Testing non-autonomous antimalarial gene drive effectors using self-eliminating drivers in the African mosquito vector Anopheles gambiae.

Gene drives for mosquito population modification are novel tools for malaria control. Strategies to safely test antimalarial effectors in the field are required. Here, we modified the Anopheles gambiae zpg locus to host a CRISPR/Cas9 integral gene drive allele (zpgD) and characterized its behaviour and resistance profile. We found that zpgD dominantly sterilizes females but can induce efficient drive at other loci when it itself encounters resistance. We combined zpgD with multiple previously characterized non-autonomous payload drives and found that, as zpgD self-eliminates, it leads to conversion of mosquito cage populations at these loci. Our results demonstrate how self-eliminating drivers could allow safe testing of non-autonomous effector-traits by local population modification. They also suggest that after engendering resistance, gene drives intended for population suppression could nevertheless serve to propagate subsequently released non-autonomous payload genes, allowing modification of vector populations initially targeted for suppression.

Understanding the causes of missingness in primary care: a realist review.

BACKGROUND: Although missed appointments in healthcare have been an area of concern for policy, practice and research, the primary focus has been on reducing single 'situational' missed appointments to the benefit of services. Little attention has been paid to the causes and consequences of more 'enduring' multiple missed appointments in primary care and the role this has in producing health inequalities. METHODS: We conducted a realist review of the literature on multiple missed appointments to identify the causes of 'missingness.' We searched multiple databases, carried out iterative citation-tracking on key papers on the topic of missed appointments and identified papers through searches of grey literature. We synthesised evidence from 197 papers, drawing on the theoretical frameworks of candidacy and fundamental causation. RESULTS: Missingness is caused by an overlapping set of complex factors, including patients not identifying a need for an appointment or feeling it is 'for them'; appointments as sites of poor communication, power imbalance and relational threat; patients being exposed to competing demands, priorities and urgencies; issues of travel and mobility; and an absence of choice or flexibility in when, where and with whom appointments take place. CONCLUSIONS: Interventions to address missingness at policy and practice levels should be theoretically informed, tailored to patients experiencing missingness and their identified needs and barriers; be cognisant of causal domains at multiple levels and address as many as practical; and be designed to increase safety for those seeking care.

R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.

Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize genome rearrangements during cellular ageing in non-dividing cells, we interrogated a single diagnostic measure, DNA breakpoint junctions, using Schizosaccharomyces pombe as a model system. Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints elsewhere in the genome, including the mitochondrial chromosome. Formation of breakpoint junctions at global hotspots was inhibited by the Sir2 histone deacetylase and might be triggered by an age-dependent de-repression of chromatin silencing. An unexpected mechanism of genomic instability may cause more local hotspots: age-associated reduction in an RNA-binding protein triggering R-loops at target loci. This result suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and possible mechanisms of genome rearrangements in non-dividing cells, which can be promoted by ageing-related changes in gene-regulatory proteins.

Behavioral Consistency in the Digital Age.

Efforts to infer personality from digital footprints have focused on behavioral stability at the trait level without considering situational dependency. We repeated a classic study of intraindividual consistency with secondary data (five data sets) containing 28,692 days of smartphone usage from 780 people. Using per-app measures of pickup frequency and usage duration, we found that profiles of daily smartphone usage were significantly more consistent when taken from the same user than from different users (d > 1.46). Random-forest models trained on 6 days of behavior identified each of the 780 users in test data with 35.8% accuracy for pickup frequency and 38.5% accuracy for duration frequency. This increased to 73.5% and 75.3%, respectively, when success was taken as the user appearing in the top 10 predictions (i.e., top 1%). Thus, situation-dependent stability in behavior is present in our digital lives, and its uniqueness provides both opportunities and risks to privacy.

Monitoring a meat-free pledge with smartphones: An experimental study.

Pledges are a popular strategy to encourage meat reduction, though experimental studies of their efficacy are lacking. Three-hundred and twenty-five participants from three different countries (UK, Germany, Australia) were randomly assigned to pledge 28 days meat-free or not, and their behavior was tracked via smartphones. Participants answered daily surveys regarding their eating behavior, meat cravings, and shared photos of their meals. Baseline data was collected prior to the pledge, after the 28 days, and one-month post-intervention. Participants assigned to the pledge condition ate less meat across the 28 days, compared to control participants. Meat reductions, observed at outtake, did not endure one-month post-intervention. Overall, German participants ate the least amount of meat, and showed the sharpest decrease in consumption when pledging. Meat cravings tended to increase among pledgers, relative to control participants. Pledgers who reported high starting intentions and conflict about meat tended to eat less meat and reported fewer cravings. All participants reported reduced meat-eating justifications one-month post-intervention. These findings provide experimental evidence that pledges can encourage meat consumers to reduce their intake, though additional mechanisms are needed to sustain commitments.

Measurement practices exacerbate the generalizability crisis: Novel digital measures can help.

Psychology's tendency to focus on confirmatory analyses before ensuring constructs are clearly defined and accurately measured is exacerbating the generalizability crisis. Our growing use of digital behaviors as predictors has revealed the fragility of subjective measures and the latent constructs they scaffold. However, new technologies can provide opportunities to improve conceptualizations, theories, and measurement practices.

Open-source smartphone app and tools for measuring, quantifying, and visualizing technology use.

Psychological science has spent many years attempting to understand the impact of new technology on people and society. However, the frequent use of self-report methods to quantify patterns of usage struggle to capture subtle nuances of human-computer interaction. This has become particularly problematic for devices like smartphones that are used frequently and for a variety of purposes. While commercial apps can provide an element of objectivity, these are 'closed' and cannot be adapted to deliver a researcher-focused 'open' platform that allows for straightforward replication. Therefore, we have developed an Android app that provides accurate, highly detailed, and customizable accounts of smartphone usage without compromising participants' privacy. Further recommendations and code are provided to assist with data analysis. All source code, materials, and data are freely available (see links in supplementary materials section).

Educational associations with missed GP appointments for patients under 35 years old: administrative data linkage study.

BACKGROUND: There is an evidence gap about whether levels of engagement with public services such as schools and health care affect people across the lifespan. Data on missed patient appointments from a nationally representative sample of Scottish general practices (GP) (2013-2016) were probabilistically linked to secondary school pupil data. We tested whether school attendance, exclusions (2007-2011) or lower educational attainment (2007-2016) was associated with an increased risk of missing general practice appointments. METHODS: School attendance data were classified into quartiles of possible days attended for years we had data. School exclusions were derived as a categorical variable of 'ever excluded'. Attainment data were categorised via the Scottish Credit and Qualifications Framework (SCQF) level 3 or 6; a cumulative measure of attainment on leaving school. The associations between school attendance, exclusions and attainment and risk of missing medical appointments were investigated using negative binomial models, offset by number of GP appointments made and controlling for potential confounders. RESULTS: 112,534 patients (all aged under 35) had GP appointment and retrospective school attendance and exclusion data, and a subset of 66,967 also had attainment data available. Patients who had lower attendance, had been excluded from school or had lower educational attainment had an increased risk of missing GP appointments (all rate ratios > 1.40). CONCLUSIONS: This study provides the first evidence from a population-representative sample in a high-income country that increased numbers of missed appointments in health care are associated with reduced school attendance, higher levels of school exclusion and lower educational attainment. Insights into the epidemiology of missingness across public services can support future research, policy and practice that aim to improve healthcare, health outcomes and engagement in services.

Opening Pandora's Box: Peeking inside Psychology's data sharing practices, and seven recommendations for change.

Open data-sharing is a valuable practice that ought to enhance the impact, reach, and transparency of a research project. While widely advocated by many researchers and mandated by some journals and funding agencies, little is known about detailed practices across psychological science. In a pre-registered study, we show that overall, few research papers directly link to available data in many, though not all, journals. Most importantly, even where open data can be identified, the majority of these lacked completeness and reusability-conclusions that closely mirror those reported outside of Psychology. Exploring the reasons behind these findings, we offer seven specific recommendations for engineering and incentivizing improved practices, so that the potential of open data can be better realized across psychology and social science more generally.

Development of an Offline-Friend Addiction Questionnaire (O-FAQ): Are most people really social addicts?

A growing number of self-report measures aim to define interactions with social media in a pathological behavior framework, often using terminology focused on identifying those who are 'addicted' to engaging with others online. Specifically, measures of 'social media addiction' focus on motivations for online social information seeking, which could relate to motivations for offline social information seeking. However, it could be the case that these same measures could reveal a pattern of friend addiction in general. This study develops the Offline-Friend Addiction Questionnaire (O-FAQ) by re-wording items from highly cited pathological social media use scales to reflect "spending time with friends". Our methodology for validation follows the current literature precedent in the development of social media 'addiction' scales. The O-FAQ had a three-factor solution in an exploratory sample of N = 807 and these factors were stable in a 4-week retest (r = .72 to .86) and was validated against personality traits, and risk-taking behavior, in conceptually plausible directions. Using the same polythetic classification techniques as pathological social media use studies, we were able to classify 69% of our sample as addicted to spending time with their friends. The discussion of our satirical research is a critical reflection on the role of measurement and human sociality in social media research. We question the extent to which connecting with others can be considered an 'addiction' and discuss issues concerning the validation of new 'addiction' measures without relevant medical constructs. Readers should approach our measure with a level of skepticism that should be afforded to current social media addiction measures.

Morbidity, mortality and missed appointments in healthcare: a national retrospective data linkage study.

BACKGROUND: Recently, studies have examined the underlying patient and practice factors for missed appointments, but less is known about the impact on patient health. People with one or more long-term conditions who fail to attend appointments may be at risk of premature death. This is the first study to examine the effect of missed primary healthcare appointments on all-cause mortality in those with long-term mental and physical health conditions. METHODS: We used a large, nationwide retrospective cohort (n = 824,374) extracted from routinely collected general practice data across Scotland over a 3-year period from September 2013 until September 2016. This data encompasses appointment history for approximately 15% of the Scottish population, and was linked to Scottish deaths records for patients who had died within a 16-month follow-up period. We generated appointment attendance history, number of long-term conditions and prescriptions data for patients. These factors were used in negative binomial and Cox's proportional hazards modelling to examine the risk of missing appointments and all-cause mortality. RESULTS: Patients with a greater number of long-term conditions had an increased risk of missing general practice appointments despite controlling for number of appointments made, particularly among patients with mental health conditions. These patients were at significantly greater risk of all-cause mortality, and showed a dose-based response with increasing number of missed appointments. Patients with long-term mental health conditions who missed more than two appointments per year had a greater than 8-fold increase in risk of all-cause mortality compared with those who missed no appointments. These patients died prematurely, commonly from non-natural external factors such as suicide. CONCLUSIONS: Missed appointments represent a significant risk marker for all-cause mortality, particularly in patients with mental health conditions. For these patients, existing primary healthcare appointment systems are ineffective. Future interventions should be developed with a particular focus on increasing attendance by these patients.

A simple location-tracking app for psychological research.

Location data gathered from a variety of sources are particularly valuable when it comes to understanding individuals and groups. However, much of this work has relied on participants' active engagement in regularly reporting their location. More recently, smartphones have been used to assist with this process, but although commercial smartphone applications are available, these are often expensive and are not designed with researchers in mind. To overcome these and other related issues, we have developed a freely available Android application that logs location accurately, stores the data securely, and ensures that participants can provide consent or withdraw from a study at any time. Further recommendations and R code are provided in order to assist with subsequent data analysis.

Widespread exon skipping triggers degradation by nuclear RNA surveillance in fission yeast.

Exon skipping is considered a principal mechanism by which eukaryotic cells expand their transcriptome and proteome repertoires, creating different splice variants with distinct cellular functions. Here we analyze RNA-seq data from 116 transcriptomes in fission yeast (Schizosaccharomyces pombe), covering multiple physiological conditions as well as transcriptional and RNA processing mutants. We applied brute-force algorithms to detect all possible exon-skipping events, which were widespread but rare compared to normal splicing events. Exon-skipping events increased in cells deficient for the nuclear exosome or the 5'-3' exonuclease Dhp1, and also at late stages of meiotic differentiation when nuclear-exosome transcripts decreased. The pervasive exon-skipping transcripts were stochastic, did not increase in specific physiological conditions, and were mostly present at less than one copy per cell, even in the absence of nuclear RNA surveillance and during late meiosis. These exon-skipping transcripts are therefore unlikely to be functional and may reflect splicing errors that are actively removed by nuclear RNA surveillance. The average splicing rate by exon skipping was ∼ 0.24% in wild type and ∼ 1.75% in nuclear exonuclease mutants. We also detected approximately 250 circular RNAs derived from single or multiple exons. These circular RNAs were rare and stochastic, although a few became stabilized during quiescence and in splicing mutants. Using an exhaustive search algorithm, we also uncovered thousands of previously unknown splice sites, indicating pervasive splicing; yet most of these splicing variants were cryptic and increased in nuclear degradation mutants. This study highlights widespread but low frequency alternative or aberrant splicing events that are targeted by nuclear RNA surveillance.

Quantifying unmet need in General Practice: a retrospective cohort study of administrative data.

OBJECTIVES: To assess whether patients attending general practices (GPs) in socioeconomically (SE) deprived areas receive the same amount of care, compared with similar patients (based on age, sex and level of morbidity) attending GPs in less deprived areas. If not, to quantify the additional resource that would be required by GPs in deprived areas to achieve parity. DESIGN: Retrospective cohort study. SETTING: 150 GPs in Scotland, UK, divided into two groups: 80 practices in Scottish Index of Multiple Deprivation (SIMD) deciles 1-5 (more SE deprived); 70 practices in SIMD deciles 6-10 (less SE deprived). PATIENTS: 437 590 patients registered with a more SE deprived GP, and 333 994 patients registered with a less SE deprived GP, for the whole study period (2013-2016), who made at least one appointment. OUTCOMES: The number of contacts and total contact time between patients and clinical staff. RESULTS: Patients in more SE deprived areas had slightly more discrete contacts over 3 years (11.8 vs 11.4), but each patient had marginally less contact time (146.1 vs 149.5 min). Stratified by sex and age, differences were also small. Stratified by the number of long-term conditions (LTCs), practices in more SE deprived areas delivered significantly less contact time than practices in less SE deprived areas. Over 3 years, 8 fewer minutes for patients with no LTCs, and 24, 27, 38 and 28 fewer minutes for patients with 1, 2, 3-4 or 5+LTCs, respectively. CONCLUSION: If GPs in more SE deprived areas were to give an equal amount of direct contact time to patients with the same level of need served by GPs in less SE deprived areas, this would require a 14% increase in patient contact time. This represents a significant unmet need, supporting the case for redistribution of resources to tackle the inverse care law.

The auditory efferent system in mosquitoes.

Whilst acoustic communication forms an integral component of the mating behavior of many insect species, it is particularly crucial for disease-transmitting mosquitoes; swarming males rely on hearing the faint sounds of flying females for courtship initiation. That males can hear females within the din of a swarm is testament to their fabulous auditory systems. Mosquito hearing is highly frequency-selective, remarkably sensitive and, most strikingly, supported by an elaborate system of auditory efferent neurons that modulate the auditory function - the only documented example amongst insects. Peripheral release of octopamine, serotonin and GABA appears to differentially modulate hearing across major disease-carrying mosquito species, with receptors from other neurotransmitter families also identified in their ears. Because mosquito mating relies on hearing the flight tones of mating partners, the auditory efferent system offers new potential targets for mosquito control. It also represents a unique insect model for studying auditory efferent networks. Here we review current knowledge of the mosquito auditory efferent system, briefly compare it with its counterparts in other species and highlight future research directions to unravel its contribution to mosquito auditory perception.

Hearing of malaria mosquitoes is modulated by a beta-adrenergic-like octopamine receptor which serves as insecticide target.

Malaria mosquitoes acoustically detect their mating partners within large swarms that form transiently at dusk. Indeed, male malaria mosquitoes preferably respond to female flight tones during swarm time. This phenomenon implies a sophisticated context- and time-dependent modulation of mosquito audition, the mechanisms of which are largely unknown. Using transcriptomics, we identify a complex network of candidate neuromodulators regulating mosquito hearing in the species Anopheles gambiae. Among them, octopamine stands out as an auditory modulator during swarm time. In-depth analysis of octopamine auditory function shows that it affects the mosquito ear on multiple levels: it modulates the tuning and stiffness of the flagellar sound receiver and controls the erection of antennal fibrillae. We show that two α- and ß-adrenergic-like octopamine receptors drive octopamine's auditory roles and demonstrate that the octopaminergic auditory control system can be targeted by insecticides. Our findings highlight octopamine as key for mosquito hearing and mating partner detection and as a potential novel target for mosquito control.

Eyes on Topical Ocular Disposition: The Considered Design of a Lead Janus Kinase (JAK) Inhibitor That Utilizes a Unique Azetidin-3-Amino Bridging Scaffold to Attenuate Off-Target Kinase Activity, While Driving Potency and Aqueous Solubility.

An unmet medical need remains for patients suffering from dry eye disease (DED). A fast-acting, better-tolerated noncorticosteroid anti-inflammatory eye drop could improve patient outcomes and quality of life. Herein, we describe a small-molecule drug discovery effort to identify novel, potent, and water-soluble JAK inhibitors as immunomodulating agents for topical ocular disposition. A focused library of known 3-(4-(2-(arylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitriles was evaluated as a molecular starting point. Structure-activity relationships (SARs) revealed a ligand-efficient (LE) JAK inhibitor series, amenable to aqueous solubility. Subsequent in vitro analysis indicated the potential for off-target toxicity. A KINOMEscan selectivity profile of 5 substantiated the likelihood of widespread series affinity across the human kinome. An sp2-to-sp3 drug design strategy was undertaken to attenuate off-target kinase activity while driving JAK-STAT potency and aqueous solubility. Tactics to reduce aromatic character, increase fraction sp3 (Fsp3), and bolster molecular complexity led to the azetidin-3-amino bridging scaffold in 31.

A weekday intervention to reduce missed appointments.

The burden of missed healthcare appointments is so great that even small reductions in Did Not Attend (DNA) rate can secure tangible benefits. Previous studies have identified demographic factors that predict DNA rate. However, it is not obvious that these insights can be used to improve attendance, as healthcare providers do not control patient demographics. One factor that providers do control is appointment scheduling. We previously reported that appointments at the beginning of the week are more likely to be missed than appointments at the end of the week. This observation suggests a simple intervention to reduce DNA rate: schedule appointments for later in the week. Using data from a UK mental health hospital, we compared attendance rates for 12-months before and 12-months after the intervention began (916 appointments in total). Overall DNA rate fell from 34.2% pre-intervention to 23.4% post-intervention [χ2 (1, N = 916) = 13.01, p < 0.001; Relative Risk Reduction, 31.6%]. This effect was carried mainly by female patients, for whom more appointments could be moved to later in the week. Our findings confirm that DNA rate can be significantly reduced by loading appointments onto high-attendance days.

The problem with the internet: An affordance-based approach for psychological research on networked technologies.

The internet is often viewed as the source of a myriad of benefits and harms. However, there are problems with using this notion of "the internet" and other high-level concepts to explain the influence of communicating via everyday networked technologies on people and society. Here, we argue that research on social influence in computer-mediated communication (CMC) requires increased precision around how and why specific features of networked technologies interact with and impact psychological processes and outcomes. By reviewing research on the affordances of networked technologies, we demonstrate how the relationship between features of "the internet" and "online behaviour" can be determined by both the affordances of the environment and the psychology of the user and community. To achieve advances in this field, we argue that psychological science must provide nuanced and precise conceptualisations, operationalisations, and measurements of "internet use" and "online behaviour". We provide a template for how future research can become more systematic by examining how and why variables associated with the individual user, networked technologies, and the online community interact and intersect. If adopted, psychological science will be able to make more meaningful predictions about online and offline outcomes associated with communicating via networked technologies.