Salivary testing for SARS-CoV-2 in the pediatric population: a diagnostic accuracy study.

BACKGROUND: Accurate and timely testing for SARS-CoV-2 in the pediatric population is crucial to control the COVID-19 pandemic; saliva testing has been proposed as a less invasive alternative to nasopharyngeal swabs. We sought to compare the detection of SARS-CoV-2 using saliva versus nasopharyngeal swab in the pediatric population, and to determine the optimum time of testing for SARS-CoV-2 using saliva. METHODS: We conducted a longitudinal diagnostic study in Ottawa, Canada, from Jan. 19 to Mar. 26, 2021. Children aged 3-17 years were eligible if they exhibited symptoms of COVID-19, had been identified as a high-risk or close contact to someone confirmed positive for SARS-CoV-2 or had travelled outside Canada in the previous 14 days. Participants provided both nasopharyngeal swab and saliva samples. Saliva was collected using a self-collection kit (DNA Genotek, OM-505) or a sponge-based kit (DNA Genotek, ORE-100) if they could not provide a saliva sample into a tube. RESULTS: Among 1580 paired nasopharyngeal and saliva tests, 60 paired samples were positive for SARS-CoV-2. Forty-four (73.3%) were concordant-positive results and 16 (26.6%) were discordant, among which 8 were positive only on nasopharyngeal swab and 8 were positive only on saliva testing. The sensitivity of saliva was 84.6% (95% confidence interval 71.9%-93.1%). INTERPRETATION: Salivary testing for SARS-CoV-2 in the pediatric population is less invasive and shows similar detection of SARS-CoV-2 to nasopharyngeal swabs. It may therefore provide a feasible alternative for diagnosis of SARS-CoV-2 infection in children.

IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs.

CD4+CD25+Foxp3+ Tregs are known to acquire tissue-specific features and exert cytoprotective and regenerative functions. The extent to which this applies to liver-resident Tregs is unknown. In this study, we aimed to explore the phenotypic and functional characteristics of adult murine liver resident Tregs during homeostasis. Additionally, we investigated their role in ameliorating liver inflammation and tissue damage. Quantification of Foxp3+CD4+CD25+ cells comparing different tissues showed that the liver contained significantly fewer resident Tregs. A combination of flow cytometry phenotyping and microarray analysis of intra-hepatic and splenic Tregs under homeostatic conditions revealed that, although intra-hepatic Tregs exhibited the core transcriptional Treg signature, they expressed a distinct transcriptional profile. This was characterized by reduced CD25 expression and increased levels of pro-inflammatory Th1 transcripts Il1b and Ifng. In vivo ablation of Tregs in the Foxp3-DTR mouse model showed that Tregs had a role in reducing the magnitude of systemic and intra-hepatic inflammatory responses following acute carbon tetrachloride (CCl4) injury, but their absence did not impact the development of hepatocyte necrosis. Conversely, the specific expansion of Tregs by administration of IL-2 complexes increased the number of intra-hepatic Tregs and significantly ameliorated tissue damage following CCl4 administration in C57BL/6 mice. The cytoprotective effect observed in response to IL-2c was associated with the increased expression of markers known to regulate Treg suppressive function. Our results offer insight into the transcriptome and complex immune network of intra-hepatic Tregs and suggest that strategies capable of selectively increasing the pool of intra-hepatic Tregs could constitute effective therapies in inflammatory liver diseases.

Postoperative Symptom Burden in Patients Undergoing Lung Cancer Surgery.

CONTEXT: Previous studies on quality of life (QOL) after lung cancer surgery have identified a long duration of symptoms postoperatively. We first performed a systematic review of QOL in patients undergoing surgery for lung cancer. A subgroup analysis was conducted focusing on symptom burden and its relationship with QOL. OBJECTIVE: To perform a qualitative review of articles addressing symptom burden in patients undergoing surgical resection for lung cancer. METHODS: The parent systematic review utilized search terms for symptoms, functional status, and well-being as well as instruments commonly used to evaluate global QOL and symptom experiences after lung cancer surgery. The articles examining symptom burden (n = 54) were analyzed through thematic analysis of their findings and graded according to the Oxford Centre for Evidence-based Medicine rating scale. RESULTS: The publication rate of studies assessing symptom burden in patients undergoing surgery for lung cancer have increased over time. The level of evidence quality was 2 or 3 for 14 articles (cohort study or case control) and level of 4 in the remaining 40 articles (case series). The most common QOL instruments used were the Short Form 36 and 12, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, and the Hospital Anxiety and Depression Score. Thematic analysis revealed several key findings: 1) lung cancer surgery patients have a high symptom burden both before and after surgery; 2) pain, dyspnea, cough, fatigue, depression, and anxiety are the most commonly studied symptoms; 3) the presence of symptoms prior to surgery is an important risk factor for higher acuity of symptoms and persistence after surgery; and 4) symptom burden is a predictor of postoperative QOL. CONCLUSION: Lung cancer patients undergoing surgery carry a high symptom burden which impacts their QOL. Measurement approaches use myriad and heterogenous instruments. More research is needed to standardize symptom burden measurement and management, with the goal to improve patient experience and overall outcomes.

Practice does not make perfect: Juvenile object play does not improve the predation skills of adult mink in "simulated prey" tests.

In carnivores, juvenile object play is hypothesized to improve the development of adult predation ability. We tested this hypothesis in a model carnivore, the American mink (Neovison vison). Play was induced via the provision of diverse "enrichment" objects to 32 litters from 4 to 15 weeks of age on a rotating schedule; control mink (32 litters) were instead provided with one static object. Behavioral observations confirmed that enriched juveniles engaged in more object play than control juveniles (p < .01). Tenacity, strength, and chasing motivations were assessed in 52 mink at 27-29 weeks of age using five "simulated prey" tests. These tests showed internal consistency, with measures from the same test being weakly to very strongly correlated (r or ρ: |.33-.95|). Across tests assessing similar skills, some measures of tenacity and strength were also moderately correlated. Treatment had little effect, however, other than on maximum force during vertical pulling, in which control mink unexpectedly scored higher (1.01 ± 0.06 kg vs. 0.84 ± 0.06 kg, p = .0458). Although we did not find evidence to support the hypothesis that object play leads to improved predatory skills, the tests developed have the potential to be used in humane, prey-free future investigations of predation abilities.

Household transmission of SARS-CoV-2 from unvaccinated asymptomatic and symptomatic household members with confirmed SARS-CoV-2 infection: an antibody-surveillance study.

BACKGROUND: Household transmission contributes to SARS-CoV-2 spread, but the role of children in transmission is unclear. We conducted a study that included symptomatic and asymptomatic children and adults exposed to SARS-CoV-2 in their households with the objective of determining how SARS-CoV-2 is transmitted within households. METHODS: In this case-ascertained antibody-surveillance study, we enrolled households in Ottawa, Ontario, in which at least 1 household member had tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction testing. The enrolment period was September 2020 to March 2021. Potentially eligible participants were identified if they had tested positive for SARS-CoV-2 at an academic emergency department or affiliated testing centre; people who learned about the study through the media could also self-identify for participation. At least 2 participants were required for a household to be eligible for study participation, and at least 1 enrolled participant per household had to be a child (age < 18 yr). Enzyme-linked immunosorbent assays were used to evaluate SARS-CoV-2-specific IgA, IgM and IgG against the spike-trimer and nucleocapsid protein. The primary outcome was household secondary attack rate, defined as the proportion of household contacts positive for SARS-CoV-2 antibody among the total number of household contacts participating in the study. We performed descriptive statistics at both the individual and household levels. To estimate and compare outcomes between patient subgroups, and to examine predictors of household transmission, we fitted a series of multivariable logistic regression with robust standard errors to account for clustering of individuals within households. RESULTS: We enrolled 695 participants from 180 households: 180 index participants (74 children, 106 adults) and 515 of their household contacts (266 children, 249 adults). A total of 487 household contacts (94.6%) (246 children, 241 adults) had SARS-CoV-2 antibody testing, of whom 239 had a positive result (secondary attack rate 49.1%, 95% confidence interval [CI] 42.9%-55.3%). Eighty-eight (36.8%, 95% CI 29.3%-43.2%) of the 239 were asymptomatic; asymptomatic rates were similar for children (51/130 [39.2%, 95% CI 30.7%-48.5%]) and adults (37/115 [32.2%, 95% CI 24.2%-41.4%]) (odds ratio [OR] 1.3, 95% CI 0.8-2.1). Adults were more likely than children to transmit SARS-CoV-2 (OR 2.2, 95% CI 1.3-3.6). The odds of transmission from asymptomatic (OR 0.6, 95% CI 0.2-1.4) versus symptomatic (OR 0.9, 95% CI 0.6-1.4) index participants to household contacts was uncertain. Predictors of household transmission included household density (number of people per bedroom), relationship to index participant and number of cases in the household. INTERPRETATION: The rate of SARS-CoV-2 transmission within households was nearly 50% during the study period, and children were an important source of spread. The findings suggest that children are an important driver of the COVID-19 pandemic; this should inform public health policy.

In pursuit of a better broiler: a comparison of the inactivity, behavior, and enrichment use of fast- and slower growing broiler chickens.

Selection for rapid growth has produced heavier, more efficient broiler chickens, but has also introduced health and welfare issues, which may cause or be caused by inactivity. Rapid growth may also limit the performance of motivated behaviors, whereas the provision of enrichment may increase these behaviors and general activity. This study aimed to evaluate the inactivity, behavior patterns, and enrichment use of 2 fast- (CONV) and 12 slower growing broiler strains (categorized as fastest [FAST], moderate [MOD], and slowest slow [SLOW]), based on their growth rates; 4 strains/category]. To evaluate inactivity, one male and one female from 153 pens were outfitted with omni-directional accelerometers from d 21 until processing (14-24 birds/strain from 8 to 12 pens/strain). Additionally, to supplement inactivity data, 5-min continuous behavioral observations of four focal birds per pen (2 males, 2 females) were conducted on days 26, 42, and 56 (72-148 observations of 8-12 pens/strain) to quantify the duration and frequency of various behaviors; at the same time, 5 to 11 instantaneous scan samples were also performed for pen-based enrichment use. Inactivity peaked at 78 to 80% of the day for all strains; however, those with slower growth rates reached these levels at older ages. Compared to slower growing strains at the same age, faster growing strains were more inactive, spent more time sitting and feeding, spent less time standing and walking, and used enrichments less; these differences mostly occurred at younger ages. Generally, at the same age, strains with similar growth rates (within the same category) behaved similarly, with only a few exceptions. Results suggest that not all strains identified as "slow-growing" broilers behave differently from fast-growing broilers, nor do they all behave similarly to each other. As such, results suggest that improved broiler welfare, particularly with respect to reduced inactivity, the performance of a wider range of normal, motivated behaviors, and/or increased enrichment use, is related to the broiler strain's specific growth rate.

The Prevalence of Benign Pathology Following Major Pulmonary Resection for Suspected Malignancy.

BACKGROUND: In the era of lung cancer screening with low-dose computed tomography, there is concern that high false-positive rates may lead to an increase in nontherapeutic lung resection. The aim of this study is to determine the current rate of major pulmonary resection for ultimately benign pathology. MATERIALS AND METHODS: A single-institution, retrospective analysis of all patients > 18 y who underwent major pulmonary resection between 2013 and 2018 for suspected malignancy and had benign final pathology was performed. RESULTS: Of 394 major pulmonary resections performed for known or presumed malignancy, 10 (2.5%) were benign. Of these 10, the mean age was 61.1 y (SD 14.6). Most were current or former smokers (60%). Ninety percent underwent a fluorodeoxyglucose positron emission tomography scan. Median nodule size was 27 mm (IQR 21-35) and most were in the right middle lobe (50%). Preoperative biopsy was performed in four (40%) but were nondiagnostic. Video-assisted thoracoscopic lobectomy (70%) was the most common surgical approach. Final pathology revealed three (30%) infectious, three (30%) inflammatory, two (20%) fibrotic, and two (20%) benign neoplastic nodules. Two (20%) patients had perioperative complications, both of which were prolonged air leaks, one (10%) patient was readmitted within 30 d, and there was no mortality. CONCLUSIONS: A small percentage of patients (2.5% in our series) may undergo major pulmonary resection for unexpectedly benign pathology. Knowledge of this rate is useful to inform shared decision-making models between surgeons and patients and evaluation of thoracic surgery program performance.

In pursuit of a better broiler: growth, efficiency, and mortality of 16 strains of broiler chickens.

To meet the growing consumer demand for chicken meat, the poultry industry has selected broiler chickens for increasing efficiency and breast yield. While this high productivity means affordable and consistent product, it has come at a cost to broiler welfare. There has been increasing advocacy and consumer pressure on primary breeders, producers, processors, and retailers to improve the welfare of the billions of chickens processed annually. Several small-scale studies have reported better welfare outcomes for slower-growing strains compared to fast-growing, conventional strains. However, these studies often housed birds with range access or used strains with vastly different growth rates. Additionally, there may be traits other than growth, such as body conformation, that influence welfare. As the global poultry industries consider the implications of using slower growing strains, there was a need for a comprehensive, multidisciplinary examination of broiler chickens with a wide range of genotypes differing in growth rate and other phenotypic traits. To meet this need, our team designed a study to benchmark data on conventional and slower-growing strains of broiler chickens reared in standardized laboratory conditions. Over a 2-year period, we studied 7,528 broilers from 16 different genetic strains. In this paper, we compare the growth, efficiency, and mortality of broilers to one of two target weights (TW): 2.1 kg (TW1) and 3.2 kg (TW2). We categorized strains by their growth rate to TW2 as conventional (CONV), fastest-slow strains (FAST), moderate-slow strains (MOD), and slowest-slow strains (SLOW). When incubated, hatched, housed, managed, and fed the same, the categories of strains differed in body weights, growth rates, feed intake, and feed efficiency. At 48 d of age, strains in the CONV category were 835 to 1,264 g heavier than strains in the other categories. By TW2, differences in body weights and feed intake resulted in a 22 to 43-point difference in feed conversion ratios. Categories of strains did not differ in their overall mortality rates.

Characterization of the Ovine Vaginal Microbiome and Inflammation Patterns as an Improved Testing Model of Human Vaginal Irritation.

The development of therapies targeted to improve the health of women has utilized direct vaginal delivery as a more effective and less toxic method of protection from HIV and other pathogens. Vaginal applicants and delivery devices that provide sustained effects have been met with increasing acceptability, but the efficacy and toxicity outcomes have not been successfully predicted by preclinical in vitro studies and animal modeling. We have explored the utilization of sheep as a model for testing the safety of vaginal applicants and devices based on spatial and structural similarities to the human vagina. As recently noted by the FDA, an additional safety measure is an impact on the vaginal microbiome (VMB) that is known to contribute to vaginal health and influence pathogen susceptibility and drug metabolism. To advance the utility of the sheep vaginal model, we completed a thorough molecular characterization of the ovine VMB utilizing both next-generation sequencing (NGS) and PCR methods. The process also created a custom PCR array to quantify ovine VMB community profiles in an affordable, higher throughput fashion. The results from vaginal swabs (>475 samples) collected from non-pregnant crossbred Dorset and Merino ewes treated with selected vaginal applicants or collected as sham samples established 16 VMB community types (VMB CTs). To associate VMB CTs with eubiosis or dysbiosis, we also completed custom ELISAs for six cytokines identifying IL1B, IL8, TNFa, and CXCL10 as useful markers to support the characterization of ovine vaginal inflammation. The results indicated that Pasteurella, Actinobacillus, Pseudomonas, Bacteroides, Leptotrichia, and E. coli were common markers of eubiosis (low inflammatory marker expression), and that Haemophilus, Ureaplasma, and Corynebacterium were associated with dysbiosis (high cytokine levels). Utilizing the optimized workflow, we also confirmed the utility of three commonly used vaginal applicants for impact on the VMB and inflammatory state, producing a dataset that supports the recommendation for the use of sheep for testing of vaginal applicants and devices as part of preclinical pipelines.

Development of Gram Stain Scoring System Based on Pro-Inflammatory Cytokines in the Sheep Model for Testing Toxicity of Vaginal Products.

Background: Development of safe, effective products to prevent the sexual transmission of HIV remains a priority. Prior to clinical testing, the products must undergo strict safety evaluations to avoid mucosal drug toxicity, inflammation, and vaginal microbiome (VMB) shifts. Based on the Food and Drug Administration (FDA) guidance, we designed a study to measure the inflammatory markers and VMB changes after intravaginal treatment with products that have been associated with toxicity, with the objective to develop a Gram stain slide scoring system, similar to Nugent scoring, correlated with the proinflammatory cytokines in sheep. Methods: Non-pregnant Dorset ewes (n = 34) were randomized to receive 5 ml intravaginal 4% nonoxynol-9 (N9) contraceptive gel, positive control (0.2% benzalkonium chloride), placebo control [hydroxethyl cellulose (HEC)], or no application daily for 10 days, with 11-day post-treatment follow-up. The vaginal swabs were collected for the cytokines, VMB, and Gram-stained slides. An enzyme-linked immunosorbent assay (ELISA) analysis of cytokines interleukin (IL)-1ß, IL-8, CXCL10, and tumor necrosis factor-α (TNF-α) was used to determine inflammatory state of the sample. Vaginal microbiome community types (CT) were utilized to create five equivalent slide subsets for iterative development of a Gram-stained slide scoring system with comparisons with inflammatory state based on the cytokine levels. Results: Digital images of the Gram-stained slides were scored based on Gram staining and morphology of bacteria, presence of sheep epithelial cells, and immune cells. The scoring system was modified in an iterative fashion with weighting based on cytokine categorization of inflamed samples, with three of four cytokine values above the mean indicating that the sample was inflamed. The parameters in the final version of the scoring system included mature epithelial cells, Gram-negative rods, and Gram-positive diplococci indicating normal and immune cells indicating inflammation. The area under the receiver operator characteristic curve (ROC AUC) was 0.725 (ROC AUCs range between 0.5 and 1.0) with a greater area indicating higher diagnostic ability of a test with a binary outcome: inflamed or normal. Conclusion: The scoring system, derived from the advanced VMB and cytokine analyses, provides a validated, practical method for quantification of Gram-stained slides that can be performed in most laboratories, increasing the potential for standardization. The training plan can assist laboratories to determine the safety of intravaginal products in their sheep studies or the methodological approach can be applied to other animal models where such data are also needed.

Development of a test method for adult ice hockey helmet evaluation.

Ice hockey helmet standards have primarily been developed to reduce risk of traumatic brain injury (TBI). While severe TBI has become a rare event in ice hockey, concussion, a type of mild TBI, remains a common head injury. Concussions, in ice hockey result from a number of head impact events including, collisions, stick impacts, puck impacts, falls into the boards, impacts to the glass, and falls to the ice. Helmet testing methods need to represent the impact events creating concussions in ice hockey. The purpose of this research was to develop a helmet test protocol and performance metric for concussive impacts in ice hockey. A protocol using concussion impact parameters from published literature was created that used monorail and linear impactors to impact a helmeted Hybrid III headform. The linear and rotational acceleration time curves were then used to calculate brain tissue strain using the University College Brain Trauma Model. The proposed test protocols created kinematic responses that were representative of levels associated with concussion in ice hockey. Rotational velocity and rotational acceleration were both identified as useful performance metrics representing levels of risk for concussion.

Biomechanical Comparison of Real World Concussive Impacts in Children, Adolescents, and Adults.

Accidental falls occur to people of all ages, with some resulting in concussive injury. At present, it is unknown whether children and adolescents are at a comparable risk of sustaining a concussion compared to adults. This study reconstructed the impact kinematics of concussive falls for children, adolescents, and adults and simulated the associated brain tissue deformations. Patients included in this study were diagnosed with a concussion as defined by the Zurich Consensus guidelines. Eleven child, 10 adolescent, and 11 adult falls were simulated using mathematical dynamic models(MADYMO), with three ellipsoid pedestrian models sized to each age group. Laboratory impact reconstruction was conducted using Hybrid III head forms, with finite element model simulations of the brain tissue response using recorded impact kinematics from the reconstructions. The results of the child group showed lower responses than the adolescent group for impact variables of impact velocity, peak linear acceleration, and peak rotational acceleration but no statistical differences existed for any other groups. Finite element model simulations showed the child group to have lower strain values than both the adolescent and adult groups. There were no statistical differences between the adolescent and adult groups for any variables examined in this study. With the cases included in this study, young children sustained concussive injuries at lower modeled brain strains than adolescents and adults, supporting the theory that children may be more susceptible to concussive impacts than adolescents or adults.

Evaluation of a simulation-based Risk Management and Communication Masterclass to reduce the risk of complaints, medicolegal and dentolegal claims.

Objectives: To understand clinicians' experiences, learning and professional impacts following participation in a Risk Management and Communication Masterclass (RMCM) designed and delivered by Medical Protection Society. To identify the course's strengths and areas for enhancement. Design: Mixed method study including semistructured telephone interviews. Interviews were conducted between October and December 2017, 6-30 months after course participation. Data were subjected to a thematic analysis. Quantitative analysis of participants' feedback ratings (n=486) on RMCMs delivered between December 2014 and May 2017 was also undertaken. Setting: RMCMs were delivered to Doctors and Dentists based in the UK and Ireland and South Africa. Participants: A sample of 12 volunteer doctors (Obstetricians/Gynaecologists, Orthopaedic/Spinal Surgeons, General Surgeons, Paediatricians, General Practitioners) and dentists chosen to represent different clinical specialities accepted the invitation to participate. Results: Study participants reported examples of person-centred communication skills such as empathy, shared-decision making and managing patient expectations in their workplaces following participation in the RMCM. Many clinicians gave examples describing how they used the communication models they learned when back at work. They also demonstrated a better understanding of the motivations for patients to complain or claim. RMCM course participants' high feedback ratings provided further evidence that the course was valuable and met learning objectives. Conclusions: It may prove difficult to demonstrate quantitatively that liability improves as a direct result of risk management and communications training. Our results on other dimensions (reactions, learning, behaviour change and impact) suggest that the RMCM has a positive and durable effect based on participant feedback.

A Statewide Curriculum Model for Teaching Simulation Education Leaders.

BACKGROUND: The Maryland Clinical Simulation Resource Consortium (MCSRC) was funded to increase the quality and quantity of simulation used in nursing education. PROBLEM: Schools of nursing are substituting simulation for clinical experience without requisite knowledge of simulation pedagogy. APPROACH: The MCSRC developed a statewide curriculum model for a 3-day train-the-trainer program framed in theory and grounded in evidence. The program teaches nurse educators across 3 levels: novice, competent, and expert. OUTCOMES: The evaluation plan was developed using Kirkpatrick's 4 levels to measure outcomes of the program. Self-confidence, satisfaction, knowledge, and behavioral changes have been realized. Nurse educators are now using theory, standards, and guidelines when conducting simulation-based experiences. CONCLUSIONS: The curriculum model has proved effective in increasing the quality and quantity of simulation used in educating Maryland's nurses. To date, 154 nurse educators have participated in the train-the-trainer program.

The influence of impact source on variables associated with strain for impacts in ice hockey.

Concussion can occur from a variety of events (falls to ice, collisions etc) in ice hockey, and as a result it is important to identify how these different impact sources affect the relationship between impact kinematics and strain that has been found to be associated to this injury. The purpose of this research was to examine the relationship between kinematic variables and strain in the brain for impact sources that led to concussion in ice hockey. Video of professional ice hockey games was analyzed for impacts that resulted in reported clinically diagnosed concussions. The impacts were reconstructed using physical models/ATDs to determine the impact kinematics and then simulated using finite element modelling to determine maximum principal strain and cumulative strain damage measure. A stepwise linear regression was conducted between linear acceleration, change in linear velocity, rotational acceleration, rotational velocity, and strain response in the brain. The results for the entire dataset was that rotational acceleration had the highest r2 value for MPS (r2 = 0.581) and change in rotational velocity for cumulative strain damage measure (r2 = 450). When the impact source (shoulder, elbow, boards, or ice impacts) was isolated the rotational velocity and acceleration r2 value increased, indicating that when evaluating the relationships between kinematics and strain based metrics the characteristics of the impact is an important factor. These results suggest that rotational measures should be included in future standard methods and helmet innovation and design in ice hockey as they have the highest association with strain in the brain tissues.

The biomechanics of concussion for ice hockey head impact events.

The purpose of this research was to conduct reconstructions of concussive and non-concussive impacts in ice hockey to determine the biomechanics and thresholds of concussive injury in ice hockey. Videos of concussive and non-concussive impacts in an elite professional ice hockey league in North America were reconstructed using physical and finite element model methods. Eighty concussive and 45 non-concussive events were studied. Logistic regressions indicate significant thresholds for concussion for linear/rotational acceleration and CSDM10%. Impacts in ice hockey were mostly long duration events, longer than 15 ms. These results have significant implications for helmet standards and development to prevent concussion.

Safety and pharmacokinetics of single, dual, and triple antiretroviral drug formulations delivered by pod-intravaginal rings designed for HIV-1 prevention: A Phase I trial.

BACKGROUND: Intravaginal rings (IVRs) for HIV pre-exposure prophylaxis (PrEP) theoretically overcome some adherence concerns associated with frequent dosing that can occur with oral or vaginal film/gel regimens. An innovative pod-IVR, composed of an elastomer scaffold that can hold up to 10 polymer-coated drug cores (or "pods"), is distinct from other IVR designs as drug release from each pod can be controlled independently. A pod-IVR has been developed for the delivery of tenofovir (TFV) disoproxil fumarate (TDF) in combination with emtricitabine (FTC), as daily oral TDF-FTC is the only Food and Drug Administration (FDA)-approved regimen for HIV PrEP. A triple combination IVR building on this platform and delivering TDF-FTC along with the antiretroviral (ARV) agent maraviroc (MVC) also is under development. METHODOLOGY AND FINDINGS: This pilot Phase I trial conducted between June 23, 2015, and July 15, 2016, evaluated the safety, pharmacokinetics (PKs), and acceptability of pod-IVRs delivering 3 different ARV regimens: 1) TDF only, 2) TDF-FTC, and 3) TDF-FTC-MVC over 7 d. The crossover, open-label portion of the trial (N = 6) consisted of 7 d of continuous TDF pod-IVR use, a wash-out phase, and 7 d of continuous TDF-FTC pod-IVR use. After a 3-mo pause to evaluate safety and PK of the TDF and TDF-FTC pod-IVRs, TDF-FTC-MVC pod-IVRs (N = 6) were evaluated over 7 d of continuous use. Safety was assessed by adverse events (AEs), colposcopy, and culture-independent analysis of the vaginal microbiome (VMB). Drug and drug metabolite concentrations in plasma, cervicovaginal fluids (CVFs), cervicovaginal lavages (CVLs), and vaginal tissue (VT) biopsies were determined via liquid chromatographic-tandem mass spectrometry (LC-MS/MS). Perceptibility and acceptability were assessed by surveys and interviews. Median participant age was as follows: TDF/TDF-FTC group, 26 y (range 24-35 y), 2 White, 2 Hispanic, and 2 African American; TDF-FTC-MVC group, 24.5 y (range 21-41 y), 3 White, 1 Hispanic, and 2 African American. Reported acceptability was high for all 3 products, and pod-IVR use was confirmed by residual drug levels in used IVRs. There were no serious adverse events (SAEs) during the study. There were 26 AEs reported during TDF/TDF-FTC IVR use (itching, discharge, discomfort), with no differences between TDF alone or in combination with FTC observed. In the TDF-FTC-MVC IVR group, there were 12 AEs (itching, discharge, discomfort) during IVR use regardless of attribution to study product. No epithelial disruption/thinning was seen by colposcopy, and no systematic VMB shifts were observed. Median (IQR) tenofovir diphosphate (TFV-DP) tissue concentrations of 303 (277-938) fmol/10(6) cells (TDF), 289 (110-603) fmol/10(6) cells (TDF-FTC), and 302 (177.1-823.8) fmol/10(6) cells (TDF-FTC-MVC) were sustained for 7 d, exceeding theoretical target concentrations for vaginal HIV prevention. The study's main limitations include the small sample size, short duration (7 d versus 28 d), and the lack of FTC triphosphate measurements in VT biopsies. CONCLUSIONS: An innovative pod-IVR delivery device with 3 different formulations delivering different regimens of ARV drugs vaginally appeared to be safe and acceptable and provided drug concentrations in CVFs and tissues exceeding concentrations achieved by highly protective oral dosing, suggesting that efficacy for vaginal HIV PrEP is achievable. These results show that an alternate, more adherence-independent, longer-acting prevention device based on the only FDA-approved PrEP combination regimen can be advanced to safety and efficacy testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT02431273.

Phase I trial of pod-intravaginal rings delivering antiretroviral agents for HIV-1 prevention: Rectal drug exposure from vaginal dosing with tenofovir disoproxil fumarate, emtricitabine, and maraviroc.

BACKGROUND: Intravaginal rings (IVRs) can deliver antiretroviral (ARV) agents for HIV pre-exposure prophylaxis (PrEP), theoretically overcoming adherence concerns associated with frequent dosing. However, topical vaginal ARV drug delivery has not simultaneously led to sufficient rectal drug exposure to likely protect from HIV infection as a result of receptive anal intercourse (RAI). Unprotected RAI has a higher risk of infection per sex act and, for women, also can be associated with vaginal exposure during a single sexual encounter, especially in higher-risk subsets of women. The physiologically inflamed, activated, immune-cell dense colorectal mucosa is increasingly appreciated as the sexual compartment with highly significant risk; this risk is increased in the setting of co-infections. Ex vivo studies have shown that colorectal tissue and rectal fluid concentrations correlated with HIV protection. Given these important results, efforts to document colorectal compartment ARV drug concentration from pod-IVR delivery was assessed to determine if vaginal application could provide protective ARV levels in both compartments. METHODOLOGY/PRINCIPAL FINDINGS: A crossover clinical trial (N = 6) evaluated 7 d of continuous TDF pod-IVR use, a wash-out phase, followed by 7 d with a TDF-FTC pod-IVR. A subsequent clinical trial (N = 6) consisted of 7 d of continuous TDF-FTC-MVC pod-IVR use. Rectal fluids were collected on Day 7 at IVR removal in all three ARV-exposures (two Phase 1 trials) and drug concentrations quantified by LC-MS/MS. Median rectal fluid concentrations of TFV, the hydrolysis product of the prodrug TDF, were between 0.66 ng mg-1 (TDF pod-IVR group) and 1.11 ng mg-1 (TDF-FTC pod-IVR group), but below the analytical lower limit of quantitation in 5/6 samples in the TDF-FTC-MVC pod-IVR group. Unexpectedly, median FTC (TDF-FTC pod-IVR, 20.3 ng mg-1; TDF-FTC-MVC pod-IVR, 0.18 ng mg-1), and MVC rectal fluid concentrations (0.84 ng mg-1) were quantifiable and higher than their respective in vitro EC50 values in most samples. Due to participant burden in these exploratory trials, rectal fluid was used as a surrogate for rectal tissue, where drug concentrations are expected to be higher. CONCLUSIONS/SIGNIFICANCE: The concentrations of FTC and MVC in rectal fluids obtained in two exploratory clinical trials of IVRs delivering ARV combinations exceeded levels associated with in vitro efficacy in HIV inhibition. Unexpectedly, MVC appeared to depress the distribution of TFV and FTC into the rectal lumen. Here we show that vaginal delivery of ARV combinations may provide adherence and coitally independent dual-compartment protection from HIV infection during both vaginal and receptive anal intercourse.

User evaluations offer promise for pod-intravaginal ring as a drug delivery platform: A mixed methods study of acceptability and use experiences.

BACKGROUND: Effective HIV prevention requires efficient delivery of safe and efficacious drugs and optimization of user adherence. The user's experiences with the drug, delivery system, and use parameters are critical to product acceptability and adherence. Prevention product developers have the opportunity to directly control a drug delivery system and its impact on acceptability and adherence, as well as product efficacy. Involvement of potential users during preclinical design and development can facilitate this process. We embedded a mixed methods user evaluation study into a safety and pharmacokinetics (PK) trial of a pod-intravaginal ring delivering antiretroviral agents. METHODOLOGY: Women enrolled in two cohorts, ultimately evaluating the safety/PK of a pod-IVRs delivering TDF-alone, TDF-FTC, and/or TDF-FTC-MVC. A 7-day use period was targeted for each pod-IVR, regardless of drug or drug combination. During the clinical study, participants provided both quantitative (i.e., survey) and qualitative (i.e., in-depth interview) data capturing acceptability, perceptibility, and adherence behaviors. Initial sexual and reproductive health history surveys, daily diaries, a final acceptability and willingness to use survey, and a qualitative in-depth interview comprised the user evaluation data for each pod-IVR experienced by the participants. FINDINGS: Overall, the majority of participants (N = 10) reported being willing to use the pod-IVR platform for HIV prevention should it advance to market. Confidence to use the pod-IVR (e.g., insertion, removal) was high. There were no differences noted in the user experience of the pod-IVR platform; that is, whether the ring delivered TDF-alone, TDF-FTC, or TDF-FTC-MVC, users' experiences of the ring were similar and acceptable. Participants did report specific experiences, both sensory and behavioral, that impacted their use behaviors with respect to the ring, and which could ultimately impact acceptability and adherence. These experiences, and user evaluations elicited by them, could both challenge use or be used to leverage use in future trials and product rollout once fully articulated. CONCLUSIONS: High willingness-to-use data and lack of salient differences in user experiences related to use of the pod-IVR platform (regardless of agents delivered) suggests that the pod-IVR is a feasible and acceptable drug delivery device in and of itself. This finding holds promise both for an anti-HIV pod-IVR and, potentially, a multipurpose prevention pod-IVR that could deliver both prevention for sexually transmitted infections (STIs) including HIV and contraception. Given the very early clinical trial context, further acceptability, perceptibility, and adherence data should continue to be explored, in the context of longer use periods (e.g., 28-day ring use), and in the contexts of sexual activity and menses. Using early design and development contexts to gain insights into potential challenges and facilitators of drug delivery systems such as the pod-IVR could save valuable resources and time as a potential biomedical technology moves through the clinical trial pipeline and into real-world use.

Brain tissue analysis of impacts to American football helmets.

Concussion in American football is a prevalent concern. Research has been conducted examining frequencies, location, and thresholds for concussion from impacts. Little work has been done examining how impact location may affect risk of concussive injury. The purpose of this research was to examine how impact site on the helmet and type of impact, affects the risk of concussive injury as quantified using finite element modelling of the human head and brain. A linear impactor was used to impact a helmeted Hybrid III headform in several locations and using centric and non-centric impact vectors. The resulting dynamic response was used as input for the Wayne State Brain Injury Model to determine the risk of concussive injury by utilizing maximum principal strain as the predictive variable. The results demonstrated that impacts that occur primarily to the side of the head resulted in higher magnitudes of strain in the grey and white matter, as well as the brain stem. Finally, commonly worn American football helmets were used in this research and significant risk of injury was incurred for all impacts. These results suggest that improvements in American football helmets are warranted, in particular for impacts to the side of the helmet.