Population Exposure to Phthalate‐containing Drugs

Phthalates are known endocrine disruptors. Not commonly recognized, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate‐containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from medstat.dk. Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the ‘defined daily dose’ (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethyl phthalate (DEP) and dibutyl phthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate‐containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low‐molecular‐weight phthalates and three high‐molecular‐weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multi‐enzymes (24.6–32.8 mg per DDD) and mesalazine (12.5–26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate‐containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.     

Comorbidity burden is not associated with higher mortality after out-of-hospital cardiac arrest*

Abstract

Objectives. We investigated whether comorbidity burden of comatose survivors of out-of-hospital cardiac arrest (OHCA) affects outcome and if comorbidity modifies the effect of target temperature management (TTM) on final outcome. Design. The TTM trial randomized 939 patients to 24?h of TTM at either 33 or 36?°C with no difference regarding mortality and neurological outcome. This post-hoc study of the TTM-trial formed a modified comorbidity index (mCI), based on available comorbidities from the Charlson comorbidity index (CCI). Results. Bystander cardiopulmonary resuscitation (CPR) decreased with higher comorbidity group, p?=?0.01. Comorbidity groups were univariately associated with higher mortality compared to mCI0 (HR_mCI1: 1.55, CI: 1.25–1.93, p?<?0.001, HR_mCI2: 2.01, CI: 1.55–2.62, p?<?0.001, HR_mCI ≥ 3: 2.16, CI: 1.57–2.97, p?<?0.001). When adjusting for confounders there was a consistent, nonsignificant association between level of comorbidity and mortality (HRm_C11: 1.17, CI: 0.92–1.48, p?=?0.21, HR_mCI2: 1.28, CI: 0.96–1.71, p?=?0.10, HR_mCI ≥ 3: 1.37, CI: 0.97–1.95, p?=?0.08). There was no interaction between comorbidity burden and level of TTM on outcome, p?=?0.61. Conclusion. Comorbidity burden was associated with higher mortality following OHCA, but when adjusting for confounders, the influence was no longer significant. The association between mCI and mortality was not modified by TTM. Comorbidity burden is associated with lower rates of bystander cardiopulmonary resuscitation after OHCA.     

Validation of Obesity Surgery Data in the Swedish National Patient Registry and Scandinavian Obesity Registry (SOReg)

Background and Aim

Swedish health registries are common sources of data for studies on the effects of obesity surgery, and there is a need to assess the quality of data in these registries. The aim of this study was to validate the registration of obesity surgery in the National Patient Registry (NPR) and the Scandinavian Obesity Surgery Registry (SOReg).

Method

We randomly selected 962 out of 8501 registrations of obesity surgery in 2011 from the NPR and SOReg. Registered surgical procedures in the NPR and SOReg were compared to the medical records, and concordance was analyzed by calculating positive predictive value (PPV) with 95 % confidence interval (CI).

Results

We received 938 (98 %) medical records for manual review. The overall PPV for obesity surgery was high in the NPR (PPV 97.0; 95 % CI 95.6–98.4) and even higher in SOReg (PPV 99.7; 95 % CI 99.3–100). Accuracy was higher for gastric bypass surgery than for other types of obesity surgery. Registrations that were misclassified as obesity surgery (n?=?44) included reoperations due to complications or reconstruction to normal anatomy after previous obesity surgery (n?=?11) and endoscopic procedures (n?=?10).

Conclusion

Obesity surgery registrations in the NPR and SOReg have high accuracy and are reliable sources of data to identify patients having undergone obesity surgery. When it is of importance to distinguish between specific surgical procedures, non-gastric bypass surgeries in the NPR should ideally be supplemented with data from other sources.

     

Liposome accumulation in irradiated tumors display important tumor and dose dependent differences

Radiation therapy may affect several important parameters in the tumor microenvironment and thereby influence the accumulation of liposomes by the enhanced permeability and retention (EPR)-effect. Here we investigate the effect of single dose radiation therapy on liposome tumor accumulation by PET/CT imaging using radiolabeled liposomes. Head and neck cancer xenografts (FaDu) and syngenic colorectal (CT26) cancer models were investigated. Radiotherapy displayed opposite effects in the two models. FaDu tumors displayed increased mean accumulation of liposomes for radiation doses up to 10 Gy, whereas CT26 tumors displayed a tendency for decreased accumulation. Tumor hypoxia was found negatively correlated to microregional distribution of liposomes. However, liposome distribution in relation to hypoxia was improved at lower radiation doses. The study reveals that the heterogeneity in liposome tumor accumulation between tumors and different radiation protocols are important factors that need to be taken into consideration to achieve optimal effect of liposome based radio-sensitizer therapy.     

The relationship between temperament and fearfulness in adult dental phobic patients

BACKGROUND: Temperament has been associated with dental fear (DF) and dental behavioural management problems (DBMP) in children, but little is known about what role temperament plays in the aetiology of DF. Thus, measures of temperament suitable for use among children, adolescents, and adults would be of value for longitudinal and family studies of DF, where relations between children's and parent's ratings are investigated. AIM: Our aim was to explore the adapted EASI (emotionality, activity, sociability, and impulsivity) in adult patients, and to evaluate the instrument in comparison with established measures of DF and general emotional reactions in adults. DESIGN: The subjects were 230 adult patients applying for treatment for DF and 41 nonfearful patients (reference group). Questionnaires investigated temperament (general and DF) and general anxiety and depression. RESULTS: The previously described factor structure of the EASI among children was confirmed and the adapted EASI had acceptable psychometric qualities. Emotionality correlated with DF and with measures of general psychological distress. No differences were found in mean scores of EASI dimensions between DF group and the reference group, which was in contrast with studies in children. CONCLUSIONS: The adapted EASI seem promising for use in future longitudinal and familial studies of development of DF and DBMP.     

Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture—A NOREPOS Population-Based Cohort Study

Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01–1.44) and 24% (HR = 1.24, 95% CI 1.03–1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).