Search

Background Over half of the South African adults aged 45 years and older have hypertension but its effective management along the treatment cascade (awareness, treatment, and control) remains poorly understood. Methods We compared the prevalence of all stages of the hypertension treatment cascade in the rural HAALSI cohort of older adults at baseline and after four years of follow-up using household surveys and blood pressure data. Hypertension was a mean systolic blood pressure >140 mm Hg or diastolic pressure >90 mm Hg, or current use of anti-hypertension medication. Control was a mean blood pressure Results Prevalence along the treatment cascade increased from baseline (B) to follow-up (F): awareness (64.4% vs. 83.6%), treatment (49.7% vs. 73.9%), and control (22.8% vs. 41.3%). At both time points, women had higher levels of awareness (B: 70.5% vs. 56.3%; F: 88.1% vs. 76.7%), treatment (B: 55.9% vs. 41.55; F: 79.9% vs. 64.7%), and control (B: 26.5% vs. 17.9%; F: 44.8% vs. 35.7%). Prevalence along the cascade increased linearly with age for everyone. Predictors of awareness included being female, elderly, or visiting a primary health clinic three times in the previous 3 months, and the latter two also predicted hypertension control. Conclusions There were significant improvements in awareness, treatment, and control of hypertension from baseline to follow-up and women fared better at all stages, at both time points.

Biomedical datasets are often modeled as knowledge graphs (KGs) because they capture the multi-relational, heterogeneous, and dynamic natures of biomedical systems. KG completion (KGC), can, therefore, help researchers make predictions to inform tasks like drug repositioning. While previous approaches for KGC were either rule-based or embedding-based, hybrid approaches based on neurosymbolic artificial intelligence are becoming more popular. Many of these methods possess unique characteristics which make them even better suited toward biomedical challenges. Here, we survey such approaches with an emphasis on their utilities and prospective benefits for biomedicine., Proceedings of the $\mathit{40}^{th}$ International Conference on Machine Learning: Workshop on Knowledge and Logical Reasoning in the Era of Data-driven Learning (https://klr-icml2023.github.io/schedule.html). PMLR 202, 2023. Condensed, workshop-ready version of previous survey, arXiv:2302.07200 , which is under review. 13 pages (9 content, 4 references), 3 figures, 1 table

By August, 2021, South Africa had been affected by three waves of SARS-CoV-2; the second associated with the beta variant and the third with the delta variant. Data on SARS-CoV-2 burden, transmission, and asymptomatic infections from Africa are scarce. We aimed to evaluate SARS-CoV-2 burden and transmission in one rural and one urban community in South Africa.We conducted a prospective cohort study of households in Agincourt, Mpumalanga province (rural site) and Klerksdorp, North West province (urban site) from July, 2020 to August, 2021. We randomly selected households for the rural site from a health and sociodemographic surveillance system and for the urban site using GPS coordinates. Households with more than two members and where at least 75% of members consented to participate were eligible. Midturbinate nasal swabs were collected twice a week from household members irrespective of symptoms and tested for SARS-CoV-2 using real-time RT-PCR (RT-rtPCR). Serum was collected every 2 months and tested for anti-SARS-CoV-2 antibodies. Main outcomes were the cumulative incidence of SARS-CoV-2 infection, frequency of reinfection, symptomatic fraction (percent of infected individuals with ≥1 symptom), the duration of viral RNA shedding (number of days of SARS-CoV-2 RT-rtPCR positivity), and the household cumulative infection risk (HCIR; number of infected household contacts divided by the number of susceptible household members).222 households (114 at the rural site and 108 at the urban site), and 1200 household members (643 at the rural site and 557 at the urban site) were included in the analysis. For 115 759 nasal specimens from 1200 household members (follow-up 92·5%), 1976 (1·7%) were SARS-CoV-2-positive on RT-rtPCR. By RT-rtPCR and serology combined, 749 of 1200 individuals (62·4% [95% CI 58·1-66·4]) had at least one SARS-CoV-2 infection episode, and 87 of 749 (11·6% [9·4-14·2]) were reinfected. The mean infection episode duration was 11·6 days (SD 9·0; range 4-137). Of 662 RT-rtPCR-confirmed episodes (14 days after the start of follow-up) with available data, 97 (14·7% [11·9-17·9]) were symptomatic with at least one symptom (in individuals aged19 years, 28 [7·5%] of 373 episodes symptomatic; in individuals aged ≥19 years, 69 [23·9%] of 289 episodes symptomatic). Among 222 households, 200 (90·1% [85·3-93·7]) had at least one SARS-CoV-2-positive individual on RT-rtPCR or serology. HCIR overall was 23·9% (195 of 817 susceptible household members infected [95% CI 19·8-28·4]). HCIR was 23·3% (20 of 86) for symptomatic index cases and 23·9% (175 of 731) for asymptomatic index cases (univariate odds ratio [OR] 1·0 [95% CI 0·5-2·0]). On multivariable analysis, accounting for age and sex, low minimum cycle threshold value (≤30 vs30) of the index case (OR 5·3 [2·3-12·4]) and beta and delta variant infection (vs Wuhan-Hu-1, OR 3·3 [1·4-8·2] and 10·4 [4·1-26·7], respectively) were associated with increased HCIR. People living with HIV who were not virally supressed (≥400 viral load copies per mL) were more likely to develop symptomatic illness when infected with SAR-CoV-2 (OR 3·3 [1·3-8·4]), and shed SARS-CoV-2 for longer (hazard ratio 0·4 [95% CI 0·3-0·6]) compared with HIV-uninfected individuals.In this study, 565 (85·3%) SARS-CoV-2 infections were asymptomatic and index case symptom status did not affect HCIR, suggesting a limited role for control measures targeting symptomatic individuals. Increased household transmission of beta and delta variants was likely to have contributed to successive waves of SARS-CoV-2 infection, with more than 60% of individuals infected by the end of follow-up.US CDC, South Africa National Institute for Communicable Diseases, and Wellcome Trust.

By November 2021, after the third wave of severe acute respiratory syndrome coronavirus 2 infections in South Africa, seroprevalence was 60% in a rural community and 70% in an urban community. High seroprevalence before the Omicron variant emerged may have contributed to reduced illness severity observed in the fourth wave.

Neurosymbolic AI is an increasingly active area of research which aims to combine symbolic reasoning methods with deep learning to generate models with both high predictive performance and some degree of human-level comprehensibility. As knowledge graphs are becoming a popular way to represent heterogeneous and multi-relational data, methods for reasoning on graph structures have attempted to follow this neurosymbolic paradigm. Traditionally, such approaches have utilized either rule-based inference or generated representative numerical embeddings from which patterns could be extracted. However, several recent studies have attempted to bridge this dichotomy in ways that facilitate interpretability, maintain performance, and integrate expert knowledge. Within this article, we survey a breadth of methods that perform neurosymbolic reasoning tasks on graph structures. To better compare the various methods, we propose a novel taxonomy by which we can classify them. Specifically, we propose three major categories: (1) logically-informed embedding approaches, (2) embedding approaches with logical constraints, and (3) rule-learning approaches. Alongside the taxonomy, we provide a tabular overview of the approaches and links to their source code, if available, for more direct comparison. Finally, we discuss the applications on which these methods were primarily used and propose several prospective directions toward which this new field of research could evolve., 21 pages, 8 figures, 1 table, currently under review. Corresponding GitHub page here: https://github.com/NeSymGraphs

Background Survival and gonotrophic cycle duration are important determinants of the vectorial capacity of malaria vectors but there are a limited number of approaches to estimate these quantities from field data. Time-series of observations of mosquitoes at different stages in the life-cycle are under-used. Methods Anopheles funestus mosquitoes were caught using various methods over a 7.6-year period in Furvela, Mozambique. Survival and oviposition cycle duration were estimated using (i) an existing time-series approach for analysing dissections of mosquitoes caught in light-traps, extended to allow for variability in the duration of the cycle; (ii) an established approach for estimating cycle duration from resting collection data; (iii) a novel time-series approach fitted to numbers and categories of mosquitoes caught in exit-traps. Results Data were available from 7,396, 6,041 and 1,527 trap-nights for exit-traps, light-traps and resting collections respectively. Estimates of cycle duration varied considerably between the different methods. The estimated proportion of female mosquitoes surviving each day of 0.740 (95% credible interval [0.650–0.815]) derived from light-trap data was much lower than the estimated daily survival of male mosquitoes from the model fitted to exit-trap data (0.881, 95% credible interval [0.747–0.987]). There was no tendency for the oviposition cycle to become shorter at higher temperature while the odds of survival of females through the cycle was estimated to be multiplied by 1.021 for every degree of mean weekly temperature increase (95% credible interval [0.991–1.051]). There was negligible temperature dependence and little inter-annual variation in male survival. Discussion The time-series approach fitted to the exit-traps suggests that male An. funestus have higher survival than do females, and that male survival was temperature independent and unaffected by the introduction of long-lasting insecticidal nets (LLINs). The patterns of temperature dependence in females are at variance with results of laboratory studies. Time series approaches have the advantage for estimating survival that they do not depend on representative sampling of mosquitoes over the whole year. However, the estimates of oviposition cycle duration were associated with considerable uncertainty, which appears to be due to variability between insects in the duration of the resting period, and the estimates based on exit-trap data are sensitive to assumptions about relative trapping efficiencies.

South Africa has introduced regulations to reduce sodium in processed foods. Assessing salt consumption with 24-h urine collection is logistically challenging and expensive. We assess the accuracy of using spot urine samples to estimate 24-h urine sodium (24hrUNa) excretion at the population level in a cohort of older adults in rural South Africa.24hrUNa excretion was measured and compared to that estimated from matched spot urine samples in 399 individuals, aged 40-75 years, from rural Mpumalanga, South Africa. We used the Tanaka, Kawasaki, International Study of Sodium, Potassium, and Blood Pressure (INTERSALT), and Population Mean Volume (PMV) method to predict 24hrUNa at the individual and population level.The population median 24hrUNa excretion from our samples collected in 2017 was 2.6 g (interquartile range: 1.53-4.21) equal to an average daily salt intake of 6.6 g, whereas 65.4% of participants had a salt excretion above the WHO recommended 5 g/day. Estimated population median 24hrUNa derived from the INTERSALT, both with and without potassium, showed a nonsignificant difference of 0.25 g (P = 0.59) and 0.21 g (P = 0.67), respectively. In contrast, the Tanaka, Kawasaki, and PMV formulas were markedly higher than the measured 24hrUNa, with a median difference of 0.51 g (P = 0.004), 0.99 g (P = 0.00), and 1.05 g (P = 0.00) respectively. All formulas however performed poorly when predicting an individual's 24hrUNa.In this population, the INTERSALT formulas are a well suited and cost-effective alternative to 24-h urine collection for the evaluation of population median 24hrUNa excretion. This could play an important role for governments and public health agencies in evaluating local salt regulations and identifying at-risk populations.

IntroductionThere has been a recent resurgence in nicotine inhalation in adolescents due to the popularity and availability of Electronic Nicotine Delivery Systems (ENDS). Data show almost five times as many US high-school seniors inhale nicotine vapor daily compared with those who smoke tobacco. This study was conducted to determine the impact of repeated adolescent vapor inhalation of nicotine on behavior in adulthood in rats.MethodsMale and female Sprague-Dawley rats were exposed to 30-minute sessions of ENDS vapor inhalation, twice daily, from Post-Natal Day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle or nicotine (30 mg/mL in the PG). Animals were assessed for effects of nicotine on open field (PND 74-105) and wheel activity (PND 126-180) and for the self-administration of nicotine vapor (PND 285-395). Plasma levels of nicotine and cotinine were assessed in separate groups of male and female Wistar and Sprague-Dawley rats after a single nicotine inhalation session.ResultsGroup mean plasma nicotine ranged from 39 to 59 ng/mL post-session with minimal strain or sex differences detected. Adolescent nicotine exposure modestly enhanced sensitivity to the locomotor stimulating effects of nicotine (0.1-0.8 mg/kg, s.c.) in an open field in female rats, but didn’t change effects of nicotine on wheel activity. Female rats exposed to nicotine (30 mg/mL) vapor as adolescents responded more vigorously than PG exposed females for nicotine vapor in a FR5 challenge.ConclusionsThe data suggest repeated adolescent nicotine vapor inhalation leads to enhanced liability for nicotine self-administration in adulthood in female rats, but minimal change in spontaneous locomotor behavior.

This study is part of the promotion of local medicinal plants by highlighting their spermicidal activity. An ethnobotanical survey carried out in Kinshasa made it possible to identify the plants used in female intimate hygiene. On the one hand, the aqueous extracts of the organs of ten (10) plants on the inventoried species were subjected to a phytochemical analysis. On the other hand, the recipes as applied by women as well as the total extracts of these plants have come into contact with human sperm. The analysis of the mobility and the evaluation of the viability of the sperm of the ejaculates, of good quality according to the WHO, were carried out according to the methods of Sander-Cramer and that of Williams, respectively. Thus, the concentration (EC100) capable of killing 100% of sperm within 30 minutes of exposure was detected. Thirty-eight (38) plant species have been identified. From thirteen sought-after phytochemical groups, extracts of Mangifera indica and Bridelia ferruginea contain twelve and eleven respectively. Four (4) groups of metabolic compounds with a contraceptive effect are present in all ten extracts of feminine hygiene plants. Three (3) herbal recipes (Abrus precatorius, Bridelia ferruginea and Ocimum basilicum) out of the ten studied resulted in the cancellation of sperm mobility after 3 hours of exposure. And, the EC100 is defined at 200 mg/mL for A. precatorius and 25 mg / mL for B. ferruginea. The results of this study show that feminine intimate hygiene plants contain compounds with spermicidal potential, which can be used for the development of vaginal contraceptives.

The aim of this study was to determine the phytochemical composition and micrographic characteristics of the plants consumed by Okapia johnstoni. The results indicate that each plant species has characteristic microscopic elements for its identification. These plants are rich in phenolic acids, anthocyanins, flavonoids, anthraquinones, coumarins, terpenoids and iridoids. Alchornea cordifolia is richer in total polyphenols (198.53±3.39 mg GAE/g DM) followed respectively by Musanga cercopioides (91.87±6.71 mg GAE/g DM), Macaranga spinosa (59.65±6.54 mg GAE/g DM), Ficus vallis-choudae (46.37±2.43 mg GAE/g DM), Cola acuminata (38.83±4.04 mg GAE/g DM), Pycnanthus angolensis (31.96±3.45 mg GAE/g DM), Alstonia boonei (31.55±1.60 mg GAE/g DM) and Trilepisium madagascariensis (25.18±0.99 mg GAE/g DM). As for flavonoids, the highest content is obtained in T. madagascariensis followed respectively by A. boonei, Pycnanthus angolensis, Cola acuminata, M. spinosa, F. vallis-choudae, M. cercopioides and A. cordifolia. The difference in the content of secondary metabolites is justified by the fact that their expression in the plant is a function of both abiotic and biotic factors and the specificity of each plant species linked to its genetic make-up. The characterization of these chemical compounds is necessary for the formulation of herbal medicines for the management of Okapi ex situ or for human health. Also, the microscopic profiles of the leaves powder of the studied plant species provide relevant information, which may be helpful for the plant authentication and for quality control of raw material.

South Africa was among the first countries to detect the SARS-CoV-2 Omicron variant. Propelled by increased transmissibility and immune escape properties, Omicron displaced other globally circulating variants within 3 months of its emergence. Due to limited testing, Omicron’s attenuated clinical severity, and an increased risk of reinfection, the size of the Omicron BA.1 and BA.2 subvariants (BA.1/2) wave remains poorly understood in South Africa and in many other countries. Using South African data from urban and rural cohorts closely monitored since the beginning of the pandemic, we analyzed sequential serum samples collected before, during, and after the Omicron BA.1/2 wave to infer infection rates and monitor changes in the immune histories of participants over time. Omicron BA.1/2 infection attack rates reached 65% (95% CI, 60% – 69%) in the rural cohort and 58% (95% CI, 61% – 74%) in the urban cohort, with repeat infections and vaccine breakthroughs accounting for >60% of all infections at both sites. Combined with previously collected data on pre-Omicron variant infections within the same cohorts, we identified 14 distinct categories of SARS-CoV-2 antigen exposure histories in the aftermath of the Omicron BA.1/2 wave, indicating a particularly fragmented immunologic landscape. Few individuals (

Understanding the build-up of immunity with successive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and the epidemiological conditions that favor rapidly expanding epidemics will help facilitate future pandemic control. We analyzed high-resolution infection and serology data from two longitudinal household cohorts in South Africa to reveal high cumulative infection rates and durable cross-protective immunity conferred by prior infection in the pre-Omicron era. Building on the history of past exposures to different SARS-CoV-2 variants and vaccination in the cohort most representative of South Africa’s high urbanization rate, we used mathematical models to explore the fitness advantage of the Omicron variant and its epidemic trajectory. Modeling suggests that the Omicron wave likely infected a large fraction (44 to 81%) of the population, leaving a complex landscape of population immunity primed and boosted with antigenically distinct variants. We project that future SARS-CoV-2 resurgences are likely under a range of scenarios of viral characteristics, population contacts, and residual cross-protection.

ObjectiveWe seek to understand the coexisting effects of population aging and a rising burden of diabetes on healthy longevity in South Africa.Research Design and MethodsWe used longitudinal data from the 2015 and 2018 waves of the “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI) study to explore life expectancy (LE) and disability-free life expectancy (DFLE) of adults aged 45 and older with and without diabetes in rural South Africa. We estimated LE and DFLE by diabetes status using Markov-based microsimulation.ResultsWe find a clear gradient in remaining LE and DFLE based on diabetes status. At age 45, a man without diabetes could expect to live 7.4 [95% CI 3.4 – 11.7] more years than a man with diabetes, and a woman without diabetes could expect to live 3.9 [95% CI: 0.8 – 6.9] more years than a woman with diabetes. Individuals with diabetes lived proportionately more years subject to disability than individuals without diabetes. Additional analyses separating individuals with diabetes based on whether they knew their disease status found that individuals with diabetes diagnosed by a healthcare worker had shorter remaining LE than those who were unaware of their status or those without diabetes.ConclusionsOur findings highlight the large and important decrements in healthy, disability-free aging for people with diabetes in South Africa. This finding should motivate efforts to strengthen prevention and treatment efforts for diabetes and its complications for older adults in this setting.

RationaleOpioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use, and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms.ObjectivesTo determine if heroin and Δ9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature, and spontaneous locomotor activity when inhaled or injected.MethodsGroups of female and male rats, implanted with radiotelemetry transmitters, were exposed to vapor generated from heroin (50mg/mL in propylene glycol vehicle; PG), THC (50mg/mL), or the combination for assessment of effects on temperature and activity. Thermal nociception was assessed with a warm water tail-withdrawal assay.ResultsHeroin inhalation increased temperature and activity whereas THC inhalation decreased temperature and activity in both female and male Sprague-Dawley rats. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5mg/kg, s.c.) and THC (10mg/kg, i.p.) alone and in combination. In contrast, the co-administration of heroin and THC by either inhalation or injection produced additive effects on thermal nociception in both male and female Sprague-Dawley and Wistar rats.ConclusionsThis study shows that additive effects of THC with an opioid on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.

Identifying groups of patients with similar morbid-ity profiles can help us understand the relationships between their pre-existing conditions and the risks of adverse events in the ICU. To find such groups, common approaches apply clustering algorithms such as k-means and latent class analysis. However, these techniques present drawbacks such as the lack of principled methods for choosing the number of clusters, the need for assumptions about the relationships between variables, and outputs which are hard to explain. To overcome these limitations, we map the problem of patient clustering to that of community detection in complex networks. We construct a bipartite network in which nodes represent patients and their features, including morbidities and demographics. Then, we find homogeneous groups of patients using stochastic block modeling (SBM), an unsupervised probabilistic approach to find structure in networks. We show that this approach has several advantages over traditional clustering methods, and enables us to retrieve more fine-grained clusters that are commonly missed by existing approaches. We also show that these clusters have a stronger relationship with mortality and sepsis rates of patients in the ICU.

We introduce a theorem proving approach to the specification and generation of temporal logical constraints for training neural networks. We formalise a deep embedding of linear temporal logic over finite traces (LTL$_f$) and an associated evaluation function characterising its semantics within the higher-order logic of the Isabelle theorem prover. We then proceed to formalise a loss function $\mathcal{L}$ that we formally prove to be sound, and differentiable to a function $d\mathcal{L}$. We subsequently use Isabelle's automatic code generation mechanism to produce OCaml versions of LTL$_f$, $\mathcal{L}$ and $d\mathcal{L}$ that we integrate with PyTorch via OCaml bindings for Python. We show that, when used for training in an existing deep learning framework for dynamic movement, our approach produces expected results for common movement specification patterns such as obstacle avoidance and patrolling. The distinctive benefit of our approach is the fully rigorous method for constrained training, eliminating many of the risks inherent to ad-hoc implementations of logical aspects directly in an "unsafe" programming language such as Python.

BackgroundAfter decades of success in reducing malaria through the scale-up of pyrethroid long-lasting insecticidal nets (LLINs), malaria decline has stalled, coinciding with the rapid spread of pyrethroid resistance. A new class of net, treated with a mixture of a pyrethroid and a synergist, piperonyl butoxide (PBO), demonstrated superior efficacy compared to standard (std) pyrethroid LLINs against malaria in an area of intense pyrethroid resistance, reducing malaria prevalence by 44% over 2 years in the present trial. However, an important question is left unanswered regarding the performance of this PBO-LLIN over the World Health Organization recommended lifespan of 3 years for LLINs.Methods and FindingsWe conducted a four-arm randomized controlled trial using a two-by-two factorial design that evaluated the effectiveness of PBO-LLIN arms (12 clusters PBO-LLIN alone and 12 clusters PBO-LLIN + Indoor Residual Spraying; IRS) compared to std-LLIN (12 clusters std-LLIN alone and 12 clusters std-LLIN + IRS) and IRS arms versus no IRS arms from January 2014 to December 2017 in Muleba, Tanzania. Malaria infection prevalence in 80 children, 6 months to 14 years, per cluster was measured twice a year and analysed in an intention to treat (ITT) and per protocol (PP) approach. Density of malaria mosquito vectors and entomological inoculation rate (EIR) were assessed monthly in 7 houses per cluster. Logistic regression allowing for within cluster correlation of responses was used to compare malaria prevalence between PBO-LLIN groups vs std-LLIN groups and IRS groups vs no IRS groups during the third-year follow-up at 28- and 33-months post-intervention. No further IRS was conducted after the first spray round in 2015; as yearly IRS is recommended by WHO, results need to be interpreted in light of this limitation. Vector density and EIR were analysed using negative binomial regression. Malaria results were available for 7471 children. At 28 months, malaria infection prevalence was lower in the PBO-LLIN groups (69.3%) compared to the std-LLIN groups (80.9%, Odds Ratio: 0.45, 95% Confidence Interval: 0.21-0.95, p value: 0.0364). The effect was weaker at 33 months post-intervention (OR: 0.60, 95%CI:0.32-1.13, p value: 0.1131), in the ITT analysis but still evident in the PP analysis (OR: 0.34, 95%CI: 0.16-0.71, p value: 0.0051). At this time point, net usage in household participants was 31% and PBO concentration in PBO-LLINs was reduced by 96% compared to those of new nets. A total of 17,451 Anopheles mosquitoes were collected during the 3150 collection nights done in the third year. There was no reduction in EIR (DR: 0.63, 95%CI: 0.25-1.61, p value: 0.3296) between the PBO groups and std-LLIN groups or between IRS and no IRS groups (DR: 0.7, 95%CI: 0.41-2.28, p value: 0.9426).ConclusionsPBO-LLINs no longer provided community protection from malaria infection, compared to std-LLINs by the third year of use due to low net usage. Children still sleeping under PBO-LLINs had lower odds of infection than those sleeping under a std-LLIN, however prevalence remained unacceptably high. It is urgent that net distribution frequencies and effective lifespan of this class of LLIN are aligned for maximum impact.Trial registrationClinicalTrials.govNCT02288637Author summaryWhy was the study done?Widespread insecticide resistance among major malaria mosquito populations threatens control efforts worldwide.A new class of long-lasting insecticidal net (LLIN), containing a pyrethroid insecticide and a synergist, piperonyl butoxide (PBO), improves insecticide toxicity by inhibiting metabolic enzyme activity, responsible for insecticide resistance.PBO-LLINs reduced malaria prevalence by 44% in Tanzania and 27% in Uganda, compared to standard pyrethroid-only LLINs, in two 24-month cluster randomised controlled trials (CRTs), as conducted per World Health Organization (WHO) recommendations.However, LLIN deployment regimens are currently based on 3 years assumed functional survival for nets, with questions remaining, regarding the effectiveness of PBO-LLINs to prevent malaria after 3 years of continuous field use.What did the researchers do and find?A 24-month CRT in Muleba, Tanzania, an area of high pyrethroid resistance, was extended for one year to assess the impact of PBO-LLINs, compared to pyrethroid-only LLINs, on malaria infection, after 3 years of use, corresponding to their expected lifespan.After 28 months, malaria infection prevalence was still lower in users of PBO-LLINs, compared to standard LLINs, but this effect was lost by 33 months in the intention to treat (ITT) analysis but was still evident in the per protocol (PP) analysis.No reduction in vector density or entomological inoculation rate was evident after 3 years of use.Reasons underlying the poorer PBO-LLIN performance after 36 months, included declining net usage, poor netting durability and diminished PBO synergist content.What do these findings mean?By 3 years of continuous field use, PBO-LLINs no longer provided community protection from malaria infection, compared to pyrethroid-only LLINs, however children sleeping under a PBO-LLIN still retained a level of protection compared to those sleeping under a standard pyrethroid-only LLIN.To maximise the impact of PBO-LLINs, net procurement and replacement strategies, must be modified to maintain high coverage.Future CRTs and additional community studies are required to determine the effective lifespan of new classes of LLINs for appropriate incorporation into resistance management schemes, to preserve gains made in malaria control over the past two decades.

Importance The most appropriate therapy for older adults with multimorbidity may depend on life expectancy (ie, mortality risk), and several scores have been developed to predict 1-year mortality risk. However, often, these mortality risk scores have not been externally validated in large sample sizes, and a head-to-head comparison in a prospective contemporary cohort is lacking. Objective To prospectively compare the performance of 6 scores in predicting the 1-year mortality risk in hospitalized older adults with multimorbidity. Design, Setting, and Participants This prognostic study analyzed data of participants in the OPERAM (Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People) trial, which was conducted between December 1, 2016, and October 31, 2018, in surgical and nonsurgical departments of 4 university-based hospitals in Louvain, Belgium; Utrecht, the Netherlands; Cork, Republic of Ireland; and Bern, Switzerland. Eligible participants in the OPERAM trial had multimorbidity (≥3 coexisting chronic diseases), were aged 70 years or older, had polypharmacy (≥5 long-term medications), and were admitted to a participating ward. Data were analyzed from April 1 to September 30, 2020. Main Outcomes and Measures The outcome of interest was any-cause death occurring in the first year of inclusion in the OPERAM trial. Overall performance, discrimination, and calibration of the following 6 scores were assessed: Burden of Illness Score for Elderly Persons, CARING (Cancer, Admissions ≥2, Residence in a nursing home, Intensive care unit admit with multiorgan failure, ≥2 Noncancer hospice guidelines) Criteria, Charlson Comorbidity Index, Gagné Index, Levine Index, and Walter Index. These scores were assessed using the following measures: Brier score (0 indicates perfect overall performance and 0.25 indicates a noninformative model); C-statistic and 95% CI; Hosmer-Lemeshow goodness-of-fit test and calibration plots; and sensitivity, specificity, and positive and negative predictive values. Results The 1879 patients in the study had a median (IQR) age of 79 (74-84) years and 835 were women (44.4%). The median (IQR) number of chronic diseases was 11 (8-16). Within 1 year, 375 participants (20.0%) died. Brier scores ranged from 0.16 (Gagné Index) to 0.24 (Burden of Illness Score for Elderly Persons). C-statistic values ranged from 0.62 (95% CI, 0.59-0.65) for Charlson Comorbidity Index to 0.69 (95% CI, 0.66-0.72) for the Walter Index. Calibration was good for the Gagné Index and moderate for other mortality risk scores. Conclusions and Relevance Results of this prognostic study suggest that all 6 of the 1-year mortality risk scores examined had moderate prognostic performance, discriminatory power, and calibration in a large cohort of hospitalized older adults with multimorbidity. Overall, none of these mortality risk scores outperformed the others, and thus none could be recommended for use in daily clinical practice.

Background: Weight loss is the cornerstone of therapy for people with overweight/obesity. Pemvidutide is a dual GLP-1/glucagon receptor agonist that provides GLP-1/glucagon agonism in a balanced (1:1) ratio, which is hypothesized to enhance weight loss and minimize gastrointestinal intolerance. Methods: 34 subjects with overweight/obesity (BMI 25.0-40.0 kg/m2) without diabetes were randomized in double-blind manner to pemvidutide (1.2, 1.8 or 2.4 mg) or placebo subcutaneously weekly for 12 weeks without dose titration or lifestyle therapy. Study endpoints included safety/tolerability, weight loss and cardiometabolic outcomes. Results: At 12 weeks, significant weight loss was achieved with 1.8 mg (10.3%) and 2.4 mg (9.0%) of pemvidutide, and significant improvements or trends in cardiometabolic risk factors were observed at all pemvidutide doses (Table 1) . No increases in heart rate, fasting glucose or HbA1c were observed in any group. Mild, transient nausea was the most frequent adverse event (AE) ; no severe/serious AEs or AE-related study discontinuations were reported. Conclusion: Pemvidutide induces robust weight loss and improves cardiometabolic risk factors without dose titration. These data support the development of pemvidutide as a promising treatment for obesity and its comorbidities. Disclosure S.Klein: Advisory Panel; Altimmune, Consultant; Janssen Research & Development, LLC, ProSciento, Research Support; Janssen Research & Development, LLC. S.K.Browne: Employee; Altimmune. J.J.Nestor: Consultant; Altimmune, Employee; EuMederis Pharmaceutials, Inc., Mederis Diabetes, LLC, Spitfire Pharma, Inc. M.Harris: Employee; Altimmune. A.Suyundikov: Employee; Altimmune. R.Casper: Employee; Altimmune. S.M.Steele: Employee; Altimmune. J.D.Payne: None. V.Krishnan: Employee; Altimmune. M.Roberts: Employee; Altimmune. Funding Altimmune, Inc.

Aim: The aim of this work is to evaluate the spermicidal, antimicrobial activity of Oncoba welwitchii Oliv. This will justify its use on reproductive health especially in the occurrence of infertility and the imbalance of vaginal flora. Carried out at the Department of Biology of the Faculty of Sciences of the University of Kinshasa, between January and May 2019, this study was initiated to determine the effect of the use of O. welwitchii Oliv. on human spermatozoa and vaginal microorganisms. Methodology: The leaves of O. welwitchii Oliv. were collected and identified at University of Kinshasa. The spermicidal effect was performed by the Sander-Cramer method and antibacterial activity were evaluated by liquid dilution method. Results: The results revealed that the juice of the leaves of O. welwitchii Oliv. have a spermicidal effect, as this juice reduce the initial mobility of the spermatozoids after 60 minutes of the exposure from 72±12% to 1±2% and their initial viability from 74±11% to 10±18%. This juice has shown bacteriostatic effects against Escherichia coli and Staphylococcus aureus (MBC/MIC > 4) and bactericidal effects against Lactobacilus acidophilus (MBC/MIC ≤ 4). Conclusion: This study gives additional information on the phytochemistry composition and a spermicidal effects of O. welwitchii Oliv. The spermicidal effects of this plant could be associated to its acidity. It should be noted that to the best of our knowledge, no study on the phytochemistry of O. welwitchii Oliv. is available in the literature.

Aim: The main aim of the present study is to validate the bioactivity of O. basilicum, a medicinal plant traditionally used to treat helminthiasis in DRC. Place and Duration of Study: Department of Chemistry, Science Faculty, University of Kinshasa, between June 2018 and March 2019. Methodology: Different parts (stems, leaves and flowers) of O. basilicum and specimens of earthworms of Benhamia rosea were collected and identified at University of Kinshasa. Micrographic examination was carried out using Biolux NV microscope and X-ray fluorescence method for mineral content determination. Radical scavenging activity was performed using the ABTS radical test. Results: Microscopic analysis of O. basilicum powder revealed various histological elements like crystalline fibres, sclerotic fibres, fragments of spiral vessels, pluricellular hairs and glandular hairs. Phytochemical screening in solution and by TLC revealed the presence of polyphenols (flavonoids, anthocyanins, saponins), alkaloids, steroids, coumarins, terpenoids, irridoids and anthraquinones. 20 elements including calcium, sodium, potassium, phosphorus, magnesium, sulphur, chlorine, aluminium, manganese, iron, zinc, copper, strontium, rubidium, bromine, silver, vanadium, neodymium, silicium and lead were determined. The aqueous extract of O. basilicum showed good dose-dependent antihelminthic activity and radical scavenging activity with IC50: 27.04 ± 4.58 µg/mL. Conclusion: This study provides an additional information on the mineral composition and antihelminthic activity of O. basilicum growing in DRC. The antihelminthic activity of this plant could be associated to the presence of flavonoids. To the current knowledge, no study on the histological elements of O. basilicum is available in the literature.

BackgroundAfter mating, female mosquitoes need animal blood to develop their eggs. In the process of acquiring blood, they may acquire pathogens, which may cause different diseases to humans such as malaria, zika, dengue, and chikungunya. Therefore, knowing the parity status of mosquitoes is useful in control and evaluation of infectious diseases transmitted by mosquitoes, where parous mosquitoes are assumed to be potentially infectious. Ovary dissections, which currently are used to determine the parity status of mosquitoes, are very tedious and limited to very few experts. An alternative to ovary dissections is near-infrared spectroscopy (NIRS), which can estimate the age in days and the infectious state of laboratory and semi-field reared mosquitoes with accuracies between 80 and 99%. No study has tested the accuracy of NIRS for estimating the parity status of wild mosquitoes.Methods and resultsIn this study, we train artificial neural network (ANN) models on NIR spectra to estimate the parity status of wild mosquitoes. We use four different datasets: An. arabiensis collected from Minepa, Tanzania (Minepa-ARA); An. gambiae collected from Muleba, Tanzania (Muleba-GA); An. gambiae collected from Burkina Faso (Burkina-GA); and An.gambiae from Muleba and Burkina Faso combined (Muleba-Burkina-GA). We train ANN models on datasets with spectra preprocessed according to previous protocols. We then use autoencoders to reduce the spectra feature dimensions from 1851 to 10 and re-train ANN models. Before the autoencoder was applied, ANN models estimated parity status of mosquitoes in Minepa-ARA, Muleba-GA, Burkina-GA and Muleba-Burkina-GA with out-of-sample accuracies of 81.9 ± 2.8% (N=927), 68.7 ± 4.8% (N=140), 80.3 ± 2.0% (N=158), and 75.7 ± 2.5% (N=298), respectively. With the autoencoder, ANN models tested on out-of-sample data achieved 97.1 ± 2.2%, (N=927), 89.8 ± 1.7% (N=140), 93.3 ± 1.2% (N=158), and 92.7 ± 1.8% (N=298) accuracies for Minepa-ARA, Muleba-GA, Burkina-GA, and Muleba-Burkina-GA, respectively.ConclusionThese results show that a combination of an autoencoder and an ANN trained on NIR spectra to estimate parity status of wild mosquitoes yields models that can be used as an alternative tool to estimate parity status of wild mosquitoes, especially since NIRS is a high-throughput, reagent-free, and simple-to-use technique compared to ovary dissections.

Two billion pyrethroid long-lasting insecticidal nets (LLINs) have been distributed since 2010 for malaria prevention in Sub-Saharan Africa. Current malaria control strategies rely on an assumed effective 3-year lifespan for LLINs. PBO synergist LLINs are a newly recommended class but there is limited information on their life span and long-term protective efficacy in communities. To assess their operational survival, a cohort of 390 PBO LLINs (Olyset Plus) and 367 standard pyrethroid LLIN (Olyset net) from 396 households were followed for 36 months in Western Tanzania. To assess the association between the condition of the LLIN and malaria infection, nets from at least 480 randomly selected households were assessed during malaria prevalence cross-sectional surveys at 4, 9, 16, 21, 28, and 33 months post-distribution. Information on the presence and condition of nets, and demographic information from the household, were collected to evaluate factors influencing net durability. After 3 years less than 17% of nets distributed were available for sleeping. The fabric condition was not associated with malaria infection in either type of net. The difference between the net types was highest when nets were between 1-2 years old, when PBO nets appeared to be similarly protective as nets less than a year old, whereas standard nets were considerably less protective as they aged, regardless of fabric condition. There was no statistical difference in the estimated median functional survival time between net types with 1.6 years (95% CI 1.38-1.87) for PBO LLIN and 1.9 years (95% CI 1.67-2.06) for standard LLINs. After 3 years, there was a loss of 55% of permethrin content for both nets, and 97% of PBO content was lost in PBO LLIN. These results highlight that functional survival is less than the recommended 3 years for both net types. However, even as the nets age, the PBO nets remained more protective than standard nets, regardless of their condition.

Long lasting insecticidal nets (LLINs) are a proven tool to reduce malaria transmission, but in Africa efficacy is being reduced by pyrethroid resistance in the major vectors. A previous study that was conducted in Muleba district, Tanzania indicated possible involvement of cytochrome P450 monooxygenases in a pyrethroid resistance in An. gambiae population where pre-exposure to piperonyl butoxide (PBO) followed by permethrin exposure in CDC bottle bioassays led to partial restoration of susceptibility. PBO is a synergist that can block pyrethroid-metabolizing enzymes in a mosquito. Insecticide resistance profiles and underlying mechanisms were investigated in Anopheles gambiae and An. funestus from Muleba during a cluster randomized trial. Diagnostic dose bioassays using permethrin, together with intensity assays, suggest pyrethroid resistance that is both strong and very common, but not extreme. Transcriptomic analysis found multiple P450 genes over expressed including CYP6M2, CYP6Z3, CYP6P3, CYP6P4, CYP6AA1 and CYP9K1 in An. gambiae and CYP6N1, CYP6M7, CYP6M1 and CYP6Z1 in An. funestus. Indeed, very similar suites of P450 enzymes commonly associated with resistant populations elsewhere in Africa were detected as over expressed suggesting a convergence of mechanisms across Sub-Saharan African malaria vectors. The findings give insight into factors that may correlate with pyrethroid PBO LLIN success, broadly supporting model predictions, but revision to guidelines previously issued by the World Health Organization is warranted.

Supplemental Material, sj-pdf-1-cob-10.1177_26335565221081288 for Definition of patient complexity in adults: A narrative review by Stefanie Nicolaus, Baptiste Crelier, Jacques D Donz��, and Carole E Aubert in Journal of Comorbidity

Conformance checking techniques allow us to evaluate how well some exhibited behaviour, represented by a trace of monitored events, conforms to a specified process model. Modern monitoring and activity recognition technologies, such as those relying on sensors, the IoT, statistics and AI, can produce a wealth of relevant event data. However, this data is typically characterised by noise and uncertainty, in contrast to the assumption of a deterministic event log required by conformance checking algorithms. In this paper, we extend alignment-based conformance checking to function under a probabilistic event log. We introduce a weighted trace model and weighted alignment cost function, and a custom threshold parameter that controls the level of confidence on the event data vs. the process model. The resulting algorithm considers activities of lower but sufficiently high probability that better align with the process model. We explain the algorithm and its motivation both from formal and intuitive perspectives, and demonstrate its functionality in comparison with deterministic alignment using real-life datasets., Comment: Extended version

How to be sure that we keep our faith in Christ, and how do we know the will of God? The Holy Spirit will lead Christians to faith and will preserve their faith in Christ. Based on Martin Luther´s writings, this project is about how the Holy Spirit guides Christians to live according to God´s will.

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

O mapeamento sistemático apresentado neste artigo teve como objetivo principal produzir um panorama quantitativo geral das experiências, pesquisas científicas e trabalhos acadêmicos relacionados ao desenvolvimento e à aplicação de Recursos Educacionais Digitais (RED) no contexto da educação básica brasileira. Foram considerados estudos primários publicados no ano de 2020 em veículos brasileiros cujos escopos contemplam a Informática na Educação e a Educação em Computação. Os resultados apresentados contribuem com subsídios quantitativos para o entendimento geral de tal contexto de desenvolvimento e aplicação de RED, bem como representam dados confiáveis sobre pesquisas correlatas disponíveis a pesquisadores que atuam em linhas de pesquisa relacionadas ao tema.

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-hour sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature postsynaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats) however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (postsynaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1mM U50488) and KOR antagonism (200nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

This is the accepted manuscript version of the work published in its final form as Charlwood, J. D., & Kampango, A. (2021). Knockdown times in a simple assay determination of insecticide resistance in malaria vectors.Transactions of The Royal Society of Tropical Medicine and Hygiene,115(11), 1348-1349. https://doi.org/10.1093/trstmh/trab140 Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

Rationale Despite a long history of use in synaptic physiology, the lobster has been a neglected model for behavioral pharmacology. A restaurateur proposed that exposing lobster to cannabis smoke reduces anxiety and pain during the cooking process. It is unknown if lobster gill respiration in air would result in significant Δ9-tetrahydrocannabinol (THC) uptake and whether this would have any detectable behavioral effects. Objective The primary goal was to determine tissue THC levels in the lobster after exposure to THC vapor. Secondary goals were to determine if THC vapor altered locomotor behavior or nociception. Methods Tissue samples were collected (including muscle, brain and hemolymph) from Homarus americanus (N = 3 per group) following 30 or 60 min of exposure to vapor generated by an e-cigarette device using THC (100 mg/mL in a propylene glycol vehicle). Separate experiments assessed locomotor behavior and hot water nociceptive responses following THC vapor exposure. Results THC vapor produced duration-related THC levels in all tissues examined. Locomotor activity was decreased (distance, speed, time-mobile) by 30 min inhalation of THC. Lobsters exhibit a temperature-dependent withdrawal response to immersion of tail, antennae or claws in warm water; this is novel evidence of thermal nociception for this species. THC exposure for 60 min had only marginal effect on nociception under the conditions assessed. Conclusions Vapor exposure of lobsters, using an e-cigarette based model, produces dose-dependent THC levels in all tissues and reduces locomotor activity. Hot water nociception was temperature dependent, but only minimal anti-nociceptive effect of THC exposure was confirmed.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors. Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

The α-pyrrolidino-phenone cathinone stimulants first came to widespread attention because of bizarre behavior consequent to the use of α-pyrrolidinopentiophenone (α-PVP, "flakka") reported in popular press. As with other designer drugs, diversification of cathinones has been driven by desirable subjective effects, but also by attempts to stay ahead of legal controls of specific molecules. The α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinopropiophenone (α-PPP) compounds have been relatively under-investigated relative to α-PVP and provide a key opportunity to also investigate structure-activity relationships, i.e., how the extension of the alpha carbon chain may affect potency or efficacy. Female rats were used to contrast the effects of α-PHP and α-PPP with those of α-PVP in altering wheel activity and effects on spontaneous locomotion, temperature and intracranial self-stimulation reward. The α-PPP, α-PHP and α-PVP compounds (5, 10 mg/kg, i.p.) suppressed wheel activity. Inhalation of α-PHP or α-PVP also suppressed wheel activity, but for an abbreviated duration compared with the injection route. Spontaneous activity was increased, and brain reward thresholds decreased, in a dose-dependent manner by all three compounds; only small decrements in body temperature were observed. These data show that all three of the α-pyrrolidino-phenone cathinones exhibit significant stimulant-like activity in female rats. Differences were minor and abuse liability is therefore likely to be equivalent for all three α-pyrrolidino-phenones.

Prediction of survival in patients diagnosed with a brain tumour is challenging because of heterogeneous tumour behaviours and responses to treatment. Better estimations of prognosis would support treatment planning and patient support. Advances in machine learning have informed development of clinical predictive models, but their integration into clinical practice is almost non-existent. One reasons for this is the lack of interpretability of models. In this paper, we use a novel brain tumour dataset to compare two interpretable rule list models against popular machine learning approaches for brain tumour survival prediction. All models are quantitatively evaluated using standard performance metrics. The rule lists are also qualitatively assessed for their interpretability and clinical utility. The interpretability of the black box machine learning models is evaluated using two post-hoc explanation techniques, LIME and SHAP. Our results show that the rule lists were only slightly outperformed by the black box models. We demonstrate that rule list algorithms produced simple decision lists that align with clinical expertise. By comparison, post-hoc interpretability methods applied to black box models may produce unreliable explanations of local model predictions. Model interpretability is essential for understanding differences in predictive performance and for integration into clinical practice.

RationaleDespite a long history of use in synaptic physiology, the lobster has been a neglected model for behavioral pharmacology. A restaurateur proposed that exposing lobster to cannabis smoke reduces anxiety and pain during the cooking process. It is unknown if lobster gill respiration in air would result in significant Δ9-tetrahydrocannabinol (THC) uptake and whether this would have any detectable behavioral effects.ObjectiveThe primary goal was to determine tissue THC levels in the lobster after exposure to THC vapor. Secondary goals were to determine if THC vapor altered locomotor behavior or nociception.MethodsTissue samples were collected (including muscle, brain and hemolymph) from Homarus americanus (N=3 per group) following 30 or 60 minutes of exposure to vapor generated by an e-cigarette device using THC (100 mg/mL in a propylene glycol vehicle). Separate experiments assessed locomotor behavior and hot water nociceptive responses following THC vapor exposure.ResultsTHC vapor produced duration-related THC levels in all tissues examined. Locomotor activity was decreased (distance, speed, time-mobile) by 30 min inhalation of THC. Lobsters exhibit a temperature-dependent withdrawal response to immersion of tail, antennae or claws in warm water; this is novel evidence of thermal nociception for this species. THC exposure for 60 minutes had only marginal effect on nociception under the conditions assessed.ConclusionsVapor exposure of lobsters, using an e-cigarette based model, produces dose-dependent THC levels in all tissues and reduces locomotor activity. Hot water nociception was temperature dependent, but only minimal anti-nociceptive effect of THC exposure was confirmed.

Author(s): Nguyen, Jacques D; Creehan, Kevin M; Kerr, Tony M; Taffe, Michael A | Abstract: Background and purposeAdolescents are regularly exposed to ∆9 -tetrahydrocannabinol (THC) via smoking and, more recently, vaping cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response to THC.Experimental approachesMale and female rats inhaled THC vapour, or that from the propylene glycol (PG) vehicle, twice daily for 30nmin from postnatal day (PND) 35-39 and PND 42-46 using an e-cigarette system. Thermoregulatory responses to vapour inhalation were assessed by radio-telemetry during adolescence and from PND 86-94. Chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after 4ndays of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults.Key resultsFemale, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC. However, enhanced potency was found in females. Repeated THC male rats consumed more food than their PG-treated control group, without significant bodyweight differences. Adolescent THC did not alter oxycodone self-administration in either sex but increased fentanyl self-administration in females.Conclusions and implicationsRepeated THC vapour inhalation in adolescent rats has lasting consequences observable in adulthood.

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.

Opioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms. This study was conducted to determine if heroin and Δ9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature and spontaneous locomotor activity when inhaled or injected.Groups of male and female rats implanted with radiotelemetry transmitters were exposed to vapor for assessment of effects on temperature and activity. Heroin (50 mg/mL in the propylene glycol; PG) inhalation increased temperature and activity whereas THC (50 mg/mL) inhalation decreased temperature and activity. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of Heroin and THC by either inhalation or injection produced additive effects on thermal nociception assessed with a warm water tail-withdrawal assay in male and female Sprague-Dawley and Wistar rats.The conclusion of this study is that additive effects of THC with heroin on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.

Cannabis use is widespread among adolescents and has been associated with long-term negative outcomes on neurocognitive functions. However, the factors that contribute to the long-term detrimental effects of cannabis use remain poorly understood. Here, we studied how Reelin deficiency influences the behavior of mice exposed to cannabis during adolescence. Reelin is a gene implicated in the development of the brain and of psychiatric disorders. To this aim, heterozygous Reeler (HR) mice, that express reduced level of Reelin, were chronically injected during adolescence with high doses (10 mg/kg) of Δ9-tetrahydrocannabinol (THC), a major psychoactive component of cannabis. Two weeks after the last injection of THC, mice were tested with multiple behavioral assays, including working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition. Compared to wild-type (WT), HR mice treated with THC showed impaired social behaviors, elevated disinhibitory phenotypes and increased reactivity to aversive situations, in a sex-specific manner. Overall, these findings show that Reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence and suggest that elucidating Reelin signaling will improve our understanding of neurobiological mechanisms underlying behavioral traits relevant to the development of psychiatric conditions.

The α-pyrrolidino-phenone cathinone stimulants first came to widespread attention because of bizarre behavior consequent to the use of α-pyrrolidinopentiophenone (α-PVP, "flakka") reported in the popular press. As with other designer drugs, diversification of cathiones has been driven by desireable subjective effects, but also by attempts to stay ahead of legal controls of specific molecules. The α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinopropiophenone (α-PPP) compounds have been relatively under-investigated relative to α-PVP and provide a key opportunity to also investigate structure-activity relationships, i.e., how the extension of the alpha carbon chain may affect potency or efficacy. Male and female rats were used to contrast the effects of α-PHP and α-PPP with those of α-PVP in altering wheel activity and effects on spontaneous locomotion and body temperature were assessed in female rats. The α-PHP and α-PVP compounds (5, 10 mg/kg, i.p.) suppressed wheel activity in female and male rats, whereas α-PPP was only effective in female rats. Inhalation of α-PHP or α-PVP by female rats suppressed wheel activity for an abbreviated duration, compared with the injection route. Spontaneous activity was increased in a dose-dependent manner by all three compounds in female rats, and a small decrements in body temperature were observed after the highest dose of all three compounds. These data show that all three of the α-pyrrolidino-phenone cathinones exhibit significant stimulant-like activity in both male and female rats. Differences were minor and were mostly in potency and the duration of activity. Abuse liability is therefore likely to be equivalent for all three pyrrolidino-phenones.

Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of prescription opioids around 2002, followed later by increased heroin use and then most recently fentanyl. Inhalation is a common route of administration for opioids, with a documented history spanning back to Mediterranean antiquity and up through modern use with e-cigarette devices. Unfortunately, preclinical studies using inhalation as the route of administration remain relatively few. This study was conducted to determine the efficacy of e-cigarette vapor inhalation of heroin in rats. Non-contingent exposure to heroin or methadone vapor produced anti-nociceptive efficacy in male and female rats. Female rats were trained to self-administer heroin vapor; the most-preferring half of the distribution obtained more vapor reinforcers when the concentration of heroin was reduced in the vapor vehicle and when pre-treated with the opioid receptor antagonist naloxone. The anti-nociceptive effect of heroin self-administered by vapor was identical in magnitude to that produced by intravenous self-administration. Finally, anxiety-like behavior increased 24-48h after last heroin vapor access, consistent with withdrawal signs observed after intravenous self-administration. In sum, these studies show that rewarding and anti-nociceptive effects of heroin are produced in rats by vapor inhalation using e-cigarette technology. Importantly, self-administration models by this route can be deployed to determine health effects of inhaled heroin or other opioids.

Background: Reducing the burden of malaria requires better understanding of vector populations, particularly in forested regions where the incidence remains elevated. Here, we characterized malaria vectors in a locality near the Yaoundé international airport, Cameroon, including species composition, abundance, Plasmodium infection rate, insecticide resistance profiles and underlying resistance mechanisms. Methods: Blood-fed adult mosquitoes resting indoors were aspirated from houses in April 2019 at Elende, a locality situated 2 km from the Yaoundé-Nsimalen airport. Female mosquitoes were forced to lay eggs to generate F 1 adults. Bioassays were performed to assess resistance profile to the four insecticides classes. The threshold of insecticide susceptibility was defined above 98% mortality rate and mortality rates below 90% were indicative of confirmed insecticide resistance. Furthermore, the molecular basis of resistance and Plasmodium infection rates were investigated. Results: Anopheles funestus s.s. was the most abundant species in Elende (85%) followed by Anopheles gambiae s.s. (15%) with both having similar sporozoite rate. Both species exhibited high levels of resistance to the pyrethroids, permethrin and deltamethrin (

OBJECTIVE: This study (1) describes the distribution of Kessler Psychological Distress Scale (K6) scores in an epidemiological sample of youth, (2) reports its item correlations and internal consistency reliability, (3) tests for measurement invariance by age (youth vs. adults) and sex, and (4) examines its predictive power for past-year psychiatric disorders. METHOD: Youth aged 15 to 19 years (n = 2010) and adults aged 20 to 64 years (n = 2010) from the Canadian Community Health Survey–Mental Health who completed the K6 were included. Past-year psychiatric disorders were measured using the World Health Organization Composite International Diagnostic Interview 3.0 (WHO-CIDI). Polychoric correlation matrices and ordinal reliability coefficients were calculated to assess internal consistency of the K6, and confirmatory factor analysis was used to test for measurement invariance. Area under the curves (AUCs) were computed to determine the extent to which the K6 predicted a positive screen on the WHO-CIDI. RESULTS: K6 scores showed a J-shaped distribution, with >50% of youth having scores ≤3. Item and total scores were higher for females versus males. Item correlations were robust (0.31-0.78) and internal consistency was high (α = 0.86). Full measurement invariance was demonstrated between youth and adults, as well as between male and female youth. The K6 was a strong predictor of major depressive episode (AUC = 0.848), generalized anxiety disorder (AUC = 0.847), and bipolar disorder (AUC = 0.853). CONCLUSIONS: The K6 is a valid and reliable measure of psychological distress among youth. Its brevity and robust predictive power for psychiatric disorder confirm its utility in clinical and community settings to identify youth needing comprehensive psychiatric assessment.

The use of Δ(9)-tetrahydrocannabinol (THC) by inhalation using e-cigarette technology grows increasingly popular for medical and recreational purposes. This has led to development of e-cigarette based techniques to study the delivery of THC by inhalation in laboratory rodents. Inhaled THC reliably produces hypothermic and antinociceptive effects in rats, similar to effects of parenteral injection of THC. This study was conducted to determine the extent to which the hypothermic response depends on interactions with the CB(1) receptor, using pharmacological antagonist (SR141716, AM-251) approaches. Groups of rats were implanted with radiotelemetry devices capable of reporting activity and body temperature, which were assessed after THC inhalation or injection. SR141716 (4 mg/kg, i.p.) blocked or attenuated antinociceptive effects of acute THC inhalation in male and female rats. SR141716 was unable to block the initial hypothermia caused by THC inhalation, but temperature was restored to normal more quickly. Alterations in antagonist pre-treatment time, dose and the use of a rat strain with less sensitivity to THC-induced hypothermia did not change this pattern. Pre-treatment with SR141716 (4 mg/kg, i.p.) blocked hypothermia induced by i.v. THC and reversed hypothermia when administered 45 or 90 minutes after THC (i.p.). SR141716 and AM-251 (4 mg/kg, i.p.) sped recovery from, but did not block, hypothermia caused by vapor THC in female rats made tolerant by prior repeated THC vapor inhalation. The CB(2) antagonist AM-630, had no effect. These results suggest that hypothermia consequent to THC inhalation is induced by other mechanisms in addition to CB(1) receptor activation.

Background:Reducing the burden of malaria requires better understanding of vector populations, particularly in forested regions where the incidence remains elevated. Here, we characterized malaria vectors in a locality near the Yaoundé international airport, Cameroon, including species composition, abundance,Plasmodiuminfection rate, insecticide resistance profiles and underlying resistance mechanisms.Methods:Blood-fed adult mosquitoes resting indoors were aspirated from houses in April 2019 at Elende, a village located 2 km from the Yaoundé-Nsimalen airport. Female mosquitoes were forced to lay eggs to generate F1adult progeny. Bioassays were performed to assess resistance profile to insecticides. The threshold of insecticide susceptibility was defined above 98% mortality rate and mortality rates below 90% were indicative of confirmed insecticide resistance. Furthermore, the molecular basis of resistance andPlasmodiuminfection rates were investigated.Results:Anopheles funestuss.s. was most abundant species in Elende (85%) followed byAnopheles gambiaes.s. (15%) with both having a similar sporozoite rate. Both species exhibited high levels of resistance to pyrethroids (An. gambiaes.s. was also resistant to DDT (9.9% mortality) and bendiocarb (54% mortality) while susceptible to organophosphate.An. funestuss.s. was resistant to dieldrin (1% mortality), DDT (86% mortality) but susceptible to carbamates and organophosphates. The L119F-GSTe2 resistance allele (8%) and G119Sace-1 resistance allele (15%) were detected inAn. funestuss.s. andAn. gambiaes.s., respectively.Furthermore, the high pyrethroid/DDT resistances inAn. gambiaes.s. corresponded with an increase frequency of 1014Fkdrallele (95%). Transcriptional profiling of candidate cytochrome P450 genes reveals the over-expression ofCYP6P5,CYP6P9aandCYP6P9b.Conclusion:The resistance to multiple insecticide classes observed in these vector populations alongside the highPlasmodiumsporozoite rate highlights the challenges that vector control programs encounter in sustaining the regular benefits of contemporary insecticide-based control interventions in forested areas.

The use of Δ9-tetrahydrocannabinol (THC) by inhalation using e-cigarette technology grows increasingly popular for medical and recreational purposes. This has led to development of e-cigarette based techniques to study the delivery of THC by inhalation in laboratory rodents. Inhaled THC reliably produces hypothermic and antinociceptive effects in rats, similar to effects of parenteral injection of THC. This study was conducted to determine the extent to which the hypothermic response depends on interactions with the CB1 receptor, using pharmacological antagonist (SR141716, AM-251) approaches. Groups of rats were implanted with radiotelemetry devices capable of reporting activity and body temperature, which were assessed after THC inhalation or injection. SR141716 (4 mg/kg, i.p.) blocked or attenuated antinociceptive effects of acute THC inhalation in male and female rats. SR141716 was unable to block the initial hypothermia caused by THC inhalation, but temperature was restored to normal more quickly. Alterations in antagonist pre-treatment time, dose and the use of a rat strain with less sensitivity to THC-induced hypothermia did not change this pattern. Pre-treatment with SR141716 (4 mg/kg, i.p.) blocked hypothermia induced by i.v. THC and reversed hypothermia when administered 45 or 90 minutes after THC (i.p.). SR141716 and AM-251 (4 mg/kg, i.p.) sped recovery from, but did not block, hypothermia caused by vapor THC in female rats made tolerant by prior repeated THC vapor inhalation. The CB2 antagonist AM-630, had no effect. These results suggest that hypothermia consequent to THC inhalation is induced by other mechanisms in addition to CB1 receptor activation.