the internet. Results 323 respondents responded to the survey. 52 were neonatologists, 188 were neonatal nurses, and 83 were parents of NICU graduates. Analysis was descriptive. Differences were noted between stakeholder groups with respect to whether current medications meet the needs of sick neonates, research as central to the mission of the NICU, availability of appropriate education/training for all members of the research team, and adequacy of information provided to parents before, during, and after a research study is completed. Conclusion Engagement of nurses and parents at all stages of NICU research is currently suboptimal; relevant good practices, including education, should be shared among neonatal units.

IntroductionThe WHO Essential Medicine List for children (EMLc) is used for promoting access to medicines. The age-appropriateness of enteral (oral and rectal) formulations for children depend on their adaptability/flexibility to allow age-related or weight-related doses to be administered/prescribed and the child’s ability to swallow, as appropriate. There is scant information on the age-appropriateness of essential enteral medicines for children.ObjectiveTo evaluate the age-appropriateness of enteral essential medicines.Materials and methodsAge-appropriateness of all enteral formulations indicated and recommended in the EMLc 3rd to 7th (2011–2019) editions were determined by assessing swallowability and/or dose adaptability for children under 12 years, stratified into five age groups.ResultsEnteral formulations in the EMLc were more age-appropriate for older children aged 6–11 years than for younger children. In the 3rd edition, for older children, 77%, n=342, of formulations were age-appropriate. For younger children, age-appropriateness decreased with age group: 34% in those aged 3–5 years, 30% in those aged 1–2 years, 22% among those aged 28 days to 11 months and 15% in those aged 0–27 days. Overall, similar proportions were found for the 7th edition. In contrast, the majority of medicines in the 7th list were age-appropriate in targeted diseases like HIV and tuberculosis.ConclusionMost recommended enteral essential medicines in EMLc 2011 and 2019 were not age-appropriate for children

Objective: To assess at 24 months corrected age (CA) the neurological, respiratory, and general health status of children born prematurely from 27 +0 to 33 +6 weeks’ gestation who were treated in a first-in-human study with a new fully synthetic surfactant (CHF5633) enriched with SP-B and SP-C proteins. Outcome measures: Children were assessed using Bayley Scales of Infant Development (BSID), with a score below normal defined as BSID-II Mental Development Index score

Membrane proteins often cluster in nanoscale membrane domains (lipid rafts) that coalesce into ceramide-rich platforms during cell stress, however the clustering mechanisms remain uncertain. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in cystic fibrosis (CF), forms clusters that are cholesterol dependent and become incorporated into long-lived platforms during hormonal stimulation. We report here that clustering does not involve known tethering interactions of CFTR with PDZ domain proteins, filamin A or the actin cytoskeleton. It also does not require CFTR palmitoylation but is critically dependent on membrane lipid order and is induced by detergents that increase the phase separation of membrane lipids. Clustering and integration of CFTR into ceramide-rich platforms are abolished by the disease mutations F508del and S13F and rescued by the CFTR modulators elexacaftor plus tezacaftor. These results indicate CF therapeutics that correct mutant protein folding restore both trafficking and normal lipid interactions in the plasma membrane. This article has an associated First Person interview with the first author of the paper.

Conduct of clinical trials in babies, children and young people is often hindered by issues that could have been foreseen before the trial opened; that is, some clinical trials are often underprepared. In order to identify a good approach to trial preparedness, the European Network of Paediatric Research at the European Medicines Agency formed a working group. The Working Group included representation from regulators, industry, academics, paediatric clinical research networks and parents. The Working Group consulted widely about how to prepare for paediatric clinical trials. The Group’s detailed recommendations have been published (https://www.ema.europa.eu/en/documents/other/preparedness-medicines-clinical-trials-paediatrics-recommendations-enpr-ema-working-group-trial_en.pdf). This paper is a summary of the key recommendations including the following: start early, preferably in parallel to designing the medicine’s development plan and individual protocols; identify the rationale and clinical need; listen to the perspectives of children and families, and of patient advocacy groups; identify how many people will be eligible for the trial; identify the resources needed, such as clinical facilities (including play therapy) and out-of-pocket expenditure by participants and their families; use all available data to estimate what is possible; present information about preparedness in a structured way; deploy proportionate resources to support the preparation of trials. A well-prepared, well-designed trial is likely to require fewer changes during its course, be run in a shorter time frame and achieve expected objectives., Clinical trials in children require careful preparation, or they risk avoidable delays. This report provides a structured approach to clinical trial preparation for paediatric populations, and includes practical suggestions to improve the process based on learning from industry, regulators, sites, and patient advocates.

Policy Points\ud Equitable access to a COVID‐19 vaccine in all countries remains a key policy objective, but experience of previous pandemics suggests access will be limited in developing countries, despite the rapid development of three successful vaccine candidates.\ud The COVAX Facility seeks to address this important issue, but the prevalence of vaccine nationalism threatens to limit the ability of the facility to meet both its funding targets and its ambitious goals for vaccine procurement.\ud A failure to adequately address the underlying lack of infrastructure in developing countries threatens to further limit the success of the COVAX Facility.\ud Context\ud Significant effort has been directed toward developing a COVID‐19 vaccine, which is viewed as the route out of the pandemic. Much of this effort has coalesced around COVAX, the multilateral initiative aimed at accelerating the development of COVID‐19 vaccines, and ensuring they are equitably available in low‐ and middle‐income countries (LMICs). This paper represents the first significant analysis of COVAX, and the extent to which it can be said to have successfully met these aims.\ud \ud Methods\ud This paper draws on the publicly available policy documents made available by the COVAX initiatives, as well as position papers and public statements from governments around the world with respect to COVID‐19 vaccines and equitable access. We analyze the academic literature regarding access to vaccines during the H1N1 pandemic. Finally, we consider the WHO Global Allocation System, and its principles, which are intended to guide COVAX vaccine deployment.\ud \ud Findings\ud We argue that the funding mechanism deployed by the COVAX Pillar appears to be effective at fostering at‐risk investments in research and development and the production of doses in advance of confirmation of clinical efficacy, but caution that this represents a win‐win situation for vaccine manufacturers, providing them with opportunity to benefit regardless of whether their vaccine candidate ever goes on to gain regulatory approval. We also argue that the success of the COVAX Facility with respect to equitable access to vaccine is likely to be limited, primarily as a result of the prevalence of vaccine nationalism, whereby countries adopt policies which heavily prioritize their own public health needs at the expense of others.\ud \ud Conclusions\ud Current efforts through COVAX have greatly accelerated the development of vaccines against COVID‐19, but these benefits are unlikely to flow to LMICs, largely due to the threat of vaccine nationalism.

Contains fulltext : 232104.pdf (Publisher’s version ) (Open Access) The need for information about new and existing drugs used in children was recognized in the European Union (EU) with the implementation of the Paediatric Regulation in 2007. In 2017, the 10-year review of the Paediatric Regulation identified barriers to the conduct of clinical trials, including delays in setting up and completing paediatric trials. Across Europe, the difficulties with clinical research are compounded by variation within countries and between countries. Ethics and regulatory review have national specificities. This paper describes the Collaborative Network for European Clinical Trials for Children (conect4children, c4c), which addresses selected difficulties in the design and conduct of paediatric clinical trials. c4c is a time-limited public-private consortium funded by the Innovative Medicines Initiative (IMI2). The elements of c4c are as follows: expert advice providing input on study design and/or paediatric development programmes (including patient involvement activities); a network of sites following harmonised procedures coordinated by National Hubs and a single point of contact for Europe; a facility for education and training for sites and trial teams; and support for managing data used by the network and a common paediatric data dictionary. c4c does not sponsor trials. c4c is taking a phased approach with careful piloting through industry and non-industry studies intended to demonstrate the viability of the network (proof-of-viability studies). c4c uses a co-design approach involving industry and academics within a clearly defined scope. A sustainable, successor organization open to all potential service users will be open for business before the end of IMI2 funding in 2024.

The concept of health equity—the attainment of the highest possible level of health for all members of society—requires equitable access to all aspects of healthcare, including pediatric drug development. However, many communities are under-represented in pediatric drug development programs. Barriers to participation include geographic, economic, racial/ethnic bias, legal, cultural, linguistic, and other factors. While there is no “one size fits all” approach to addressing these barriers, community engagement and collaboration is recognized by the Centers for Disease Control, the World Health Organization, and other global health organizations as a cornerstone for building a more equitable healthcare system. In this article, we will present case studies of stakeholder and community engagement in clinical research for rare diseases and other areas of healthcare, as examples of strategies and practices for actively involving under-represented communities and fostering their participation in pediatric drug development programs. These studies may serve as templates for facilitating equity in pediatric drug development from aspiration into operation.

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of pro-inflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function, thus there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects, therefore we examined whether ensifentrine alters the production of pro-inflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 (MCP-1) and granulocyte monocyte colony stimulating factor (GM-CSF) during challenge with Interleukin-1β. Comparing the effect of ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors respectively, demonstrated that the anti-inflammatory effect of ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when ensifentrine was combined with low concentrations of the β2-adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with β2-adrenergic agonists or corticosteroids. Significance Statement Airways inflammation that is disproportionate to the burden of chronic airway infection causes much of the pathology in the Cystic Fibrosis (CF) lung. We show here that ensifentrine beneficially modulates the release of pro-inflammatory factors in well-differentiated CF bronchial epithelial cells that is further enhanced when combined with β2-adrenergic agonists or low-concentration corticosteroids. The results encourage further clinical testing of ensifentrine, alone and in combination with β2-adrenergic agonists or low-concentration corticosteroids, as a novel anti-inflammatory therapy for CF.

Purpose of review Prevalence of metabolic-associated fatty liver disease (MAFLD) is increasing, and as pharmacological treatment does not exist, lifestyle interventions (i.e. diet and exercise) represent the cornerstone management and treatment strategy. Although the available data clearly demonstrate that changes in lifestyle influence intrahepatic triglyceride (IHTG) content, the mechanisms through which this is achieved are seldom investigated. Here, we review recent evidence demonstrating the influence of lifestyle interventions on hepatic fatty acid metabolism and IHTG content. Recent findings Diet and exercise influence IHTG content through various, and often interrelated factors. These include alterations in whole-body and tissue-specific insulin sensitivity, which may influence the flux of fatty acid and lipogenic substrates to the liver, and changes in intrahepatic fatty acid synthesis and partitioning. Notably, there are only a few studies that have investigated intrahepatic fatty acid metabolism in vivo in humans before and after an intervention. Summary Lifestyle interventions represent an effective means of influencing hepatic fatty acid metabolism. IHTG content is decreased without weight-loss either through exercise or by changing the macronutrient composition of the diet, although what the optimal macronutrient composition is to achieve this has yet to be defined.

BACKGROUND:Clostridium difficile is capable of causing severe enterocolitis in adults. The significance of toxin-producing C. difficile in children with diarrhea is unclear and practice differs on whether to institute treatment. We aimed to characterize the microbiome in relation to the presence of C. difficile and co-infection with other pathogens and to describe host response to infection. METHODS:Participants were children with acute diarrhea, 0-16 years of age, from whom stool samples had been submitted to the hospital laboratory for routine microbiology/virology. Convenience sampling was used for 50 prospective and 150 retrospective samples. No participants were treated for C. difficile. Rates of culture positivity for C. difficile, presence of toxin and PCR-ribotype were compared between age groups. Presence of other potential pathogens, comorbidities and complications were recorded. Microbiotal diversity was measured by 16S profiling. RESULTS:Nineteen of 77 (25%) children 2 years of age were C. difficile positive, of whom 10 (53%) and 9 (69%), respectively, carried toxigenic strains. Increased Shannon diversity was seen in children carrying C. difficile, with altered milieu. Presence of C. difficile was not associated with adverse clinical outcomes. In stools containing both Norovirus and C. difficile, there was increased relative abundance of verrucomicrobia. CONCLUSIONS:Children with diarrhea regularly carried toxigenic and non-toxigenic strains of C. difficile, demonstrating enhanced microbiotal diversity, and change in milieu, without apparent morbidity. This unexpected finding is contrary to that seen in adults with C. difficile disease.

ispartof: JOURNAL OF PEDIATRICS vol:219 pages:243-+ ispartof: location:United States status: published

In September 2021, after inaugurating the Berlin-based World Health Organization (WHO) Hub for Pandemic and Epidemic Intelligence, German Health Minister Jens Spahn indicated that sanctions might be an appropriate tool to deal with WHO member states that do not cooperate on data sharing during disease outbreaks. Tedros Adhanom Ghebreyesus, director general of the WHO, affirmed this, stating that "exploring the [idea of ] sanctions may be important" in cases where collaboration fails. Such comments indicate that the WHO Hub has been designed without much consideration of data sovereignty and "access and benefit sharing" (ABS) debates occurring across multiple United Nations (UN) bodies, including the WHO. Threats of sanctions do little to promote the ideals of equity and solidarity often touted as foundational to global health governance. They entrench the idea that pathogen samples and associated data are "bargaining chips" rather than vital inputs to public health research and pandemic response.

Carnosine is a pleiotropic histidine-containing dipeptide synthesized from β-alanine and l-histidine, with the intact dipeptide and constituent amino acids being available from the diet. The therapeutic application of carnosine in myocardial tissue is promising, with carnosine playing a potentially beneficial role in both healthy and diseased myocardial models. This narrative review discusses the role of carnosine in myocardial function and health, including an overview of the metabolic pathway of carnosine in the myocardial tissue, the roles carnosine may play in the myocardium, and a critical analysis of the literature, focusing on the effect of exogenous carnosine and its precursors on myocardial function. By so doing, we aim to identify current gaps in the literature, thereby identifying considerations for future research.

The International Health Regulations, 2005 revision; IHR (2005) govern how countries address collective threats in global solidarity; yet international travel bans can drive countries apart through economic isolation, trade disruptions, discriminatory restrictions and rights violations. This editoria discusses under which conditions travel restrictions can be legally justified.

Cystic fibrosis transmembrane conductance regulator (CFTR), the anion channel that is defective in cystic fibrosis (CF), is phosphorylated and activated by cAMP-dependent protein kinase (PKA). cAMP levels are downregulated by a large family of phosphodiesterases that have variable expression in different cell types. We have previously observed high levels of PDE8A expression in well-differentiated primary human bronchial epithelial (pHBE) cells and thus aimed to assess whether it played a role in cAMP-dependent regulation of CFTR activity.We assessed the effect of the selective PDE8 inhibitor PF-04957325 (PF) on intracellular cAMP levels ([cAMP]PDE8 inhibition elevated [cAMP]These results provide the first evidence that PDE8A regulates CFTR and identifies PDE8A as a potential target for adjunct therapies to treat CF.

Summary Background Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. Methods NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov ( NCT02790996 ). Findings Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). Interpretation In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. Funding EU Seventh Framework Programme for research, technological development and demonstration.

Developing suitable paediatric formulations and ensuring access to them by the greatest number of the 2.2 billion children worldwide are equally important to provide optimal pharmacotherapy. This review focuses on the progress made over the last two decades with paediatric oral formulations with respect to evidence for acceptability and dosing flexibility of liquid and solid oral dosage forms. It also discusses the clinical needs for, and the access to, paediatric formulations for existing authorised medicines. A significant body of new knowledge now supports the acceptability of solid oral dosage forms in children, resulting in an increasing number of medicines commercialised as multiparticulates, including minitablets that are starting to be brought to market. However, there are gaps with these formulations that deserve more research. Even though efforts have been made to identify medicines in need of age-appropriate formulations, there is no common priority list shared internationally. Such prioritisation would help to develop paediatric formulations with the greatest potential for providing a health benefit to children worldwide. In addition, available data highlight that paediatric formulation access is fragmented and unequal, with commercialisation of suitable paediatric formulations too often limited to some countries/regions. We propose actions to better align decisions during the development of paediatric formulations and promote a more globalised approach to facilitate registration pathways between different jurisdictions. Furthermore, discussions about alignment between approval, pricing and reimbursement processes should also happen, leaving working in siloes behind us. It is time for adults to start thinking outside the box for children.

Objectives Induction of labour (IOL), or starting labour artificially, can be a lifesaving intervention for pregnant women and their babies, and rates are rising significantly globally. As rates increase, it becomes increasingly important to fully evaluate all available data, especially that from low income settings where the potential benefits and harms are greater. The goal of this paper is to describe the datasets collected as part of the Induction with Foley OR Misoprostol (INFORM) Study, a randomised trial comparing two of the recommended methods of cervical ripening for labour induction, oral misoprostol and Foley catheter, in women being induced for hypertension in pregnancy, at two sites in India during 2013–15. Data description This dataset includes comprehensive data on 602 women who underwent IOL for hypertensive disorders in pregnancy. Women were randomly assigned to cervical ripening with oral misoprostol or a transcervical Foley catheter in two government hospitals in India. The main dataset has 367 variables including monitoring during the induction of labour, medications administered, timing and mode of delivery, measures of neonatal morbidity and mortality, maternal mortality and morbidity, maternal satisfaction and health economic data. The dataset is anonymised and available on ReShare.

Background Every year approximately 30,000 women die from hypertensive disease in pregnancy. Magnesium sulphate and anti-hypertensives reduce morbidity, but delivery is the only cure. Low dose oral misoprostol, a prostaglandin E1 analogue, is a highly effective method for labour induction. Usually, once active labour has commenced, the misoprostol is replaced with an intravenous oxytocin infusion if ongoing stimulation is required. However, some studies have shown that oral misoprostol can be continued into active labour, a simpler and potentially more acceptable protocol for women. To date, these two protocols have never been directly compared. Methods This pragmatic, open-label, randomised trial will compare a misoprostol alone labour induction protocol with the standard misoprostol plus oxytocin protocol in three Indian hospitals. The study will recruit 520 pregnant women being induced for hypertensive disease in pregnancy and requiring augmentation after membrane rupture. Participants will be randomised to receive either further oral misoprostol 25mcg every 2 h, or titrated intravenous oxytocin. The primary outcome will be caesarean birth. Secondary outcomes will assess the efficacy of the induction process, maternal and fetal/neonatal complications and patient acceptability. This protocol (version 1.04) adheres to the SPIRIT checklist. A cost-effectiveness analysis, situational analysis and formal qualitative assessment of women’s experience are also planned. Discussion Avoiding oxytocin and continuing low dose misoprostol into active labour may have a number of benefits for both women and the health care system. Misoprostol is heat stable, oral medication and thus easy to store, transport and administer; qualities particularly desirable in low resource settings. An oral medication protocol requires less equipment (e.g. electronic infusion pumps) and may free up health care providers to assist with other aspects of the woman’s care. The simplicity of the protocol may also help to reduce human errors associated with the delivery of intravenous infusions. Finally, women may prefer to be mobile during labour and not restricted by an intravenous infusion. There is a need, therefore, to assess whether augmentation using oral misoprostol is superior clinically and economically to the standard protocol of intravenous oxytocin. Trial registration Clinical Trials.gov, NCT03749902, registered on 21st Nov 2018.

IntroductionIn conjunction with a beta-lactam, aminoglycosides are the first-choice antibiotic for empirical treatment of sepsis in the neonatal period. The m.1555A>G variant predisposes to ototoxicity after aminoglycoside administration and has a prevalence of 1 in 500. Current genetic testing can take over 24 hours, an unacceptable delay in the acute setting. This prospective-observational trial will implement a rapid point of care test (POCT), facilitating tailored antibiotic prescribing to avoid hearing loss.Methods and analysisThe genedrive POCT can detect the m.1555A>G variant in 26 min from buccal swab. This system will be integrated into the clinical pathways at two large UK neonatal centres over a minimum 6-month period. The primary outcome is the number of neonates successfully tested for the variant out of all babies prescribed antibiotics. As a secondary outcome, clinical timings will be compared with data collected prior to implementation, measuring the impact on routine practice.Ethics and disseminationApproval for the trial was granted by the Research Ethics Committee (REC) and Human Research Authority in August 2019. Results will be published in full on completion of the study.Trial registration numberISRCTN13704894.Protocol versionV 1.3.

COVID-19 has impacted the provision of orthognathic surgery globally. Uncertainty around its effects and transmission in aerosol generating procedures (AGP’s) has led to disagreement within maxillofacial surgeons into the safety of orthognathic surgery during the pandemic. We present a local case series of orthognathic surgery undertaken during the COVID-19 pandemic. To our knowledge no such similar study has been reported worldwide. Data was collected from the 1st June to 30th November 2020 for all patients undergoing orthognathic surgery by a single consultant. All procedures and inpatient stays were performed ‘off site’ at the local Spire Healthcare Group plc© facility. A strict preoperative two-week self-isolation period and negative COVID-19 testing was mandatory. All procedures were classified as AGP’s and personal protective equipment (PPE) was worn in line with local guidelines. The primary outcome was 30-day COVID-19 infection among patients, with day 0 the date of surgery. Secondary outcome measures included duration of stay, return to theatre and complications. A total of 59 patients were identified. 42/59 had bimaxillary procedures and 17/59 single jaw. 9/17 had maxillary and 8/17 had mandibular procedures. A total of 3/59 had simultaneous genioplasty. Median duration of stay was one night (range 1-3). Immediate and late complications were seen in 3% (2/59) and 3% (2/59) respectively. Only 1% (1/59) returned to theatre. Zero patients tested positive in the 30-day postoperative period. No staff members tested positive for the duration of the study. Adopting strict safety protocols, orthognathic surgery can be safely delivered during the pandemic without detriment to the patient or staff.

Law can serve as both an enabler and a barrier to global health, equity, and justice.1 The impact of legal determinants of health on the COVID-19 pandemic is evident where law is being used as a mechanism to enable or prevent global equitable access to COVID-19 vaccines. Barriers to equitable access are partly driven by vaccine nationalism2 with governments seeking to use law to secure priority access to future vaccines through Advance Purchase Agreements (APAs) with vaccine manufacturers. These bilateral legal agreements can be in a nation's interest, but given the uncertain success of individual COVID-19 vaccine candidates and the global spread of SARS-CoV-2, APAs are a gamble and erode collaboration between countries. Importantly, such bilateral legal agreements are likely to contribute to inequities and potentially extend the pandemic's time frame. By contrast, multilateral legal agreements could be the path back to global health security and justice by re-establishing norms of international solidarity, committing to global equitable vaccine access initiatives, and laying a foundation for a post-pandemic era built on multilateralism and cooperation.

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated the critical importance and persistent challenges of rapidly sharing public health and scientific information, biological samples, and genetic sequence data (GSD). Sharing these resources is crucial to characterizing the causative agent, understanding its spread, and developing diagnostics, antiviral treatments, and vaccines. But even though these resources are critical for the global health community, there is currently no legal obligation for countries to share physical pathogen samples or associated GSD. To date, researchers have often shared such resources in a spirit of scientific openness. Yet ongoing scientific cooperation has been insufficient (1) despite the scale of the pandemic threat. The lack of a clear legal obligation to share pathogens or associated GSD during a health emergency represents a blind spot in international law and governance, impeding pandemic response and scientific progress. We examine the sharing of public health information, biological samples, and GSD in the still early days of the COVID-19 pandemic, identify barriers to sharing under the current international legal system, and propose legal and policy reforms needed to enhance international scientific cooperation.

In imposing travel restrictions against China during the current outbreak of 2019 novel coronavirus disease (COVID-19), many countries are violating the IHR. We—16 global health law scholars—came to this conclusion after applying the interpretive framework of the Vienna Convention on the Law of Treaties and reaching a jurisprudential consensus on the legal meaning of Article 43 of the International Health Regulations (2005).

Preparing for the Next Pandemic Given the ongoing threat posed by influenza, the WHO earlier this year released its Global Influenza Strategy 2019–2030. Although the strategy is a welcome step, add...

Objective: To assess spontaneous reports of suspected adverse drug reactions in children aged 0–12 years from the Brazilian Health Regulatory Agency between 2008 and 2013. Methods: A cross-sectional study on suspected adverse drug reactions reports related to medicines and health products in children was carried out for a six-year period (2008–2013). Year of report, origin of report by Brazilian state, gender, age, suspected drug, adverse reaction description and seriousness were included in the analysis. The data obtained was compared to the number of pediatric beds in health services and to global data from the VigiBase (World Health Organization). Results: A total of 3330 adverse drug reactions were reported in children in Brazil in the investigated period (54% were in boys). About 28% of suspected adverse drug reactions reports involved 0 to 1-year-old children. Almost 40% of reports came from the Southeast region. Approximately 60% were classified as serious events. There was death in 75 cases. Nearly 30% of deaths involved off-label use; 3875 medicines (465 active substances) were considered suspected drugs. Anti-infective (vancomycin, ceftriaxone, oxacillin, and amphotericin), nervous system (metamizole) and alimentary tract and metabolism medicines were more frequent in reports. Conclusions: The distribution of suspected adverse drug reactions reports by sex and age group corresponded to the profile of children hospitalized in Brazil. Data about seriousness and medicines reported may be useful to encourage regulatory actions and improve the safe use of medicines in children. Resumo: Objetivo: Analisar relatos espontâneos de suspeitas de Reação Adversa a Medicamento (RAM) em crianças de 0 a 12 anos notificadas pela Agência Nacional de Vigilância Sanitária entre 2008 e 2013. Métodos: Um estudo transversal a partir de notificações de suspeitas de RAM relacionadas a medicamentos e produtos para a saúde em crianças foi realizado por um período de seis anos (2008-2013). O ano da notificação, a origem do relato por estado brasileiro, sexo, idade, o medicamento suspeito, a descrição da reação adversa e a gravidade foram incluídos na análise, bem como o número de leitos nos serviços de saúde e dados global da VigiBase. Resultados: Um total de 3330 reações adversas foram relatadas em crianças no Brasil no período investigado (54% em meninos). Cerca de 28% dos relatos de suspeitas de RAM envolveram crianças de 0 a 1 ano de idade. Quase 40% dos relatos vieram da região Sudeste. Aproximadamente 60% foram classificados como eventos graves. Houve ocorrência de morte em 75 casos. Quase 30% das mortes envolveram o uso off-label dos medicamentos. Um total de 3875 medicamentos (465 substâncias ativas) foram considerados fármacos suspeitos. Medicamentos anti-infecciosos (vancomicina, ceftriaxona, oxacilina e anfotericina), com ação no sistema nervoso (dipirona) e no trato digestivo foram os mais frequentemente notificados. Conclusões: As notificações de suspeitas de RAM por sexo e faixa etária corresponderam ao perfil de crianças hospitalizadas no Brasil. Os dados sobre gravidade e medicamentos relatados podem ser úteis para encorajar ações reguladoras e melhorar o uso seguro de medicamentos em crianças. Keywords: Adverse reactions, Children, Pediatrics, Database study reporting, Drug monitoring, Pharmacoepidemiology, Palavras-chave: Reações adversas, Crianças, Pediatria, Relato de estudo de banco de dados, Monitoramento de medicamentos, Farmacoepidemiologia

Background Probiotic bacteria can provide health benefits when delivered in functional foods. This study involved isolation of lactic acid bacteria (LAB) from traditionally dried and salted anchovy fish and characterization of their survival in simulated gastrointestinal digestion. Promising strains were used to prepare fermented fish sausages which were then evaluated for cytotoxicity activity against two cancer cell-lines, antidiabetic activity as determined by α-amylase and α-glucosidase inhibition, and antioxidant and proteolytic activities in vitro, as compared to non-fermented control sausages. Results Out of 85 LAB obtained, 13 isolates with high tolerance to simulated gastrointestinal digestion were obtained, which were identified as Enterococcus spp. Four E. faecium strains, one E. faecalis, and one E. durans were used separately to make fermented fish sausages. The α-amylase and α-glucosidase inhibition from fish sausages fermented by Enterococcus spp. ranged from 29.2 to 68.7% and 23.9 to 41.4%, respectively, during 21 days of storage. The cytotoxicity activities against Caco2 and MCF-7 cells of fish sausages fermented with Enterococcus spp. ranged from 18.0 to 24% and 13.9 to 27.9%, respectively. Cytotoxicity activities correlated positively with proteolysis and antioxidant activities, α-amylase and α-glucosidase inhibition activities, but negatively with the pH in fermented fish sausages. Strains also exhibited antimicrobial activity against foodborne pathogens and presented no significant concerns with regards to antibiotic resistance or virulence gene content. Conclusions Fish sausages fermented by potential probiotic isolates of Enterococcus spp. from dried fish had valuable health-promoting benefits compared with non-fermented control sausages.

Aim: The European Network of Excellence for Paediatric Clinical Research, known as the TEDDY Network, carried out a survey to determine the capacity and competence of paediatric centres to perform research studies. Methods: A cross-sectional, web-based pilot survey was conducted from October 2016 to April 2017 with paediatric clinical research centres in 11 countries: Albania, Austria, Belgium, Denmark, Iceland, Ireland, Italy, Norway, Spain, Switzerland and the United Kingdom. All were registered with the TEDDY Network database. Results: We approached 107 centres and 63 provided data on their experiences and expertise in paediatric clinical trials. Four groups of performance indicators were identified, referring to scientific experience, trial readiness, trial competence, regulatory issues, ethics and patients. Most centres were actively involved in paediatric clinical research: 53 centres (84.1%) had received funds for more than five paediatric studies in the last 5 years, and 42 (66.7%) had a specific clinical trial unit and dedicated study coordinators. We concluded that the European centres we studied had the capability and capacity to conduct paediatric trials, but there was still room for improvement, including enhanced collaboration. Conclusion: This pilot survey demonstrated that there is potential for performing paediatric trials across Europe, but improvements are possible.

BackgroundSevere early-onset fetal growth restriction (FGR) predisposes to fetal death, neonatal death, neonatal morbidity and neurodisability. The use of placental biomarkers has been proposed for risk stratification in pre-eclampsia, but they could be equally useful in fetal growth restriction in aiding management.ObjectiveTo determine the efficacy of angiogenic biomarkers at predicting adverse pregnancy outcome in severe early-onset fetal growth restriction.Study designThis is a secondary analysis of the multicentre, placebo-controlled STRIDER UK randomised controlled trial of singleton pregnancies with severe early-onset fetal growth restriction.Women with FGR pregnancies between 22+0 and 29+6 weeks of gestation were randomly assigned to receive either sildenafil 25 mg three times daily or placebo until 32+0 weeks’ gestation or delivery. We developed prediction models based upon maternal demographics (age, parity, blood pressure, preeclampsia, gestational hypertension), fetal biometric (estimated fetal weight) and Doppler measurements (Middle Cerebral Artery (MCA), Umbilical Artery (UA)) and maternal angiogenic biomarkers [placental growth factor (PlGF), soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt-1) and sFlt-1:PlGF ratio) using both univariate and multivariate analysis.ResultsA complete data set was available for 105 of 135 randomised women. Multivariate regression analysis identified estimated fetal weight (EFW) and sFlt-1:PlGF as independent predictors of livebirth (EFW OR: 1.01 (1.008, 1.021); p ConclusionsIn severe early-onset FGR pregnancies livebirth and overall survival can be predicted using a model involving EFW and sFlt-1:PlGF ratio. This model require validation in a larger cohort but may allow informed decision making about pregnancy management, especially in previable cases.

AimsDrug disposition in children may vary from adults due to age‐related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [14C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose.MethodsPreterm to 2‐year‐old infants admitted to the intensive care unit received [14C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [14C]midazolam and [14C]1‐hydroxy‐midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed.ResultsOf 15 infants (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), 6 received a microtracer and 9 a microdose of [14C]midazolam (111 Bq kg−1; 37.6 ng kg−1). In a 2‐compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [14C]1‐OH‐midazolam/[14C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses.ConclusionOur data support the dose linearity of the PK of an IV [14C]midazolam microdose in children. Hence, a [14C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children.

ObjectiveThe aim of our study was to determine if a genetic background of high blood pressure is a survival factor in preterm infants.DesignProspective cohort study.SettingPatients were enrolled in 53 neonatal intensive care units.PatientsPreterm infants with a birth weight below 1500 g.ExposuresGenetic score blood pressure estimates were calculated based on adult data. We compared infants with high genetic blood pressure estimates (>75th percentile of the genetic score) to infants with low genetic blood pressure estimates (Main outcome measuresLowest blood pressure on the first day of life and mortality.Results5580 preterm infants with a mean gestational age of 28.1±2.2 weeks and a mean birth weight of 1022±299 g were genotyped and analysed. Infants with low genetic blood pressure estimates had significantly lower blood pressure if compared with infants with high genetic blood pressure estimates (27.3±6.2vs 27.9±6.4, p=0.009, t-test). Other risk factors for low blood pressure included low gestational age (−1.26 mm Hg/week) and mechanical ventilation (−2.24 mm Hg, pConclusionsOur study provides first evidence that a genetic background of high blood pressure may be beneficial with regard to survival of preterm infants.

Background There is limited data on adrenal function in the early days after birth in extremely premature infants. The relationship between plasma adrenocorticotrophic (ACTH) and cortisol hormone is central to the integrity of the hypothalamic-pituitary-adrenal (HPA) axis yet there are no studies examining this relationship in prematurity. Methods The aim of this study was to examine the relationship between early morning plasma cortisol and ACTH concentrations during the first 5 days after birth in infants born at less than 28 weeks’ gestation and to identify any independent factors that determine plasma cortisol levels in these infants during extreme prematurity. We prospectively studied early morning plasma ACTH and cortisol concentrations in infants born below 28 weeks’ gestation during the first 5 days of birth. Plasma cortisol was measured without extraction, using DPC Immulite® 2000 using a solid phase 2 site chemiluminescent immunometric assay. ACTH was measured using a radioimmunoassay. Spearman’s correlation was used to examine the relationship between cortisol and ACTH. Multiple regression analysis was used to examine the relationship between plasma cortisol and clinical risk index for babies (CRIB) score, antenatal dexamethasone, mode of delivery and gestation. Results There were 95 infants (53 males) of mean gestation 25.3 ± 1.3 standard deviation (SD) (range 23–27 + 6) weeks. The mean birth weight was 809 ± 17.0 g. The mean plasma cortisol was 400.5 ± 42.6 nmol/L and the mean plasma ACTH was 4.5 ± 0.9 pmol/L. Early morning plasma cortisol correlated significantly with gestation (R = 0.4, p = 0.005). Early morning plasma ACTH did not correlate with early morning plasma cortisol (R = −0.12, p = 0.7). Multiple regression analysis showed that gestation was the only independent determinant of early morning plasma cortisol concentration (beta coefficient = −0.4, p = 0.04). Conclusions The relationship between early morning plasma ACTH and plasma cortisol is either not established or is impaired in infants of less than 28 weeks’ gestation in the first 5 days after birth. The plasma cortisol level is mainly determined by gestation and is not directly related to illness severity, antenatal steroids or plasma ACTH in these infants in the first 5 days after birth.

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development. ispartof: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY vol:88 issue:12 pages:4965-4984 ispartof: location:England status: published

Importance The emerging paradigm of treat-to-target in psoriasis requires accurate monitoring of treatment response. The commonly used physician global assessment tool does not capture the patient’s perception of their disease. Patient assessments facilitate shared decision-making and foster patient-centered care; however, recent research reports a discordance between patient- and physician-reported psoriasis severity. Understanding the factors underlying this discordance may improve treatment satisfaction and disease outcomes. Objectives To evaluate the discordance between patient- and physician-reported measures of psoriasis severity and assess the association with patient mental health status. Design, Setting, and Participants A cohort study using repeated cross-sectional analysis of real-world longitudinal data was conducted at a large specialist psoriasis service serving London and Southeast England. A total of 502 patients attending the psoriasis service between May 12, 2016, and November 1, 2018, were included. Data analysis was conducted July 22 to October 22, 2019. Main Outcomes and Measures Psoriasis severity was assessed on each visit with identical 5-point physician and patient global assessment scales (clear/nearly clear, mild, moderate, severe, and very severe). Each patient completed validated self-report screens for depression and anxiety on each visit. Results Longitudinal data from 502 individuals with psoriasis (1985 total observations) were available. A total of 339 patients (68%) were men, 396 (79%) were White, mean (SD) age was 47 (13) years, and 197 patients (39%) had concurrent psoriatic arthritis, 43 (9%) screened positive for depression, and 49 (10%) screened positive for anxiety. There was discordance between physician and patient measures of disease severity in 768 of 1985 office appointments (39%); on 511 visits (26%) patients rated their psoriasis as less severe and on 257 visits (13%) patients rated their psoriasis as more severe compared with their physician. Individuals who screened positive for depression or anxiety were more likely to overestimate their psoriasis severity compared with their physician (relative risk ratio: depression, 2.7; 95% CI, 1.6-4.5; anxiety, 2.1; 95% CI, 1.3-3.4). These findings remained statistically significant after adjustment for age, ethnicity, sex, body mass index, smoking, number of comorbidities, treatment modality, and presence of psoriatic arthritis. Conclusions and Relevance The findings of this cohort study suggest that discordance between patient and physician assessments of psoriasis severity is associated with patients’ mental health status. Recognition of anxiety and depression in individuals with psoriasis appears to be important when interpreting patient-reported outcome measures and informing appropriate treatment decisions.

Neonates experience adverse drug reactions (ADRs), but under-reporting of suspected ADRs to national spontaneous reporting schemes in this population is particularly high. A prospective observational study collected suspected neonatal ADRs at a tertiary neonatal unit. Cases were analysed for causality by six assessors using three existing methods. Sixty-three suspected ADR cases were identified in 35/193 neonates (18.1%). The proportion of suspected ADRs where the drug was prescribed "off-label" was 30/68 (44.1%). When 34 cases were assessed for causality using three methods, global kappa scores of less than 0.3 for each tool suggested only "fair" inter-rater reliability. Neonatal ADRs can be captured and occur from a variety of drugs affecting many organ systems. The current tools for assessing causality need to be adapted before they can reliably assess neonatal ADRs.

Objectives To determine whether a permanent pacemaker (PPM) in situ can enhance survival after transcatheter aortic valve implantation (TAVI), in a predominantly inoperable or high risk cohort. Background New conduction disturbances are the most frequent complication of TAVI, often necessitating PPM implantation before hospital discharge. Methods We performed an observational cohort analysis of the UK TAVI registry (2007-2015). Primary and secondary endpoints were 30-day post-discharge all-cause mortality and long-term survival, respectively. Results Of 8,651 procedures, 6,815 complete datasets were analyzed. A PPM at hospital discharge, irrespective of when implantation occurred (PPM 1.68% [22/1309] vs. no PPM 1.47% [81/5506], odds ratio [OR] 1.14, 95% confidence interval [CI] 0.71-1.84; p = .58), or a PPM implanted peri- or post-TAVI only (PPM 1.44% [11/763] vs. no PPM 1.47% [81/5506], OR 0.98 [0.51-1.85]; p = .95) did not significantly reduce the primary endpoint. Patients with a PPM at discharge were older, male, had right bundle branch block at baseline, were more likely to have received a first-generation self-expandable prosthesis and had experienced more peri- and post-procedural complications including bailout valve-in-valve rescue, bleeding and acute kidney injury. A Cox proportional hazards model demonstrated significantly reduced long-term survival in all those with a PPM, irrespective of implantation timing (hazard ratio [HR] 1.14 [1.02-1.26]; p = .019) and those receiving a PPM only at the time of TAVI (HR 1.15 [1.02-1.31]; p = .032). The reasons underlying this observation warrant further investigation. Conclusions A PPM did not confer a survival advantage in the first 30 days after hospital discharge following TAVI.

Viewpoint paper.

Importance There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions Intramuscular administration of 3A-HBV (10 μg) or 1A-HBV (20 μg) on days 0, 28, and 168. Main Outcomes and Measures Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22

IntroductionChronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia (BPD), is a cause of significant respiratory morbidity in childhood and beyond. Coupled with lung immaturity, infections (especially by Ureaplasma spp) are implicated in the pathogenesis of CLD through promotion of pulmonary inflammation. Azithromycin, which is a highly effective against Ureaplasma spp also has potent anti-inflammatory properties. Thus, azithromycin therapy may improve respiratory outcomes by targeting infective and inflammatory pathways. Previous trials using macrolides have not been sufficiently powered to definitively assess CLD rates. To address this, the azithromycin therapy for chronic lung disease of prematurity (AZTEC) trial aims to determine if a 10-day early course of intravenous azithromycin improves rates of survival without CLD when compared with placebo with an appropriately powered study.Methods and analysis796 infants born at less than 30 weeks’ gestational age who require at least 2 hours of continuous respiratory support within the first 72 hours following birth are being enrolled by neonatal units in the UK. They are being randomised to receive a double-blind, once daily dose of intravenous azithromycin (20 mg/kg for 3 days, followed by 10 mg/kg for a further 7 days), or placebo. CLD is being assessed at 36 weeks’ PMA. Whether colonisation with Ureaplasma spp prior to randomisation modifies the treatment effect of azithromycin compared with placebo will also be investigated. Secondary outcomes include necrotising enterocolitis, intraventricular/cerebral haemorrhage, retinopathy of prematurity and nosocomial infections, development of antibiotic resistance and adverse reactions will be monitored.Ethics and disseminationEthics permission has been granted by Wales Research Ethics Committee 2 (Ref 18/WA/0199), and regulatory permission by the Medicines and Healthcare Products Regulatory Agency (Clinical Trials Authorisation reference 21323/0050/001–0001). The study is registered on ISRCTN (ISRCTN11650227). The study is overseen by an independent Data Monitoring Committee and an independent Trial Steering Committee. We shall disseminate our findings via national and international peer-reviewed journals, and conferences. A summary of the findings will also be posted on the trial website.

This chapter describes methods used to isolate, identify, and partially characterize lactic acid bacteria (LAB) which exhibit inhibitory activity against Listeria monocytogenes from foods. Vegetal (plant based) sources are rich in naturally occurring LAB and therefore provide an easily accessible source of strains with potential antimicrobial activity for use in food-processing applications. From our previous work, the majority of LAB with inhibitory activity against L. monocytogenes were identified as generally recognized as safe (GRAS) Lactococcus lactis. Although these bacteria are most commonly known for their role in industrial dairy fermentations, they are believed to have originally derived from natural plant-based habitats. These isolates with anti-Listeria activity were all found to carry the genes involved in the production of nisin, which is an approved food-grade preservative (E234). These isolates may find various applications for in situ production of nisin allowing control of L. monocytogenes in various fermented and non-fermented foods and other environments.