Comparison of trueness and repeatability of facial prosthesis design using a 3D morphable model approach, traditional computer-aided design methods, and conventional manual sculpting techniques.

STATEMENT OF PROBLEM: Manually sculpting a wax pattern of a facial prosthesis is a time-, skill-, and resource-intensive process. Computer-aided design (CAD) methods have been proposed as a substitute for manual sculpting, but these techniques can still require high technical or artistic abilities. Three-dimensional morphable models (3DMMs) could semi-automate facial prosthesis CAD. Systematic comparisons of different design approaches are needed. PURPOSE: The purpose of this study was to compare the trueness and repeatability of replacing facial features with 3 methods of facial prosthesis design involving 3DMM, traditional CAD, and conventional manual sculpting techniques. MATERIAL AND METHODS: Fifteen participants without facial defects were scanned with a structured light scanner. The facial meshes were manipulated to generate artificial orbital, nasal, or combined defects. Three methods of facial prosthesis design were compared for the 15 participants and repeated to produce 5 of each design for 2 participants. For the 3DMM approach, the Leeds face model informed the designs in a statistically meaningful way. For the traditional CAD methods, designs were created by using mirroring techniques or from a nose model database. For the conventional manual sculpting techniques, wax patterns were manually created on 3D printed full face baseplates. For analysis, the unedited facial feature was the standard. The unsigned distance was calculated from each of the several thousand vertices on the unedited facial feature to the closest point on the external surface of the prosthesis prototype. The mean absolute error was calculated, and a Friedman test was performed (α=.05). RESULTS: The median mean absolute error was 1.13 mm for the 3DMM group, 1.54 mm for the traditional CAD group, and 1.49 mm for the manual sculpting group, with no statistically significant differences among groups (P=.549). Boxplots showed substantial differences in the distribution of mean absolute error among groups, with the 3DMM group showing the greatest consistency. The 3DMM approach produced repeat designs with the lowest coefficient of variation. CONCLUSIONS: The 3DMM approach shows potential as a semi-automated method of CAD. Further clinical research is planned to explore the 3DMM approach in a feasibility trial.

IMproving facial PRosthesis construction with contactlESs Scanning and Digital workflow (IMPRESSeD): study protocol for a feasibility crossover randomised controlled trial of digital versus conventional manufacture of facial prostheses in patients with orbital or nasal facial defects.

BACKGROUND: Facial prostheses can have a profound impact on patients' appearance, function and quality of life. There has been increasing interest in the digital manufacturing of facial prostheses which may offer many benefits to patients and healthcare services compared with conventional manufacturing processes. Most facial prosthesis research has adopted observational study designs with very few randomised controlled trials (RCTs) documented. There is a clear need for a well-designed RCT to compare the clinical and cost-effectiveness of digitally manufactured facial prostheses versus conventionally manufactured facial prostheses. This study protocol describes the planned conduct of a feasibility RCT which aims to address this knowledge gap and determine whether it is feasible to conduct a future definitive RCT. METHODS: The IMPRESSeD study is a multi-centre, 2-arm, crossover, feasibility RCT with early health technology assessment and qualitative research. Up to 30 participants with acquired orbital or nasal defects will be recruited from the Maxillofacial Prosthetic Departments of participating NHS hospitals. All trial participants will receive 2 new facial prostheses manufactured using digital and conventional manufacturing methods. The order of receiving the facial prostheses will be allocated centrally using minimisation. The 2 prostheses will be made in tandem and marked with a colour label to mask the manufacturing method to the participants. Participants will be reviewed 4 weeks following the delivery of the first prosthesis and 4 weeks following the delivery of the second prosthesis. Primary feasibility outcomes include eligibility, recruitment, conversion, and attrition rates. Data will also be collected on patient preference, quality of life and resource use from the healthcare perspective. A qualitative sub-study will evaluate patients' perception, lived experience and preference of the different manufacturing methods. DISCUSSION: There is uncertainty regarding the best method of manufacturing facial prostheses in terms of clinical effectiveness, cost-effectiveness and patient acceptability. There is a need for a well-designed RCT to compare digital and conventional manufacturing of facial prostheses to better inform clinical practice. The feasibility study will evaluate key parameters needed to design a definitive trial and will incorporate early health technology assessment and a qualitative sub-study to identify the potential benefits of further research. TRIAL REGISTRATION: ISRCTN ISRCTN10516986). Prospectively registered on 08 June 2021,  https://www.isrctn.com/ISRCTN10516986 .

Digital database for nasal prosthesis design with a 3D morphable face model approach.

Designing nasal prostheses can be challenging because of the unpaired nature of the facial feature, especially in patients lacking preoperative information. Various nose model databases have been developed as a helpful starting point for the computer-aided design of nasal prostheses, but these do not appear to be readily accessible. Therefore, an open-access digital database of nose models has been generated based on a 3-dimensional (3D) morphable face model approach. This article describes the generation of the database, highlights steps for designing a nasal prosthesis, and points readers to the database for future clinical application and research.

Decision Making About Disease-Modifying Treatments for Relapsing-Remitting Multiple Sclerosis: Stated Preferences and Real-World Choices.

BACKGROUND: People with relapsing-remitting multiple sclerosis can benefit from disease-modifying treatments (DMTs). Several DMTs are available that vary in their efficacy, side-effect profile and mode of administration. OBJECTIVE: We aimed to measure the preferences of people with relapsing-remitting multiple sclerosis for DMTs using a discrete choice experiment and to assess which stated preference attributes correlate with the attributes of the DMTs they take in the real world. METHODS: Discrete choice experiment attributes were developed from literature reviews, interviews and focus groups. In a discrete choice experiment, participants were shown two hypothetical DMTs, then chose whether they preferred one of the DMTs or no treatment. A mixed logit model was estimated from responses and individual-level estimates of participants' preferences conditional on their discrete choice experiment choices calculated. Logit models were estimated with stated preferences predicting current real-world on-treatment status, DMT mode of administration and current DMT. RESULTS: A stated intrinsic preference for taking a DMT was correlated with currently taking a DMT, and stated preferences for mode of administration were correlated with the modes of administration of the DMTs participants were currently taking. Stated preferences for treatment effectiveness and adverse effects were not correlated with real-world behaviour. CONCLUSIONS: There was variation in which discrete choice experiment attributes correlated with participants' real-world DMT choices. This may indicate patient preferences for treatment efficacy/risk are not adequately taken account of in prescribing. Treatment guidelines must ensure they take into consideration patients' preferences and improve communication around treatment efficacy/risk.

Development and evaluation of a novel topically applied sildenafil citrate hydrogel and its influence on wound healing in dogs.

OBJECTIVE: To develop a topical sildenafil hydrogel and evaluate its effect on wound healing in dogs. ANIMALS: 6 purpose-bred, sexually intact, adult Beagles. PROCEDURES: Hydrogels containing sildenafil citrate, N-methyl-2-pyrrolidone, propylene glycol, and poloxamer 407 were developed. Four excision wounds were created along the dorsum of the dogs. Each wound was treated for 21 days with a nonadherent bandage (C) or with a hydrogel containing 0% (G), 5% (5S), or 10% (10S) sildenafil. Daily bandage changes with wound imaging were performed. Biopsy specimens were collected 5 times. RESULTS: Hydrogels were homogenous at room temperature and released > 90% of the sildenafil within 8 hours in vitro. Time to first granulation tissue was significantly shorter for the sildenafil groups (mean ± SD, 2.8 ± 0.8 days [5S and 10S]), compared with the control groups (5.2 ± 0.4 days [C] and 6.3 ± 1.4 days [G]). The G wounds had a 10% to 14% lower contraction rate, compared with the C, 5S, and 10S wounds. 5S wounds had a total wound area 0.7 ± 0.3 cm2 larger than 10S wounds. No significant differences were present when C wounds were compared with 5S and 10S wounds for total wound area, contraction, or epithelialization. Histologic acute inflammatory scores were higher for 5S and 10S wounds in the early and late stages of wound healing, with higher reparative scores on day 7. Neovascularization was higher for 10S wounds on day 7 and 14. CLINICAL RELEVANCE: The topical sildenafil hydrogel promoted early granulation tissue, which may be beneficial for secondary wound closure in clinical settings.

Structure-Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and "branched-tail" oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors' IC50 values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure-activity relationship and computer modeling for the oxyquinoline series of inhibitors led to the identification of novel inhibitors, which were an order of magnitude more active in the reporter assay than roxadustat and vadadustat. Unexpectedly, 2-methyl-substitution in the oxyquinoline core of the best HIF PHD inhibitor was found to be active in the reporter assay and almost equally effective in the pretreatment paradigm of the oxygen-glucose deprivation in vitro model. Comparative transcriptomic analysis of the signaling pathways induced by HIF PHD inhibitors showed high potency of the two novel oxyquinoline inhibitors (#4896-3249 and #5704-0720) at 2 µM concentrations matching the effect of 30 µM roxadustat and 500 µM dimethyl oxalyl glycine in inducing HIF1 and HIF2-linked pathways. The two oxyquinoline inhibitors exerted the same activation of HIF-triggered glycolytic pathways but opposite effects on signaling pathways linked to alternative substrates of HIF PHD 1 and 3, such as p53, NF-κB, and ATF4. This finding can be interpreted as the specificity of the 2-methyl-substitute variant for HIF PHD2.

Phototunable Lignin Plastics to Enable Recyclability.

The accumulation of non-degradable petrochemical plastics imposes a significant threat to the environment and ecosystems. We addressed this challenge by designing a new type of phototunable plastics based on the unique lignin chemistry to enable readily end-life recycling. The advanced material design leveraged the efficient photocatalytic lignin depolymerization by ZnO nanoparticles to build lignin-polymethyl methacrylate (PMMA)-ZnO blends. We first demonstrated the highly effective phototunable lignin depolymerization in the complex polymer blend matrix and explored the molecular mechanisms. The technical barriers of mechanical property and recycling processing were then addressed by a new blend design with lignin core grafted with PMMA polymer. The new process has resulted in a new type of PMMA-g-lignin blend, which significantly improved the mechanical properties, making it comparable to PMMA alone. More importantly, the mechanical properties of the UV-treated blend decreased drastically in the new design, whereas the properties did not reduce in the non-grafted blends upon UV exposure. The results highlighted that the new blend design based on graftization maximized the impact of lignin depolymerization on blend structure and recyclability. Based on the results, we developed a process integrating UV and alkaline treatments to recycle PMMA for plastics and fractionated lignin for bioconversion or other applications in the new phototunable plastics.

Management of penicillin allergy in primary care: a qualitative study with patients and primary care physicians.

BACKGROUND: Six percent of patients are allergic to penicillin according to their medical records. While this designation protects a small number of truly allergic patients from serious reactions, those who are incorrectly labelled may be denied access to recommended first line treatment for many infections. Removal of incorrect penicillin allergy may have positive health consequences for the individual and the general population. We aimed to explore primary care physicians' (PCPs) and patients' views and understanding of penicillin allergy with a focus on clinical management of infections in the face of a penicillin allergy record. METHODS: We conducted an interview study with 31 patients with a penicillin allergy record, and 19 PCPs in the North of England. Data were analysed thematically. RESULTS: Patients made sense of their allergy status by considering the timing and severity of symptoms. Diagnosis of penicillin allergy was reported to be 'imperfect' with PCPs relying on patient reports and incomplete medical records. PCPs and patients often suspected that an allergy record was incorrect, but PCPs were reluctant to change records. PCPs had limited knowledge of allergy services. PCPs often prescribed alternative antibiotics which were easy to identify. Both patients and PCPs differed in the extent to which they were aware of the negative consequences of incorrect penicillin allergy records, their relevance and importance to their lives, and management of penicillin allergy. CONCLUSIONS: PCPs and patients appear insufficiently aware of potential harms associated with incorrect penicillin allergy records. Some of the problems experienced by PCPs could be reduced by ensuring the details of newly diagnosed reactions to antibiotics are clearly documented. In order for PCPs to overturn more incorrect penicillin records through appropriate use of allergy services, more information and training about these services will be needed.

Organizational Barriers to Oral Health Conversations Between Health Visitors and Parents of Children Aged 9-12 Months Old.

Background: Dental caries is the most prevalent preventable childhood disease and a major public health priority. Local authorities in England have a statutory responsibility to improve child health, including oral health, through the "Healthy Child Programme." The "Healthy Child Programme," which includes the provision of oral health advice is delivered by health visitors to parents of young children. To date, research has mainly concentrated on individual interactions between health visitors and parents, with less attention given to the broader context in which these oral health conversations between health visitor and parents take place. Objective: Our study explored the organizational factors that obstruct health visitors from engaging in meaningful conversations with parents about young children's oral health. Methods: Qualitative interviews and focus groups were held with health visiting teams (n = 18) conducting home visits with parents of 9-12-month olds in a deprived, urban area in England. Results: The study revealed the wide variation in what and how oral health advice is delivered to parents at home visits. Several barriers were identified and grouped into four key themes: (1) Priority of topics discussed in the home visits; (2) Finance cuts and limited resources; (3) Oral health knowledge and skills; and (4) Collaborative working with other professionals. It was evident that organizational factors in current public health policy and service provision play an important role in shaping oral health practices and opportunities for behavior change. Conclusion: Organizational practices and procedures play an important role in creating interaction patterns between health visiting teams and parents of young children. They often limit effective engagement with and positive change in oral health. For future oral health interventions to be effective, awareness of these barriers is essential alongside them being founded on evidence-based advice and underpinned by appropriate theory.

Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer's Disease and Type 2 Diabetes.

Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease (CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization. The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding cassette transporter A1 (ABCA1) inducers (NLAIs): screening for ABCA1-luciferase activation in astrocytoma cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of LXRß agonists mediated by ABCA1 include the following: control of cholesterol and phospholipid efflux to lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties. In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery.

Outcome measures in facial prosthesis research: A systematic review.

STATEMENT OF PROBLEM: Facial prosthesis research uses a wide variety of outcome measures, which results in challenges when comparing the effectiveness of interventions among studies. Consensus is lacking regarding the most appropriate and meaningful outcome measures to use in facial prosthesis research to capture important perspectives. PURPOSE: The purpose of the systematic review was to identify and synthesize outcome measures used in facial prosthesis research. MATERIAL AND METHODS: Electronic searches were performed in 11 databases (including nonpeer-reviewed literature). The citations were searched, and expert societies were contacted to identify additional studies. Inclusion criteria comprised studies of participants with facial defects who required or had received prosthetic rehabilitation with an external facial prosthesis. Exclusion criteria comprised participants with ocular prostheses, case reports, case series with fewer than 5 participants, laboratory-based studies, and studies published before 1980. Study selection was performed independently by 2 reviewers. Discrepancies were resolved through discussion or by a third reviewer. Outcome measures were synthesized with a categorization approach based on the perspective, theme, and subtheme of the outcome measures. Quality assessment was performed with an appraisal tool that enabled evaluation of studies with diverse designs. RESULTS: Database searching identified 13 058 records, and 7406 remained after duplications were removed. After initial screening, 189 potentially relevant records remained, and 186 full texts were located (98% retrieval rate). After full-text screening, 124 records were excluded. Citation searches and contact with expert societies identified 4 further records. In total, 69 articles (grouped into 65 studies) were included. Studies were categorized as per the perspective of their outcome measures, with the following findings: patient-reported (74% of studies), clinical indicators (34%), clinician-reported (8%), multiple viewpoints (6%), and independent observer-reported (3%). Patient-reported outcome measures included tools to assess satisfaction, quality of life, and psychologic health. Variability in the choice of outcome measures was evident among the studies, with many self-designed, unvalidated, condition-specific questionnaires reported. A greater number of outcome measure themes emerged over time; themes such as service delivery and health state utility have recently been evaluated. CONCLUSIONS: Over the past 40 years, facial prosthesis research has focused on patient-reported outcome measures. Outcome measures relating to other perspectives have been used less frequently, although new themes appear to be emerging in the literature. Future research should use outcome measures with appropriate measurement properties for use with facial prosthetics.

COPD Comorbidity Profiles and 2-Year Trajectory of Acute and Postacute Care Use.

BACKGROUND: Multiple morbidity is the norm in advanced COPD and contributes to high symptom burden and worse outcomes. RESEARCH QUESTION: Can distinct comorbidity profiles be identified and validated in a community-based sample of patients with COPD from a large integrated health care system using a standard, commonly used diagnostic code-based comorbidity index and downstream 2-year health care use data? STUDY DESIGN AND METHODS: In this retrospective cohort study, we used latent class analysis (LCA) to identify comorbidity profiles in a population-based sample of 91,453 patients with a COPD diagnosis between 2011 and 2015. We included specific comorbid conditions from the Charlson Comorbidity Index (CCI) and accounted for variation in underlying prevalence of different comorbidities across the three study sites. Sociodemographic, clinical, and health-care use data were obtained from electronic health records (EHRs). Multivariate logistic regression analysis was used to compare rates of acute and postacute care use by class. RESULTS: The mean age was 71 ± 11 years, 55% of patients were women, 23% of patients were people of color, and 80% of patients were former or current smokers. LCA identified four distinct comorbidity profiles with progressively higher CCI scores: low morbidity (61%; 1.9 ± 1.4), metabolic renal (21%; 4.7 ± 1.8), cardiovascular (12%; 4.6 ± 1.9), and multimorbidity (7%; 7.5 ± 1.7). In multivariate models, during 2 years of follow-up, a significant, nonoverlapping increase was found in the odds of having any all-cause acute (hospitalizations, observation stays, and ED visits) and postacute care use across the comorbidity profiles. INTERPRETATION: Distinct comorbidity profiles can be identified in patients with COPD using standard EHR-based diagnostic codes, and these profiles are associated with subsequent acute and postacute care use. Population-based risk stratification schemes for end-to-end, comprehensive COPD management should consider integrating comorbidity profiles such as those found in this study.

Patient and Public Involvement Refines the Design of ProtOeus: A Proposed Phase II Trial of Proton Beam Therapy in Oesophageal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy for oesophageal cancer significantly improves overall survival but is associated with severe post-operative complications. Proton beam therapy may reduce these toxicities by sparing normal tissues compared with standard radiotherapy. ProtOeus is a proposed randomised phase II study of neoadjuvant chemoradiotherapy in oesophageal cancer that compares proton beam therapy to standard radiotherapy techniques. As proton beam therapy services are often centralised in academic centres in major cities, proton beam therapy trials raise distinct challenges including patient acceptance of travelling for proton beam therapy, coordination of treatments with local centres and ensuring equity of access for patients. METHODS: Focus groups were held early in the trial development process to establish patients' views on the trial proposal. Topics discussed include perception of proton beam therapy, patient acceptability of the trial pathway and design, patient-facing materials, and common clinical scenarios. Focus groups were led by the investigators and facilitated by patient involvement teams from the institutions who are involved in this research. Responses for each topic were analysed, and fed back to the trial's development group. RESULTS: Three focus groups were held in separate locations in the UK (Manchester, Cardiff, Wigan). Proton beam therapy was perceived as superior to standard radiotherapy making the trial attractive. Patients felt strongly that travel costs should be reimbursed to ensure equity of access to proton beam therapy. They were very supportive of a shorter treatment schedule and felt that toxicity reduction was the most important endpoint. DISCUSSION AND CONCLUSIONS: Incorporating patient views early in the trial development process resulted in significant trial design refinements including travel/accommodation provisions, choice of primary endpoint, randomisation ratio and fractionation schedule. Focus groups are a reproducible and efficient method of incorporating the patient and public voice into research.

Clinical Feasibility and Airway Deposition of Nebulized Voriconazole in Healthy Horses.

Voriconazole (VRC) is a potential treatment for pneumomycosis in horses. The objectives of this study were to determine if the delivery of Vfend using a Flexineb nebulizer produced clinically significant [VRC] in lower airways. The hypothesis was that [VRC] after delivery by nebulization would be greater in the pulmonary epithelial lining fluid than plasma. A secondary objective was to determine [VRC] in upper airways through the collection of nasopharyngeal wash (NPW) samples. Voriconazole solution [Vfend-6.25 mg/mL, 100 (n = 2), 200 (n = 3), 500 (n = 1) mg] was nebulized once in 6 healthy geldings. Clinical responses, duration of nebulization, and [VRC] at various time points (up to 8 hours) in plasma, bronchoalveolar lavage fluid (BALF) supernatant and cell pellet, and NPW samples were recorded. Voriconazole (Vfend-6.25 mg/mL, 200 mg) was nebulized in 5 additional, healthy geldings, and [VRC] was measured in NPW samples pre- and postnebulization at time points up to 8 hours. The antifungal activity of BALF and NPW samples was determined using agar disk diffusion. Concentrations of voriconazole were below detection in plasma, BALF supernatant, and cell pellets for all time points and doses except the BALF cell pellet (0.4 µg/g) immediately after nebulization of 500 mg. For 5 horses, administered 200 mg of Vfend, mean [VCR] in NPW at the end of nebulization and 1, 6, and 8 hours postnebulization were: 30.8 ± 29, 1.0 ± 0.84, 0.2 ± 0.19, and 0.34 ± 0.67 µg/mL, respectively. Only NPW samples obtained immediately postnebulization showed antifungal activity. A nebulized Vfend solution is not recommended for the treatment of pneumomycosis in horses.

VOLCORE, a global database of visible tephra layers sampled by ocean drilling.

The VOLCORE (Volcanic Core Records) database is a collection of 34,696 visible tephra (volcanic ash and lithological or grain size variations) occurrences reported in the initial reports volumes of all of the Deep Sea Drilling Project (DSDP; 1966-1983), the Ocean Drilling Program (ODP; 1983-2003), the Integrated Ocean Drilling Program (IODP; 2003-2013) and the International Ocean Discovery Program (IODP; 2013-present) up to and including IODP Expedition 381. The combined international ocean drilling programmes (OD) have locations with global coverage. Cored tephra layers and tephra-bearing sediments span timescales from recent to ~150 million years in age. This database is a collection of information about reported visible tephra layers entirely or predominantly composed of volcanic ash. Data include the depth below sea floor, tephra thickness, location, and any reported comments. An approximate age was estimated for most (29,493) of the tephra layers using published age-depth models. The database can be used as a starting point for studies of tephrochronology, volcanology, geochemistry, studies of sediment transport and palaeoclimatology.

Cognitive and sensorimotor function in participants being treated for trigeminal neuralgia pain.

BACKGROUND: Trigeminal neuralgia (TN) is an orofacial condition defined by reoccurring, spontaneous, short-lived but excruciating stabbing pain. Pharmacological interventions constitute the first-line treatment for TN, with antiepileptic drugs commonly prescribed. People treated for TN pain with antiepileptic drugs describe cognitive and motor difficulties affecting activities of daily living, and report poorer quality of life. We undertook the first comprehensive objective evaluation of sensorimotor and cognitive performance in participants being treated for TN pain with antiepileptic drugs relative to age-matched controls. METHODS: Participants (43 TN, 41 control) completed a battery of sensorimotor (steering, aiming and tracking) and cognitive (working memory, processing speed, inhibition) tasks. RESULTS: The TN group performed significantly worse than controls on the sensorimotor tracking and aiming tasks and across all cognitive measures. CONCLUSIONS: The data explain why patients treated with antiepileptic drugs report impairment when conducting activities of daily living (given the need for cognitive and motor capability within most of these). The study is an important first step in: (i) ensuring there is adequate information on the impact of pharmacological treatment; (ii) identifying measures to determine optimal medication dosage and track change over time; (iii) creating an evidence base that could allow scientific justification of alternative pain treatment options for TN (e.g. the costs/benefits of surgery).

The Impact of Reproductive Issues on Preferences of Women with Relapsing Multiple Sclerosis for Disease-Modifying Treatments.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is an incurable disease characterised by relapses (periods of function loss) followed by full or partial recovery, and potential permanent disability over time. Many disease-modifying treatments (DMTs) exist that help reduce relapses and slow disease progression. Most are contraindicated during conception/pregnancy and some require a discontinuation period before trying to conceive. Although around three-quarters of people with RRMS are women, there is limited knowledge about how reproductive issues impact DMT preference. OBJECTIVE: The aim of this study was to measure the preferences for DMTs of women with RRMS who are considering pregnancy. DESIGN: An online discrete choice experiment (DCE). METHODS: Participants chose between two hypothetical DMTs characterised by a set of attributes, then indicated if they preferred their choice to no treatment. Attributes were identified from interviews and focus groups with people with RRMS and MS professionals, as well as literature reviews, and included the probability of problems with pregnancy, discontinuation of DMTs, and breastfeeding safety. In each DCE task, participants were asked to imagine making decisions in three scenarios: now; when trying to conceive; and when pregnant. ANALYSIS: Two mixed logit models were estimated, one to assess the statistical significance between scenarios and one in maximum acceptable risk space to allow comparison of the magnitudes of parameters between scenarios. SAMPLE: Women with RRMS who were considering having a child in the future, recruited from a UK MS patient register. RESULTS: Sixty respondents completed the survey. Participants preferred no treatment in 12.6% of choices in the 'now' scenario, rising significantly to 37.6% in the 'trying to conceive' scenario and 60.3% in the 'pregnant' scenario (Kruskal-Wallis p < 0.001). This pattern corresponds with results from models that included a no-treatment alternative-specific constant (ASC) capturing differences between taking and not taking a DMT not specified by the attributes. The ASC was lower in the trying to conceive scenario than in the now scenario, and lower still in the pregnant scenario, indicating an intrinsic preference for no treatment. Participants also placed relatively less preference on reducing relapses and avoiding disease progression in the trying to conceive and pregnant scenarios compared with a lower risk of problems with pregnancy. In the trying to conceive scenario, participants' preference for treatments with shorter washout periods increased. CONCLUSION: Women with RRMS considering having a child prefer DMTs with more favourable reproduction-related attributes, even when not trying to conceive. Reproductive issues also influenced preferences for DMT attributes not directly related to pregnancy, with preferences dependent on the life circumstances in which choices were made. The design of the DCE highlights the benefits of considering the scenario in which participants make choices, as they may change over time.

Pharmacokinetics of multivesicular liposomal encapsulated cytarabine when administered subcutaneously in dogs.

BACKGROUND: Prolonged cytotoxic concentrations of cytarabine (CA) are required for maximum cytotoxicity. DepoCyt is a human liposomal cytarabine (LC) product that lasts longer in plasma and CSF compared with free CA (FC). The use of LC has not been evaluated in dogs. OBJECTIVES: To perform a LC pharmacokinetic (PK) study when administered SC in dogs. ANIMALS: Five healthy female beagles. METHODS: Three-period, 3-treatment, nonblinded, randomized, and crossover design, including a pilot study. LC was administered at 50 mg/m2 SC and FC was administered at 25 and 50 mg/m2 SC and IV. Plasma CA concentrations were measured until 240, 72, and 8 hours after SC LC, SC FC, and IV FC administration, respectively. CA plasma concentrations were quantitated by ultra-high-performance liquid chromatography with mass spectrometry (MS/MS) detection and concentration-time profiles were evaluated by noncompartmental analysis. RESULTS: Subcutaneous LC administration resulted in a maximum plasma concentration of 26.3 to 59.78 ng/mL, time to reach maximum plasma concentration of 2 hours, area under the concentration-time curve to last measurable concentration of 669.3 to 1126 h × ng/mL, and plasma bioavailability (%F) of 19.6% to 31.3%. The PK profiles of FC after SC and IV administration differed when compared with LC. CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy dogs, SC LC administration at 50 mg/m2 results in measurable plasma CA concentrations, is apparently safe and well tolerated, but does not result in prolonged cytotoxic plasma concentrations. Poor absorption of LC prevented establishment of a complete LC PK profile.

Impact of communication on first treatment decisions in people with relapsing-remitting multiple sclerosis.

OBJECTIVE: Disease-Modifying Treatments (DMTs) have contributed to a new clinical landscape for people with relapsing-remitting multiple sclerosis (pwRRMS). A challenge for services is how to support DMT decisions with changing clinical evidence, and differing treatment goals. This article investigates how pwRRMS weigh up the pros and cons of DMTs by examining how communication at the point of diagnosis is related to DMT decisions. METHODS: 30 semi-structured interviews with pwRRMS in England were conducted using a theoretical purposive sampling strategy and analysed using the thematic approach to answer: How does communication about RRMS during diagnosis influence decisions about when and which DMT to choose? RESULTS: Three meta-themes were identified: a) communication context; b) delayed communication and hope for people with "non-active" RRMS at diagnosis; c) people with "active" RRMS at diagnosis: Conflated, generic, selective and simplified information CONCLUSION: At the time of diagnosis, patient-physician interactions are characterised by emotions and information complexity. Clinical, social and psychological DMT filtering mechanisms are activated during first decisions. Personalised evidence is needed to make informed decisions. PRACTICE IMPLICATIONS: Patient decision aids should consider first and consecutive decisions and should not encourage a false sense of large choices that could add to decision anxiety.

Interaction of oxidative stress and neurotrauma in ALDH2-/- mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury.

Oxidative stress induced by lipid peroxidation products (LPP) accompanies aging and has been hypothesized to exacerbate the secondary cascade in traumatic brain injury (TBI). Increased oxidative stress is a contributor to loss of neural reserve that defines the ability to maintain healthy cognitive function despite the accumulation of neuropathology. ALDH2-/- mice are unable to clear aldehyde LPP by mitochondrial aldehyde dehydrogenase-2 (Aldh2) detoxification and provide a model to study mild TBI (mTBI), therapeutic interventions, and underlying mechanisms. The ALDH2-/- mouse model presents with elevated LPP-mediated protein modification, lowered levels of PSD-95, PGC1-α, and SOD-1, and mild cognitive deficits from 4 months of age. LPP scavengers are neuroprotective in vitro and in ALDH2-/- mice restore cognitive performance. A single-hit, closed skull mTBI failed to elicit significant effects in WT mice; however, ALDH2-/- mice showed a significant inflammatory cytokine surge in the ipsilateral hemisphere 24 h post-mTBI, and increased GFAP cleavage, a biomarker for TBI. Known neuroprotective agents, were able to reverse the effects of mTBI. This new preclinical model of mTBI, incorporating significant perturbations in behavior, inflammation, and clinically relevant biomarkers, allows mechanistic study of the interaction of LPP and neurotrauma in loss of neural reserve.