Management of Cylindrical Battery Ingestion.

Presentation A female presented to the Emergency Department following ingestion of an unknown number of cylindrical batteries. Diagnosis Abdominal X-ray confirmed the presence of multiple batteries located throughout the abdomen. Treatment A trial of conservative management was pursued, and five AA batteries were successfully passed per rectum. Serial X-rays over three weeks revealed that the majority of batteries failed to pass. A decision was made to perform a laparotomy, and 46 cylindrical batteries were removed from the stomach through a small gastrotomy. Four batteries located in the colon were milked into the rectum and removed via the transanal route. Discussion Using daily clinical exams and weekly plain films of the abdomen, conservative management is possible if a small number of batteries are ingested and make it to the stomach. However, the potential of cylindrical batteries to result in acute surgical emergencies should not be underestimated.

Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients.

Next generation risk assessment (NGRA) is an exposure-led, hypothesis-driven approach that has the potential to support animal-free safety decision-making. However, significant effort is needed to develop and test the in vitro and in silico (computational) approaches that underpin NGRA to enable confident application in a regulatory context. A workshop was held in Montreal in 2019 to discuss where effort needs to be focussed and to agree on the steps needed to ensure safety decisions made on cosmetic ingredients are robust and protective. Workshop participants explored whether NGRA for cosmetic ingredients can be protective of human health, and reviewed examples of NGRA for cosmetic ingredients. From the limited examples available, it is clear that NGRA is still in its infancy, and further case studies are needed to determine whether safety decisions are sufficiently protective and not overly conservative. Seven areas were identified to help progress application of NGRA, including further investments in case studies that elaborate on scenarios frequently encountered by industry and regulators, including those where a 'high risk' conclusion would be expected. These will provide confidence that the tools and approaches can reliably discern differing levels of risk. Furthermore, frameworks to guide performance and reporting should be developed.

Position statement for the diagnosis and management of anogenital warts.

BACKGROUND: Anogenital warts (AGW) can cause economic burden on healthcare systems and are associated with emotional, psychological and physical issues. OBJECTIVE: To provide guidance to physicians on the diagnosis and management of AGW. METHODS: Fourteen global experts on AGW developed guidance on the diagnosis and management of AGW in an effort to unify international recommendations. Guidance was developed based on published international and national AGW guidelines and an evaluation of relevant literature published up to August 2016. Authors provided expert opinion based on their clinical experiences. RESULTS: A checklist for a patient's initial consultation is provided to help physicians when diagnosing AGW to get the relevant information from the patient in order to manage and treat the AGW effectively. A number of frequently asked questions are also provided to aid physicians when communicating with patients about AGW. Treatment of AGW should be individualized and selected based on the number, size, morphology, location, and keratinization of warts, and whether they are new or recurrent. Different techniques can be used to treat AGW including ablation, immunotherapy and other topical therapies. Combinations of these techniques are thought to be more effective at reducing AGW recurrence than monotherapy. A simplified algorithm was created suggesting patients with 1-5 warts should be treated with ablation followed by immunotherapy. Patients with >5 warts should use immunotherapy for 2 months followed by ablation and a second 2-month course of immunotherapy. Guidance for daily practice situations and the subsequent action that can be taken, as well as an algorithm for treatment of large warts, were also created. CONCLUSION: The guidance provided will help physicians with the diagnosis and management of AGW in order to improve the health and quality of life of patients with AGW.

A probabilistic intake model to estimate the impact of reformulation by the food industry among Irish consumers.

This project quantified the impact that voluntary reformulation efforts of the food industry had on the Irish population's nutrient intake. Nutrient composition data on reformulated products were collected from 14 major food companies for two years, 2005 and 2012. Probabilistic intake assessments were performed using the Irish national food consumption surveys as dietary intake data. The nutrient data were weighted by market shares replacing existing food composition data for these products. The reformulation efforts assessed, significantly reduced mean energy intakes by up to 12 kcal/d (adults), 15 kcal/d (teens), 19 kcal/d (children) and 9 kcal/d (pre-schoolers). Mean daily fat intakes were reduced by up to 1.3 g/d, 1.3 g/d, 0.9 g/d and 0.6 g/d, saturated fat intakes by up to 1.7 g/d, 2.3 g/d, 1.8 g/d and 1 g/d, sugar intakes by up to 1 g/d, 2 g/d, 3.5 g/d and 1 g/d and sodium intakes by up to 0.6 g/d, 0.5 g/d, 0.2 g/d, 0.3 g/d for adults, teenagers, children and pre-school children, respectively. This model enables to assess the impact of industry reformulation amongst Irish consumers' nutrient intakes, using consumption, food composition and market share data.

Inferior Outcomes on the Waiting List in Low-Volume Pediatric Heart Transplant Centers.

Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective was to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis. We studied a cohort of 6482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4665 (72%) of the candidates underwent transplantation. Candidates were divided into groups according to the average annual transplantation volume of the listing center during the study period: more than 10, six to 10, three to five, or fewer than three transplantations. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and posttransplantation mortality. Of the 6482 candidates, 24% were listed in low-volume centers (fewer than three annual transplantations). Of these listed candidates in low-volume centers, only 36% received a transplant versus 89% in high-volume centers (more than 10 annual transplantations) (p < 0.001). Listing at a low-volume center was the most significant risk factor for waitlist death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 3.5-5.7 in multivariate Cox regression and HR 5.6, CI 4.4-7.3 in multivariate competing risk regression) and was significant for posttransplantation death (HR 1.27, 95% CI 1.0-1.6 in multivariate Cox regression). During the study period, one-fourth of pediatric transplant candidates were listed in low-volume transplant centers. These children had a limited transplantation rate and a much greater risk of dying while on the waitlist.

Application of the expanded Creme RIFM consumer exposure model to fragrance ingredients in cosmetic, personal care and air care products.

As part of a joint project between the Research Institute for Fragrance Materials (RIFM) and Creme Global, a Monte Carlo model (here named the Creme RIFM model) has been developed to estimate consumer exposure to ingredients in personal care products. Details of the model produced in Phase 1 of the project have already been published. Further data on habits and practises have been collected which enable the model to estimate consumer exposure from dermal, oral and inhalation routes for 25 product types. . In addition, more accurate concentration data have been obtained which allow levels of fragrance ingredients in these product types to be modelled. Described is the use of this expanded model to estimate aggregate systemic exposure for eight fragrance ingredients. Results are shown for simulated systemic exposure (expressed as µg/kg bw/day) for each fragrance ingredient in each product type, along with simulated aggregate exposure. Highest fragrance exposure generally occurred from use of body lotions, body sprays and hydroalcoholic products. For the fragrances investigated, aggregate exposure calculated using this model was 11.5-25 fold lower than that calculated using deterministic methodology. The Creme RIFM model offers a very comprehensive and powerful tool for estimating aggregate exposure to fragrance ingredients.

Integrating habits and practices data for soaps, cosmetics and air care products into an existing aggregate exposure model.

In order to accurately assess aggregate exposure to a fragrance material in consumers, data are needed on consumer habits and practices, as well as the concentration of the fragrance material in those products. The present study describes the development of Phase 2 Creme RIFM model by expanding the previously developed Phase 1 model to include an additional six product types. Using subject-matching algorithms, the subjects in the Phase 1 Creme RIFM database were paired with subjects in the SUPERB and BodyCare surveys based on age and gender. Consumption of the additional products was simulated to create a seven day diary allowing full data integration in a consistent format. The inhalation route was also included for air care and other products where a fraction of product used is inhaled, derived from the RIFM 2-box model. The expansion of the Phase 1 Creme RIFM model has resulted in a more extensive and refined model, which covers a broader range of product categories and now, includes all relevant routes of exposure. An evaluation of the performance of the model has been carried out in an accompanying publication to this one.

Survival Outcomes Following Pediatric Liver Transplantation (Pedi-SOFT) Score: A Novel Predictive Index.

A prognostic index to predict survival after liver transplantation could address several clinical needs. Here, we devised a scoring system that predicts recipient survival after pediatric liver transplantation. We used univariate and multivariate analysis on 4565 pediatric liver transplant recipients data and identified independent recipient and donor risk factors for posttransplant mortality at 3 months. Multiple imputation was used to account for missing variables. We identified five factors as significant predictors of recipient mortality after pediatric liver transplantation: two previous transplants (OR 5.88, CI 2.88-12.01), one previous transplant (OR 2.54, CI 1.75-3.68), life support (OR 3.68, CI 2.39-5.67), renal insufficiency (OR 2.66, CI 1.84-3.84), recipient weight under 6 kilograms (OR 1.67, CI 1.12-2.36) and cadaveric technical variant allograft (OR 1.38, CI 1.03-1.83). The Survival Outcomes Following Pediatric Liver Transplant score assigns weighted risk points to each of these factors in a scoring system to predict 3-month recipient survival after liver transplantation with a C-statistic of 0.74. Although quite accurate when compared with other posttransplant survival models, we would not advocate individual clinical application of the index.

A strategy for structuring and reporting a read-across prediction of toxicity.

Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested.

Novel database for exposure to fragrance ingredients in cosmetics and personal care products.

Exposure of fragrance ingredients in cosmetics and personal care products to the population can be determined by way of a detailed and robust survey. The frequency and combinations of products used at specific times during the day will allow the estimation of aggregate exposure for an individual consumer, and to the sample population. In the present study, habits and practices of personal care and cosmetic products have been obtained from market research data for 36,446 subjects across European countries and the United States in order to determine the exposure to fragrance ingredients. Each subject logged their product uses, time of day and body application sites in an online diary for seven consecutive days. The survey data did not contain information on the amount of product used per occasion or body measurements, such as weight and skin surface area. Nevertheless, this was found from the literature where the likely amount of product used per occasion or body measurement could be probabilistically chosen from distributions of data based on subject demographics. The daily aggregate applied consumer product exposure was estimated based on each subject's frequency of product use, and Monte Carlo simulations of their likely product amount per use and body measurements. Statistical analyses of the habits and practices and consumer product exposure are presented, which show the robustness of the data and the ability to estimate aggregate consumer product exposure. Consequently, the data and modelling methods presented show potential as a means of performing ingredient safety assessments for personal care and cosmetics products.

Use of an aggregate exposure model to estimate consumer exposure to fragrance ingredients in personal care and cosmetic products.

Ensuring the toxicological safety of fragrance ingredients used in personal care and cosmetic products is essential in product development and design, as well as in the regulatory compliance of the products. This requires an accurate estimation of consumer exposure which, in turn, requires an understanding of consumer habits and use of products. Where ingredients are used in multiple product types, it is important to take account of aggregate exposure in consumers using these products. This publication investigates the use of a newly developed probabilistic model, the Creme RIFM model, to estimate aggregate exposure to fragrance ingredients using the example of 2-phenylethanol (PEA). The output shown demonstrates the utility of the model in determining systemic and dermal exposure to fragrances from individual products, and aggregate exposure. The model provides valuable information not only for risk assessment, but also for risk management. It should be noted that data on the concentrations of PEA in products used in this article were obtained from limited sources and not the standard, industry wide surveys typically employed by the fragrance industry and are thus presented here to illustrate the output and utility of the newly developed model. They should not be considered an accurate representation of actual exposure to PEA.

Intradermal Administration of Influenza Vaccine with Trehalose and Pullulan-Based Dissolving Microneedle Arrays.

Most influenza vaccines are administered via intramuscular injection which has several disadvantages that might jeopardize the compliance of vaccinees. Intradermal administration of dissolving-microneedle-arrays (dMNAs) could serve as minimal invasive alternative to needle injections. However, during the production process of dMNAs antigens are subjected to several stresses, which may reduce their potency. Moreover, the needles need to have sufficient mechanical strength to penetrate the skin and subsequently dissolve effectively to release the incorporated antigen. Here, we investigated whether blends of trehalose and pullulan are suitable for the production of stable dMNA fulfilling these criteria. Our results demonstrate that production of trehalose/pullulan-based dMNAs rendered microneedles that were sharp and stiff enough to pierce into ex vivo human skin and subsequently dissolve within 15 min. The mechanical properties of the dMNAs were maintained well even after four weeks of storage at temperatures up to 37°C. In addition, immunization of mice with influenza antigens via both freshly prepared dMNAs and dMNAs after storage (four weeks at 4°C or 37°C) resulted in antibody titers of similar magnitude as found in intramuscularly injected mice and partially protected mice from influenza virus infection. Altogether, our results demonstrate the potential of trehalose/pullulan-based dMNAs as alternative dosage form for influenza vaccination.

An early regional experience with expansion of Milan Criteria for liver transplant recipients.

The Milan Criteria (MC) showed that orthotopic liver transplantation (OLT) was an effective treatment for patients with nonresectable, nonmetastatic HCC. There is growing evidence that expanding the MC does not adversely affect patient or allograft survival following OLT. The adult OLT programs in UNOS Region 4 reached an agreement allowing lesions outside MC (one lesion <6 cm, ≤3 lesions, none >5 cm and total diameter <9 cm-[R4 T3]) to receive the same exception points as MC lesions. Kaplan-Meier curves and log-rank tests were used to compare survival data. Chi-squared and Mann-Whitney U tests were used to compare patient data. A p-value of <0.05 was considered significant. All statistical analyses were performed on SPSS 15 (SPSS, Chicago, IL). Four hundred and forty-five patients were transplanted for HCC (363-MC and 82-R4 T3). Patient demographics were found to be similar between the two groups. Three year patient, allograft and recurrence free survival between MC and R4 T3 were found to be 72.9% and 77.1%, 71% and 70.2% and 90.5% and 86.9%, respectively (all p > 0.05). We report the first regionalized multicenter, prospective study showing benefit of OLT in patients exceeding MC based on preoperative imaging.

More than a decade on: review of the use of imiquimod in lower anogenital intraepithelial neoplasia.

To assess the effectiveness of 5% imiquimod cream (IQ) in the treatment of vulvar, penile and anal intraepithelial neoplasias (VIN, PIN and AIN), we searched Medline, Embase, PubMed and Cochrane Library databases. With regard to VIN there were two randomized controlled trials (RCTs), eight uncontrolled/cohort studies, nine case reports and one review article. Use of IQ in PIN and AIN were only supported by cohort studies (two each for PIN and AIN) and case reports (15 for PIN and 3 for AIN). On pooled analysis of RCTs, uncontrolled and cohort studies, the mean complete response (CR) rate for VIN, PIN and AIN were 51%, 70% and 48%, respectively. The mean partial response (PR) rate for VIN, PIN and AIN were 25%, 30% and 34% respectively. The recurrence (RR) rate for VIN, PIN and AIN were 16%, 0% and 36%, respectively. The follow-up period for VIN, PIN and AIN ranged from 2 to 32 months, 10 to 12 months and 11 to 39 months, respectively. Although the results for PIN look the best, the strongest evidence regarding efficacy of IQ in anogenital intraepithelial neoplasia is for VIN supported by RCTs. Evidence for use of IQ in AIN was essentially limited to HIV-positive men who have sex with men. IQ was reasonably well tolerated with side-effects being managed with reduction in frequency of drug usage and/or rest periods. Based on these results, IQ seems to be a safe mode of treatment and is possibly an alternative to currently available methods of treatment. However, there are no comparative studies assessing its efficacy against traditional modes of treatment.

Imiquimod use in the genital area and development of lichen sclerosus and lichen planus.

Imiquimod has immune-stimulant properties that can precipitate autoimmune conditions like eczema, psoriasis and lichenoid conditions. We report two cases here where imiquimod induced florid lichen sclerosus in one patient and lichen planus in another. In both patients the condition was so aggressive and unresponsive to steroid treatment that circumcision was necessary.

Diphtheria toxoid dissolving microneedle vaccination: Adjuvant screening and effect of repeated-fractional dose administration.

In this study the effect of repeated-fractional intradermal administration of diphtheria toxoid (DT) compared to a single administration in the presence or absence of adjuvants formulated in dissolving microneedles (dMNs) was investigated. Based on an adjuvant screening with a hollow microneedle (hMN) system, poly(I:C) and gibbsite, a nanoparticulate aluminum salt, were selected for further studies: they were co-encapsulated with DT in dMNs with either a full or fractional DT-adjuvant dose. Sharp dMNs were prepared regardless the composition and were capable to penetrate the skin, dissolve within 20 min and deposit the intended antigen-adjuvant dose, which remained in the skin for at least 5 h. Dermal immunization with hMN in repeated-fractional dosing (RFrD) resulted in a higher immune response than a single-full dose (SFD) administration. Vaccination by dMNs led overall to higher responses than hMN but did not show an enhanced response after RFrD compared to a SFD administration. Co-encapsulation of the adjuvant in dMNs did not increase the immune response further. Immunization by dMNs without adjuvant gave a comparable response to subcutaneously injected DT-AlPO4 in a 15 times higher dose of DT, as well as subcutaneous injected DT-poly(I:C) in a similar DT dose. Summarizing, adjuvant-free dMNs showed to be a promising delivery tool for vaccination performed in SFD administration.

Shortening the voiding interval for men having chlamydia nucleic acid amplification tests.

Male patients are assessed for a sexually transmitted infection provided a considerable length of time has elapsed since last micturition. The current availability of highly sensitive nucleic acid amplification tests (NAATs) for Chlamydia trachomatis (CT) and Neisseria gonorrhoea such as APTIMA Combo2 (AC2) led us to investigate the impact of voiding interval on the positivity of urine tests for CT. Male patients attending a genitourinary medicine clinic at high clinical risk for CT infection and known CT positives returning for treatment were included. Two first-void urine (FVU) specimens were collected: the first sample in the standard manner and the second sample was collected 20 minutes later or as soon as possible thereafter. Fifty-two CT-positive males were included in the analysis. All of the second samples were also CT positive and none were in the equivocal range. Paired t-test analysis did not show a significant difference between relative light unit readings of the first and second urine samples (P = 0.127). Even in male patients who have recently passed urine, FVU tested by AC2 can still reliably detect CT. This provides us opportunity for more flexible and effective patient management.

Extensive vulval oedema secondary to severe pelvic infection.

A 17-year-old female developed a complex pelvic abscess a few weeks post-surgical abortion. Despite surgical drainage, a debilitating infection induced a low albumen. The resulting pelvic oedema caused gross vulval oedema that was difficult to manage. She had previously been treated for chlamydia.