A mathematical model on the propagation of tau pathology in neurodegenerative diseases.

A system of partial differential equations is developed to study the spreading of tau pathology in the brain for Alzheimer's and other neurodegenerative diseases. Two cases are considered with one assuming intracellular diffusion through synaptic activities or the nanotubes that connect the adjacent cells. The other, in addition to intracellular spreading, takes into account of the secretion of the tau species which are able to diffuse, move with the interstitial fluid flow and subsequently taken up by the surrounding cells providing an alternative pathway for disease spreading. Cross membrane transport of the tau species are considered enabling us to examine the role of extracellular clearance of tau protein on the disease status. Bifurcation analysis is carried out for the steady states of the spatially homogeneous system yielding the results that fast cross-membrane transport combined with effective extracellular clearance is key to maintain the brain's healthy status. Numerical simulations of the first case exhibit solutions of travelling wave form describing the gradual outward spreading of the pathology; whereas the second case shows faster spreading with the buildup of neurofibrillary tangles quickly elevated throughout. Our investigation thus indicates that the gradual progression of the intracellular spreading case is more consistent with the clinical observations of the development of Alzheimer's disease.

Prevalence of hepatitis C virus exposure and infection among Indigenous and tribal populations: a global systematic review and meta-analysis.

OBJECTIVES: The objective of this study was to estimate prevalence of hepatitis C virus (HCV) exposure and infection among Indigenous and tribal populations globally. STUDY DESIGN: Systematic review and meta-analysis. METHODS: We systematically searched bibliographic databases and grey literature (1/01/2000-16/06/2022). Prevalence estimates were synthesised overall, by World Health Organization region and HCV-risk group. For studies with comparator populations, prevalence ratios were estimated and pooled. RESULTS: Ninety-two studies were included. Globally, among general Indigenous and tribal populations, the median prevalence of HCV antibody (HCV Ab) was 1.3% (interquartile range [IQR]: 0.3-3.8%, I2 = 98.5%) and HCV RNA was 0.4% (IQR: 0-1.3%, I2 = 96.1%). The Western Pacific Region had the highest prevalence (HCV Ab: median: 3.0% [IQR: 0.4-11.9%], HCV RNA: median 5.6% [IQR: 2.0-8.8%]). Prevalence was highest in people who injected drugs (HCV Ab: median: 59.5%, IQR: 51.5-67.6%, I2 = 96.6%; and HCV RNA: median: 29.4%, IQR: 21.8-35.2%, I2 = 97.2%). There was no association between HCV Ab prevalence and Indigenous/tribal status for general populations (prevalence ratio = 0.91; 95% CI: 0.56, 1.49) or key risk groups. CONCLUSIONS: Indigenous and tribal peoples from the Western Pacific Region and recognised at-risk sub-populations had higher HCV prevalence. HCV prevalence showed no association with Indigenous/tribal status. However, this review was limited by heterogeneity and poor quality of constituent studies, varying definitions of Indigenous/tribal status, regional data gaps, and limited studies on chronic infection (HCV RNA). Comprehensive quality evidence on HCV epidemiology in Indigenous and tribal peoples is needed to tailor preventive and treatment interventions so these populations are not left behind in elimination efforts.

Nylon microfibers develop a distinct plastisphere but have no apparent effects on the gut microbiome or gut tissue status in the blue mussel, Mytilus edulis.

Ingestion of microplastics (MP) by suspension-feeding bivalves has been well-documented. However, it is unclear whether exposure to MP could damage the stomach and digestive gland (gut) of these animals, causing ramifications for organism and ecosystem health. Here, we show no apparent effects of nylon microfiber (MF) ingestion on the gut microbiome or digestive tissues of the blue mussel, Mytilus edulis. We exposed mussels to two low concentrations (50 and 100 particles/L) of either nylon MF or Spartina spp. particles (dried, ground marsh grass), ca. 250-500 µm in length, or a no particle control laboratory treatment for 21 days. Results showed that nylon MF, when aged in coarsely filtered seawater, developed a different microbial community than Spartina spp. particles and seawater, however, even after exposure to this different community, mussel gut microbial communities resisted disturbance from nylon MF. The microbial communities of experimental mussels clustered together in ordination and were similar in taxonomic composition and measures of alpha diversity. Additionally, there was no evidence of damage to gut tissues after ingestion of nylon MF or Spartina spp. Post-ingestive particle processing likely mediated a short gut retention time of these relatively large particles, contributing to the negligible treatment effects.

A multi-study analysis of gut microbiome data from the blue mussel (Mytilus edulis) emphasises the impact of depuration on biological interpretation.

The blue mussel (Mytilus edulis) is a suspension feeder which has been used in gut-microbiome surveys. Although raw 16S sequence data are often publicly available, unifying secondary analyses are lacking. The present work analysed raw data from seven projects conducted by one group over 7 years. Although each project had different motivations, experimental designs and conclusions, all selected samples were from the guts of M. edulis collected from a single location in Long Island Sound. The goal of this analysis was to determine which independent factors (e.g., collection date, depuration status) were responsible for governing composition and diversity in the gut microbiomes. Results indicated that whether mussels had undergone depuration, defined here as voidance of faeces in a controlled, no-food period, was the primary factor that governed gut microbiome composition. Gut microbiomes from non-depurated mussels were mixtures of resident and transient communities and were influenced by temporal factors. Resident communities from depurated mussels were influenced by the final food source and length of time host mussels were held under laboratory conditions. These findings reinforce the paradigm that gut microbiota are divided into resident and transient components and suggest that depuration status should be taken into consideration when designing and interpreting future experiments.

Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.

Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication. We hypothesized that succinate prodrugs would bypass FA-induced mitochondrial dysfunction, provide metabolic support, and prevent metabolic crisis during acute FA intoxication. To test this hypothesis, rats were exposed to FA (0.75 mg/kg) and treated with the succinate prodrug candidate NV354. Treatment efficacy was evaluated based on cardiac and cerebral mitochondrial respiration, mitochondrial content, metabolic profiles and tissue pathology. In the heart, FA increased concentrations of the TCA metabolite citrate (+ 4.2-fold, p < 0.01) and lowered ATP levels (- 1.9-fold, p < 0.001), confirming the inhibition of the TCA cycle by FA. High-resolution respirometry of cardiac mitochondria further revealed an impairment of mitochondrial complex V (CV)-linked metabolism, as evident by a reduced phosphorylation system control ratio (- 41%, p < 0.05). The inhibition of CV-linked metabolism is a novel mechanism of FA cardiac toxicity, which has implications for drug development and which NV354 was unable to counteract at the given dose. In the brain, FA induced the accumulation of ß-hydroxybutyrate (+ 1.4-fold, p < 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOSCI) (- 20%, p < 0.01), the latter of which was successfully alleviated by NV354. This promising effect of NV354 warrants further investigations to determine its potential neuroprotective effects.

Trajectories of otitis media and association with health determinants among Indigenous children in Australia: the Longitudinal Study of Indigenous Children.

OBJECTIVES: Indigenous children in Australia experience high burden of persistent otitis media (OM) from very early age. The aim was to identify distinct trajectories of OM in children up to age 10-12 years and examine the association with socio-economic determinants. STUDY DESIGN: A multistage clustered national panel survey. METHODS: The study analysed the birth cohort of the Longitudinal Study of Indigenous Children from 2008 to 2018, comprising 11 study waves. Group-based trajectory modelling was used to identify different trajectories of OM outcome. Multinomial logistic regression was applied to examine the relationship between trajectories and individual, household and community-level socio-economic determinants. RESULTS: This analysis included 894 children with at least three responses on OM over the 11 waves, and the baseline mean age was 15.8 months. Three different trajectories of OM were identified: non-severe OM prone, early/persistent severe OM and late-onset severe OM. Overall, 11.4% of the children had early/persistent severe OM from birth to 7.5 to nine years, while late-onset severe OM consisted of 9.8% of the children who had first OM from age 3.5 to five years. Children in communities with middle and the highest socio-economic outcomes have lower relative risk of early/persistent severe OM (adjusted relative risk ratio = 0.39, 95% confidence interval = 0.22-0.70 and adjusted relative risk ratio = 0.22, 95% confidence interval = 0.09-0.52, respectively) compared to children in communities with lowest socio-economic outcomes. CONCLUSION: Efforts to close the gap in the quality of life of Indigenous children must prioritise strategies that prevent severe ear disease (runny ears and perforation), including improved healthcare access, reduced household crowding, and better education, and more employment opportunities.

An in-field evaluation of rapid DNA instruments for disaster victim identification.

In 2019 and 2020, disaster victim identification (DVI) simulations were conducted at the Australian Facility for Taphonomic Experimental Research. Whole and fragmented cadavers were positioned to replicate a building collapse scenario and left to decompose for up to 4 weeks. This study evaluated the utility of the ANDE™ 6C Rapid DNA System and the RapidHITTM ID System for DVI in the field and mortuary. Applying post-mortem nail and tissue biopsy samples showed promise, with the added benefit of minimally invasive collection procedures and limited preparation requirements. The preferred platform will depend on a number of factors, including its intended use and operating environment.

Determining the Properties that Govern Selective Ingestion and Egestion of Microplastics by the Blue Mussel (Mytilus edulis) and Eastern Oyster (Crassostrea virginica).

Suspension feeding bivalve molluscs interact with different types of microplastics (MP) suspended in the water column. Most bivalves are selective suspension feeders and, thus, do not consume all particles to which they are exposed. Selection depends upon the physicochemical properties and size of the particle. Recent work has provided evidence that blue mussels, Mytilus edulis, and eastern oysters, Crassostrea virginica, ingest and egest microspheres (polystyrene) and microfibers (nylon) differently, but whether other factors, such as polymer type and shape, mediate selection have not been explored. To investigate these factors, mussels and oysters were offered similar sized nylon (Ny) and polyester (PES) microfibers or polyethylene (PE) and polystyrene (PS) microspheres, or different sized PES microfibers during a 2 h exposure. Feces and pseudofeces were collected separately and analyzed for MPs, and the data were used to develop a linear regression model for selection. Results demonstrated clear species-specific differences in the efficiency of particle selection. Both mussels and oysters, however, exhibited size-based rejection of PES microfibers, ingesting a higher proportion of shorter fibers than longer fibers. Polymer type did not impact selection of fibers or spheres. The relative size of particles (area and perimeter) was found to be the most important factor in predicting whether a MP will be rejected or ingested.

Direct Comparison of Fecal and Gut Microbiota in the Blue Mussel (Mytilus edulis) Discourages Fecal Sampling as a Proxy for Resident Gut Community.

Bivalves have ecological and economic importance but information regarding their associated microbiomes is lacking. As suspension feeders, bivalves capture and ingest a myriad of particles, and their digestive organs have a high throughput of particle-associated microbiota. To better understand the complement of transient and resident microbial communities, standard methods need to be developed. For example, fecal sampling could represent a convenient proxy for the gut microbiome and is simple, nondestructive, and allows for sampling of individuals through time. The goal of this study was to evaluate fecal sampling as a reliable proxy for gut microbiome assessment in the blue mussel (Mytilus edulis). Mussels were collected from the natural environment and placed into individual sterilized microcosms for 6 h to allow for fecal egestion. Feces and gut homogenates from the same individuals were sampled and subjected to 16S rRNA gene amplicon sequencing. Fecal communities of different mussels resembled each other but did not resemble gut communities. Fecal communities were significantly more diverse, in terms of amplicon sequence variant (ASV) richness and evenness, than gut communities. Results suggested a mostly transient nature for fecal microbiota. Nonetheless, mussels retained a distinct resident microbial community in their gut after fecal egestion that was dominated by ASVs belonging to Mycoplasma. The use of fecal sampling as a nondestructive substitute for direct sampling of the gut is strongly discouraged. Experiments that aim to study solely resident bivalve gut microbiota should employ an egestion period prior to gut sampling to allow time for voidance of transient microbes.

Aerosolisation during tracheal intubation and extubation in an operating theatre setting.

Aerosol-generating procedures such as tracheal intubation and extubation pose a potential risk to healthcare workers because of the possibility of airborne transmission of infection. Detailed characterisation of aerosol quantities, particle size and generating activities has been undertaken in a number of simulations but not in actual clinical practice. The aim of this study was to determine whether the processes of facemask ventilation, tracheal intubation and extubation generate aerosols in clinical practice, and to characterise any aerosols produced. In this observational study, patients scheduled to undergo elective endonasal pituitary surgery without symptoms of COVID-19 were recruited. Airway management including tracheal intubation and extubation was performed in a standard positive pressure operating room with aerosols detected using laser-based particle image velocimetry to detect larger particles, and spectrometry with continuous air sampling to detect smaller particles. A total of 482,960 data points were assessed for complete procedures in three patients. Facemask ventilation, tracheal tube insertion and cuff inflation generated small particles 30-300 times above background noise that remained suspended in airflows and spread from the patient's facial region throughout the confines of the operating theatre. Safe clinical practice of these procedures should reflect these particle profiles. This adds to data that inform decisions regarding the appropriate precautions to take in a real-world setting.

What is the Link Between Mental Imagery and Sensory Sensitivity? Insights from Aphantasia.

People with aphantasia have impoverished visual imagery so struggle to form mental pictures in the mind's eye. By testing people with and without aphantasia, we investigate the relationship between sensory imagery and sensory sensitivity (i.e., hyper- or hypo-reactivity to incoming signals through the sense organs). In Experiment 1 we first show that people with aphantasia report impaired imagery across multiple domains (e.g., olfactory, gustatory etc.) rather than simply vision. Importantly, we also show that imagery is related to sensory sensitivity: aphantasics reported not only lower imagery, but also lower sensory sensitivity. In Experiment 2, we showed a similar relationship between imagery and sensitivity in the general population. Finally, in Experiment 3 we found behavioural corroboration in a Pattern Glare Task, in which aphantasics experienced less visual discomfort and fewer visual distortions typically associated with sensory sensitivity. Our results suggest for the very first time that sensory imagery and sensory sensitivity are related, and that aphantasics are characterised by both lower imagery, and lower sensitivity. Our results also suggest that aphantasia (absence of visual imagery) may be more accurately defined as a subtype of a broader imagery deficit we name dysikonesia, in which weak or absent imagery occurs across multiple senses.

Public perceptions of scientific advice: toward a science savvy public culture?

OBJECTIVES: Both the political appetite for a science-based coronavirus disease 2019 (COVID-19) policy and its acceptability to the public are little understood, at a time of sharp distrust not only of governments but also of scientists and their journals' review practices. We studied the case of France, where the independent Scientific Council on COVID-19 was appointed by President Macron on March 12, 2020. STUDY DESIGN: We conducted a survey on a representative sample of the French adult population. METHODS: Our data were collected by the French Institute of Public Opinion using a self-administered online questionnaire. This was completed by a sample of 1016 people stratified to match French official census statistics for gender, age, occupation, and so on. We conducted statistical analysis using Python (Pandas-SciPy-Statsmodels) with Chi-squared and Wilcoxon rank-sum tests to control for statistical significance. RESULTS: Intense media coverage has given the council a very high public profile, with three respondents out of four (73%) having heard about it. Perceptions are positive but complex. French citizens expect science to be important in political decision-making. Four of five (81.5%) want political decisions, in general, to be based on scientific knowledge. But one in two (55%) says that the government has not relied enough on science and only 36% are satisfied with the government's crisis management to date. Although most feel that the council has a legitimate advisory role even in situations of uncertainty (only 15% disagree), it is not perceived as fully independent. Only 44% think that it directly represents the scientific community, and only one of three people considers it completely independent from the government (39%) and the pharmaceutical industry (36%). CONCLUSIONS: Our study confirms that while the transparency of scientific advice is important, it alone cannot ensure public confidence in political decision-making. We suggest that efforts made today to instill a 'science-savvy' public culture-one that allows the complex articulation between scientific knowledge, uncertainty, and political decision-making to be understood and accounted for would greatly benefit evidence-based policy in future crises.

A tellurite glass optical microbubble resonator.

We present a method for making microbubble whispering gallery resonators (WGRs) from tellurite, which is a soft glass, using a CO2 laser. The customized fabrication process permits us to process glasses with low melting points into microbubbles with loaded quality factors as high as 2.3 × 106. The advantage of soft glasses is that they provide a wide range of refractive index, thermo-optical, and optomechanical properties. The temperature and air pressure dependent optical characteristics of both passive and active tellurite microbubbles are investigated. For passive tellurite microbubbles, the measured temperature and air pressure sensitivities are 4.9 GHz/K and 7.1 GHz/bar, respectively. The large thermal tuning rate is due to the large thermal expansion coefficient of 1.9 × 10-5 K-1 of the tellurite microbubble. In the active Yb3+-Er3+ co-doped tellurite microbubbles, C-band single-mode lasing with a threshold of 1.66 mW is observed with a 980 nm pump and a maximum wavelength tuning range of 1.53 nm is obtained. The sensitivity of the laser output frequency to pressure changes is 6.5 GHz/bar. The microbubbles fabricated using this method have a low eccentricity and uniform wall thickness, as determined from electron microscope images and the optical spectra. The compound glass microbubbles described herein have the potential for a wide range of applications, including sensing, nonlinear optics, tunable microcavity lasers, and integrated photonics.

Characterisation of four hotdog-fold thioesterases for their implementation in a novel organic acid production system.

With increasing interest in the diverse properties of organic acids and their application in synthetic pathways, developing biological tools for producing known and novel organic acids would be very valuable. In such a system, organic acids may be activated as coenzyme A (CoA) esters, then modified by CoA-dependent enzymes, followed by CoA liberation by a broad-acting thioesterase. This study has focused on the identification of suitable thioesterases (TE) for utilisation in such a pathway. Four recombinant hotdog-fold TEs were screened with a range of CoA esters in order to identify a highly active, broad spectrum TE. The TesB-like TE, RpaL, from Rhodopseudomonas palustris was found to be able to use aromatic, alicyclic and both long and short aliphatic CoA esters. Size exclusion chromatography, revealed RpaL to be a monomer of fused hotdog domains, in contrast to the complex quaternary structures found with similar TesB-like TEs. Nonetheless, sequence alignments showed a conserved catalytic triad despite the variation in quaternary arrangement. Kinetic analysis revealed a preference towards short-branched chain CoA esters with the highest specificity towards DL-ß-hydroxybutyryl CoA (1.6 × 104 M-1 s-1), which was found to decrease as the acyl chain became longer and more functionalised. Substrate inhibition was observed with the fatty acyl n-heptadecanoyl CoA at concentrations exceeding 0.3 mM; however, this was attributed to its micellar aggregation properties. As a result of the broad activity observed with RpaL, it is a strong candidate for implementation in CoA ester pathways to generate modified or novel organic acids.

The final reason paediatric Cardiac ICU patients require care prior to discharge to the floor: a single-centre survey.

OBJECTIVE: To determine the Final ICU Need in the 24 hours prior to ICU discharge for children with cardiac disease by utilising a single-centre survey. METHODS: A cross-sectional survey was utilised to determine Final ICU Need, which was categorised as "Cardiovascular", "Respiratory", "Feeding", "Sedation", "Systems Issue", or "Other" for each encounter. Survey responses were obtained from attending physicians who discharged children (≤18 years of age with ICU length of stay >24 hours) from the Cardiac ICU between April 2016 and July 2018. MEASUREMENTS AND RESULTS: Survey response rate was 99% (n = 1073), with 667 encounters eligible for analysis. "Cardiovascular" (61%) and "Respiratory" (26%) were the most frequently chosen Final ICU Needs. From a multivariable mixed effects logistic regression model fitted to "Cardiovascular" and "Respiratory", operations with significantly reduced odds of having "Cardiovascular" Final ICU Need included Glenn palliation (p = 0.003), total anomalous pulmonary venous connection repair (p = 0.024), truncus arteriosus repair (p = 0.044), and vascular ring repair (p < 0.001). Short lengths of stay (<7.9 days) had significantly higher odds of "Cardiovascular" Final ICU Need (p < 0.001). "Cardiovascular" and "Respiratory" Final ICU Needs were also associated with provider and ICU discharge season. CONCLUSIONS: Final ICU Need is a novel metric to identify variations in Cardiac ICU utilisation and clinical trajectories. Final ICU Need was significantly influenced by benchmark operation, length of stay, provider, and season. Future applications of Final ICU Need include targeting quality and research initiatives, calibrating provider and family expectations, and identifying provider-level variability in care processes and mental models.

Temperature-Dependent Biomarkers of Estrogenic Exposure in a Piscivore Freshwater Fish.

The biological effects of endocrine-active compounds and increasing water temperatures as a result of climate change have been studied extensively and independently, but there is a dearth of research to examine the combined effect of these factors on exposed organisms. Recent data suggest that estrogenic exposure and rising ambient temperatures independently impact predator-prey relationships. However, establishing these connections in natural settings is complex. These obstacles can be circumvented if biomarkers of estrogenic exposure in resident fish can predict changes in predator-prey relationships. To test the effects of estrone and temperature, the piscivore bluegill sunfish (Lepomis macrochirus) was exposed for 30 days to estrone at concentrations (90 ± 17.6 ng/L [mean ± standard deviation] and 414 ± 146 ng/L) previously shown to reduce prey-capture success. Exposures were conducted at four temperatures (15 °C, 18 °C, 21 °C, 24 °C) to simulate breeding season ambient temperatures across the natural range of this species. A suite of morphological and physiological biomarkers previously linked to estrogenic exposures were examined. Biomarkers of estrone exposure were more commonly and severely impacted in male fish than in female fish. Notably, the gonadosomatic index was lower and gonads were less mature in exposed males. Additionally, temperature modulated the effects of estrone similarly in males and females with fish exposed at higher temperatures typically exhibiting a decreased morphological index. This study provides evidence that alterations in hepatic function and gonadal function may cause shifts in metabolism and energy allocation that may lead to declining prey capture performance.

Modelling the outbreak of infectious disease following mutation from a non-transmissible strain.

In-host mutation of a cross-species infectious disease to a form that is transmissible between humans has resulted with devastating global pandemics in the past. We use simple mathematical models to describe this process with the aim to better understand the emergence of an epidemic resulting from such a mutation and the extent of measures that are needed to control it. The feared outbreak of a human-human transmissible form of avian influenza leading to a global epidemic is the paradigm for this study. We extend the SIR approach to derive a deterministic and a stochastic formulation to describe the evolution of two classes of susceptible and infected states and a removed state, leading to a system of ordinary differential equations and a stochastic equivalent based on a Markov process. For the deterministic model, the contrasting timescale of the mutation process and disease infectiousness is exploited in two limits using asymptotic analysis in order to determine, in terms of the model parameters, necessary conditions for an epidemic to take place and timescales for the onset of the epidemic, the size and duration of the epidemic and the maximum level of the infected individuals at one time. Furthermore, the basic reproduction number R0 is determined from asymptotic analysis of a distinguished limit. Comparisons between the deterministic and stochastic model demonstrate that stochasticity has little effect on most aspects of an epidemic, but does have significant impact on its onset particularly for smaller populations and lower mutation rates for representatively large populations. The deterministic model is extended to investigate a range of quarantine and vaccination programmes, whereby in the two asymptotic limits analysed, quantitative estimates on the outcomes and effectiveness of these control measures are established.

Cannabis use and risk of schizophrenia: a Mendelian randomization study.

Cannabis use is observationally associated with an increased risk of schizophrenia, but whether the relationship is causal is not known. Using a genetic approach, we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia. Genetic variants were employed as instruments to recapitulate a randomized controlled trial involving two groups (cannabis users vs nonusers) to estimate the causal effect of cannabis use on risk of schizophrenia in 34 241 cases and 45 604 controls from predominantly European descent. Genetically-derived estimates were compared with a meta-analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders. Based on the genetic approach, use of cannabis was associated with increased risk of schizophrenia (odds ratio (OR) of schizophrenia for users vs nonusers of cannabis: 1.37; 95% confidence interval (CI), 1.09-1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.43 (95% CI, 1.19-1.67; P-value for heterogeneity =0.76). The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association (OR of schizophrenia for users vs nonusers of cannabis, adjusted for ever vs never smoker: 1.41; 95% CI, 1.09-1.83). This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia, by suggesting that the relationship is causal. Such robust evidence may inform public health messages about cannabis use, especially regarding its potential mental health consequences.

Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

Persistent socioeconomic and racial and ethnic disparities in pathogen burden in the United States, 1999-2014.

The disproportionate burden of prevalent, persistent pathogens among disadvantaged groups may contribute to socioeconomic and racial/ethnic disparities in long-term health. We assessed if the social patterning of pathogen burden changed over 16 years in a U.S.-representative sample. Data came from 17 660 National Health and Nutrition Examination Survey participants. Pathogen burden was quantified by summing the number of positive serologies for cytomegalovirus, herpes simplex virus-1, HSV-2, human papillomavirus and Toxoplasma gondii and dividing by the number of pathogens tested, giving a percent-seropositive for each participant. We examined sex- and age-adjusted mean pathogen burdens from 1999-2014, stratified by race/ethnicity and SES (poverty-to-income ratio (PIR); educational attainment). Those with a PIR < 1.3 had a mean pathogen burden 1.4-1.8 times those with a PIR > 3.5, with no change over time. Educational disparities were even greater and showed some evidence of increasing over time, with the mean pathogen burden among those with less than a high school education approximately twice that of those who completed more than high school. Non-Hispanic Black, Mexican American and other Hispanic participants had a mean pathogen burden 1.3-1.9 times non-Hispanic Whites. We demonstrate that socioeconomic and racial/ethnic disparities in pathogen burden have persisted across 16 years, with little evidence that the gap is closing.