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The prejunctional norepinephrine transporter (NET) is responsible for the clearance of released norepinephrine (NE) back into the sympathetic nerve terminal. NET regulation must be tightly controlled as variations could have important implications for neurotransmission. Thus far, the effects of sympathetic neuronal activity on NET function have been unclear. Here, we optically monitor single-terminal cardiac NET activity ex vivo in response to a broad range of sympathetic postganglionic action potential (AP) firing frequencies. Isolated murine left atrial appendages were loaded with a fluorescent NET substrate [Neurotransmitter Transporter Uptake Assay (NTUA)] and imaged with confocal microscopy. Sympathetic APs were induced with electrical field stimulation at 0.2-10 Hz (0.1-0.2 ms pulse width). Exogenous NE was applied during the NTUA uptake- and washout phases to investigate substrate competition and displacement, respectively, on transport. Single-terminal NET reuptake rate was rapidly suppressed in a frequency-dependent manner with an inhibitory EF 50 of 0.9 Hz. At 2 Hz, the effect was reversed by the α 2 -adrenoceptor antagonist yohimbine (1 μM) (p < 0.01) with no further effect imposed by the muscarinic receptor antagonist atropine (1 μM). Additionally, high exogenous NE concentrations abolished NET reuptake (1 μM NE; p < 0.0001) and displaced terminal specific NTUA during washout (1-100 μM NE; p < 0.0001). We have also identified α 2 -adrenoceptor-induced suppression of NET reuptake rate during resting stimulation frequencies, which could oppose the effect of autoinhibition-mediated suppression of exocytosis and thus amplify the effects of sympathetic drive on cardiac function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species 1-4 . To address this issue, the international Genome 10K (G10K) consortium 5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.

Adenovirus-based vaccines are demonstrating promising clinical potential for multiple infectious diseases, including COVID-19. However, the immunogenicity of the vector itself decreases its effectiveness as a boosting vaccine due to the induction of strong anti-vector neutralizing immunity. Here we determined how dissolvable microneedle patches (DMN) for skin immunization can overcome this issue, using a clinically-relevant adenovirus-based Plasmodium falciparum malaria vaccine, AdHu5-PfRH5, in mice. Incorporation of vaccine into patches significantly enhanced its thermostability compared to the liquid form. Conventional high dose repeated immunization by the intramuscular (IM) route induced low antigen-specific IgG titres and high anti-vector immunity. A low priming dose of vaccine, by the IM route, but more so using DMN patches, induced the most efficacious immune responses, assessed by parasite growth inhibitory activity (GIA) assays. Administration of low dose AdHu5-PfRH5 using patches to the skin, boosted by high dose IM, induced the highest antigen-specific serum IgG response after boosting, the greatest skewing of the antibody response towards the antigen and away from the vector, and the highest efficacy. This study therefore demonstrates that repeated use of the same adenovirus vaccine can be highly immunogenic towards the transgene if a low dose is used to prime the response. It also provides a method of stabilizing adenovirus vaccine, in easy-to-administer dissolvable microneedle patches, permitting storage and distribution out of cold chain.

Background: Attractive targeted sugar baits (ATSBs) are a promising new tool for malaria control as they can target outdoor-feeding mosquito populations, in contrast to current vector control tools which predominantly target indoor-feeding mosquitoes., Methods: It was sought to estimate the potential impact of these new tools on Plasmodium falciparum malaria prevalence in African settings by combining data from a recent entomological field trial of ATSBs undertaken in Mali with mathematical models of malaria transmission. The key parameter determining impact on the mosquito population is the excess mortality due to ATSBs, which is estimated from the observed reduction in mosquito catch numbers. A mathematical model capturing the life cycle of P. falciparum malaria in mosquitoes and humans and incorporating the excess mortality was used to estimate the potential epidemiological effect of ATSBs., Results: The entomological study showed a significant reduction of ~ 57% (95% CI 33-72%) in mosquito catch numbers, and a larger reduction of ~ 89% (95% CI 75-100%) in the entomological inoculation rate due to the fact that, in the presence of ATSBs, most mosquitoes do not live long enough to transmit malaria. The excess mortality due to ATSBs was estimated to be lower (mean 0.09 per mosquito per day, seasonal range 0.07-0.11 per day) than the bait feeding rate obtained from one-day staining tests (mean 0.34 per mosquito per day, seasonal range 0.28-0.38 per day)., Conclusions: From epidemiological modelling, it was predicted that ATSBs could result in large reductions (> 30% annually) in prevalence and clinical incidence of malaria, even in regions with an existing high malaria burden. These results suggest that this new tool could provide a promising addition to existing vector control tools and result in significant reductions in malaria burden across a range of malaria-endemic settings.

As countries in the Greater Mekong Sub-region (GMS) increasingly focus their malaria control and elimination efforts on reducing forest-related transmission, greater understanding of the relationship between deforestation and malaria incidence will be essential for programs to assess and meet their 2030 elimination goals. Leveraging village-level health facility surveillance data and forest cover data in a spatio-temporal modeling framework, we found evidence that deforestation is associated with short-term increases, but long-term decreases confirmed malaria case incidence in Lao People's Democratic Republic (Lao PDR). We identified strong associations with deforestation measured within 30 km of villages but not with deforestation in the near (10 km) and immediate (1 km) vicinity. Results appear driven by deforestation in densely forested areas and were more pronounced for infections with Plasmodium falciparum ( P. falciparum ) than for Plasmodium vivax ( P. vivax ). These findings highlight the influence of forest activities on malaria transmission in the GMS., Competing Interests: FR, ED, AL, JM, BH, HS, AB No competing interests declared, (© 2021, Rerolle et al.)

Homing-based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification home-and-rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy. Finally, we conduct mathematical modeling comparing HomeR to contemporary gene drive architectures for population modification over wide ranges of fitness costs, transmission rates, and release regimens. HomeR could potentially be adapted to other species, as a means for safe, confinable, modification of wild populations., Competing Interests: NK is a consultant for Agragene. JL, JB, JM No competing interests declared, OA is a founder of Agragene, Inc, has an equity interest, and serves on the company's Scientific Advisory Board., (© 2021, Kandul et al.)

CRISPR-based gene-drive systems, which copy themselves via gene conversion mediated by the homology-directed repair (HDR) pathway, have the potential to revolutionize vector control. However, mutant alleles generated by the competing non-homologous end-joining (NHEJ) pathway, resistant to Cas9 cleavage, can interrupt the spread of gene-drive elements. We hypothesized that drives targeting genes essential for viability or reproduction also carrying recoded sequences that restore endogenous gene functionality should benefit from dominantly-acting maternal clearance of NHEJ alleles combined with recessive Mendelian culling processes. Here, we test split gene-drive (sGD) systems in Drosophila melanogaster that are inserted into essential genes required for viability (rab5, rab11, prosalpha2) or fertility (spo11). In single generation crosses, sGDs copy with variable efficiencies and display sex-biased transmission. In multigenerational cage trials, sGDs follow distinct drive trajectories reflecting their differential tendencies to induce target chromosome damage and/or lethal/sterile mosaic Cas9-dependent phenotypes, leading to inherently confinable drive outcomes.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged recently and has created a global pandemic. Symptomatic SARS-CoV-2 infection, termed coronavirus disease 2019 (COVID-19), has been associated with a host of symptoms affecting numerous organ systems, including the lungs, cardiovascular system, kidney, central nervous system, gastrointestinal tract, and skin, among others., Objective: Although several risk factors have been identified as related to complications from and severity of COVID-19, much about the virus remains unknown. The host immune response appears to affect the outcome of disease. It is not surprising that patients with intrinsic or secondary immune compromise might be particularly susceptible to complications from SARS-CoV-2 infection. Pathogenic loss-of-function or gain-of-function heterozygous variants in nuclear factor-κB2 have been reported to be associated with either a combined immunodeficiency or common variable immunodeficiency phenotype., Methods: We evaluated the functional consequence and immunologic phenotype of a novel NFKB2 loss of function variant in a 17-year-old male patient and describe the clinical management of SARS-CoV-2 infection in this context., Results: This patient required a 2-week hospitalization for SARS-CoV-2 infection, including 7 days of mechanical ventilation. We used biologic therapies to avert potentially fatal acute respiratory distress syndrome and treat hyperinflammatory responses. The patient had an immunologic phenotype of B-cell dysregulation with decreased switched memory B cells. Despite the underlying immune dysfunction, he recovered from the infection with intense management., Conclusions: This clinical case exemplifies some of the practical challenges in management of patients with SARS-CoV-2 infection, especially in the context of underlying immune dysregulation., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Barley yellow dwarf virus (BYDV) is an important vector-borne pathogen of cereals. Although many species of grasses are known to host BYDV, knowledge of their role in virus spread in regional agroecosystems remains limited. Between 2012 and 2016, Idaho winter wheat production was affected by BYDV. BYDV-PAV and the bird cherry-oat aphid (BCOA) ( Rhopalosiphum padi L.) vector were commonly present in the affected areas. A series of greenhouse bioassays were performed to examine whether two types of corn ( Zea mays L.), dent and sweet, and three commonly found grassy weeds, downy brome ( Bromus tectorum L.), green foxtail ( Setaria viridis L.), and foxtail barley ( Hordeum jubatum L.), can be inoculated with BYDV (species BYDV-PAV) by BCOA and also act as sources of the virus in winter wheat. BCOA successfully transmitted BYDV-PAV to both corn types and all weed species. Virus titers differed between the weed species ( P = 0.032) and between corn types ( P = 0.001). In transmission bioassays, aphids were able to survive on these host plants during the 5-day acquisition access period and later successfully transmitted BYDV-PAV to winter wheat (var. SY Ovation). Transmission success was positively correlated with the virus titer of the source plant ( P < 0.001) and influenced by weed species ( P = 0.028) but not corn type. Overall, the results of our inoculation and transmission assays showed that the examined weed species and corn types can be inoculated with BYDV-PAV by BCOA and subsequently act as sources of infections in winter wheat.

Background: Severe postoperative pain is principally managed by opioids. While effective, opioids do not provide adequate relief in many patients and cause many side effects, including antinociceptive tolerance and opioid-induced hyperalgesia. To evaluate if a combination of intravenous Magnesium, Lidocaine, Ketorolac (MLK cocktail) is a useful rescue therapy through synergistic pharmacological mechanisms for acute pain relief. We present the intravenous combination of magnesium, lidocaine, and ketorolac (MLK cocktail) as a possible rescue for opioid insensitive severe post-operative pain., Materials and Methods: The principal settings were the post-operative care unit (PACU) and the surgical ward. We retrospectively analyzed the electronic medical record and anesthesia documents of 14 patients experiencing severe postoperative pain, >7/10 visual-analogue pain score (VAS), despite receiving at least 8 mg of intravenous morphine milligram equivalents (MME) after arrival in the LAC+USC Medical Center PACU between September 2012 and January 2013. The data reviewed included patients' demographics, disease etiology, surgical procedure, opioids received perioperatively, and visual-analogue pain scores before and after each analgesic received, and after the MLK cocktail. The a priori primary outcome and a posteriori secondary outcome of this study are mean visual-analogue pain score and morphine milligram equivalent dose administered per hour, respectively. The main tool evaluated has been VAS score., Results: In patients who failed to respond to opioid analgesics, administration of the MLK cocktail improved the VAS pain scores immediately from 9.4 ± 1.0 to 3.6 ± 3.5. The MLK cocktail also decreased the MME doses/hour in the immediate 12 hours postoperative period from 12.4 ± 5.6 to 1.1 ± 0.9., Conclusion: In patients experiencing opioid-resistant severe postoperative pain, the magnesium, lidocaine, and ketorolac combination may be an effective nonopioid rescue therapy. Additionally, magnesium, lidocaine, and ketorolac may be utilized in cases complicated by either antinociceptive tolerance or opioid-induced hyperalgesia and can restore opioid responsiveness., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The transition of new technologies for public health from laboratory to field is accompanied by a broadening scope of engagement challenges. Recent developments of vector control strategies involving genetically engineered mosquitoes with gene drives to assist in the eradication of malaria have drawn significant attention. Notably, questions have arisen surrounding community and regulatory engagement activities and of the need for examples of models or frameworks that can be applied to guide engagement. A relationship-based model (RBM) provides a framework that places stakeholders and community members at the center of decision-making processes, rather than as recipients of predetermined strategies, methods, and definitions. Successful RBM application in the transformation of healthcare delivery has demonstrated the importance of open dialogue and relationship development in establishing an environment where individuals are actively engaged in decision-making processes regarding their health. Although guidelines and recommendations for engagement for gene drives have recently been described, we argue here that communities and stakeholders should lead the planning, development, and implementation phases of engagement. The RBM provides a new approach to the development of ethical, transparent, and effective engagement strategies for malaria control programs.

Cas9/gRNA-mediated gene-drive systems have advanced development of genetic technologies for controlling vector-borne pathogen transmission. These technologies include population suppression approaches, genetic analogs of insecticidal techniques that reduce the number of insect vectors, and population modification (replacement/alteration) approaches, which interfere with competence to transmit pathogens. Here, we develop a recoded gene-drive rescue system for population modification of the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function. Non-functional resistant alleles are eliminated via a dominantly-acting maternal effect combined with slower-acting standard negative selection, and rare functional resistant alleles do not prevent drive invasion. Small cage trials show that single releases of gene-drive males robustly result in efficient population modification with ≥95% of mosquitoes carrying the drive within 5-11 generations over a range of initial release ratios.

CRISPR-Cas9-based gene drive systems possess the inherent capacity to spread progressively throughout target populations. Here we describe two self-copying (or active) guide RNA-only genetic elements, called e-CHACRs and ERACRs. These elements use Cas9 produced in trans by a gene drive either to inactivate the cas9 transgene (e-CHACRs) or to delete and replace the gene drive (ERACRs). e-CHACRs can be inserted at various genomic locations and carry two or more gRNAs, the first copying the e-CHACR and the second mutating and inactivating the cas9 transgene. Alternatively, ERACRs are inserted at the same genomic location as a gene drive, carrying two gRNAs that cut on either side of the gene drive to excise it. e-CHACRs efficiently inactivate Cas9 and can drive to completion in cage experiments. Similarly, ERACRs, particularly those carrying a recoded cDNA-restoring endogenous gene activity, can drive reliably to fully replace a gene drive. We compare the strengths of these two systems., Competing Interests: Declaration of Interests E.B., V.M.G., and O.S.A. have equity interest in Synbal Inc. (E.B. and V.M.G.) and Agragene (E.B., V.G., and O.S.A.). These companies may potentially benefit from the research results. E.B. and V.M.G. also serve on the Board of Directors and Scientific Advisory Board for Synbal Inc., and E.B., V.M.G., and O.S.A. serve on the Scientific Advisory Board for Agragene Inc. The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict-of-interest policies. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Information about genetic engineering (GE) for vector control in the United States is disseminated primarily in English, though non-English speakers are equally, and in some geographic regions even more affected by such technologies. Non-English-speaking publics should have equal access to such information, which is especially critical when the technology in question may impact whole communities. We convened an interdisciplinary workgroup to translate previously developed narrated slideshows on gene drive mosquitoes from English into Spanish, reviewing each iteration for scientific accuracy and accessibility to laypeople. Using the finalised stimuli, we conducted five online, chat-based focus groups with Spanish-speaking adults from California. Overall, participants expressed interest in the topic and were able to summarise the information presented in their own words. Importantly, participants asked for clarification and expressed scepticism about the information presented, indicating critical engagement with the material. Through collaboration with Spanish-speaking scientists engaged in the development of GE methods of vector control, we translated highly technical scientific information into Spanish that successfully engaged Spanish-speaking participants in conversations about this topic. In this manuscript, we document the feasibility of consulting Spanish-speaking publics about a complex emerging technology by drawing on the linguistic diversity of the scientific teams developing the technology.

The Safe to Sleep campaign started in 1994, reducing the risk of sudden infant death syndrome (SIDS) by 40% to 60%. However, an undesirable consequence has been a 400% to 600% increase in positional head deformities. We review the risks for positional plagiocephaly or brachycephaly, treatment modalities, and when to refer. Differential diagnoses for non-positional deformities are discussed. Risks for positional head deformities include prenatal, perinatal and postnatal factors. These include torticollis, inadequate tummy time, abnormal intrauterine positioning, premature or postmature birth, prolonged labor, complex medical conditions, prolonged hospitalizations, developmental delay, and use of supportive or convenience devices. Recommended treatment involves repositioning techniques or physical therapy with or without helmet use. Early referral to physical therapy or a head shape program insures better outcomes for full correction of the deformity. The severity of residual deformities is directly related to the age at which the child is referred. [Pediatr Ann. 2020;49(10):e440-e447.]., (Copyright 2020, SLACK Incorporated.)

With the COVID-19 pandemic confronting health systems worldwide, medical practitioners are treating a myriad of physical symptoms that have, sadly, killed many thousands of people. There are signs that the public is also experiencing psychological trauma as they attempt to navigate their way through the COVID-19 restrictions impinging on many aspects of society. With unprecedented demand for health professionals' time, people who are unable to access face-to-face assistance are turning to smartphone apps to help them deal with symptoms of trauma. However, the evidence for smartphone apps to treat trauma is limited, and clinicians need to be aware of the limitations and unresolved issues involved in using mental health apps., (Copyright © 2020 Marshall, Dunstan and Bartik.)

Demand for telehealth services with psychologists and other health professionals has increased during the COVID-19 pandemic, and as a result some members of the community are unable to access face-to-face assistance for trauma-related mental health issues. This has led to an increase in usage of alternative digital mental health options such as smartphone apps and other Internet-enabled assistance. The Australian Federal Government has promoted digital mental health options for many years, and it has a comprehensive architecture of digital resources in place, but will it be enough to deal with the expected rise in symptoms of trauma among the general population in the wake of COVID-19? (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Crucial to the successful conservation of endangered species is the overlap of their ranges with protected areas. We analyzed protected areas in the continental USA to assess the extent to which they covered the ranges of endangered tetrapods. We show that in 80% of ecoregions, protected areas offer equal (25%) or worse (55%) protection for species than if their locations were chosen at random. Additionally, we demonstrate that it is possible to achieve sufficient protection for 100% of the USA's endangered tetrapods through targeted protection of undeveloped public and private lands. Our results highlight that the USA is likely to fall short of its commitments to halting biodiversity loss unless more considerable investments in both public and private land conservation are made.

Background: The use of mental health mobile apps to treat anxiety and depression is widespread and growing. Several reviews have found that most of these apps do not have published evidence for their effectiveness, and existing research has primarily been undertaken by individuals and institutions that have an association with the app being tested. Another reason for the lack of research is that the execution of the traditional randomized controlled trial is time prohibitive in this profit-driven industry. Consequently, there have been calls for different methodologies to be considered. One such methodology is the single-case design, of which, to the best of our knowledge, no peer-reviewed published example with mental health apps for anxiety and/or depression could be located., Objective: The aim of this study is to examine the effectiveness of 5 apps (Destressify, MoodMission, Smiling Mind, MindShift, and SuperBetter) in reducing symptoms of anxiety and/or depression. These apps were selected because they are publicly available, free to download, and have published evidence of efficacy., Methods: A multiple baseline across-individuals design will be employed. A total of 50 participants will be recruited (10 for each app) who will provide baseline data for 20 days. The sequential introduction of an intervention phase will commence once baseline readings have indicated stability in the measures of participants' mental health and will proceed for 10 weeks. Postintervention measurements will continue for a further 20 days. Participants will be required to provide daily subjective units of distress (SUDS) ratings via SMS text messages and will complete other measures at 5 different time points, including at 6-month follow-up. SUDS data will be examined via a time series analysis across the experimental phases. Individual analyses of outcome measures will be conducted to detect clinically significant changes in symptoms using the statistical approach proposed by Jacobson and Truax. Participants will rate their app on several domains at the end of the intervention., Results: Participant recruitment commenced in January 2020. The postintervention phase will be completed by June 2020. Data analysis will commence after this. A write-up for publication is expected to be completed after the follow-up phase is finalized in January 2021., Conclusions: If the apps prove to be effective as hypothesized, this will provide collateral evidence of their efficacy. It could also provide the benefits of (1) improved access to mental health services for people in rural areas, lower socioeconomic groups, and children and adolescents and (2) improved capacity to enhance face-to-face therapy through digital homework tasks that can be shared instantly with a therapist. It is also anticipated that this methodology could be used for other mental health apps to bolster the independent evidence base for this mode of treatment., International Registered Report Identifier (irrid): PRR1-10.2196/17159., (©Jamie M Marshall, Debra A Dunstan, Warren Bartik. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 05.07.2020.)

Pretreatment with sublethal concentrations (LC 10 ) of three insecticides (chlorfenapyr, dinotefuran, and spinosad) enhanced tolerance to a lethal dose of the respective insecticide in the Western flower thrips, Frankliniella occidentalis. To identify genes responding to sublethal treatment with insecticides, transcriptome analysis was conducted for thrips treated with LC 10 of the three insecticides. When based on a fold change >1.5 or < -1.5 as a selection criterion, 199 transcripts were commonly up-regulated, whereas 31 transcripts were commonly down-regulated following all three insecticide treatments. The differential expression levels of representative genes were validated by quantitative PCR. Most over-transcribed transcripts could be categorized as basic biological processes, such as proteolysis and lipid metabolism. Detoxification genes, such as one glutathione S transferase S1, three UDP-glucuronosyltransferases, four CYP450s, and one ABC transporter G family member 20, were commonly overexpressed in all three insecticide-treated groups. Knockdown of the five representative commonly overexpressed genes via ingestion RNA interference increased mortalities to all the three test insecticides, supporting their common role in tolerance induction. In contrast, three C 2 H 2 -type zinc finger-containing proteins were significantly down-regulated in all insecticide-treated thrip groups. Since the tested insecticides have distinct structures and modes of action, the roles of commonly expressed genes in tolerance were discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Mobile mental health apps have become ubiquitous tools to assist people in managing symptoms of anxiety and depression. However, due to the lack of research and expert input that has accompanied the development of most apps, concerns have been raised by clinicians, researchers, and government authorities about their efficacy., Objective: This review aimed to estimate the proportion of mental health apps offering comprehensive therapeutic treatments for anxiety and/or depression available in the app stores that have been developed using evidence-based frameworks. It also aimed to estimate the proportions of specific frameworks being used in an effort to understand which frameworks are having the most influence on app developers in this area., Methods: A systematic review of the Apple App Store and Google Play store was performed to identify apps offering comprehensive therapeutic interventions that targeted anxiety and/or depression. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist was adapted to guide this approach., Results: Of the 293 apps shortlisted as offering a therapeutic treatment for anxiety and/or depression, 162 (55.3%) mentioned an evidence-based framework in their app store descriptions. Of the 293 apps, 88 (30.0%) claimed to use cognitive behavioral therapy techniques, 46 (15.7%) claimed to use mindfulness, 27 (9.2%) claimed to use positive psychology, 10 (3.4%) claimed to use dialectical behavior therapy, 5 (1.7%) claimed to use acceptance and commitment therapy, and 20 (6.8%) claimed to use other techniques. Of the 162 apps that claimed to use a theoretical framework, only 10 (6.2%) had published evidence for their efficacy., Conclusions: The current proportion of apps developed using evidence-based frameworks is unacceptably low, and those without tested frameworks may be ineffective, or worse, pose a risk of harm to users. Future research should establish what other factors work in conjunction with evidence-based frameworks to produce efficacious mental health apps., (©Jamie M Marshall, Debra A Dunstan, Warren Bartik. Originally published in JMIR Mental Health (http://mental.jmir.org), 24.06.2020.)

The role of prostaglandins (PGs) in exercise hyperemia is controversial. We tested their contributions in moderate intensity forearm exercise, whether their release is oxygen (O 2 )-dependent or affected by aging. A total of 12 young (21 ± 1 years) and 11 older (66 ± 2 years) recreationally active men performed rhythmic and isometric handgrip contractions at 60% maximum voluntary contraction for 3 min during air breathing after placebo, after cyclooxygenase (COX) inhibition with aspirin, while breathing 40% O 2 and during their combination (aspirin + 40% O 2 ). Forearm blood flow (FBF) was recorded with venous occlusion plethysmography (forearm vascular conductance (FVC): FBF/mean arterial pressure). Venous efflux of PGI 2 and PGE 2 were assessed by immunoassay. Postcontraction increases in FVC were similar for rhythmic and isometric contractions in young and older men, and accompanied by similar increases in efflux of PGI 2 and PGE 2 . Aspirin attenuated the efflux of PGI 2 by 75%-85%, PGE 2 by 50%-70%, (p < .05 within group; p > .05 young versus. older), and postcontraction increases in FVC by 22%-27% and 17%-21% in young and older men, respectively (p < .05 within group and young versus. older). In both age groups, 40% O 2 and aspirin + 40% O 2 caused similar inhibition of the increases in FVC and efflux of PGs as aspirin alone (p < .05 within group). These results indicate that PGs make substantial contributions to the postcontraction hyperemia of rhythmic and isometric contractions at moderate intensities in recreationally active young and older men. Given PGI 2 is mainly released by endothelium and PGE 2 by muscle fibers, we propose PG generation is dependent on the contraction-induced falls in O 2 at these sites., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: The discovery of CRISPR-based gene editing and its application to homing-based gene drive systems has been greeted with excitement, for its potential to control mosquito-borne diseases on a wide scale, and concern, for the invasiveness and potential irreversibility of a release. Gene drive systems that display threshold-dependent behavior could potentially be used during the trial phase of this technology, or when localized control is otherwise desired, as simple models predict them to spread into partially isolated populations in a confineable manner, and to be reversible through releases of wild-type organisms. Here, we model hypothetical releases of two recently engineered threshold-dependent gene drive systems-reciprocal chromosomal translocations and a form of toxin-antidote-based underdominance known as UD MEL -to explore their ability to be confined and remediated., Results: We simulate releases of Aedes aegypti, the mosquito vector of dengue, Zika, and other arboviruses, in Yorkeys Knob, a suburb of Cairns, Australia, where previous biological control interventions have been undertaken on this species. We monitor spread to the neighboring suburb of Trinity Park to assess confinement. Results suggest that translocations could be introduced on a suburban scale, and remediated through releases of non-disease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UD MEL requires fewer releases to introduce, but more releases to remediate, including of females capable of disease transmission. Both systems are expected to be confineable to the release site; however, spillover of translocations into neighboring populations is less likely., Conclusions: Our analysis supports the use of translocations as a threshold-dependent drive system capable of spreading disease-refractory genes into Ae. aegypti populations in a confineable and reversible manner. It also highlights increased release requirements when incorporating life history and population structure into models. As the technology nears implementation, further ecological work will be essential to enhance model predictions in preparation for field trials.

People's motives for casual sex moderate associations between their sexual behavior and the outcomes they experience. Derived from self-determination theory, autonomous motives for casual sex (e.g., I wanted the fun and enjoyment) and non-autonomous motives (e.g., I wanted to please someone else) correlated in previous research differentially with measures of well-being and incidence of casual sex. In a sample of American college students (N = 284), we replicated these prior findings and extended them as follows: autonomous and non-autonomous motives for sex were correlated with two measures of casual sex (i.e., the three behavior questions from the Sociosexual Orientation Inventory; the number of partners with whom participants had penetrative sex but did not wish to become emotionally involved); two measures of well-being (i.e., self-esteem, depression), and a measure of overall sexual victimization (i.e., a combined score from the Sexual Experiences Survey). We found that autonomous motives were more strongly associated with casual sexual behavior than were non-autonomous motives in both sexes. Autonomous motives were positively associated with sexual victimization in women but not in men. Compared to autonomous motives, sex for non-autonomous motives was linked to less self-esteem in both sexes, and with more depression and sexual victimization in women. Sex differences in associations between motives and victimization persisted even when the general effects of participant's sex and casual sex were controlled in hierarchical regressions. Our findings further revealed the importance of agency (or lack thereof) in predicting sexual behavior and psychological health.

Mosquitoes are important vectors for pathogens that infect humans and other vertebrate animals. Some aspects of adult mosquito behavior and mosquito ecology play an important role in determining the capacity of vector populations to transmit pathogens. Here, we re-examine factors affecting the transmission of pathogens by mosquitoes using a new approach. Unlike most previous models, this framework considers the behavioral states and state transitions of adult mosquitoes through a sequence of activity bouts. We developed a new framework for individual-based simulation models called MBITES (Mosquito Bout-based and Individual-based Transmission Ecology Simulator). In MBITES, it is possible to build models that simulate the behavior and ecology of adult mosquitoes in exquisite detail on complex resource landscapes generated by spatial point processes. We also developed an ordinary differential equation model which is the Kolmogorov forward equations for models developed in MBITES under a specific set of simplifying assumptions. While mosquito infection and pathogen development are one possible part of a mosquito's state, that is not our main focus. Using extensive simulation using some models developed in MBITES, we show that vectorial capacity can be understood as an emergent property of simple behavioral algorithms interacting with complex resource landscapes, and that relative density or sparsity of resources and the need to search can have profound consequences for mosquito populations' capacity to transmit pathogens., Competing Interests: The authors have declared that no competing interests exist.

Mosquitoes containing gene drive systems are being developed as complementary tools to prevent transmission of malaria and other mosquito-borne diseases. As with any new tool, decision makers and other stakeholders will need to balance risks (safety) and benefits (efficacy) when considering the rationale for testing and deploying gene drive-modified mosquito products. Developers will benefit from standards for judging whether an investigational gene drive product meets acceptability criteria for advancing to field trials. Such standards may be formalized as preferred product characteristics and target product profiles, which describe the desired attributes of the product category and of a particular product, respectively. This report summarizes discussions from two scientific workshops aimed at identifying efficacy and safety characteristics that must be minimally met for an investigational gene drive-modified mosquito product to be deemed viable to move from contained testing to field release and the data that will be needed to support an application for first field release.

Vector-borne diseases, such as dengue, Zika and malaria, are a major cause of morbidity and mortality worldwide. These diseases have proven difficult to control and currently available management tools are insufficient to eliminate them in many regions. Gene drives have the potential to revolutionize vector-borne disease control. This suite of technologies has advanced rapidly in recent years as a result of the availability of new, more efficient gene editing technologies. Gene drives can favorably bias the inheritance of a linked disease-refractory gene, which could possibly be exploited (i) to generate a vector population incapable of transmitting disease or (ii) to disrupt an essential gene for viability or fertility, which could eventually eliminate a population. Importantly, gene drives vary in characteristics such as their transmission efficiency, confinability and reversibility, and their potential to develop resistance to the drive mechanism. Here, we discuss recent advancements in the gene drive field, and contrast the benefits and limitations of a variety of technologies, as well as approaches to overcome these limitations. We also discuss the current state of each gene drive technology and the technical considerations that need to be addressed on the pathway to field implementation. While there are still many obstacles to overcome, recent progress has brought us closer than ever before to genetic-based vector modification as a tool to support vector-borne disease elimination efforts worldwide., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Aedes aegypti is the principal mosquito vector for many arboviruses that increasingly infect millions of people every year. With an escalating burden of infections and the relative failure of traditional control methods, the development of innovative control measures has become of paramount importance. The use of gene drives has sparked significant enthusiasm for genetic control of mosquitoes; however, no such system has been developed in Ae. aegypti . To fill this void, here we develop several CRISPR-based split gene drives for use in this vector. With cleavage rates up to 100% and transmission rates as high as 94%, mathematical models predict that these systems could spread anti-pathogen effector genes into wild populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effector-linked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission., Competing Interests: ML, TY, NK, MB, SG, RR, JB, HS, GL, HS, YL, JM, OA No competing interests declared, (© 2020, Li et al.)

CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split-gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small-molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.

Many human pathogens use host cell-surface receptors to attach and invade cells. Often, the host-pathogen interaction affinity is low, presenting opportunities to block invasion using a soluble, high-affinity mimic of the host protein. The Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) provides an exciting candidate for mimicry: it is highly conserved and its moderate affinity binding to the human receptor basigin (K D  ≥1 μM) is an essential step in erythrocyte invasion by this malaria parasite. We used deep mutational scanning of a soluble fragment of human basigin to systematically characterize point mutations that enhance basigin affinity for RH5 and then used Rosetta to design a variant within the sequence space of affinity-enhancing mutations. The resulting seven-mutation design exhibited 1900-fold higher affinity (K D approximately 1 nM) for RH5 with a very slow binding off rate (0.23 h -1 ) and reduced the effective Plasmodium growth-inhibitory concentration by at least 10-fold compared to human basigin. The design provides a favorable starting point for engineering on-rate improvements that are likely to be essential to reach therapeutically effective growth inhibition., (© 2019 Wiley Periodicals, Inc.)

Here, we validate the use of a novel fluorescent norepinephrine transporter (NET) substrate for dynamic measurements of transporter function in rodent cardiovascular tissue; this technique avoids the use of radiotracers and provides single-terminal resolution. Rodent (Wistar rats and C57BL/6 mice) hearts and mesenteric arteries (MA) were isolated, loaded with NET substrate Neurotransmitter Transporter Uptake Assay (NTUA) ex vivo and imaged with confocal microscopy. NTUA labelled noradrenergic nerve terminals in all four chambers of the heart and on the surface of MA. In all tissues, a temperature-dependent, stable linear increase in intra-terminal fluorescence upon NTUA exposure was observed; this was abolished by NET inhibitor desipramine (1 μM) and reversed by indirectly-acting sympathomimetic amine tyramine (10 μM). NET reuptake rates were similar across the mouse cardiac chambers. In both species, cardiac NET activity was significantly greater than in MA (by 62 ± 29% (mouse) and 21 ± 16% (rat)). We also show that mouse NET reuptake rate was twice as fast as that in the rat (for example, in the heart, by 94 ± 30%). Finally, NET reuptake rate in the mouse heart was attenuated with muscarinic agonist carbachol (10 μM) thus demonstrating the potential for parasympathetic regulation of norepinephrine clearance. Our data provide the first demonstration of monitoring intra-terminal NET function in rodent cardiovascular tissue. This straightforward method allows dynamic measurements of transporter rate in response to varying physiological conditions and drug treatments; this offers the potential to study new mechanisms of sympathetic dysfunction associated with cardiovascular disease., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The increase in ownership of smartphones and tablet devices has seen a worldwide government push, championed by the World Health Organization, towards digital healthcare services generally. Mental health has been a strong presence in the digitisation of healthcare because of the potential to solve some of the difficulties in accessing face-to-face services. This review summarises the recent history of e-mental health services and illuminates two very different paths. The first is the considerable amount of research that has proven the effectiveness of many online mental health programmes for personal computers and laptops, resulting in widespread acceptance of their ability to make a contribution in an individual's recovery from anxiety and depression. The second is associated with the more recent development of apps for smartphones and tablet devices and the contrasting paucity of research that has accompanied this burgeoning area of e-mental health. This review also outlines the current state of play for research into the effectiveness of mobile mental health apps for anxiety and depression, including issues associated with methodology, and offers sources of practical advice for clinicians wanting more information about these new digital tools., Conclusion: Research into the effectiveness of mental health apps is lacking, and the majority have no evidence of efficacy. Clinicians need to be aware of what apps have such evidence and should exercise caution when recommending apps to patients. Suggestions are offered on the direction of future research, including an appeal to further include clinicians in the development and efficacy testing of mental health apps.

Small laboratory cage trials of non-drive and gene-drive strains of the Asian malaria vector mosquito, Anopheles stephensi, were used to investigate release ratios and other strain properties for their impact on transgene spread during simulated population modification. We evaluated the effects of transgenes on survival, male contributions to next-generation populations, female reproductive success and the impact of accumulation of gene drive-resistant genomic target sites resulting from nonhomologous end-joining (NHEJ) mutagenesis during Cas9, guide RNA-mediated cleavage. Experiments with a non-drive, autosomally-linked malaria-resistance gene cassette showed 'full introduction' (100% of the insects have at least one copy of the transgene) within 8 weeks (≤ 3 generations) following weekly releases of 10:1 transgenic:wild-type males in an overlapping generation trial design. Male release ratios of 1:1 resulted in cages where mosquitoes with at least one copy of the transgene fluctuated around 50%. In comparison, two of three cages in which the malaria-resistance genes were linked to a gene-drive system in an overlapping generation, single 1:1 release reached full introduction in 6-8 generations with a third cage at ~80% within the same time. Release ratios of 0.1:1 failed to establish the transgenes. A non-overlapping generation, single-release trial of the same gene-drive strain resulted in two of three cages reaching 100% introduction within 6-12 generations following a 1:1 transgenic:wild-type male release. Two of three cages with 0.33:1 transgenic:wild-type male single releases achieved full introduction in 13-16 generations. All populations exhibiting full introduction went extinct within three generations due to a significant load on females having disruptions of both copies of the target gene, kynurenine hydroxylase. While repeated releases of high-ratio (10:1) non-drive constructs could achieve full introduction, results from the 1:1 release ratios across all experimental designs favor the use of gene drive, both for efficiency and anticipated cost of the control programs., Competing Interests: The authors have declared that no competing interests exist.

One of the biggest growth areas in e-mental health resources has been the development and use of mobile mental health apps for smartphones and tablet devices. Such apps are being downloaded at increasing rates, but there have been questions about their efficacy and the research methodologies used to examine this. A review of the major app marketplaces, the Apple App Store and Google Play store, was conducted to locate apps claiming to offer a therapeutic treatment for depression and/or anxiety, and have research evidence for their effectiveness, according to their app store descriptions. App store descriptions were also analyzed to determine whether the app had been developed with mental health expert input; whether they had been developed in association with a government body, academic institution, or medical facility; and, whether or not they were free to download. Overall, 3.41% of apps had research to justify their claims of effectiveness, with the majority of that research undertaken by those involved in the development of the app. Other results indicated that 30.38% of shortlisted apps claimed to have expert development input; 20.48% had an affiliation with a government body, academic institution, or medical facility; and, 74.06% were free to download. Future research must consider other methodologies that may facilitate more research being completed on a greater number of apps, and future development needs to incorporate greater levels of input by mental health experts. Ways in which app stores could play a key role in encouraging more scientific research into the effectiveness of the mental health apps they sell are discussed., (Copyright © 2019 Marshall, Dunstan and Bartik.)

While efforts to control malaria with available tools have stagnated, and arbovirus outbreaks persist around the globe, the advent of clustered regularly interspaced short palindromic repeat (CRISPR)-based gene editing has provided exciting new opportunities for genetics-based strategies to control these diseases. In one such strategy, called "population replacement", mosquitoes, and other disease vectors are engineered with effector genes that render them unable to transmit pathogens. These effector genes can be linked to "gene drive" systems that can bias inheritance in their favor, providing novel opportunities to replace disease-susceptible vector populations with disease-refractory ones over the course of several generations. While promising for the control of vector-borne diseases on a wide scale, this sets up an evolutionary tug-of-war between the introduced effector genes and the pathogen. Here, we review the disease-refractory genes designed to date to target Plasmodium falciparum malaria transmitted by Anopheles gambiae , and arboviruses transmitted by Aedes aegypti , including dengue serotypes 2 and 3, chikungunya, and Zika viruses. We discuss resistance concerns for these effector genes, and genetic approaches to prevent parasite and viral escape variants. One general approach is to increase the evolutionary hurdle required for the pathogen to evolve resistance by attacking it at multiple sites in its genome and/or multiple stages of development. Another is to reduce the size of the pathogen population by other means, such as with vector control and antimalarial drugs. We discuss lessons learned from the evolution of resistance to antimalarial and antiviral drugs and implications for the management of resistance after its emergence. Finally, we discuss the target product profile for population replacement strategies for vector-borne disease control. This differs between early phase field trials and wide-scale disease control. In the latter case, the demands on effector gene efficacy are great; however, with new possibilities ushered in by CRISPR-based gene editing, and when combined with surveillance, monitoring, and rapid management of pathogen resistance, the odds are increasingly favoring effector genes in the upcoming evolutionary tug-of-war., (Copyright © 2019 Marshall, Raban, Kandul, Edula, León and Akbari.)

Background: Increasing resistance of head lice against neurotoxic agents and safety concerns have led to the search for treatment alternatives. Dimeticones with a physical mode of action are safe, and bear a reduced risk for the development of resistance., Methods: We performed in vitro bioassays to assess pediculicidal and ovicidal activities of a new dimeticone-based product, and a randomized controlled clinical trial to assess efficacy, following 10 min application. Of 153 individuals screened, 100 participants with active head louse infestations were randomly assigned to treatment with either a dimeticone-based test product, or a 0.5% permethrin-based reference product (50 participants per group). Participants received two topical applications of either the test (10 min) or reference products (45 min) at days 0 and 7 or 8. Outcome measures included the efficacies of treatment and their safety, as well as global and local tolerability at baseline, and days 1, 7, and 10., Results: After 10 min exposure, all lice treated with the dimeticone test product were classified as non-viable in the in vitro assay. Ovicidal activity after treatment of eggs with the dimeticone test product was 96.8%. In the clinical trial, 96 patients completed all study visits. In the full analysis set (FAS) population, on day 1 after one application, 98% of patients were cured in the test group, as compared to 84% cured in the reference group. All participants in both groups were free of head lice on day 10, following two applications (100% cure rate). In total, 42 adverse events (AEs) in 23 patients of both treatment groups were recorded, with the majority of AEs classified as mild., Conclusions: We have shown a high level of pediculicidal and ovicidal activity, and clinical efficacy and safety, of a brief application of a new dimeticone-based product. The short application time and reduced risk for the development of resistance are key drivers for improved patients' compliance., Trial Registration: EU Clinical Trials Register EudraCT  2016-004635-20 . Registered 14 November 2016.

The contribution of prostaglandins (PGs) to exercise hyperaemia is controversial. In this review, we argue this is partly explained by differences in exercise intensity between studies. The effects of cyclooxygenase (COX) inhibition and PG assays indicate that PGs contribute more at moderate to heavy than at light workloads and are mainly released by low tissue O 2 . But, the release and actions of PGs also depend on other O 2 -dependent dilators including ATP, adenosine and NO. K + may inhibit the action of PGs and other mediators by causing hyperpolarization, but contributes to the hyperaemia. Thus, at lighter loads, the influence of PGs may be blunted by K + , while COX inhibition leads to compensatory increases in other O 2 -dependent dilators. In addition, we show that other sources of variability are sex and ethnicity. Our findings indicate that exercise hyperaemia following rhythmic contractions at 60% maximum voluntary contraction, is smaller in young black African (BA) men and women than in their white European (WE) counterparts, but larger in men than in women of both ethnicities. We propose the larger absolute force in men causes greater vascular occlusion and accumulation of dilators, while blunted hyperaemia in BAs may reflect lower oxidative capacity and O 2 requirement. Nevertheless, COX inhibition attenuated peak hyperaemia by ∼30% in WE, BA men and WE women, indicating PGs make a substantial contribution in all three groups. There was no effect in BA women. Lack of PG involvement may provide early evidence of endothelial dysfunction, consistent in BA women with their greater risk of cardiovascular disease., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

The most widespread form of malaria is caused by Plasmodium vivax. To replicate, this parasite must invade immature red blood cells through a process requiring interaction of the P. vivax Duffy binding protein (PvDBP) with its human receptor, the Duffy antigen receptor for chemokines. Naturally acquired antibodies that inhibit this interaction associate with clinical immunity, suggesting PvDBP as a leading candidate for inclusion in a vaccine to prevent malaria due to P. vivax. Here, we isolated a panel of monoclonal antibodies from human volunteers immunized in a clinical vaccine trial of PvDBP. We screened their ability to prevent PvDBP from binding to the Duffy antigen receptor for chemokines, and their capacity to block red blood cell invasion by a transgenic Plasmodium knowlesi parasite genetically modified to express PvDBP and to prevent reticulocyte invasion by multiple clinical isolates of P. vivax. This identified a broadly neutralizing human monoclonal antibody that inhibited invasion of all tested strains of P. vivax. Finally, we determined the structure of a complex of this antibody bound to PvDBP, indicating the molecular basis for inhibition. These findings will guide future vaccine design strategies and open up possibilities for testing the prophylactic use of such an antibody.

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mangrove forests, one of the world's most endangered ecosystems, are also some of the most difficult to access. This is especially true along the Pacific coast of Costa Rica, where 99% of the country's mangroves occur. Unmanned Aerial Systems (UAS), or drones, have become a convenient tool for natural area assessment, and offer a solution to the problems of remote mangrove monitoring. This study is the first to use UAS to analyze the structure of a mangrove forests within Central America. Our goals were to (1) determine the forest structure of two estuaries in northwestern Costa Rica through traditional ground measurements, (2) assess the accuracy of UAS measurements of canopy height and percent coverage and (3) determine whether the normalized difference vegetation index (NDVI) could discriminate between the most abundant mangrove species. We flew a UAS equipped with a single NDVI sensor during the peak wet (Sept-Nov) and dry (Jan-Feb) seasons. The structure and species composition of the estuaries showed a possible transition between the wet mangroves of southern Costa Rica and the drier northern mangroves. UAS-derived measurements at 100 cm/pixel resolution of percent canopy coverage and maximum and mean canopy height were not statistically different from ground measurements (p > 0.05). However, there were differences in mean canopy height at 10 cm/pixel resolution (p = 0.043), indicating diminished returns in accuracy as resolution becomes extremely fine. Mean NDVI values of Avicennia germinans (most abundant species) changed significantly between seasons (p < 0.001). Mean NDVI of Rhizophora racemosa (second most abundant species) was significantly different from A. germinans and dry forest dominant plots during the dry season (p < 0.001), demonstrating NDVI's capability of discriminating mangrove species. This study provides the first structural assessment of the studied estuaries and a framework for future studies of mangroves using UAS., Competing Interests: The authors have declared that no competing interests exist.

Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. We previously demonstrated a strong association between protection and merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test the mechanism of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb. Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.

Background: In the summer of 2013, Aedes aegypti Linnaeus was first detected in three cities in central California (Clovis, Madera and Menlo Park). It has now been detected in multiple locations in central and southern CA as far south as San Diego and Imperial Counties. A number of published reports suggest that CA populations have been established from multiple independent introductions., Results: Here we report the first population genomics analyses of Ae. aegypti based on individual, field collected whole genome sequences. We analyzed 46 Ae. aegypti genomes to establish genetic relationships among populations from sites in California, Florida and South Africa. Based on 4.65 million high quality biallelic SNPs, we identified 3 major genetic clusters within California; one that includes all sample sites in the southern part of the state (South of Tehachapi mountain range) plus the town of Exeter in central California and two additional clusters in central California., Conclusions: A lack of concordance between mitochondrial and nuclear genealogies suggests that the three founding populations were polymorphic for two main mitochondrial haplotypes prior to being introduced to California. One of these has been lost in the Clovis populations, possibly by a founder effect. Genome-wide comparisons indicate extensive differentiation between genetic clusters. Our observations support recent introductions of Ae. aegypti into California from multiple, genetically diverged source populations. Our data reveal signs of hybridization among diverged populations within CA. Genetic markers identified in this study will be of great value in pursuing classical population genetic studies which require larger sample sizes.

Purpose: We tested whether the values of limb blood flow calculated with strain-gauge venous occlusion plethysmography (VOP) differ when venous occlusion is achieved by automated, or manual inflation, so providing rapid and slower inflation, respectively., Method: In 9 subjects (20-30 years), we calculated forearm blood flows (FBF) values at rest and following isometric handgrip at 70% maximum voluntary contraction (MVC) when rapid, or slower inflation was used., Result: Rapid and slower cuff inflation took 0.23 ± 0.01 (mean ± SEM) and 0.92 ± 0.02 s, respectively, reflecting the range reported in published studies. At rest, FBF calculated from the 1st cardiac cycle after rapid and slower inflation gave similar values: 10.5 ± 1.4 vs. 9.6 ± 1.3 ml dl - 1  min - 1 , respectively (P > 0.05). However, immediately post-contraction, FBF was ~ 40% lower with slower inflation: 54.6 ± 5.1 vs. 33.8 ± 4.2 ml dl - 1  min - 1 (P < 0.01). The latter value was similar to that calculated over the 3rd cardiac cycle following rapid inflation: 2nd cardiac cycle: 40.5 ± 4.5; 3rd cycle: 32.6 ± 4.5 ml dl - 1  min - 1 . Regression analyses of FBFs recorded at intervals post-contraction showed those calculated over the 1st, 2nd, or 3rd cardiac cycles with rapid inflation correlated well with those from the 1st cardiac cycle with manual inflation (r = 0.79, 0.82, 0.79; P < 0.01). However, only the slope for the 3rd cycle with rapid inflation vs. slower inflation was close to unity (2.07, 1.34, and 0.94, respectively)., Conclusion: These findings confirm that the 1st cardiac cycle following venous occlusion should be used when calculating FBF using VOP and, but importantly, indicate that cuff inflation should be almost instantaneous; just ≥ 0.9 s leads to substantial underestimation, especially at high flows.

ABSTRACTThe intensely active 2017 Atlantic basin hurricane season provided an opportunity to examine how climate drivers, including warming oceans and rising seas, exacerbated tropical cyclone hazards. The season also highlighted the unique vulnerabilities of populations residing on Small Island Developing States (SIDS) to the catastrophic potential of these storms. During 2017, 22 of the 29 Caribbean SIDS were affected by at least one named storm, and multiple SIDS experienced extreme damage. This paper aims to review the multiplicity of storm impacts on Caribbean SIDS throughout the 2017 season, to explicate the influences of climate drivers on storm formation and intensity, to explore the propensity of SIDS to sustain severe damage and prolonged disruption of essential services, to document the spectrum of public health consequences, and to delineate the daunting hurdles that challenged emergency response and recovery operations for island-based, disaster-affected populations. (Disaster Med Public Health Preparedness. 2019;13:5-17).

The sterile insect technique (SIT) is an environmentally safe and proven technology to suppress wild populations. To further advance its utility, a novel CRISPR-based technology termed precision guided SIT (pgSIT) is described. PgSIT mechanistically relies on a dominant genetic technology that enables simultaneous sexing and sterilization, facilitating the release of eggs into the environment ensuring only sterile adult males emerge. Importantly, for field applications, the release of eggs will eliminate burdens of manually sexing and sterilizing males, thereby reducing overall effort and increasing scalability. Here, to demonstrate efficacy, we systematically engineer multiple pgSIT systems in Drosophila which consistently give rise to 100% sterile males. Importantly, we demonstrate that pgSIT-generated sterile males are fit and competitive. Using mathematical models, we predict pgSIT will induce substantially greater population suppression than can be achieved by currently-available self-limiting suppression technologies. Taken together, pgSIT offers to potentially transform our ability to control insect agricultural pests and disease vectors.