Concurrent nonavalent human papillomavirus (HPV) vaccination and immune stimulation with imiquimod to treat recalcitrant HPV-associated high grade vaginal intra-epithelial neoplasia.

This is the first report describing detailed T cell responses to viral-like proteins contained in an HPV specific vaccine given in combination with Imiquimod for treatment of persistent VAIN2/3. We postulate that stimulation of the innate immune system with Imiquimod and the specific CD4 and CD8T cell responses following HPV vaccination with Gardasil9@ combined to induce clinical remission in a woman with treatment-refractory disease.

Thalassophilia and marine identity: Drivers of 'thick' marine citizenship.

Changing humanity's relationship with the ocean is identified as one of ten key challenges in the UN Decade of Ocean Science for Sustainable Development (2021-2030). Marine citizenship is one potential policy approach for reducing anthropogenic harms to the ocean and promoting ocean recovery, and there is a need to better understand marine citizenship motivating factors and their interactions. To contribute to a more holistic understanding, we approached this problem using an interdisciplinary, mixed methodology, which prioritised the voices and experiences of active marine citizens. An online survey and semi-structured interviews were conducted to examine factors spanning environmental psychology (values, environmental identity) and human geography (place attachment and dependency). Our data uncovered a unique marine place attachment, or thalassophilia, which is a novel conceptualisation of the human capacity to bond with a type of place beyond human settlements or defined localities. It is the product of strong emotional responses to the sensorial experience of the ocean and shared social or cultural understanding of ocean place identifications. A key driver of deeper marine citizenship is marine place dependency, and it is positively influence by stimulation and non-conformity values, environmental identity, and thalassophilia. We map significant motivating factors to identity process theory and describe a novel marine identity concept. We propose this as an operational mechanism of marine citizenship action, potentially filling the value- and knowledge-action gaps in the context of marine environmental action. This research provides a cornerstone in marine citizenship research by analysing together in one study a multitude of variables, which cross human-ocean relationships and experiences. The identification and characterisation of thalassophilia and marine identity process theory will enable research and practice to move forwards with a clearer framework of the role of the ocean as a place in environmental action.

A Quantitative Method to Measure the Kinetics of Elemental Mercury Emissions From Black Shale (Nova Scotia, Canada).

A controlled chamber method using continuous gold trap atomic fluorescence spectroscopy (AFS) (Tekran 2537X) for the analysis of Hg(0) emissions from moderate mass rock samples was developed and tested. A series of black shale and other bedrock samples from Nova Scotia, Canada, were used to test the method and its reproducibility. Hg(0) emissions at 170°C were measured to quantify both free surficial Hg(0) and Hg(0) that had penetrated the rock structure. High volumes of chamber air (45 L) were sampled using 30 min collection times to achieve detectable elemental mercury (Hg(0)) emissions. We found higher percentage masses of Hg(0) were released (1.1%-4.1% of total Hg mass present) in black shale samples as compared to granite and basalt samples from the same region (0.0%-0.3% released) over 350 h of continuous analysis time. The pseudo first order emission rate constants ranged from 0.015-0.245 h-1 (mean 0.063 h-1, standard deviation (SD) 0.102) for the black shale samples analyzed and was 0.004 h-1 for the granite sample. The 24-h zero-order emission rate constants ranged between 0.41 and 3.54 ng h-1 (mean 1.4 ng h-1, SD 1.3) for the black shale samples analyzed and were ~ 0.01 ng h-1 for the granite and basalt samples. This technique has useful implications for examining rock properties and Hg(0) emission rates.

Conceptualizing Trust and Distrust as Alternative Stable States: Lessons from the Flint Water Crisis.

Despite the universally recognized importance of fostering trust and avoiding distrust in governance relationships, there remains considerable debate on core questions like the relation between (dis)trust and the evaluations of the characteristics that make a governance agent appear (un)worthy of trust. In particular, it remains unclear whether levels of (dis)trust simply follow levels of (dis)trustworthiness-such that building trust is primarily a question of increasing evidence of trustworthiness and avoiding evidence of distrustworthiness, or if their dynamics are more complicated. The current paper adds novel theory for thinking about the management of trust and distrust in the governance context through the application of principles borrowed from resilience theory. Specifically, we argue that trust and distrust exist as distinct, self-reinforcing (i.e., stable) states separated by a threshold. We then theorize as to the nature of the self-reinforcing processes and use qualitative data collected from and inductively coded in collaboration with Flint residents as part of a participatory process to look for evidence of our argument in a well-documented governance failure. We conclude by explaining how this novel perspective allows for clearer insight into the experience of this and other communities and speculate as to how it may help to better position governance actors to respond to future crises.

Computing committors via Mahalanobis diffusion maps with enhanced sampling data.

The study of phenomena such as protein folding and conformational changes in molecules is a central theme in chemical physics. Molecular dynamics (MD) simulation is the primary tool for the study of transition processes in biomolecules, but it is hampered by a huge timescale gap between the processes of interest and atomic vibrations that dictate the time step size. Therefore, it is imperative to combine MD simulations with other techniques in order to quantify the transition processes taking place on large timescales. In this work, the diffusion map with Mahalanobis kernel, a meshless approach for approximating the Backward Kolmogorov Operator (BKO) in collective variables, is upgraded to incorporate standard enhanced sampling techniques, such as metadynamics. The resulting algorithm, which we call the target measure Mahalanobis diffusion map (tm-mmap), is suitable for a moderate number of collective variables in which one can approximate the diffusion tensor and free energy. Imposing appropriate boundary conditions allows use of the approximated BKO to solve for the committor function and utilization of transition path theory to find the reactive current delineating the transition channels and the transition rate. The proposed algorithm, tm-mmap, is tested on the two-dimensional Moro-Cardin two-well system with position-dependent diffusion coefficient and on alanine dipeptide in two collective variables where the committor, the reactive current, and the transition rate are compared to those computed by the finite element method (FEM). Finally, tm-mmap is applied to alanine dipeptide in four collective variables where the use of finite elements is infeasible.

Whole-brain MR-registered cryo-imaging of a porcine-human glioma model to compare contrast agent biodistributions.

As rapidly accelerating technology, fluorescence guided surgery (FGS) has the potential to place molecular information directly into the surgeon's field of view by imaging administered fluorescent contrast agents in real time, circumnavigating pre-operative MR registration challenges with brain deformation. The most successful implementation of FGS is 5-ALA-PpIX guided glioma resection which has been linked to improved patient outcomes. While FGS may offer direct in-field guidance, fluorescent contrast agent distributions are not as familiar to the surgical community as Gd-MRI uptake, and may provide discordant information from previous Gd-MRI guidance. Thus, a method to assess and validate consistency between fluorescence-labeled tumor regions and Gd-enhanced tumor regions could aid in understanding the correlation between optical agent fluorescence and Gd-enhancement. Herein, we present an approach for comparing whole-brain fluorescence biodistributions with Gd-enhancement patterns on a voxel-by-voxel basis using co-registered fluorescent cryo-volumes and Gd-MRI volumes. In this initial study, a porcine-human glioma xenograft model was administered 5-ALA-PpIX, imaged with MRI, and euthanized 22 hours following 5-ALA administration. Following euthanization, the extracted brain was imaged with the cryo-macrotome system. After image processing steps and non-rigid, point-based registration, the fluorescence cryo-volume and Gd-MRI volume were compared for similarity metrics including: image similarity, tumor shape similarity, and classification similarity. This study serves as a proof-of-principle in validating our screening approach for quantitatively comparing 3D biodistributions between optical agents and Gd-based agents.

Marine protected areas in the context of climate change: key challenges for coastal social-ecological systems.

Climate and ecological emergencies play out acutely in coastal systems with devastating impacts on biodiversity, and the livelihoods of communities and their cultural values. Marine Protected Areas (MPAs) are one of the key management and regulatory tools against biodiversity loss, playing a role in strengthening bio-cultural diversity and sustainability of coastal social-ecological systems. What is unclear though is the effectiveness of static protections under climate change as species move. Next to ecological uncertainty, regulatory uncertainty may play a role in weakening marine conservation. We asked whether MPAs are ecologically effective now and can sustain or improve to be so in the future while facing key climate and regulatory uncertainties. MPAs can support the protection of cultural values and have an impact on activities of sea-users and the sustainability of social-ecological systems. As such, questions surrounding their legitimacy under a changing climate and increased uncertainty are pertinent. We argue that MPA governance must be cognisant of the interdependency between natural and human systems and their joint reaction to climate change impacts based on an integrated, co-developed, and interdisciplinary approach. Focusing on the UK as a case study, we highlight some of the challenges to achieve effective, adaptive and legitimate governance of MPAs. This article is part of the theme issue 'Nurturing resilient marine ecosystems'.

Evaluating the performance of temporal pattern discovery: new application using statins and rhabdomyolysis in OMOP databases.

BACKGROUND: Temporal pattern discovery (TPD) is a method of signal detection using electronic healthcare databases, serving as an alternative to spontaneous reporting of adverse drug events. Here, we aimed to replicate and optimise a TPD approach previously used to assess temporal signals of statins with rhabdomyolysis (in The Health Improvement Network (THIN) database) by using the OHDSI tools designed for OMOP data sources. METHODS: We used data from the Truven MarketScan US Commercial Claims and the Commercial Claims and Encounters (CCAE). Using an extension of the OHDSI ICTemporalPatternDiscovery package, we ran positive and negative controls through four analytical settings and calculated sensitivity, specificity, bias and AUC to assess performance. RESULTS: Similar to previous findings, we noted an increase in the Information Component (IC) for simvastatin and rhabdomyolysis following initial exposure and throughout the surveillance window. For example, the change in IC was 0.266 for the surveillance period of 1-30 days as compared to the control period of - 180 to - 1 days. Our modification of the existing OHDSI software allowed for faster queries and more efficient generation of chronographs. CONCLUSION: Our OMOP replication matched the we can account forwe can account for of the original THIN study, only simvastatin had a signal. The TPD method is a useful signal detection tool that provides a single statistic on temporal association and a graphical depiction of the temporal pattern of the drug outcome combination. It remains unclear if the method works well for rare adverse events, but it has been shown to be a useful risk identification tool for longitudinal observational databases. Future work should compare the performance of TPD with other pharmacoepidemiology methods and mining techniques of signal detection. In addition, it would be worth investigating the relative TPD performance characteristics using a variety of observational data sources.

Analysis of the Cellular Immune Responses to Vaccines.

Flow cytometry, enzyme-linked immunospot (ELISpot), and cellular cytotoxicity assays are powerful tools for studying the cellular immune response toward intracellular pathogens and vaccines in livestock species. Lymphocytes from immunized animals can be purified using Ficoll-Paque density gradient centrifugation and evaluated for their antigen specificity or reactivity toward a vaccine. Here, we describe staining of bovine lymphocytes with peptide (p)-MHC class I tetramers and antibodies specific toward cellular activation markers for evaluation by multiparametric flow cytometry, as well as interferon (IFN)-γ ELISpot and cytotoxicity using chromium (51Cr) release assays. A small component on the use of immunoinformatics for fine-tuning the identification of a minimal CTL epitope is included, and a newly developed and simple assay to measure TCR avidity.

Meta-analysis of the outcomes of Trans Rectus Sheath Extra-Peritoneal Procedure (TREPP) for inguinal hernia.

OBJECTIVES: To evaluate the outcomes of Trans Rectus Sheath Extra-Peritoneal Procedure (TREPP) in patients undergoing elective inguinal hernia repair. METHODS: In compliance with PRISMA statement standards, electronic databases were searched to identify all studies reporting the outcomes of TREPP in patients undergoing elective inguinal hernia repair. The outcomes of interest included recurrence, chronic pain, haematoma, and wound infection. Proportion meta-analysis model was constructed to quantify the risk of postoperative complications and direct comparison meta-analysis model was constructed to compare the outcomes of TREPP and other open techniques. Random-effects modelling was applied to calculate pooled outcome data. RESULTS: Seven studies enrolling 1891 patients undergoing TREPP were included. The mean operative time was 26 min (95% CI 15-36). Pooled analyses showed that TREPP was associated with 3.00% (95% CI 1.00-6.00%) risk of recurrence, 3.00% (95% CI 2.00-6.00%) risk of chronic pain, 8.00% (95% CI 0.00-20.00%) risk of haematoma, and 3.00% (95% CI 0.00-6.00%) risk of wound infection. The results remained consistent through subgroup analysis of patients with primary hernias and those with recurrent hernias. Analysis of a limited number of comparative studies showed no difference between TREPP and Lichtenstein technique in terms of recurrence (OR 1.57, P = 0.26) and chronic pain (OR 1.16, P = 0.59). CONCLUSIONS: The best available evidence suggests that TREPP may be a promising technique for elective repair of inguinal hernias as indicated by low risks of recurrence, chronic pain, haematoma, and wound infection. The available evidence is limited to studies from a same country conducted by almost the same research group which may affect generalisability of the findings. Moreover, there is a lack of comparative evidence on outcomes of TREPP versus other techniques highlighting a need for high-quality randomised controlled trials for definite conclusions. Although the available evidence is not adequate for definite conclusions, the results of current study can be used for sample size calculation and power analysis in future trials.

Behavior Sequence Analysis of Victims' Accounts of Intimate Partner Violence.

Intimate partner violence (IPV) relates not only to physical forms of abuse, but also psychological, emotional, economic, and financial controlling behaviors. IPV is a dynamic, complex phenomenon that occurs over a relatively long period of time. While several measures of IPV exist, a method that can track the progression and escalation of such behaviors in relationships could offer more understanding and highlight key intervention points for individuals in such relationships. Behavior Sequence Analysis is used in the current research to map the chain and progression of behaviors in multiple real-world cases of IPV. Results indicate clear sequential clusters of behaviors such as physical and psychological abuse, and coercive controlling behaviors such as gaslighting, restricting movement, and removing freedoms. Overall, this research stands as a foundation framework to build a greater understanding of the processes and pathways of IPV, and offers workers in the field a novel method to assist with interviewing and intervening in such cases.

Controlled synthesis of dicalcium phosphate dihydrate (DCPD) from metastable solutions: insights into pathogenic calcification.

Calcium phosphate (CaP) compounds may occur in the body as abnormal pathogenic phases in addition to their normal occurrence as bones and teeth. Dicalcium phosphate dihydrate (DCPD; CaPO4·2H2O), along with other significant CaP phases, have been observed in pathogenic calcifications such as dental calculi, kidney stones and urinary stones. While other studies have shown that polar amino acids can inhibit the growth of CaPs, these studies have mainly focused on hydroxyapatite (HAp; Ca10(PO4)6(OH)2) formation from highly supersaturated solutions, while their effects on DCPD nucleation and growth from metastable solutions have been less thoroughly explored. By further elucidating the mechanisms of DCPD formation and the influence of amino acids on those mechanisms, insights may be gained into ways that amino acids could be used in treatment and prevention of unwanted calcifications. The current study involved seeded growth of DCPD from metastable solutions at constant pH in the presence of neutral, acidic and phosphorylated amino acid side chains. As a comparison, solutions were also seeded with calcium pyrophosphate (CPP; Ca2P2O7), a known calcium phosphate inhibitor. The results show that polar amino acids inhibit DCPD growth; this likely occurs due to electrostatic interactions between amino acid side groups and charged DCPD surfaces. Phosphoserine had the greatest inhibitory ability of the amino acids tested, with an effect equal to that of CPP. Clustering of DCPD crystals giving rise to a "chrysanthemum-like" morphology was noted with glutamic acid. This study concludes that molecules containing an increased number of polar side groups will enhance the inhibition of DCPD seeded growth from metastable solutions.

The effect of human immunodeficiency virus infection on adverse events during treatment of drug-resistant tuberculosis: A systematic review and meta-analysis.

BACKGROUND: Adverse events (AEs) during drug-resistant tuberculosis (DR-TB) treatment, especially with human immunodeficiency virus (HIV) co-infection, remains a major threat to poor DR-TB treatment adherence and outcomes. This meta-analysis aims to investigate the effect of HIV infection on the development of AEs during DR-TB treatment. METHODS: Eligible studies evaluating the association between HIV seropositivity and risks of AE occurrence in DR-TB patients were included in this systematic review. Interventional and observational studies were assessed for risk of bias using the Risk of Bias in Nonrandomized Studies of Intervention and Newcastle-Ottawa Scale tool, respectively. Random-effects meta-analysis was performed to estimate the pooled risk ratio (RR) along with their 95% confidence intervals (CIs). RESULTS: A total of 37 studies involving 8657 patients were included in this systematic review. We discovered that HIV infection independently increased the risk of developing AEs in DR-TB patients by 12% (RR 1.12 [95% CI: 1.02-1.22]; I2 = 0%, p = 0.75). In particular, the risks were more accentuated in the development of hearing loss (RR 1.44 [95% CI: 1.18-1.75]; I2 = 60%), nephrotoxicity (RR 2.45 [95% CI: 1.20-4.98], I2 = 0%), and depression (RR 3.53 [95% CI: 1.38-9.03]; I2 = 0%). Although our findings indicated that the augmented risk was primarily driven by antiretroviral drug usage rather than HIV-related immunosuppression, further studies investigating their independent effects are required to confirm our findings. CONCLUSION: HIV co-infection independently increased the risk of developing AEs during DR-TB treatment. Increased pharmacovigilance through routine assessments of audiological, renal, and mental functions are strongly encouraged to enable prompt diagnosis and treatment in patients experiencing AEs during concomitant DR-TB and HIV treatment.

Life expectancy inequalities in Wales before COVID-19: an exploration of current contributions by age and cause of death and changes between 2002 and 2018.

OBJECTIVES: The COVID-19 pandemic in Wales and the UK has highlighted significant and historic inequalities in health between social groups. To better understand the composition of these inequalities and inform planning after the pandemic, we undertook a decomposition of life expectancy inequalities between the most and least deprived quintiles for men and women by age and cause of death and explored trends between 2002 and 2018. STUDY DESIGN: Statistical decomposition of life expectancy inequalities by age and cause of death using routine population mortality datasets. METHODS: We used routine statistics from the Office for National Statistics for the period 2002-2018 on population and deaths in Wales stratified by age, gender, Welsh Index of Multiple Deprivation (WIMD) 2019 quintile and cause of death, categorised by International Classification of Disease, version 10, code into 15 categories of public health relevance. We aggregated data to 3-year rolling figures to account for low numbers of events in some groups annually. Next, we estimated life expectancy at birth by quintile, gender and period using life table methods. Lastly, we performed a decomposition analysis using the Arriaga method to identify the specific disease categories and ages at which excess deaths occur in more disadvantaged areas to highlight potential areas for action. RESULTS: Life expectancy inequalities between the most and least WIMD quintiles rose for both genders between 2002 and 2018: from 4.69 to 6.02 years for women (an increase of 1.33 years) and from 6.34 to 7.42 years for men (an increase of 1.08 years). Exploratory analysis of these trends suggested that the following were most influential for women: respiratory disease (1.50 years), cancers (1.36 years), circulatory disease (1.35 years) and digestive disease (0.51 years). For men, the gap was driven by circulatory disease (2.01 years), cancers (1.39 years), respiratory disease (1.25 years), digestive disease (0.79 years), drug- and alcohol-related conditions (0.54 years) and external causes (0.54 years). Contributions for women from respiratory disease, cancers, dementia and drug- and alcohol-related conditions appeared to be increasing, while among men, there were rising contributions from respiratory, digestive and circulatory disease. CONCLUSIONS: Life expectancy inequalities in Wales remain wide and have been increasing, particularly among women, with indications of worsening trends since 2010 following the introduction of fiscal austerity. As agencies recover from the pandemic, these findings should be considered alongside any resumption of services in Wales or future health and public policy.

Enhancement of a low-fidelity surgical simulator. Is it possible?

BACKGROUND: Simulation training has become a core component in the training of ENT surgeons. It provides the opportunity for the repetitive practice of a surgical technique. Simulators are broadly categorised into low- and high-fidelity simulators. A method using a home microprocessor to enhance a low-fidelity surgical simulator is introduced. METHOD: The Yorick tonsil tie trainer was enhanced using an Arduino microcontroller attached to the simulated inferior pole of the tonsil. The Arduino was coded to give a visual stimulus when linear motion exceeded parameters. The prototype simulator was tested to gain information on whether the enhancement could identify differences between novice and expert users. CONCLUSION: An enhanced low-fidelity tonsil trainer was produced using a low-cost, simple home microprocessing board. The enhanced simulator gives objective feedback allowing for self-directed learning. Further research is required to evaluate the benefits of these enhancements above non-enhanced simulation training.

Predicting population responses to environmental change from individual-level mechanisms: towards a standardized mechanistic approach.

Animal populations will mediate the response of global biodiversity to environmental changes. Population models are thus important tools for both understanding and predicting animal responses to uncertain future conditions. Most approaches, however, are correlative and ignore the individual-level mechanisms that give rise to population dynamics. Here, we assess several existing population modelling approaches and find limitations to both 'correlative' and 'mechanistic' models. We advocate the need for a standardized mechanistic approach for linking individual mechanisms (physiology, behaviour, and evolution) to population dynamics in spatially explicit landscapes. Such an approach is potentially more flexible and informative than current population models. Key to realizing this goal, however, is overcoming current data limitations, the development and testing of eco-evolutionary theory to represent interactions between individual mechanisms, and standardized multi-dimensional environmental change scenarios which incorporate multiple stressors. Such progress is essential in supporting environmental decisions in uncertain future conditions.

Mining for natural product antileishmanials in a fungal extract library.

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Most of these collaborative efforts have relied upon the small molecule synthetic compound libraries held by industry, but the number of New Chemical Entities (NCE) identified and entering development as antileishmanials has been very low. In light of this, here we describe a public-private effort to identify natural products with activity against Leishmania mexicana, a causative agent of cutaneous leishmanaisis (CL). Utilising Hypha Discovery's fungal extract library which is rich in small molecule (<500 molecular weight) secondary metabolites, we undertook an iterative phenotypic screening and fractionation approach to identify potent and selective antileishmanial hits. This led to the identification of a novel oxidised bisabolane sesquiterpene which demonstrated activity in an infected cell model and was shown to disrupt multiple processes using a metabolomic approach. In addition, and importantly, this study also sets a precedent for new approaches for CL drug discovery.