OPTIma: simplifying calorimetry for proton computed tomography in high proton flux environments.

Objective.Proton computed tomography (pCT) offers a potential route to reducing range uncertainties for proton therapy treatment planning, however the current trend towards high current spot scanning treatment systems leads to high proton fluxes which are challenging for existing systems. Here we demonstrate a novel approach to energy reconstruction, referred to as 'de-averaging', which allows individual proton energies to be recovered using only a measurement of their integrated energy without the need for spatial information from the calorimeter.Approach.The method is evaluated in the context of the Optimising Proton Therapy through Imaging (OPTIma) system which uses a simple, relatively inexpensive, scintillator-based calorimeter that reports only the integrated energy deposited by all protons within a cyclotron period, alongside a silicon strip based tracking system capable of reconstructing individual protons in a high flux environment. GEANT4 simulations have been performed to examine the performance of such a system at a modern commercial cyclotron facility using aσ≈ 10 mm beam for currents in the range 10-50 pA at the nozzle.Main results.Apart from low-density lung tissue, a discrepancy of less than 1% on the Relative Stopping Power is found for all other considered tissues when embedded within a 150 mm spherical Perspex phantom in the 10-30 pA current range, and for some tissues even up to 50 pA.Significance.By removing the need for the calorimeter system to provide spatial information, it is hoped that the de-averaging approach can facilitate clinically relevant, cost effective and less complex calorimeter systems for performing high current pCTs.

A CAF01-adjuvanted whole asexual blood-stage liposomal malaria vaccine induces a CD4+ T-cell-dependent strain-transcending protective immunity in rodent models.

IMPORTANCE: Malaria is a devastating disease that has claimed many lives, especially children <5 years of age in Sub-Saharan Africa, as documented in World Malaria Reports by WHO. Even though vector control and chemoprevention tools have helped with elimination efforts in some, if not all, endemic areas, these efforts have been hampered by serious issues (including drug and insecticide resistance and disruption to social cohesion caused by the COVID-19 pandemic). Development of an effective malaria vaccine is the alternative preventative tool in the fight against malaria. Vaccines save millions of lives each year and have helped in elimination and/or eradication of global diseases. Development of a highly efficacious malaria vaccine that will ensure long-lasting protective immunity will be a "game-changing" prevention strategy to finally eradicate the disease. Such a vaccine will need to counteract the significant obstacles that have been hampering subunit vaccine development to date, including antigenic polymorphism, sub-optimal immunogenicity, and waning vaccine efficacy.

Effects of exogenous amylolytic or fibrolytic enzymes inclusion on in vitro fermentation of lactating dairy cow diets in a dual-flow continuous-culture system.

The objective of this study was to determine the effects of including exogenous amylolytic or fibrolytic enzymes in a diet for high-producing dairy cows on in vitro ruminal fermentation. Eight dual-flow continuous-culture fermentors were used in a replicated 4 × 4 Latin square. The treatments were control (CON), a xylanase and glucanase mixture (T1), an α-amylase mixture (T2), or a xylanase, glucanase, and α-amylase mixture (T3). Treatments were included at a rate of 0.008% of diet dry matter (DM) for T1 and T2 and at 0.02% for T3. All treatments replaced the equivalent amount of soybean meal in the diet compared with CON. All diets were balanced to have the same nutrient composition [30.2% neutral detergent fiber (NDF), 16.1% crude protein (CP), and 30% starch; DM basis], and fermentors were fed 106 g/d divided into 2 feedings. At each feeding, T2 was pipetted into the respective fermentor and an equivalent amount of deionized water was added to each fermentor to eliminate potential variation. Experimental periods were 10 d (7 d for adaptation and 3 d for sample collection). Composite samples of daily effluent were collected and analyzed for volatile fatty acids (VFA), NH3-N, and lactate concentrations, degradability of DM, organic matter, NDF, CP, and starch, and flow and metabolism of N. Samples of fermentor contents were collected from each fermentor at 0, 1, 2, 4, 6, and 8 h after feeding to determine kinetics of pH, NH3-N, lactate, and VFA concentrations over time. All data were analyzed using PROC GLIMMIX of SAS (SAS Institute Inc.), and the repeated variable of time was included for kinetics measurements. Treatment did not affect mean pH, degradability, N flow and metabolism, or the concentrations of VFA, NH3-N, or lactate in the effluent samples. Treatment did not affect pH, acetate:propionate ratio, or the concentrations of lactate, NH3-N, total VFA, acetate, propionate, butyrate, isobutyrate, valerate, or caproate. However, the concentration of total VFA tended to change at each time point depending upon the treatment, and T2 tended to have a greater proportion of 2-methylbutyrate and isovalerate than CON, T1, or T3. As 2-methylbutyrate and isovalerate are branched-chain VFA that are synthesized from branched-chain amino acids, T2 may have an increased fermentation of branched-chain amino acids or decreased uptake by fibrolytic microorganisms. Although we did not observe changes in N metabolism due to the enzymes, there could be changes in microbial populations that utilize branched-chain VFA. Overall, the tested enzymes did not improve in vitro ruminal fermentation in the diet of high-producing dairy cows.

Added value of the measles-rubella supplementary immunization activity in reaching unvaccinated and under-vaccinated children, a cross-sectional study in five Indian districts, 2018-20.

INTRODUCTION: Supplementary immunization activities (SIAs) aim to interrupt measles transmission by reaching susceptible children, including children who have not received the recommended two routine doses of MCV before the SIA. However, both strategies may miss the same children if vaccine doses are highly correlated. How well SIAs reach children missed by routine immunization is a key metric in assessing the added value of SIAs. METHODS: Children aged 9 months to younger than 5 years were enrolled in cross-sectional household serosurveys conducted in five districts in India following the 2017-2019 measles-rubella (MR) SIA. History of measles containing vaccine (MCV) through routine services or SIA was obtained from documents and verbal recall. Receipt of a first or second MCV dose during the SIA was categorized as "added value" of the SIA in reaching un- and under-vaccinated children. RESULTS: A total of 1,675 children were enrolled in these post-SIA surveys. The percentage of children receiving a 1st or 2nd dose through the SIA ranged from 12.8% in Thiruvananthapuram District to 48.6% in Dibrugarh District. Although the number of zero-dose children prior to the SIA was small in most sites, the proportion reached by the SIA ranged from 45.8% in Thiruvananthapuram District to 94.9% in Dibrugarh District. Fewer than 7% of children remained measles zero-dose after the MR SIA (range: 1.1-6.4%) compared to up to 28% before the SIA (range: 7.3-28.1%). DISCUSSION: We demonstrated the MR SIA provided considerable added value in terms of measles vaccination coverage, although there was variability across districts due to differences in routine and SIA coverage, and which children were reached by the SIA. Metrics evaluating the added value of an SIA can help to inform the design of vaccination strategies to better reach zero-dose or undervaccinated children.

Beamshaping for infrared hyperspectral imaging: a sequential optimization for infrared source coupling.

Focal plane array (FPA) detectors have escalated Fourier transform infrared (FTIR) microspectroscopy to a potent hyperspectral imaging method. Yet, despite the instrumental multiplex/multichannel advantages, the fidelity of the hyperspectral images relies on the throughput as the total flux of the source is divided among each FPA pixel. Additionally, maintaining the spectral resolution requires a certain level of collimation of the beam which adversely affect the flux of high étendue source. To this end, we propose an implementation of two deformable mirror (DM) sensorless adaptive optics system for infrared (IR) source coupling. The deflection shape of each DM membrane is optimized individually to deal with the beam intensity and the rays' direction in a separate manner, while preserving the spectral quality across the entire mid-IR range. This paper contemplates the choice of metrics in sequential optimization in conjunction with two variations of stochastic parallel gradient descent optimization algorithm. We discuss this approach with respect to a state-of-the-art FTIR microscope.

Investigating the use of support in secondary school: the role of self-reliance and stigma towards help-seeking.

Purpose: Adolescents are the least likely to seek help for their mental health problems. School may be an important route to improve early recognition of adolescents with mental health problems in need for support, but little is known about the barriers to school support.Materials and methods: Data were collected in a longitudinal cohort study of Dutch adolescents (age 12-16) in secondary school (n = 956). We assessed the relation between level of psychosocial problems at the beginning of the school year (T1) and the support used in school at the end of that school year (T2), whether the willingness to talk to others (measured at T1) mediates this relation, and whether stigma towards help-seeking (T1) moderates this mediation.Results: Adolescents with more psychosocial problems were more likely to use support in school and were less willing to talk to others about their problems, but the willingness to talk to others was not a mediator. Stigma moderated the relationship between psychosocial problems and willingness to talk to others.Conclusions: Most adolescents with psychosocial problems get support in Dutch secondary school regardless of their willingness to talk to others about their problems. However, perceiving stigma towards help-seeking makes it less likely for someone to talk about their problems.

A propensity-score matched analysis of ventral-TAPP vs. laparoscopic IPOM for small and mid-sized ventral hernias. Comparison of perioperative data, surgical outcome and cost-effectiveness.

PURPOSE: Laparoscopic techniques have been used and refined in hernia surgery for several years. The aim of this study was to compare an established method such as laparoscopic intra-peritoneal onlay mesh repair (lap. IPOM) with ventral Transabdominal Preperitoneal Patch Plasty (ventral-TAPP) in abdominal wall hernia repair. METHODS: Patient-related data of 180 laparoscopic ventral hernia repairs between June 2014 and August 2020 were extracted from our prospectively maintained database. Of these patients, 34 underwent ventral-TAPP and 146 lap. IPOM. After excluding hernias with a defect size > 5 cm and obtaining balanced groups with propensity-score matching, a comparative analysis was performed in terms perioperative data, surgical outcomes and cost-effectiveness. RESULTS: Propensity-score matching suggested 27 patients in each of the two cohorts. The statistical evaluation showed that intake of opiates was significantly higher in the lap. IPOM group compared to ventral-TAPP patients (p = 0.001). The Visual Analogue Scale (VAS) score after lap. IPOM repair was significantly higher at movement (p = 0.008) and at rest (p = 0.023). Also, maximum subjective pain during hospital stay was significantly higher in the lap. IPOM group compared to ventral-TAPP patients (p = 0.004). No hernia recurrence was detected in either group. The material costs of ventral-TAPP procedure (34.37 ± 0.47 €) were significantly lower than those of the lap. IPOM group (742.57 ± 128.44 € p = 0.001). The mean operation time was 65.19 ± 26.43 min in the lap. IPOM group and 58.65 ± 18.43 min in the ventral-TAPP cohort. Additionally, the length of hospital stay in the lap. IPOM cohort was significantly longer (p = 0.043). CONCLUSION: Ventral-TAPP procedures represent an alternative technique to lap. IPOM repair to reduce the risk of complications related to intra-peritoneal position of mesh and fixating devices. In addition, our study showed that postoperative pain level, material costs and hospital stay of the ventral-TAPP cohort are significantly lower compared to lap. IPOM patients.

Diagnosing ventilator-associated pneumonia (VAP) in UK NHS ICUs: the perceived value and role of a novel optical technology.

BACKGROUND: Diagnosing ventilator-associated pneumonia (VAP) in an intensive care unit (ICU) is a complex process. Our aim was to collect, evaluate and represent the information relating to current clinical practice for the diagnosis of VAP in UK NHS ICUs, and to explore the potential value and role of a novel diagnostic for VAP, which uses optical molecular alveoscopy to visualise the alveolar space. METHODS: Qualitative study performing semi-structured interviews with clinical experts. Interviews were recorded, transcribed, and thematically analysed. A flow diagram of the VAP patient pathway was elicited and validated with the expert interviewees. Fourteen clinicians were interviewed from a range of UK NHS hospitals: 12 ICU consultants, 1 professor of respiratory medicine and 1 professor of critical care. RESULTS: Five themes were identified, relating to [1] current practice for the diagnosis of VAP, [2] current clinical need in VAP diagnostics, [3] the potential value and role of the technology, [4] the barriers to adoption and [5] the evidence requirements for the technology, to help facilitate a successful adoption. These themes indicated that diagnosis of VAP is extremely difficult, as is the decision to stop antibiotic treatment. The analysis revealed that there is a clinical need for a diagnostic that provides an accurate and timely diagnosis of the causative pathogen, without the long delays associated with return of culture results, and which is not dangerous to the patient. It was determined that the technology would satisfy important aspects of this clinical need for diagnosing VAP (and pneumonia, more generally), but would require further evidence on safety and efficacy in the patient population to facilitate adoption. CONCLUSIONS: Care pathway analysis performed in this study was deemed accurate and representative of current practice for diagnosing VAP in a UK ICU as determined by relevant clinical experts, and explored the value and role of a novel diagnostic, which uses optical technology, and could streamline the diagnostic pathway for VAP and other pneumonias.

Multimorbidity prevalence and patterns and their associations with health literacy among chronic kidney disease patients.

BACKGROUND: Health literacy is the ability to deal with information related to one's health. Patients with low health literacy have poor disease-management skills for chronic diseases, such as chronic kidney disease (CKD). This could influence the number and combination of their diseases. METHODS: We included adult patients with CKD stages 1-5 from the Lifelines Study (n = 2,742). We assessed the association between low health literacy and the number and patterns of comorbidities, considering them globally and stratified by age and sex, using multinomial logistic regression and latent class analysis, respectively. RESULTS: Low health literacy was associated with a higher number of comorbidities in the crude models, and after adjustment for age, sex, eGFR, smoking, and BMI. In the crude model, the OR for low health literacy increased from 1.71 (1.25-2.33) for two comorbidities to 2.71 (2.00-3.68) for four comorbidities. In the fully-adjusted model, the associations remained significant with a maximum OR of 1.70 (1.16-2.49) for four comorbidities. The patterns of multimorbidity were similar for low and adequate health literacy, overall and by sex, bur tended to be different for patients older than 65. Older patients with low health literacy had higher comorbidity prevalence and a relatively greater share of cardiovascular, psychiatric, and central nervous system diseases. CONCLUSIONS: Among CKD patients, low health literacy is associated with more multimorbidity. Health literacy is not associated with patterns of multimorbidity in younger patients, but a difference was observed in older ones. Improving low health literacy could be an intervention efficient also in decreasing multimorbidity in CKD patients.

[Digital documentation of complications in visceral surgery: possibilities and evaluation of an instrument for quality management]. / Digitale Komplikationserfassung in der Viszeralchirurgie: Möglichkeiten und Evaluation eines Instrumentes für das Qualitätsmanagement.

Against the background of the growing economization of clinical medicine, in the last decades the topics of risk and complication management have also become more important in surgical disciplines. The standardization and reproducible documentation of outcome and complication data play a key role for valid quality control. In this article a digital system implemented at the surgical clinic of the Charité University Medicine in Berlin is analyzed with respect to its practicability for perioperative and postoperative monitoring of complications within the framework of quality assurance.

Beamline K11 DIAD: a new instrument for dual imaging and diffraction at Diamond Light Source.

The Dual Imaging and Diffraction (DIAD) beamline at Diamond Light Source is a new dual-beam instrument for full-field imaging/tomography and powder diffraction. This instrument provides the user community with the capability to dynamically image 2D and 3D complex structures and perform phase identification and/or strain mapping using micro-diffraction. The aim is to enable in situ and in operando experiments that require spatially correlated results from both techniques, by providing measurements from the same specimen location quasi-simultaneously. Using an unusual optical layout, DIAD has two independent beams originating from one source that operate in the medium energy range (7-38 keV) and are combined at one sample position. Here, either radiography or tomography can be performed using monochromatic or pink beam, with a 1.4 mm × 1.2 mm field of view and a feature resolution of 1.2 µm. Micro-diffraction is possible with a variable beam size between 13 µm × 4 µm and 50 µm × 50 µm. One key functionality of the beamline is image-guided diffraction, a setup in which the micro-diffraction beam can be scanned over the complete area of the imaging field-of-view. This moving beam setup enables the collection of location-specific information about the phase composition and/or strains at any given position within the image/tomography field of view. The dual beam design allows fast switching between imaging and diffraction mode without the need of complicated and time-consuming mode switches. Real-time selection of areas of interest for diffraction measurements as well as the simultaneous collection of both imaging and diffraction data of (irreversible) in situ and in operando experiments are possible.

CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with Plasmodium infection.

CD47 is an antiphagocytic "don't eat me" signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47-/- mice infected with Plasmodium yoelii, which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the Plasmodium berghei ANKA (Pb-A) murine model. In vitro we tested the effect of anti-CD47 mAb on Plasmodium-infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of Plasmodium-infected RBCs. Infection of C57BL/6 mice with Pb-A is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of Pb-A infection. Anti-CD47-treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47-treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47-treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood-brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8+ T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.

Impact of different types of dental prostheses on oral-health-related quality of life: a prospective bicenter study of definitive and interim restorations.

PURPOSE: To assess the impact of different types of dental prostheses, including definitive and interim restorations, on oral health-related quality of life (OHRQoL) before and after prosthetic treatment. MATERIALS AND METHODS: A total of 151 patients received prosthetic treatment at one of two German departments of prosthetic dentistry. The patients' OHRQoL was assessed using the German version of the Oral Health Impact Profile (OHIP-G53) at baseline (T0) and at 1 week (T1) and 3 months (T2) after treatment. Patients were divided into 10 subgroups according to their pre- and posttreatment status. The effect of the type (no prosthesis; fixed prosthesis; removable prosthesis) and duration of wear (definitive; interim) of the restorations was evaluated. Results were analyzed using Kolmogorov-Smirnov, Kruskal-Wallis, and Mann-Whitney U tests with a significance level of P = .05. RESULTS: The highest OHRQoL was recorded for patients with fixed restorations, as indicated by the fact that their OHIP scores were lowest. A significant improvement in OHRQoL (P ≤ .034) was observed for patients who needed prostheses and were then treated with removable or fixed restorations. The OHIP score was affected by a change in restoration type. Rehabilitation with definitive prostheses had a significant effect on posttreatment OHRQoL (P ≤ .006). CONCLUSION: In general, prosthetic rehabilitation by use of fixed or removable prostheses resulted in an improvement in OHRQoL. The use of the same type of restoration before and after treatment had a positive effect on OHRQoL. If possible, a change of restoration type should be avoided. For patients who require permanent prostheses, the use of fixed and removable restorations is recommended. For oral rehabilitation, fixed restorations should be preferred in order to achieve best possible improvement of OHIP score.

Oral health-related impact profile of patients treated with fixed, removable, and telescopic dental prostheses in student courses-a prospective bicenter clinical trial.

OBJECTIVES: To analyze the oral health-related impact profile in patients treated with three different types of dental prosthesis in student courses. MATERIALS AND METHODS: This prospective bicenter clinical trial was conducted with 151 patients being treated with fixed (n = 70), removable (n = 61), or telescopic dental prostheses (n = 20) in clinical student courses of two German universities from October 2018 to October 2019. All patients completed three standardized German versions of the Oral Health Impact Profile (OHIP-G49/53) before prosthetic treatment (T0), at control after 1 week (T1), and after 3 months (T2), divided into five dimensions: (a) appearance, (b) oral function, (c) psychosocial impact, (d) linguistic limitations, and (e) orofacial pain. Data were analyzed with Kolmogorov-Smirnov, Wilcoxon signed-rank, Kruskal-Wallis, Mann-Whitney, and Cronbach's alpha tests. RESULTS: Within T0-T1 and T0-T2, greater improvements were determined for removable compared with fixed dental prostheses for the dimensions' oral function (p ≤ 0.014), linguistic limitations (p ≤ 0.016), and appearance (p ≤ 0.003). No significant differences were found between fixed and telescopic dental prostheses (p ≥ 0.104) or between removable (partial dental prosthesis with clasps and complete dental prosthesis) and telescopic dental prostheses (p ≥ 0.100). Within T1-T2, a significant improvement in orofacial pain could be determined (p = 0.007). CONCLUSIONS: Restorations presented an improvement in oral health-related quality of life. Removable dental prostheses showed better improvement than fixed ones in various dimensions. CLINICAL RELEVANCE: Knowledge about the influence of oral health-related quality of life on the three different types of prosthesis used in student courses can be of decisive help in dental consultations.

Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial.

BACKGROUND: We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis. METHODS: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis. RESULTS: Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls. CONCLUSIONS: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy. CLINICAL TRIALS REGISTRATION: NCT03341767.

Toxicity of topically applied drugs beyond skin irritation: Static skin model vs. Two organs-on-a-chip.

Skin model cultivation under static conditions limits the observation of the toxicity to this single organ. Biology-inspired microphysiological systems associating skin with a liver in the same circulating medium provide a more comprehensive insight into systemic substance toxicity; however, its advantages or limitations for topical substance toxicity remain unknown. Herein, we performed topical (OECD test guideline no. 439) and systemic administration of terbinafine in reconstructed human skin (RHS) vs. a RHS plus liver model cultured in TissUse' HUMIMIC Chip2 (Chip2). Aiming for a more detailed insight into the cutaneous substance irritancy/toxicity, we assessed more than the MTT cell viability: lactate dehydrogenase (LDH), lactate and glucose levels, as well as inherent gene expressions. Sodium dodecyl sulfate (SDS) was the topical irritant positive control. We confirmed SDS irritancy in both static RHS and Chip2 culture by the damage in the morphology, reduction in the lactate production and lower glucose consumption. In the static RHS, the SDS-treated tissues also released significantly high LDH (82%; p < 0.05) and significantly lower IL-6 release (p < 0.05), corroborating with the other metabolic levels. In both static RHS and Chip2 conditions, we confirmed absence of irritancy or systemic toxicity by LDH, glucose or lactate levels for topical 1% and 5% terbinafine and systemic 0.1% terbinafine treatment. However, topical 5% terbinafine treatment in the Chip2 upregulated IL-1α in the RHS, unbalanced apoptotic and proliferative cell ratios in the liver and significantly increased its expression of CYP1A2 and 3A4 enzymes (p < 0.05), proving that it has passed the RHS barrier promoting a liver impact. Systemic 0.1% terbinafine treatment in the Chip2 increased RHS expression of EGFR, increased apoptotic cells in the liver, downregulated liver albumin expression and upregulated CYP2C9 significantly (p < 0.05), acting as an effective hepatotoxic terbinafine control. The combination of the RHS and liver model in the Chip2 allowed a more sensitive assessment of skin and hepatic effects caused by chemicals able to pass the skin (5% terbinafine and SDS) and after systemic 0.1% terbinafine application. The present study opens up a more complex approach based on the microphysiological system to assess more than a skin irritation process.

Using Serology to Anticipate Measles Post-honeymoon Period Outbreaks.

Measles vaccination is a public health 'best buy', with the highest cost of illness averted of any vaccine-preventable disease (Ozawa et al., Bull. WHO 2017;95:629). In recent decades, substantial reductions have been made in the number of measles cases, with an estimated 20 million deaths averted from 2000 to 2017 (Dabbagh et al., MMWR 2018;67:1323). Yet, an important feature of epidemic dynamics is that large outbreaks can occur following years of apparently successful control (Mclean et al., Epidemiol. Infect. 1988;100:419-442). Such 'post-honeymoon period' outbreaks are a result of the nonlinear dynamics of epidemics (Mclean et al., Epidemiol. Infect. 1988;100:419-442). Anticipating post-honeymoon outbreaks could lead to substantial gains in public health, helping to guide the timing, age-range, and location of catch-up vaccination campaigns (Grais et al., J. Roy. Soc. Interface 2008003B6:67-74). Theoretical conditions for such outbreaks are well understood for measles, yet the information required to make these calculations policy-relevant is largely lacking. We propose that a major extension of serological studies to directly characterize measles susceptibility is a high priority.

The role of functional health literacy in long-term treatment outcomes in psychosocial care for adolescents.

Although among adolescents with psychosocial problems low health literacy may increase the risk of poor treatment outcomes, the contributing mechanisms within treatment remain unclear. A better understanding of these mechanisms could contribute to improved treatment processes and outcomes. This study aims to examine the relationship between functional health literacy, treatment processes (treatment adherence, learning processes), and treatment outcome (level of psychosocial problems) in adolescents in psychosocial care. We used data from a prospective cohort study among adolescents aged 12-18 (N = 390), collected in four successive measurements: at entry into care, and 3, 12, and 24 months thereafter. We used a mixed effect model to investigate the association between level of functional health literacy (adequate vs. inadequate) and treatment processes (treatment adherence, learning processes) and treatment outcome (level of psychosocial problems). Between adolescents with adequate and inadequate functional health literacy, we found no differences or change over time in adherence or learning processes. The level of psychosocial problems significantly declined over time (ß = - 1.70, 95% CI [- 2.72, - 0.69], p = .001) to a similar degree in both groups, though, in all measurements, the level was consistently higher for adolescents with inadequate health literacy. We conclude that health literacy levels did not affect change in treatment processes nor in outcomes of psychosocial treatment. However, the consistently higher level of psychosocial problems among adolescents with inadequate health literacy suggests an unaddressed need in psychosocial care.

Using models to shape measles control and elimination strategies in low- and middle-income countries: A review of recent applications.

After many decades of vaccination, measles epidemiology varies greatly between and within countries. National immunization programs are therefore encouraged to conduct regular situation analyses and to leverage models to adapt interventions to local needs. Here, we review applications of models to develop locally tailored interventions to support control and elimination efforts. In general, statistical and semi-mechanistic transmission models can be used to synthesize information from vaccination coverage, measles incidence, demographic, and/or serological data, offering a means to estimate the spatial and age-specific distribution of measles susceptibility. These estimates complete the picture provided by vaccination coverage alone, by accounting for natural immunity. Dynamic transmission models can then be used to evaluate the relative impact of candidate interventions for measles control and elimination and the expected future epidemiology. In most countries, models predict substantial numbers of susceptible individuals outside the age range of routine vaccination, which affects outbreak risk and necessitates additional intervention to achieve elimination. More effective use of models to inform both vaccination program planning and evaluation requires the development of training to enhance broader understanding of models and where feasible, building capacity for modelling in-country, pipelines for rapid evaluation of model predictions using surveillance data, and clear protocols for incorporating model results into decision-making.