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INTRODUCTION: The inclusion of herbal medicinal products and herbal supplements in pharmacovigilance systems is important because a systematic approach of collecting and analyzing adverse drug reactions related to these products will help practitioners, patients, and regulators to gain more knowledge and prevent harm.OBJECTIVE: We aimed to categorize the adverse drug reaction reports on herbal medicinal products and herbal supplements submitted to the Pharmacovigilance Centre Lareb between 1991 and February 2021 on the basis of their regulatory status, herbs included, and adverse drug reactions involved.METHODS: We categorized products on the basis of their registration status and herbal ingredients. The products were then categorized according to the Herbal Anatomical Therapeutic Chemical Classification System. We used descriptive statistics in Microsoft Excel 2019. Pivot tables were used for the analysis and presentation of the data.RESULTS: Until February 2021, a total of 789 reports of herbal medicinal products and herbal supplements were received by Lareb. In these reports, a total of 823 herbal products were labeled as suspect. These products caused a total of 1727 adverse drug reactions. Of the 823 products, 229 were registered as a medicine, and 594 were on the market as a herbal supplement. Of the 823 herbal products, 522 reports concerned single-herb products, 256 reports concerned combination products, 27 reports concerned vitamin products containing herbal ingredients, and 18 reports concerned product issues. Approximately 15% of reports concerned serious adverse drug reactions, and adulterated products harbored a high risk of causing serious adverse drug reactions.CONCLUSIONS: Analysis of the herbal medicinal products and herbal supplements in the Dutch pharmacovigilance database revealed a variety of suspected herbal ingredients. The reports provide insight into the variety of herbal products used in the Netherlands and the adverse reactions associated with their use. Pharmacovigilance of herbal products is essential to ensure their safe use.

The inclusion of herbal medicinal products and herbal supplements in pharmacovigilance systems is important because a systematic approach of collecting and analyzing adverse drug reactions related to these products will help practitioners, patients, and regulators to gain more knowledge and prevent harm.We aimed to categorize the adverse drug reaction reports on herbal medicinal products and herbal supplements submitted to the Pharmacovigilance Centre Lareb between 1991 and February 2021 on the basis of their regulatory status, herbs included, and adverse drug reactions involved.We categorized products on the basis of their registration status and herbal ingredients. The products were then categorized according to the Herbal Anatomical Therapeutic Chemical Classification System. We used descriptive statistics in Microsoft Excel 2019. Pivot tables were used for the analysis and presentation of the data.Until February 2021, a total of 789 reports of herbal medicinal products and herbal supplements were received by Lareb. In these reports, a total of 823 herbal products were labeled as suspect. These products caused a total of 1727 adverse drug reactions. Of the 823 products, 229 were registered as a medicine, and 594 were on the market as a herbal supplement. Of the 823 herbal products, 522 reports concerned single-herb products, 256 reports concerned combination products, 27 reports concerned vitamin products containing herbal ingredients, and 18 reports concerned product issues. Approximately 15% of reports concerned serious adverse drug reactions, and adulterated products harbored a high risk of causing serious adverse drug reactions.Analysis of the herbal medicinal products and herbal supplements in the Dutch pharmacovigilance database revealed a variety of suspected herbal ingredients. The reports provide insight into the variety of herbal products used in the Netherlands and the adverse reactions associated with their use. Pharmacovigilance of herbal products is essential to ensure their safe use.

After the pH dependency of novel pH-dependent ileocolonic drug delivery systems is confirmed in vitro, their performance should be evaluated in human volunteers.

Background Hexavalent chromium has been found to increase the risk of lung cancer in occupational studies. It has been suggested that the relative risk of lung cancer may vary by age. Methods The cohort examined is the Baltimore cohort of chromium production workers. The effect of age on the lung cancer risk from hexavalent chromium exposure was examined using a conditional Poisson regression modeling approach of Richardson and Langholz (R&L) and Cox models with interaction terms of age and cumulative hexavalent chromium exposure. Results The inclusion of multiple age groups in the R&L approach suggests the existence of an age effect that is also supported by a Cox proportional hazard analysis. The hazard ratio in Cox models with age‐cumulative exposure interaction terms was significantly elevated for the youngest age group and significantly decreased for the oldest age group. Conclusions Our analyses are consistent with the observation that younger chromium production workers have a greater lung cancer risk than older workers.

Background A frequent problem in ageing patients, and thus in nursing home residents, is dysphagia, affecting the ability to swallow solid dosage forms. A promising and personalized drug delivery system for this patient group is the orodispersible film. Orodispersible films could be prepared extemporaneously in a (hospital) pharmacy setting or in specialty compounding community pharmacies using the solvent casting method. Little has been done to systematically investigate which medications should be chosen for orodispersible film formulation development. Objective In this study, the medication use of nursing home residents was examined to identify medications that are suitable for orodispersible film formulation development. Setting Nursing homes of three Northern provinces of Netherlands. Method Medication intake data from 427 nursing home residents from nine nursing homes from the three northern provinces of the Netherlands were used to identify candidates for orodispersible film formulation development. A stepwise approach, with exclusion steps, was used. Selection criteria included systemic use with a maximum amount of 100 mg per dose unit, no commercially available suitable dosage forms for administration in dysphagia, indication for diseases associated with dysphagia. Furthermore, the characteristics of the active pharmaceutical ingredient needed for the orodispersible film formulation development, such as water solubility and taste, were reviewed. Main outcome measure Active pharmaceutical ingredients suitable for orodispersible film formulation development. Results The nursing home residents used three hundred forty one different medications. Of those, 34 active pharmaceutical ingredients from six therapeutic groups were considered as candidates for orodispersible film formulation development. Most of these active pharmaceutical ingredients have a bitter taste and poor water solubility, which is a challenge for orodispersible film production. Conclusions The most suitable active pharmaceutical ingredient candidates for manufacturing of orodispersible films for the ageing patient population may be the combination of levodopa and carbidopa used to treat the symptoms of Parkinson’s disease, and baclofen used to treat spasticity.

Introduction: E-Exercise is an effective 12-week blended intervention consisting of around five face-to-face physiotherapy sessions and a web-based application for patients with hip/knee osteoarthritis. In order to facilitate effective implementation of e-Exercise, this study aims to identify physiotherapists' experiences and determinants related to the usage of e-Exercise. Methods: An explanatory sequential mixed methods design embedded in a randomized controlled trial comparing e-Exercise with usual physiotherapy in patients with hip/knee osteoarthritis. Usage of e-Exercise was based on recruitment rates of 123 physiotherapists allocated to e-Exercise and objective web-based application usage data. Experiences and determinants related to e-Exercise usage were investigated with a questionnaire and clarified with semi-structured interviews. Results: Of the 123 physiotherapists allocated to e-Exercise, 54 recruited more than one eligible patient, of whom 10 physiotherapists continued using e-Exercise after the study period. Physiotherapists had mixed experiences with e-Exercise. Determinants related to intervention usage were appropriateness, added value, time, workload, professional autonomy, environmental factors, and financial consequences. Physiotherapists recommended to improve the ability to tailor e-Exercise to the individual needs of the patient patients' individual needs. Discussion: Determinants related to the usage of e-Exercise provided valuable information for the implementation of e-Exercise on broader scale. Most importantly, the flexibility of e-Exercise needs to be improved. Next, there is a need for education on how to integrate an online program within physiotherapy.

BACKGROUND: Health economic evaluations are often required before implementing a vaccination programme. Such evaluations rarely consider the historical context of a vaccination programme. We review the financial history of vaccination programmes in the Netherlands, and compare these to demographic and macroeconomic developments as well as avoided mortality burden.METHODS: Previously uncatalogued historical expenditures on the Dutch National Immunisation Programme (NIP) and influenza vaccination were obtained from official reports. Costs were adjusted for inflation using Consumer Price Indices and expressed in Euro of 2016. Estimates on mortality burden averted were obtained from previous research and used to calculate the ratio of expenses to averted mortality burden for vaccinations against diphtheria, tetanus, pertussis, polio, measles, mumps and rubella for birth cohorts 1953-1992.RESULTS: Developments towards a uniform government funded NIP started early 1950s with vaccinations against diphtheria, pertussis and tetanus, culminating in its official launch in 1957 together with polio vaccinations. Since the 1980s, expenditure increased nearly five-fold mostly due to the addition of new vaccines, while spending on already implemented vaccinations tended to decline. Overall, expenditure increased from € 5 million in 1957 to € 93 million in 2014. Relative to total healthcare expenditure, the NIP contributed little, ranging between 0.05% and 0.14%. Spending on influenza vaccination increased from € 37 million in 1996 to € 52 million in 2014, while relative to total healthcare expenditure it decreased from 0.069% to 0.055%. In 2014, 0.15% of healthcare expenditure and € 533 per birth was spent on vaccination programmes. Overall, for birth cohorts 1953-1992, € 5.4 thousand (95% confidence interval: 4.0-7.3) was expended per year-of-life-lost averted.CONCLUSION: The actual costs per year-of-life gained are more favorable than estimated here since averted medical costs were not included. Although expenditure on vaccination programmes increased substantially, the contribution to overall healthcare expenditure remained small.

Introduction: Respiratory syncytial virus (RSV) causes high morbidity and mortality rates among infants, young children, and the elderly worldwide. Unfortunately, a safe and effective vaccine is still unavailable. In 1966, a formalin-inactivated RSV vaccine failed and resulted in the death of two young children. This failure shifted research toward the development of subunit-based vaccines for pregnant women (to passively vaccinate infants) and the elderly. Among these subunit-based vaccines, the viral envelope glycoproteins show great potential as antigens. Areas covered: In this review, progress in the development of safe and effective subunit RSV vaccines based on the viral envelope glycoproteins and intended for pregnant women and the elderly, are reviewed and discussed. Studies published in the period 2012-2018 were included. Expert opinion: Researchers are close to bringing safe and effective subunit-based RSV vaccines to the market using the viral envelope glycoproteins as antigens. However, it remains a major challenge to elicit protective immunity, with a formulation that has sufficient (storage) stability. These issues may be overcome by using the RSV fusion protein in its pre-fusion conformation, and by formulating this protein as a dry powder. It may further be convenient to administer this powder via the pulmonary route.

Introduction: Oromucosal films, comprising mucoadhesive buccal films (MBFs) and orodispersible films (ODFs), are considered patient-centric dosage forms. Target groups are patients with special needs. Various active pharmaceutical ingredients have been shown to be suitable for oromucosal film production. A shift is seen in the production techniques, from conventional solvent casting to printing techniques. Areas covered: In this review, the patient acceptability of oromucosal films is discussed. An overview is given of the small molecule drugs, biopharmaceuticals and herbal extracts that have been incorporated so far. Finally, the current state of 2D and 3D printing techniques for production purposes is discussed. Expert opinion: The patient-centric features are important for the further development and acceptance of this oral solid dosage form. Oromucosal films perfectly fit in the current attention for personalized medicine. Both MBFs and ODFs are intended for either a local or a systemic effect. For buccal absorption, sufficient mucoadhesion is one of the most important criteria an oromucosal film must comply with. For the preparation, the solvent casting technique is still predominately used. Some limitations of this production method can be tackled by printing techniques. However, these novel techniques introduce new requirements, yet to be set, for oromucosal film preparation.

Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant risk for human cancer and non-cancer diseases. It is now evident that arsenic contamination in food, especially rice and grains, presents a significant exposure to hundreds of millions of individuals worldwide. However, the disease risk from chronic exposure to the low amounts of arsenic found in food remains to be established. Thus, this research estimates the global burdens of disease expressed as Disability-Adjusted Life Years (DALYs) for lung, skin and bladder cancers, as well as coronary heart disease (CHD) attributable to inorganic arsenic in food. To determine foodborne inorganic arsenic exposures worldwide, we used the World Health Organization (WHO) estimates of food consumption in 17 country clusters, in conjunction with the reported measurements of total and inorganic arsenic in different foods. We estimated cancer potency factors for arsenic related bladder and lung cancers, and from US Environmental Protection Agency risk estimates for skin cancer to calculate the cancer incidence in males and females within each of the WHO member states. Summary relative risk estimates and population attributable fractions were developed to estimate the YLD, YLL, and DALYs for arsenic-induced CHD. The findings indicate that, globally, each year the combined DALYs for all cancers attributable to inorganic arsenic in food are approximately 1.4 million with variation in global distribution based on population and food consumption patterns. The global burden of CHD attributable to foodborne inorganic arsenic also varied with WHO region and may contribute as much as 49 million DALYs. However, in contrast to cancer burden, there is a threshold effect for arsenic-associated CHD with no increased risk of heart disease at the expected lower bound of arsenic consumption in food. These estimates indicate that foodborne arsenic exposure causes a significant yet avoidable global burden of human disease.

Chronic exposures to cadmium (Cd) are associated with reduced glomerular filtration rate (GFR), increasing the risk of chronic kidney disease (CKD). In support of the World Health Organization (WHO)'s initiative to estimate the global burden of foodborne diseases, a risk assessment was performed to estimate the Disability-Adjusted Life Years (DALYs) due to late-stage CKD associated with dietary exposures to cadmium. Using the distribution of population GFRs, the prevalence of CKD was calculated as the proportion of humans whose GFR fall in the ranges corresponding to Stage 4 or Stage 5 CKD. The increase in the CKD prevalence due to cadmium exposure was simulated based on a previously reported pharmacokinetic model describing the relationship between dietary cadmium intake and urinary cadmium (UCd), as well as a previously published dose-response relationship between UCd and GFR. Cadmium-related incidence rate, calculated as the change in the prevalence during a one-year period, were used to compute the mortality and DALY in all WHO regions. It is estimated that dietary cadmium would result in a median of 12,224 stage 4 and stage 5 new CKD cases per year worldwide, resulting in 2064 global deaths and 70,513 DALYs. These data translate into a median global burden of 1.0 DALY per 100,000 population, which account for 0.2% of the global DALYs of CKD. While these results suggest that the overall impact of dietary cadmium exposure on global CKD is low, they do indicate that reasonable efforts to reduce dietary exposure will result a positive public health impact. This would be particularly the case in areas with elevated levels of dietary cadmium.

BACKGROUND CONTEXT Vertebral fragility fractures (VFFs), mostly due to osteoporosis, are very common and are associated with significant morbidity and mortality. There is a lack of consensus on the appropriate management of patients with or suspected of having a VFF. PURPOSE This work aimed at developing a comprehensive clinical care pathway (CCP) for VFF. STUDY DESIGN/SETTING The RAND/UCLA Appropriateness Method was used to develop patient-specific recommendations for the various components of the CCP. The study included two individual rating rounds and two plenary discussion sessions. METHODS A multispecialty expert panel (orthopedic and neurosurgeons, interventional [neuro]radiologists and pain specialists) assessed the importance of 20 signs and symptoms for the suspicion of VFF, the relevance of 5 diagnostic procedures, the appropriateness of vertebral augmentation versus nonsurgical management for 576 clinical scenarios, and the adequacy of 6 aspects of follow-up care. RESULTS The panel identified 10 signs and symptoms believed to be relatively specific for VFF. In patients suspected of VFF, advanced imaging was considered highly desirable, with MRI being the preferred diagnostic modality. Vertebral augmentation was considered appropriate in patients with positive findings on advanced imaging and in whom symptoms had worsened and in patients with 2 to 4 unfavorable conditions (eg, progression of height loss and severe impact on functioning), dependent on their relative weight. Time since fracture was considered less relevant for treatment choice. Follow-up should include evaluation of bone mineral density and treatment of osteoporosis. CONCLUSIONS Using the RAND/UCLA Appropriateness Method, a multispecialty expert panel established a comprehensive CCP for the management of VFF. The CCP may be helpful to support decision-making in daily clinical practice and to improve quality of care.

ObjectiveTo examine if chest pain increases the risk of depression and anxiety, or, on the other hand, depression and anxiety increase the risk of chest pain onset in patients with coronary heart disease (CHD).DesignProspective clinical study.Setting16 general practices in the Greater London Primary Care Research Network.Participants803 participants with a confirmed diagnosis of CHD at baseline on the Quality and Outcomes Framework (QOF) CHD registers.Main outcome measuresRose Angina Questionnaire, HADS depression and anxiety subscales and PHQ-9 were assessed at seven time points, each 6 months apart. Multi-Level Analysis (MLA) and Structural Equation Modelling (SEM) were applied.ResultsChest pain predicts both more severe anxiety and depression symptoms at all time points until 30 months after baseline. However, although anxiety predicted chest pain in the short term with a strong association, this association did not last after 18 months. Depression had only a small, negative association with chest pain.ConclusionsIn persons with CHD, chest pain increases the risk of both anxiety and depression to a great extent. However, anxiety and depression have only limited effects on the risk for chest pain. This evidence suggests that anxiety and depression tend to be consequences rather than causes of cardiac chest pain. Intervention studies that support persons with CHD by providing this information should be devised and evaluated, thus deconstructing potentially catastrophic cognitions and strengthening emotional coping.

Background Several acylcarnitines used as primary markers on dried blood filter papers (DBS) for newborn screening lack specificity and contribute to a higher false positive rate. The analysis of urine acylglycines is useful in the diagnosis of inborn errors of metabolism (IEM) including medium chain acyl-CoA dehydrogenase deficiency (MCADD), isovaleric acidemia, and beta-ketothiolase deficiency (BKTD). Currently, no method for analyzing acylglycines from DBS has been published. Methods Acylglycines were extracted from two 3.2 mm DBS punches and butylated using Butanol-HCl. Ultra Performance Liquid Chromatography (UPLC-MS/MS) with run time of 10 min permits resolution and quantitation of 15 acylglycines; including several isobaric. Method development was completed. Reference intervals (n = 573) were established for four birth weight groups. Furthermore, samples from patients with a confirmed IEM (n = 11), and false positive screens (n = 78) were analyzed to validate the interpretation obtained from the newly established reference intervals. Results Calibration curves were linear from 0.005 to 25.0 μM. Ion suppression was evaluated as minimal (2 to 10%). Samples from known patients were used to validate the reference intervals. For C5OH-related disorders, tiglylglycine (TG), TG/acetylglycine (AG) ratio, 3methylcrotonylglycine (3MCG) and 3MCG/AG ratio increased specificity. Propionylglycine (PG) and PG/acetylglycine ratio were two discriminatory markers in the investigation of C3-related disorders. Hexanoylglycine (HG), octanoylglycine (OG), suberylglycine (SG), and the ratios HG/AG, OC/AG and SG/AG were excellent markers of MCADD deficiency. Conclusion This method shows potential application as a second tier screen in order to reduce the false positive rate for a number of IEM targeted by newborn screening.

The addition of enalapril maleate to a casting solution for orodispersible films (ODFs) containing hypromellose and carbomer 974P as film forming agents (standard casting solution, SCS) caused a dose dependent reduction of the viscosity. This phenomenon was a serious problem in the preparation of ODFs with an increased enalapril load (> 1 mg per ODF) when using the solvent casting method.The aim of the present work was twofold. Firstly, the influence of enalapril on the viscosity of SCS was studied in more detail. Secondly, two methods for increasing the enalapril load of an ODF were investigated that did not negatively influence the properties of SCS. The casting height was increased and the preparation of bilayered ODF, using the double-casting method, was explored. In the framework of the bilayered ODFs the compatibility between the film forming agents hydroxypropyl cellulose (HPC), sodium alginate (SA), hydroxyethyl cellulose (HEC) and the combination hypromellose-carbomer 974P (SCS) was investigated.Results and conclusions: We found that enalapril concentration dependently reduced the pH, thereby negatively influencing the gel formation and the viscosity of SCS.An increased casting height did not result in a proportionally increased enalapril load.The enalapril load could be doubled when a bilayered ODF containing two layers of SCS was produced.Finally, not all combinations of film forming agents could be used for the preparation of bilayered ODFs. Besides, the sequence in which the different polymer layers were casted affected the appearance of the ODFs. In conclusion, the best formulations were produced with the polymer combinations SCS/SCS and SCS/HPC.

Background The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog ( MDM2 ) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema. Methods This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured. Results The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE. Conclusions Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.

The aim of this cohort study was to document the potential of laser Doppler flowmetry (LDF) for diagnosing tooth vitality in traumatized teeth in a population of 88 referred patients with dental trauma over a period of 8 years (2011-2018). The main reason to refer was tooth discoloration (26%), and the main trauma cause was a traffic injury (35%). Taking into account that referral for LDF is best given within the week after trauma, 66% of referrals were overdue. In 73% of cases, root canal treatment could be avoided, and in 65%, the presence of a fixed orthodontic retainer showed beneficial for pulp recovery. Data of 394 teeth were collected and submitted to multilevel modelling statistics. As a general conclusion, both LDF perfusion and concentration values proved to be highly reliable in the appreciation of tooth vitality. The difference of variability of standard deviation and range of LDF measurements involving intra-subject control teeth showed statistically significant in discriminating between vital and non-vital pulps. In non-vital teeth, the diagnostic combination of LDF, sensibility tests and peri-apical X-ray is advised.

Objective Roux-en-Y gastric bypass (RYGB) surgery induces major changes in the gastrointestinal tract that may alter the pharmacokinetics of orally administered drugs. Results from pharmacokinetic studies are sparse. This study aimed to investigate the effect of RYGB on the bioavailability of metoprolol from immediate release (IR) and controlled release (CR) tablets in female patient volunteers before and after surgery.Methods An explorative, two-phase, single oral dose pharmacokinetic study of metoprolol in female patients undergoing RYGB was carried out. The dose was administered twice in each patient, 1month before and 6months after surgery. After intake of either 100mg of metoprolol IR or CR tablet serum concentration-time profiles of metoprolol were determined. The endpoint was the ratio of AUC(after)/AUC(before) of metoprolol.Results Twelve patients were included in the study (metoprolol IR: 7; metoprolol CR: 5). After intake of a metoprolol IR tablet major intraindividual and interindividual differences for area under the serum concentration versus time curve (AUC) of metoprolol before and after surgery were observed (range ratio AUC(0-10 hours after)/AUC(0-10 hours before): 0.74-1.98). For metoprolol CR tablets a significant reduction in bioavailability of metoprolol was observed after surgery (range ratio AUC(0-24 hours after)/AUC(0-24 hours before): 0.43-0.77).Conclusion RYGB may influence the bioavailability of metoprolol from an IR tablet. The magnitude of changes in bioavailability after RYGB requires close monitoring of patients using metoprolol IR tablets and dose adjustment if deemed necessary. RYGB clearly reduces the bioavailability of metoprolol from a CR tablet. After RYGB clinicians may consider to increase the dose according to clinical response.

Phthalates are ubiquitous chemical compounds, and two—di-ethyl phthalate (DEP) and di-isobutyl phthalate (DiBP)—are not currently regulated by the U.S. Congress or the European Union. While many reviews of phthalates have been published, none have examined bone health, inflammation, or oxidative stress; anogenital distance was most recently reviewed in 2014. The objective of this paper is to determine if an association exists between mono-ethyl phthalate (MEP) or mono-isobutyl phthalate (MiBP), metabolites of DEP and DiBP, respectively, and the four outcomes indicated above. We conducted a literature search of PubMed through December 2017 and included 29 observational epidemiologic studies published in English that assessed MEP and/or MiBP in relation to one of the above four health outcomes in humans. Two authors rated each paper using a modified Downs and Black (DB) assessment tool; a third author settled score disagreements. A single author extracted information related to the study population, exposure and outcome assessment, covariates, and significant results from each article. Ten studies were identified on anogenital distance, four on bone health, five on inflammation, and thirteen on oxidative stress. Score percentages (total points given out of total possible points) were calculated for each study. The current research suggests a positive association between MiBP and two measures of oxidative stress, 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane. MEP is potentially associated with 8-OHdG as well, although the evidence is limited by fewer high-quality studies. There does not appear to be an association between anogenital distance and MEP or MiBP, and it is unclear if relationships exist between these phthalate metabolites and bone health and inflammation. Given the role that oxidative stress plays in a number of diseases and the ubiquity of MEP and MiBP, it is important that individuals be aware of potential sources of exposure to these chemicals.

Background In a small proportion of patients experiencing unspecified back pain, a specified underlying pathology is present. Objective The purposes of this study were: (1) to identify the prevalence of physician-specified causes of back pain and (2) to assess associations between “red flags” and vertebral fractures, as diagnosed by the patients' general practitioner (GP), in older adults with back pain. Methods The Back Complaints in the Elders (BACE) study is a prospective cohort study. Patients (aged >55 years) with back pain were included when consulting their GP. A questionnaire was administered and a physical examination and heel bone densitometry were performed, and the results determined back pain and patient characteristics, including red flags. Participants received a radiograph, and reports were sent to their GP. The final diagnoses established at 1 year were collected from the GP's patient registry. Results Of the 669 participants included, 6% were diagnosed with a serious underlying pathology during the 1-year follow-up. Most of these participants (n=33, 5%) were diagnosed with a vertebral fracture. Multivariable regression analysis showed that age of ≥75 years, trauma, osteoporosis, a back pain intensity score of ≥7, and thoracic pain were associated with a higher chance of getting the diagnosis of a vertebral fracture. Of these variables, trauma showed the highest positive predictive value for vertebral fracture of 0.25 (95% confidence interval=0.09, 0.41) and a positive likelihood ratio of 6.2 (95% confidence interval=2.8, 13.5). A diagnostic prediction model including the 5 red flags did not increase these values. Limitations Low prevalence of vertebral fractures could have led to findings by chance. Conclusions In these older adults with back pain presenting in general practice, 6% were diagnosed with serious pathology, mainly a vertebral fracture (5%). Four red flags were associated with the presence of vertebral fracture.

We describe analyses to estimate the global burden of disease associated with methylmercury (MeHg). An intelligence quotient

Lead is a ubiquitous dietary contaminant that occurs in food because of natural and anthropogenic sources and pathways of exposure. Lead adversely affects a number of tissues and organ systems and the severity of effect on each is dependent on the level and duration of exposure. The most sensitive and notable effects are those that occur on the nervous system. This is particularly the case in the exposure to the fetus, infant and child. Infants and children generally have higher lead exposures on a body weight basis. While lead exposure can come from many sources, a major source of exposure for at least some individuals comes from food. Estimates for the impact of dietary lead on IQ were developed from published total diet studies. While most of these were designed to characterize intake of chemical contaminants on a national basis, some sampled market baskets from a single city. To develop global estimates, default ranges were created for countries with no data which encompassed the values encountered elsewhere. Blood lead levels and IQ decrements were estimated using functions previously developed by the WHO Joint Expert Committee for Food Additives. Since both the exposure and dose response components were variable and uncertain, a two dimensional Monte-Carlo simulation was used to develop the estimates for the impact of dietary lead on IQ. In addition to estimating blood lead and IQ decrements attributable to dietary lead from those countries with published market basket data, simulations were also run for WHO regions that sampled in the variability dimension based on the population size of the individual countries in each region. Dietary exposure to lead occurs throughout the world. The global average IQ decrement attributable to dietary lead was 1.1. The total number of Disability-Adjusted Life Years (DALYs) arising from those IQ decrements were estimated to be 5.2 million DALYs, with an uncertainty range of 0–31 million DALYs. Significant uncertainties regarding exposure and dose-response relationships, however, warrant continued investigation.

A pharmaceutical suspension is a semi-liquid dosage form suitable for patients being unable to swallow solid medicines such as tablets and capsules. A vehicle used for the preparation of pharmaceutical oral suspensions preferably shows pseudo-plastic behavior. In a product that gets thinner with agitation and thicker upon standing, slow settlement of the suspended active pharmaceutical ingredient is combined with good pourability and rehomogenization. This gives the best guarantee of uniformity of dose for oral suspensions. In this study, the rheological behavior of commercially available ready-to-use vehicles for oral pharmaceutical preparations was compared, and the sedimentation of paracetamol dispersed in these vehicles was investigated. With SuspendIt and SyrSpend SF PH4 (Liquid), both pseudoplastic vehicles, very stable paracetamol suspensions were obtained. Of these two vehicles, SyrSpend SF PH4 (Liquid) displayed somewhat higher viscosity, which is a favorable quality characteristic for suspensions.

Purpose: Management of patients with persisting pain after spine surgery (PPSS) shows significant variability, and there is limited evidence from clinical studies to support treatment choice in daily practice. This study aimed to develop patient-specific recommendations on the management of PPSS. Methods: Using the RAND/UCLA appropriateness method (RUAM), an international panel of 6 neurosurgeons, 6 pain specialists, and 6 orthopaedic surgeons assessed the appropriateness of 4 treatment options (conservative, minimally invasive, neurostimulation, and re-operation) for 210 clinical scenarios. These scenarios were unique combinations of patient characteristics considered relevant to treatment choice. Appropriateness had to be expressed on a 9-point scale (1 = extremely inappropriate, 9 = extremely appropriate). A treatment was considered appropriate if the median score was ≥ 7 in the absence of disagreement (≥ 1/3 of ratings in each of the opposite sections 1–3 and 7–9). Results: Appropriateness outcomes showedclear and specific patterns. In 48% of the scenarios, exclusively one of the 4 treatments was appropriate. Conservative treatment was usually considered appropriate for patients without clear anatomic abnormalities and for those with new pain differing from the original symptoms. Neurostimulation was considered appropriate in the case of (predominant) neuropathic leg pain in the absence of conditions that may require surgical intervention. Re-operation could be considered for patients with recurrent disc, spinal/foraminal stenosis, or spinal instability. Conclusions: Using the RUAM, an international multidisciplinary panel established criteria for appropriate treatment choice in patients with PPSS. These may be helpful to educate physicians and to improve consistency and quality of care. Graphical abstract: These slides can be retrieved under Electronic Supplementary Material. [Figure not available: see fulltext.].

MRI equipment with its complex instrumentation and adaptable software applications is vulnerable to technical and image quality problems, and maintaining quality assurance is essential. Accreditation of MRI centers by the ACR has become a routine practice for radiology departments and imaging centers across the country. In its prior format, the ACR MRI Accreditation Program had examination anatomic modules designed primarily to measure quality and validate MR performance primarily in adult imaging practices. In an effort to more closely meet the specific imaging requirements of pediatric patients, an ad hoc MR accreditation committee was created under the ACR Commission on Pediatric Imaging. The committee, consisting of ACR members from five children’s hospitals, was tasked with creating suggested revisions to the anatomic modules and helping develop pediatric-specific studies that could be adopted into the ACR MRI Accreditation Program. Updated ACR MRI accreditation anatomic modules incorporating the ad hoc committee’s recommendations were released by ACR in May 2017. This article highlights the recommendations made by the ad hoc committee. The revised modules should allow pediatric imaging centers to achieve ACR MRI accreditation for all anatomic modules and will underscore best imaging practices for patients of all ages.

Objective The primary objective of this study was to identify factors that have predictive value in determining total hospital length of stay in patients with febrile neutropenia, particularly time to first antibiotic dose. Methods This study was a retrospective chart review analyzing patients admitted to a 443 bed tertiary county teaching hospital from 1 November 2010 through 1 November 2015. Patients were eligible for enrollment into the study if they met Infectious Diseases Society of America accepted criteria for febrile neutropenia. Results Ninety-three patients were included for analysis. Time to first antibiotic dose, first empirically appropriate antibiotic dose, and time to first isolate-appropriate antibiotic did not show a significant correlation to total hospital length of stay (p = 0.71, p = 0.342, and p = 0.77, respectively). Subject’s Multinational Association for Supportive Care in Cancer and Simplified Acute Physiology II scores were significantly correlated with hospital lengths of stay (p = 0.0052, rs = −0.243 and p = 0.0001, rs = 0.344, respectively). Higher median (interquartile ranges) Simplified Acute Physiology II scores were also associated with hospital mortality [dead = 46 (34.8–51.7) vs. alive = 34 (28–43.3), p = 0.0173]. Conclusions Measures of patient acuity, such as the Multinational Association for Supportive Care in Cancer and Simplified Acute Physiology II scores, did show a correlation to clinical outcomes in patients with febrile neutropenia. Timing of initial antibiotics between 2.32 and 6.27 hours after presentation in patients with febrile neutropenia did not correlate with clinical outcomes.

The aim of this article was to investigate the use of laser Doppler flowmetry (LDF) combined with a fast Fourier transformation (FFT). LDF data in relation to three different scenarios were evaluated: (a) LDF records of a right central upper incisor of one patient were used for FFT analysis. These records were obtained by means of 30 pre-manufactured splints, handled by dentists without any experience in LDF recording. (b) Diurnal variations in one patient were analysed with LDF and FFT using 11 splints by one and same experienced investigator at four specific moments of the day. (c) Pulpal status was analysed using 17 splints. Eleven for a patient, standing as case model and six splints for six other patients. In this specific group, each patient had one vital and one non-vital central maxillary incisor and was analysed separately by LDF and FFT. The data of assessment (b) showed diurnal variations on LDF values of almost 80%, indicating that LDF registration is best performed in the same time period of the day. Data verification with FFT confirmed the findings without FFT of assessment (a) and (b). In assessment, (c) FFT demonstrated a clear distinction between a vital and a non-vital pulp for those cases with one vital tooth and one root canal treated tooth. In those cases with one vital incisor and the other traumatised, FFT was undeterminated. Considered that FFT was obtained after LDF recording and remained undeterminated for a decision in cases with decreasing pulpal blood flow in time, the added value of FFT in pulpal traumatology was minimal.

Contains fulltext : 182286.pdf (Publisher’s version ) (Open Access) To inform the development of recommendations to facilitate learning of skilled doctor-patient communication in the workplace, this qualitative study explores experiences of trainees and supervisors regarding how trainees learn communication and how supervisors support trainees' learning in the workplace. We conducted a qualitative study in a general practice training setting, triangulating various sources of data to obtain a rich understanding of trainees and supervisors' experiences: three focus group discussions, five discussions during training sessions and five individual interviews. Thematic network analysis was performed during an iterative process of data collection and analysis. We identified a communication learning cycle consisting of six phases: impactful experience, change in frame of reference, identification of communication strategies, experimentation with strategies, evaluation of strategies and incorporation into personal repertoire. Supervisors supported trainees throughout this process by creating challenges, confronting trainees with their behaviour and helping them reflect on its underlying mechanisms, exploring and demonstrating communication strategies, giving concrete practice assignments, creating safety, exploring the effect of strategies and facilitating repeated practice and reflection. Based on the experiences of trainees and supervisors, we conclude that skilled communication involves the development of a personal communication repertoire from which learners are able to apply strategies that fit the context and their personal style. After further validation of our findings, it may be recommended to give learners concrete examples, opportunities for repeated practise and reflection on personal frames of reference and the effect of strategies, as well as space for authenticity and flexibility. In the workplace, the clinical supervisor is able to facilitate all these essential conditions to support his/her trainee in becoming a skilled communicator.

Resurrection species are a group of land plants that can tolerate extreme desiccation of their vegetative tissues during harsh drought stress, and still quickly – often within hours – regain normal physiological and metabolic functions following rehydration. At the molecular level, this desiccation tolerance is attributed to basal cellular mechanisms including the constitutive expression of stress-associated genes and high levels of protective metabolites present already in the absence of stress, as well as to transcriptome and metabolome reconfigurations rapidly occurring during the initial phases of drought stress. Parts of this response are conferred by unique metabolites, including a diverse array of sugars, phenolic compounds, and polyols, some of which accumulate to high concentrations within the plant cell. In addition to drought stress, these metabolites are proposed to contribute to the protection against other abiotic stresses and to an increased oxidative stress tolerance. Recently, extracts of resurrection species and particular secondary metabolites therein were reported to display biological activities of importance to medicine, with e.g. antibacterial, anticancer, antifungal, and antiviral activities, rendering them possible candidates for the development of novel drug substances as well as for cosmetics. Herein, we provide an overview of the metabolite composition of resurrection species, summarize the latest reports related to the use of natural products from resurrection plants, and outline their potential for medical applications.

Background Recently the World Health Organization, Foodborne Disease Burden Epidemiology Reference Group (FERG) estimated that 31 foodborne diseases (FBDs) resulted in over 600 million illnesses and 420,000 deaths worldwide in 2010. Knowing the relative role importance of different foods as exposure routes for key hazards is critical to preventing illness. This study reports the findings of a structured expert elicitation providing globally comparable food source attribution estimates for 11 major FBDs in each of 14 world subregions. Methods and findings We used Cooke’s Classical Model to elicit and aggregate judgments of 73 international experts. Judgments were elicited from each expert individually and aggregated using both equal and performance weights. Performance weighted results are reported as they increased the informativeness of estimates, while retaining accuracy. We report measures of central tendency and uncertainty bounds on food source attribution estimate. For some pathogens we see relatively consistent food source attribution estimates across subregions of the world; for others there is substantial regional variation. For example, for non-typhoidal salmonellosis, pork was of minor importance compared to eggs and poultry meat in the American and African subregions, whereas in the European and Western Pacific subregions the importance of these three food sources were quite similar. Our regional results broadly agree with estimates from earlier European and North American food source attribution research. As in prior food source attribution research, we find relatively wide uncertainty bounds around our median estimates. Conclusions We present the first worldwide estimates of the proportion of specific foodborne diseases attributable to specific food exposure routes. While we find substantial uncertainty around central tendency estimates, we believe these estimates provide the best currently available basis on which to link FBDs and specific foods in many parts of the world, providing guidance for policy actions to control FBDs.

Although pulmonary arterial hypertension originates in the lung and is caused by progressive remodeling of the small pulmonary arterioles, patients die from the consequences of pressure-overload-induced right heart failure. Prognosis is poor, and currently there are no selective treatments targeting the failing right ventricle. Therefore, it is of utmost importance to obtain more insights into the mechanisms of right ventricular adaptation and the transition toward right heart failure. In this review, we propose that the same adaptive mechanisms, which initially preserve right ventricular systolic function and maintain cardiac output, eventually initiate the transition toward right heart failure.

ObjectiveGeneralized anxiety and panic disorders are a burden on the society because they are costly and have a significant adverse effect on quality of life. The aim of this study was to evaluate the cost-utility of a collaborative stepped care intervention for panic disorder and generalized anxiety disorder in primary care compared to care as usual from a societal perspective.MethodsThe design of the study was a two armed cluster randomized controlled trial. In total 43 primary care practices in the Netherlands participated in the study. Eventually, 180 patients were included (114 collaborative stepped care, 66 care as usual). Baseline measures and follow-up measures (3, 6, 9 and 12 months) were assessed using questionnaires. We applied the TiC-P, the SF-HQL and the EQ-5D respectively measuring health care utilization, production losses and health related quality of life.ResultsThe average annual direct medical costs in the collaborative stepped care group were 1854 Euro (95% C.I., 1726 to 1986) compared to €1503 (95% C.I., 1374 to 1664) in the care as usual group. The average quality of life years (QALYs) gained was 0.05 higher in the collaborative stepped care group, leading to an incremental cost effectiveness ratio (ICER) of 6965 Euro per QALY. Inclusion of the productivity costs, consequently reflecting the full societal costs, decreased the ratio even more.ConclusionThe study showed that collaborative stepped care was a cost effective intervention for panic disorder and generalized anxiety disorder and was even dominant when a societal perspective was taken.Keywords: Anxiety, Cost utility, Panic, Randomized trial, Societal perspective, Stepped care

The SU5416 combined with hypoxia (SuHx) rat model features angio-obliterative pulmonary hypertension resembling human pulmonary arterial hypertension. Despite increasing use of this model, a comprehensive haemodynamic characterisation in conscious rats has not been reported. We used telemetry to characterise haemodynamic responses in SuHx rats and associated these with serial histology. Right ventricular systolic pressure (RVSP) increased to a mean±sd of 106±7 mmHg in response to SuHx and decreased but remained elevated at 72±8 mmHg upon return to normoxia. Hypoxia-only exposed rats showed a similar initial increase in RVSP, a lower maximum RVSP and near-normalisation of RVSP during subsequent normoxia. Progressive vascular remodelling consisted of a four-fold increase in intima thickness, while only minimal changes in media thickness were found. The circadian range in RVSP provided an accurate longitudinal estimate of vascular remodelling. In conclusion, in SuHx rats, re-exposure to normoxia leads to a partial decrease in pulmonary artery pressure, with persisting hypertension and pulmonary vascular remodelling characterised by progressive intima obstruction.

Background: Collaborative stepped care (CSC) may be an appropriate model to provide evidence-based treatment for anxiety disorders in primary care. Methods: In a cluster randomised controlled trial, the effectiveness of CSC compared to care as usual (CAU) for adults with panic disorder (PD) or generalised anxiety disorder (GAD) in primary care was evaluated. Thirty-one psychiatric nurses who provided their services to 43 primary care practices in the Netherlands were randomised to deliver CSC (16 psychiatric nurses, 23 practices) or CAU (15 psychiatric nurses, 20 practices). CSC was provided by the psychiatric nurses (care managers) in collaboration with the general practitioner and a consultant psychiatrist. The intervention consisted of 3 steps, namely guided self-help, cognitive behavioural therapy and antidepressants. Anxiety symptoms were measured with the Beck Anxiety Inventory (BAI) at baseline and after 3, 6, 9 and 12 months. Results: We recruited 180 patients with a DSM-IV diagnosis of PD or GAD, of whom 114 received CSC and 66 received usual primary care. On the BAI, CSC was superior to CAU [difference in gain scores from baseline to 3 months: -5.11, 95% confidence interval (CI) -8.28 to -1.94; 6 months: -4.65, 95% CI -7.93 to -1.38; 9 months: -5.67, 95% CI -8.97 to -2.36; 12 months: -6.84, 95% CI -10.13 to -3.55]. Conclusions: CSC, with guided self-help as a first step, was more effective than CAU for primary care patients with PD or GAD.

Background: although back pain is a frequently recurring disorder, the course of back pain remains uncertain. Therefore, this study aimed to identify different trajectories in older adults with back pain who presented in general practice and to determine which baseline characteristics are associated with these trajectories.Methods: the BACE study is a prospective cohort study including 675 patients (aged >55 years) with back pain who consulted a general practitioner; patients were followed for 3 years. Latent class growth analysis was used to identify different trajectories in back pain severity measured at eight different time points. A multinomial regression analysis was used to assess variables associated with membership of an identified trajectory.Results: using the different indices of fit and the usefulness of the different trajectories in clinical practice, a 3-class cubic model was determined to be the best model. The three trajectories were defined as 'low pain trajectory', 'high pain trajectory' and 'intermediate pain trajectory'. Baseline variables associated with a higher chance of being in the intermediate or high trajectory were: female gender, higher body mass index, chronic back pain, more disability, lower scores on the SF-36 physical summary scale, and negative expectations of recovery.Conclusions: three different back pain trajectories were identified in older adults presenting with back pain in general practice. Various baseline characteristics were associated with a higher chance of being in the high or intermediate back pain trajectory. These characteristics might help identify patients at risk for a less favourable outcome.

Background: The heterogeneity of patients with osteoporotic vertebral compression fractures (VCF) necessitates a tailored approach of balancing the benefits and limitations of available treatments. Current guidelines are divergent, sometimes contradictory, and often insufficiently detailed to guide practice decisions. Objectives: This study aimed at establishing treatment recommendations at the patientspecific level. Study Design: Using the RAND/UCLA Appropriateness Method (RAM), the appropriateness of different treatment options for osteoporotic VCFs was assessed. Setting: The assessment was conducted by a European multidisciplinary panel of 12 experts. Methods: The appropriateness of non-surgical management (NSM), vertebroplasty (VP), and balloon kyphoplasty (BKP) was determined for 128 hypothetical patient profiles. These were unique combinations of clinical factors considered relevant to treatment choice (time since fracture, MRI findings, impact and evolution of symptoms, spinal deformity, ongoing fracture process, and pulmonary dysfunction). After 2 individual rating rounds and plenary meetings, appropriateness statements (appropriate, inappropriate, and uncertain) were calculated for all clinical scenarios. Results: Disagreement dropped from 31% in the first round to 7% in the second round. Appropriateness outcomes showed specific patterns for the 3 treatments. For three-quarters of the profiles, only one treatment was considered appropriate: NSM 25%, VP 6%, and BKP 45%. NSM was usually appropriate in patients with a negative MRI or a positive MRI without other unfavorable conditions (poor outcomes for the other variables). VP was usually appropriate in patients with a positive MRI, time since fracture ≥ 6 weeks, and no spinal deformity. BKP was recommended for all patients with an ongoing fracture process, and also in most patients with a positive MRI and ≥ 1 other unfavorable factor. Limitations: The prevalence of the patient profiles in daily practice is yet unknown. Conclusion: The panel results may help to support treatment choice in the heterogeneous population of patients with osteoporotic VCF. Key words: Appropriateness criteria, balloon kyphoplasty, non-surgical management, osteoporosis, RAND/UCLA Appropriateness Method, treatment choice, vertebral compression fractures, vertebroplasty

To the Editor: Pulmonary arterial hypertension (PAH) is a disease in which remodelling of the small pulmonary arteries leads to an increase in pulmonary artery pressure (PAP). The most important genetic predisposing factor related to PAH is a mutation in the bone morphogenetic protein receptor type 2 gene ( BMPR2 ) [1, 2]. BMPR2 mutation carriers are known to present with disease at an earlier age and with worse haemodynamics [3]. We recently showed in a cohort of patients with idiopathic and hereditary PAH that a very low diffusion capacity for carbon monoxide ( D LCO) is exclusively found in some of the patients without identified BMPR2 mutations, whereas BMPR2 mutation carriers have a relatively preserved D LCO [4]. D LCO is a noninvasive marker of the quality of the alveolar capillary structure [5] and the observed difference in D LCO supports the hypothesis that distinct vascular disease processes are at play in BMPR2 mutation-related PAH and non BMPR2 mutation-related idiopathic PAH. Until recently, insufficient availability of lung samples has prohibited the performance of a detailed comparison of the pulmonary vascular pathologies in these two disease groups [6]. Therefore, we sought, in the present study, to confirm the previously found influence of BMPR2 mutations on diffusion capacity in a much larger multinational patient cohort. We performed a retrospective collaborative study at the VU University Medical Center in Amsterdam, the Netherlands and the Universite Paris-Sud, Assistance Publique Hopitaux de Paris, Le Kremlin-Bicetre, France. Patients were eligible for this study when classified in the database with idiopathic or familial PAH, and when the results from BMPR2 mutation analysis and D LCO measurements were available. Patients were diagnosed with idiopathic …

BACKGROUND: The Foodborne Disease Burden Epidemiology Reference Group (FERG) was established in 2007 by the World Health Organization (WHO) to estimate the global burden of foodborne diseases (FBDs). This estimation is complicated because most of the hazards causing FBD are not transmitted solely by food; most have several potential exposure routes consisting of transmission from animals, by humans, and via environmental routes including water. This paper describes an expert elicitation study conducted by the FERG Source Attribution Task Force to estimate the relative contribution of food to the global burden of diseases commonly transmitted through the consumption of food. METHODS AND FINDINGS: We applied structured expert judgment using Cooke's Classical Model to obtain estimates for 14 subregions for the relative contributions of different transmission pathways for eleven diarrheal diseases, seven other infectious diseases and one chemical (lead). Experts were identified through international networks followed by social network sampling. Final selection of experts was based on their experience including international working experience. Enrolled experts were scored on their ability to judge uncertainty accurately and informatively using a series of subject-matter specific 'seed' questions whose answers are unknown to the experts at the time they are interviewed. Trained facilitators elicited the 5th, and 50th and 95th percentile responses to seed questions through telephone interviews. Cooke's Classical Model uses responses to the seed questions to weigh and aggregate expert responses. After this interview, the experts were asked to provide 5th, 50th, and 95th percentile estimates for the 'target' questions regarding disease transmission routes. A total of 72 experts were enrolled in the study. Ten panels were global, meaning that the experts should provide estimates for all 14 subregions, whereas the nine panels were subregional, with experts providing estimates for one or more subregions, depending on their experience in the region. The size of the 19 hazard-specific panels ranged from 6 to 15 persons with several experts serving on more than one panel. Pathogens with animal reservoirs (e.g. non-typhoidal Salmonella spp. and Toxoplasma gondii) were in general assessed by the experts to have a higher proportion of illnesses attributable to food than pathogens with mainly a human reservoir, where human-to-human transmission (e.g. Shigella spp. and Norovirus) or waterborne transmission (e.g. Salmonella Typhi and Vibrio cholerae) were judged to dominate. For many pathogens, the foodborne route was assessed relatively more important in developed subregions than in developing subregions. The main exposure routes for lead varied across subregions, with the foodborne route being assessed most important only in two subregions of the European region. CONCLUSIONS: For the first time, we present worldwide estimates of the proportion of specific diseases attributable to food and other major transmission routes. These findings are essential for global burden of FBD estimates. While gaps exist, we believe the estimates presented here are the best current source of guidance to support decision makers when allocating resources for control and intervention, and for future research initiatives.

BackgroundUp to 70% of children and teenagers referred to a paediatric gastroenterology centre with suspected inflammatory bowel disease (IBD) do not have the disease.ObjectiveTo evaluate whether faecal calprotectin as an ‘add-on test’ improves the specificity of the clinical case definition for suspected IBD in a general paediatric practice.DesignA prospective diagnostic accuracy study.SettingSix outpatient clinics for general paediatrics and one tertiary care hospital in the Netherlands.Patients117 children and teenagers with a clinical suspicion of IBD.Diagnostic testsFaecal calprotectin was measured (index test) in all patients. Patients with a high index of suspicion on the basis of the paediatrician's global assessment, physical examination and blood results were referred for endoscopy (reference standard). Children and teenagers who were not selected for endoscopy initially were followed for half a year for the appearance of possible additional symptoms (delayed type reference standard).Primary outcomeThe proportion of referred patients with confirmed IBD.ResultsThe mean age of patients was 14 years (range 6–18). A total of 42 (36%) had confirmed IBD. The paediatricians, who were blinded to the faecal calprotectin result, referred 68 children and teenagers for endoscopy. If they had referred only those patients with a positive faecal calprotectin result (>50 μg/g), 54 patients would have undergone endoscopy.LimitationThe study relied on clinical follow-up to detect missed IBD.ConclusionsA diagnostic strategy in general paediatric practice of using a simple clinical case definition for suspected IBD in combination with a positive faecal calprotectin result increases the specificity to detect IBD and reduces the need for referral to a paediatric gastroenterology centre with a very low risk of missing cases.

CONTEXT: A Consumer Quality Index (CQ-index) is a questionnaire assessing the actual care experiences and how important the recipient finds certain care aspects, as well as the priorities for improving quality. A CQ-index Palliative Care (CQ-index PC) for bereaved relatives was developed to measure the quality of palliative care. OBJECTIVES: This article provides insight into the development and psychometric characteristics of this questionnaire, as well as quality improvement priorities. METHODS: The content of the CQ-index PC was based on existing questionnaires, literature, and interviews and focus group discussions with relatives, patients, and caregivers. The questionnaire was tested in 31 care facilities providing palliative care. Close relatives/contact persons of patients who died non-suddenly six weeks to six months earlier were eligible for inclusion. Psychometric analyses were performed to shorten the questionnaire and to assess its reliability. "Need for improvement scores" also were computed to identify care aspects with the highest priority for quality improvement. RESULTS: Three hundred ninety-two bereaved relatives were eligible for inclusion. The net response was 52% (n=204). Psychometric analyses resulted in six scales (Cronbach's alphas ranging from 0.71 to 0.90). The quality aspects relatives considered most important were dying peacefully, getting help in good time in acute situations, and personal attention. Aftercare was the aspect with the highest priority for quality improvement. CONCLUSION: The CQ-index PC for relatives can be used to assess the quality of palliative care from the perspective of bereaved relatives. This instrument gives health care professionals insight into care aspects with the highest priority for quality improvement.

PURPOSE: Conventional bioavailability testing of dosage forms based on plasma concentration-time graphs of two products in a two-period, crossover-design, is not applicable to topical treatment of intestinal segments. We introduce an isotope dual-label approach ((13)C- and (15)N(2)-urea) for colon drug delivery systems that can be performed in a one-day, non-invasive study-design.METHODS: Four healthy volunteers took an uncoated or a ColoPulse-capsule containing (13)C-urea and an uncoated capsule containing (15)N(2)-urea. In case of colon-release (13)C-urea is fermented and (13)C detected as breath (13)CO(2). Absorbed (13)C-urea and (15)N-urea are detected in urine.RESULTS: C and (15)N in urine released from uncoated capsules showed a ratio of 1.01 ± 0.06. The (13)C/(15)N-recovery ratio after intake of a ColoPulse-capsule was constant and lower >12 h post-dose (median 0.22, range 0.13-0.48). The (13)C/(15)N-ratio in a single urine sample at t ≥ 12 h predicted the 24 h non-fermented fraction (13)C of 3 h) release and a fermented fraction (13)C >54 %.CONCLUSIONS: Breath and urine (13)C and (15)N data describe the release-profile and local bioavailability of a colon delivery device. This allows non-invasive bioavailability studies for evaluation of colon-specific drug delivery systems without radioactive exposure and with increased power and strongly reduced costs.

The BCG vaccine was introduced in 1921 and remains the only licensed vaccine for the prevention of TB worldwide. Despite its extensive use, the BCG vaccine lacks the ability to fully control the TB-endemic and -pandemic situations. The BCG vaccine is most effective in preventing pediatric TB, in particular, miliary TB and tuberculous meningitis. However, it has a limited effect in preventing pulmonary TB, which occurs more frequently in adults. BCG vaccination has now been implemented in more than 157 countries worldwide. For various countries, the benefits of vaccination are only limited and potentially not cost effective. The International Union Against Tuberculosis and Lung Diseases had set the criteria for discontinuation of BCG vaccination in 1994. This decision, however, was not based on economic considerations. Many developed countries have met the criteria set by the International Union Against Tuberculosis and Lung Disease and stopped universal BCG vaccination. For developing countries, the BCG vaccine is still an effective intervention in protecting young children from TB infection. A lot of effort has been spent on R&D of new TB vaccines, the first of which are expected to be available within 5-7 years from now. Novel TB vaccines are expected to be better and more effective than the current BCG vaccine and should provide a viable strategy in controlling TB morbidity and mortality. In this review, the aim is to explore economic evaluations that have been carried out for vaccination against TB worldwide. In addition to epidemiological evidence, economic evidence can play a crucial role in supporting the governments of countries in making proper public health decisions on BCG vaccination policies, in particular, to implement, continue, or discontinue.

Background and purpose In this study, we explore the quality aspects of radiation care from the patient's perspective in order to develop a draft Consumer Quality Index (CQI) Radiation Care instrument. Materials and methods Four focus group discussions with (former) cancer patients were held to explore the aspects determining the quality of radiation care. The list of aspects generated was categorised based on similarity and importance in a concept mapping procedure. Results Four focus group discussions revealed seven main themes related to the quality of radiation care: information provision, a patient-centred approach, professional competence, planning and waiting times, accessibility, cooperation and communication, and follow-up care. Results of concept mapping procedures revealed which items the patients considered to be most important. A radiation oncologist who is up to date about the patient's file is of paramount importance for cancer patients receiving radiotherapy. Conclusions The quality aspects found through focus group discussions provided useful insight into how patients experience radiation care. Furthermore, concept mapping made these results more solid. To evaluate the quality of radiation care from the patient's perspective, these quality aspects will be guiding in the development of a CQI Radiation Care.

To systematically assess contemporary knowledge regarding behavioral physical activity interventions including an activity monitor (BPAI+) in adults with overweight or obesity.PubMed/MEDLINE, Embase, CINAHL, PsycINFO, CENTRAL, and PEDro were searched for eligible full-text articles up to 1 July 2015. Studies eligible for inclusion were (randomized) controlled trials describing physical activity outcomes in adults with overweight or obesity. Methodological quality was independently assessed employing the Cochrane Collaboration's tool for risk of bias.Fourteen studies (1,157 participants) were included for systematic review and 11 for meta-analysis. A positive trend in BPAI+ effects on several measures of physical activity was ascertained compared with both wait list or usual care and behavioral physical activity interventions without an activity monitor (BPAI-). No convincing evidence of BPAI+ effectiveness on weight loss was found compared with BPAI-.Behavioral physical activity interventions with an activity monitor increase physical activity in adults with overweight or obesity. Also, adding an activity monitor to behavioral physical activity interventions appears to increase the effect on physical activity, although current evidence has not yet provided conclusive evidence for its effectiveness.

Illness and death from diseases caused by contaminated food are a constant threat to public health and a significant impediment to socio-economic development worldwide. To measure the global and regional burden of foodborne disease (FBD), the World Health Organization (WHO) established the Foodborne Disease Burden Epidemiology Reference Group (FERG), which here reports their first estimates of the incidence, mortality, and disease burden due to 31 foodborne hazards. We find that the global burden of FBD is comparable to those of the major infectious diseases, HIV/AIDS, malaria and tuberculosis. The most frequent causes of foodborne illness were diarrheal disease agents, particularly norovirus and Campylobacter spp. Diarrheal disease agents, especially non-typhoidal Salmonella enterica, were also responsible for the majority of deaths due to FBD. Other major causes of FBD deaths were Salmonella Typhi, Taenia solium and hepatitis A virus. The global burden of FBD caused by the 31 hazards in 2010 was 33 million Disability Adjusted Life Years (DALYs); children under five years old bore 40% of this burden. The 14 subregions, defined on the basis of child and adult mortality, had considerably different burdens of FBD, with the greatest falling on the subregions in Africa, followed by the subregions in South-East Asia and the Eastern Mediterranean D subregion. Some hazards, such as non-typhoidal S. enterica, were important causes of FBD in all regions of the world, whereas others, such as certain parasitic helminths, were highly localised. Thus, the burden of FBD is borne particularly by children under five years old–although they represent only 9% of the global population–and people living in low-income regions of the world. These estimates are conservative, i.e., underestimates rather than overestimates; further studies are needed to address the data gaps and limitations of the study. Nevertheless, all stakeholders can contribute to improvements in food safety throughout the food chain by incorporating these estimates into policy development at national and international levels., An overview of foodborne diseases worldwide; part of the World Health Organization’s investigation into the incidence, mortality, and disease burden of foodborne hazards.

INTRODUCTION: According to the European Pharmacopoeia, oromucosal films comprise mucoadhesive buccal films and orodispersible films. Both oral dosage forms receive considerable interest in the recent years as commercially available pharmaceutical products and as small scale personalized extemporaneous preparations. Areas covered: In this review, technological issues such as viscosity of the casting liquid, mechanical properties of the film, upscaling and the stability of the casting solution and produced films will be discussed. Furthermore, patient-related problems like appearance, mucosal irritation, taste, drug load, safety and biopharmaceutics are described. Current knowledge and directions for solutions are summarized. Expert opinion: The viscosity of the casting solution is a key factor for producing suitable films. This parameter is amongst others dependent on the polymer and active pharmaceutical ingredient, and the further excipients that are used. For optimal patient compliance, an acceptable taste and palatability are desirable. Safe and inert excipients should be used and appropriate packaging should be provided to produced films. Absorption through the oral mucosa will vary for each active compound, formulation and patient, which gives rise to pharmacokinetic questions. Finally, the European Pharmacopoeia needs to specify methods, requirement and definitions for oromucosal film preparations based on bio-relevant data.

Objective The purpose of this review is to evaluate the impact of recent epidemiologic literature on the National Research Council (NRC) assessment of the lung and bladder cancer risks from ingesting low concentrations (< 100 μg/L) of arsenic-contaminated water. Data sources, extraction, and synthesis PubMed was searched for epidemiologic studies pertinent to the lung and bladder cancer risk estimates from low-dose arsenic exposure. Articles published from 2001, the date of the NRC assessment, through September 2010 were included. Fourteen epidemiologic studies on lung and bladder cancer risk were identified as potentially useful for the analysis. Conclusions Recent epidemiologic studies that have investigated the risk of lung and bladder cancer from low arsenic exposure are limited in their ability to detect the NRC estimates of excess risk because of sample size and less than lifetime exposure. Although the ecologic nature of the Taiwanese studies on which the NRC estimates are based present certain limitations, the data from these studies have particular strengths in that they describe lung and bladder cancer risks resulting from lifetime exposure in a large population and remain the best data on which to conduct quantitative risk assessment. Continued follow-up of a population in northeastern Taiwan, however, offers the best opportunity to improve the cancer risk assessment for arsenic in drinking water. Future studies of arsenic < 100 μg/L in drinking water and lung and bladder cancer should consider adequacy of the sample size, the synergistic relationship of arsenic and smoking, duration of arsenic exposure, age when exposure began and ended, and histologic subtype.

The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1α in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples were taken from patients with moderate COPD (n = 6; stage I and II Global Initiative for Chronic Obstructive Lung Disease classification) and severe COPD (n = 13; stage III and IV). We analysed mRNA and protein expression in the lung tissue samples and found that: 1) HIF-1α and histone deacetylase 2 proteins were significantly decreased and were correlated; 2) HIF-1α and vascular endothelial growth factor (VEGF) proteins, and forced expiratory volume in 1 s % predicted were correlated in all patients; 3) the changes in VEGF and HIF-1α protein levels in all patients were not age-related and not related to the pack-yr smoking history; and 4) the reduced HIF-1α protein expression was seen in lung endothelial cells and alveolar septal cells by immunohistochemistry. In conclusion, reduced expression of HIF-1α protein in severe COPD is consistent with the concept of a lung structure maintenance programme which is impaired on a molecular level.

Background and Objective: Allowing children with inflammatory bowel disease (IBD) to live with subnormal hemoglobin (Hb) levels affects their quality of life. The therapeutic approach to normalize Hb varies according to the cause of IBD-associated anemia. In exclusive iron-deficiency anemia (IDA) repletion of iron stores is obligatory, whereas controlling inflammation is the treatment of choice for anemia of chronic disease (ACD). In daily practice the focus is on control of intestinal inflammation, and spontaneous hematological recovery is awaited. The aim of the present study was to evaluate the hematological effect of "expectant management" on newly diagnosed pediatric patients with IBD with anemia.Patients and Methods: Medical records of children with IBD were reviewed. Study endpoints were the difference in Hb from the moment of IBD diagnosis (T-0) to the end of the induction phase (T-1), and time until normalization of Hb, stratified for the type of anemia at T-0.Results: A total of 103 children were included in the study, of whom 80 (78%) had anemia at T-0. Exclusive IDA was found in 58% of them. Expectant management caused a modest increase in Hb between T-0 and T-1 for both types of anemia (IDA 0.4 mmol/L; ACD 0.5 mmol/L), but 65 of 80 children (81%) still had anemia at T-1. The proportion of children with exclusive IDA had increased to 74%. One third of the cases initially classified as having ACD had progressed to exclusive IDA. There was no significant difference in time until normalization of Hb between children with exclusive IDA and ACD. Twelve months after IBD diagnosis 24% of the group initially diagnosed as having exclusive IDA and 50% of the ACD group were still anemic.Conclusions: Hematological recovery in children with IBD-associated anemia is slow with expectant management, regardless of the type of anemia at T-0. Present results underline the need for a more active approach to improve Hb.