Selection drives divergence of eye morphology in sympatric Heliconius butterflies.

When populations experience different sensory conditions, natural selection may favor sensory system divergence, affecting peripheral structures and/or downstream neural pathways. We characterized the outer eye morphology of sympatric Heliconius species from different forest types and their first-generation reciprocal hybrids to test for adaptive visual system divergence and hybrid disruption. In Panama, Heliconius cydno occurs in closed forests, whereas Heliconius melpomene resides at the forest edge. Among wild individuals, H. cydno has larger eyes than H. melpomene, and there are heritable, habitat-associated differences in the visual brain structures that exceed neutral divergence expectations. Notably, hybrids have intermediate neural phenotypes, suggesting disruption. To test for similar effects in the visual periphery, we reared both species and their hybrids in common garden conditions. We confirm that H. cydno has larger eyes and provide new evidence that this is driven by selection. Hybrid eye morphology is more H. melpomene-like despite body size being intermediate, contrasting with neural trait intermediacy. Overall, our results suggest that eye morphology differences between H. cydno and H. melpomene are adaptive, and that hybrids may suffer fitness costs due to a mismatch between the peripheral visual structures and previously described neural traits that could affect visual performance.

The experiences and perspectives of people with gout on urate self-monitoring.

INTRODUCTION: Gout management remains suboptimal despite safe and effective urate-lowering therapy. Self-monitoring of urate may improve gout management, however, the acceptability of urate self-monitoring by people with gout is unknown. The aim of this study was to explore the experiences of urate self-monitoring in people with gout. METHODS: Semistructured interviews were conducted with people taking urate-lowering therapy (N = 30) in a 12-month trial of urate self-monitoring in rural and urban Australia. Interviews covered the experience of monitoring and its effect on gout self-management. Deidentified transcripts were analysed thematically. RESULTS: Participants valued the ability to self-monitor and gain more understanding of urate control compared with the annual monitoring ordered by their doctors. Participants indicated that self-monitoring at home was easy, convenient and informed gout self-management behaviours such as dietary modifications, hydration, exercise and medication routines. Many participants self-monitored to understand urate concentration changes in response to feeling a gout flare was imminent or whether their behaviours, for example, alcohol intake, increased the risk of a gout flare. Urate concentrations were shared with doctors mainly when they were above target to seek management support, and this led to allopurinol dose increases in some cases. CONCLUSION: Urate self-monitoring was viewed by people with gout as convenient and useful for independent management of gout. They believed self-monitoring achieved better gout control with a less restricted lifestyle. Urate data was shared with doctors at the patient's discretion and helped inform clinical decisions, such as allopurinol dose changes. Further research on implementing urate self-monitoring in routine care would enable an evaluation of its impact on medication adherence and clinical outcomes, as well as inform gout management guidelines. PATIENT OR PUBLIC CONTRIBUTION: One person with gout, who was not a participant, was involved in the study design by providing feedback and pilot testing the semistructured interview guide. In response to their feedback, subsequent modifications to the interview guide were made to improve the understandability of the questions from a patient perspective. No additional questions were suggested.

Patient-Led Urate Self-Monitoring to Improve Clinical Outcomes in People With Gout: A Feasibility Study.

OBJECTIVE: Self-monitored point-of-care urate-measuring devices are an underexplored strategy to improve adherence to urate-lowering therapy and clinical outcomes in gout. This study observed patient-led urate self-monitoring practice and assessed its influence on allopurinol adherence, urate control, and health-related quality of life. METHODS: People with gout (n = 31) and prescribed allopurinol self-monitored their urate concentrations (HumaSens2.0plus) at baseline and thereafter monthly for 12 months (3 months per quarter). Adherence to allopurinol was measured using medication event monitoring technology (Medication Event Monitoring System cap). Time spent below the target urate concentration (<0.36 mmol/L) was determined. Health-related quality of life was measured using a survey (EuroQoL EQ-5D-5L). Gout flares were recorded. Two-tailed Spearman correlation and the Wilcoxon matched-pairs signed-rank test (P < 0.05) were used for statistical comparisons. RESULTS: Most participants were male (94%) and had urate concentrations below the target (74%) at baseline. Overall, seven participants demonstrated repeated periods of "missed doses" (two or fewer allopurinol doses missed consecutively) and "drug holidays" (three or more missed doses). Most participants (94%) persisted with allopurinol. Time spent within the target urate concentration increased 1.3-fold (from 79% to 100%; P = 0.346), and the incidence of gout flares decreased 1.6-fold (from 8 to 5; P = 0.25) in the final quarter compared to that in the first quarter of the study. Health-related quality of life was reduced for participants reporting at least one gout flare (median utility values 0.9309 vs 0.9563, P = 0.04). CONCLUSION: Patient-led urate self-monitoring may support the maintenance of allopurinol adherence and improve urate control, thus reducing the incidence of gout flares. Further research on patient-led urate self-monitoring in a randomized controlled study is warranted.

Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial.

BACKGROUND: Mycobacterium tuberculosis is the main causative agent of tuberculosis. BCG, the only licensed vaccine, provides inadequate protection against pulmonary tuberculosis. Controlled human infection models are useful tools for vaccine development. We aimed to determine a safe dose of aerosol-inhaled live-attenuated Mycobacterium bovis BCG as a surrogate for M tuberculosis infection, then compare the safety and tolerability of infection models established using aerosol-inhaled and intradermally administered BCG. METHODS: This phase 1 controlled human infection trial was conducted at two clinical research facilities in the UK. Healthy, immunocompetent adults aged 18-50 years, who were both M tuberculosis-naive and BCG-naive and had no history of asthma or other respiratory diseases, were eligible for the trial. Participants were initially enrolled into group 1 (receiving the BCG Danish strain); the trial was subsequently paused because of a worldwide shortage of BCG Danish and, after protocol amendment, was restarted using the BCG Bulgaria strain (group 2). After a dose-escalation study, during which participants were sequentially allocated to receive either 1 × 103, 1 × 104, 1 × 105, 1 × 106, or 1 × 107 colony-forming units (CFU) of aerosol BCG, the maximum tolerated dose was selected for the randomised controlled trial. Participants in this trial were randomly assigned (9:12), by variable block randomisation and using sequentially numbered sealed envelopes, to receive aerosol BCG (1 × 107 CFU) and intradermal saline or intradermal BCG (1 × 106 CFU) and aerosol saline. Participants were masked to treatment allocation until day 14. The primary outcome was to compare the safety of a controlled human infection model based on aerosol-inhaled BCG versus one based on intradermally administered BCG, and the secondary outcome was to evaluate BCG recovery in the airways of participants who received aerosol BCG or skin biopsies of participants who received intradermal BCG. BCG was detected by culture and by PCR. The trial is registered at ClinicalTrials.gov, NCT02709278, and is complete. FINDINGS: Participants were assessed for eligibility between April 7, 2016, and Sept 29, 2018. For group 1, 15 participants were screened, of whom 13 were enrolled and ten completed the study; for group 2, 60 were screened and 33 enrolled, all of whom completed the study. Doses up to 1 × 107 CFU aerosol-inhaled BCG were sufficiently well tolerated. No significant difference was observed in the frequency of adverse events between aerosol and intradermal groups (median percentage of solicited adverse events per participant, post-aerosol vs post-intradermal BCG: systemic 7% [IQR 2-11] vs 4% [1-13], p=0·62; respiratory 7% [1-19] vs 4% [1-9], p=0·56). More severe systemic adverse events occurred in the 2 weeks after aerosol BCG (15 [12%] of 122 reported systemic adverse events) than after intradermal BCG (one [1%] of 94; difference 11% [95% CI 5-17]; p=0·0013), but no difference was observed in the severity of respiratory adverse events (two [1%] of 144 vs zero [0%] of 97; 1% [-1 to 3]; p=0·52). All adverse events after aerosol BCG resolved spontaneously. One serious adverse event was reported-a participant in group 2 was admitted to hospital to receive analgesia for a pre-existing ovarian cyst, which was deemed unrelated to BCG infection. On day 14, BCG was cultured from bronchoalveolar lavage samples after aerosol infection and from skin biopsy samples after intradermal infection. INTERPRETATION: This first-in-human aerosol BCG controlled human infection model was sufficiently well tolerated. Further work will evaluate the utility of this model in assessing vaccine efficacy and identifying potential correlates of protection. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Thames Valley Clinical Research Network, and TBVAC2020.

Anesthesia-Related Closed Claims in Free-Standing Ambulatory Surgery Centers.

BACKGROUND: As higher acuity procedures continue to move from hospital-based operating rooms (HORs) to free-standing ambulatory surgery centers (ASCs), concerns for patient safety remain high. We conducted a contemporary, descriptive analysis of anesthesia-related liability closed claims to understand risks to patient safety in the free-standing ASC setting, compared to HORs. METHODS: Free-standing ASC and HOR closed claims between 2015 and 2022 from The Doctors Company that involved an anesthesia provider responsible for the claim were included. We compared the coded data of 212 free-standing ASC claims with 268 HOR claims in terms of severity of injury, major injuries, allegations, comorbidities, contributing factors, and financial value of the claim. RESULTS: Free-standing ASC claims accounted for almost half of all anesthesia-related cases (44%, 212 of 480). Claims with high severity of injury were less frequent in free-standing ASCs (22%) compared to HORs (34%; P = .004). The most common types of injuries in both free-standing ASCs and HORs were dental injury (17% vs 17%) and nerve damage (14% vs 11%). No difference in frequency was noted for types of injuries between claims from free-standing ASCs versus HORs--except that burns appeared more frequently in free-standing ASC claims than in HORs (6% vs 2%; P = .015). Claims with alleged improper management of anesthesia occurred less frequently among free-standing ASC claims than HOR claims (17% vs 29%; P = .01), as well as positioning-related injury (3% vs 8%; P = .025). No difference was seen in frequency of claims regarding alleged improper performance of anesthesia procedures between free-standing ASCs and HORs (25% vs 19%; P = .072). Technical performance of procedures (ie, intubation and nerve block) was the most common contributing factor among free-standing ASC (74%) and HOR (74%) claims. Free-standing ASC claims also had a higher frequency of communication issues between provider and patient/family versus HOR claims (20% vs 10%; P = .004). Most claims were not associated with major comorbidities; however, cardiovascular disease was less prevalent in free-standing ASC claims versus HOR claims (3% vs 11%; P = .002). The mean ± standard deviation total of expenses and payments was lower among free-standing ASC claims ($167,000 ± $295,000) than HOR claims ($332,000 ± $775,000; P = .002). CONCLUSIONS: This analysis of medical malpractice claims may indicate higher-than-expected patient and procedural complexity in free-standing ASCs, presenting patient safety concerns and opportunities for improvement. Ambulatory anesthesia practices should consider improving safety culture and communication with families while ensuring that providers have up-to-date training and resources to safely perform routine anesthesia procedures.

The impact of peritoneal dialysis on oxypurinol and urate elimination in people with gout.

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.

Psychometric evaluation of the Trust in Science and Scientists Scale.

Reliable and valid measurement of trust in science and scientists is important. Assessing levels of such trust is important in determining attitudes and predicting behaviours in response to medical and scientific interventions targeted at managing public crises. However, trust is a complex phenomenon that has to be understood in relation to both distrust and mistrust. The Trust in Science and Scientists Scale has been adopted with increasing frequency in large-scale public health research. Detailed psychometric evaluation of the scale is overdue and makes meaningful comparisons between studies that use the scale difficult. Here, we examine the scale's dimensionality across five separate samples. We find that two factors emerge that are divided by their item polarity. Implications for scale use and trust in science measurement are discussed.

From wires to waves, a novel sensor system for in vivo pressure monitoring.

Pressure monitoring in various organs of the body is essential for appropriate diagnostic and therapeutic purposes. In almost all situations, monitoring is performed in a hospital setting. Technological advances not only promise to improve clinical pressure monitoring systems, but also engage toward the development of fully implantable systems in ambulatory patients. Such systems would not only provide longitudinal time monitoring to healthcare personnel, but also to the patient who could adjust their way-of-life in response to the measurements. In the past years, we have developed a new type of piezoresistive pressure sensor system. Different bench tests have demonstrated that it delivers precise and reliable pressure measurements in real-time. The potential of this system was confirmed by a continuous recording in a patient that lasted for almost a day. In the present study, we further characterized the functionality of this sensor system by conducting in vivo implantation experiments in nine female farm pigs. To get a step closer to a fully implantable system, we also adapted two different wireless communication solutions to the sensor system. The communication protocols are based on MICS (Medical Implant Communication System) and BLE (Bluetooth Low Energy) communication. As a proof-of-concept, implantation experiments in nine female pigs demonstrated the functionality of both systems, with a notable technical superiority of the BLE.

Adaptive introgression of a visual preference gene.

Visual preferences are important drivers of mate choice and sexual selection, but little is known of how they evolve at the genetic level. In this study, we took advantage of the diversity of bright warning patterns displayed by Heliconius butterflies, which are also used during mate choice. Combining behavioral, population genomic, and expression analyses, we show that two Heliconius species have evolved the same preferences for red patterns by exchanging genetic material through hybridization. Neural expression of regucalcin1 correlates with visual preference across populations, and disruption of regucalcin1 with CRISPR-Cas9 impairs courtship toward conspecific females, providing a direct link between gene and behavior. Our results support a role for hybridization during behavioral evolution and show how visually guided behaviors contributing to adaptation and speciation are encoded within the genome.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

Estimation of adherence to urate-lowering therapy in people living with gout using Australia's Pharmaceutical Benefits Scheme and patient-reported dosing.

AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.

The Sensory Ecology of Speciation.

In this work, we explore the potential influence of sensory ecology on speciation, including but not limited to the concept of sensory drive, which concerns the coevolution of signals and sensory systems with the local environment. The sensory environment can influence individual fitness in a variety of ways, thereby affecting the evolution of both pre- and postmating reproductive isolation. Previous work focused on sensory drive has undoubtedly advanced the field, but we argue that it may have also narrowed our understanding of the broader influence of the sensory ecology on speciation. Moreover, the clearest examples of sensory drive are largely limited to aquatic organisms, which may skew the influence of contributing factors. We review the evidence for sensory drive across environmental conditions, and in this context discuss the importance of more generalized effects of sensory ecology on adaptive behavioral divergence. Finally, we consider the potential of rapid environmental change to influence reproductive barriers related to sensory ecologies. Our synthesis shows the importance of sensory conditions for local adaptation and divergence in a range of behavioral contexts and extends our understanding of the interplay between sensory ecology and speciation.

Developmental and environmental plasticity in opsin gene expression in Lake Victoria cichlid fish.

In many organisms, sensory abilities develop and evolve according to the changing demands of navigating, foraging, and communication across different environments and life stages. Teleost fish inhabit heterogeneous light environments and exhibit a large diversity in visual system properties among species. Cichlids are a classic example of this diversity; visual system variation is generated by different tuning mechanisms that involve both genetic factors and phenotypic plasticity. Here, we document the developmental progression of visual pigment gene expression in Lake Victoria cichlids and test if these patterns are influenced by variation in light conditions. We reared two sister species of Pundamilia to adulthood in two distinct visual conditions that resemble the light environments that they naturally inhabit in Lake Victoria. We also included interspecific first-generation hybrids. We focused on the four opsins that are expressed in Pundamilia adults (using real-time quantitative polymerase chain reaction (RT-qPCR)) (SWS2B, SWS2A, RH2A, and LWS) at 17 time points. We find that opsin expression profiles progress from shorter-wavelength sensitive opsins to longer-wavelength sensitive opsins with increasing age, in both species and their hybrids. The developmental trajectories of opsin expression also responded plastically to the visual conditions. Developmental and environmental plasticity in opsin expression may provide an important stepping stone in the evolution of cichlid visual system diversity.

Quantifying visual acuity in Heliconius butterflies.

Heliconius butterflies are well-known for their colourful wing patterns, which advertise distastefulness to potential predators and are used during mate choice. However, the relative importance of different aspects of these signals will depend on the visual abilities of Heliconius and their predators. Previous studies have investigated colour sensitivity and neural anatomy, but visual acuity (the ability to perceive detail) has not been studied in these butterflies. Here, we provide the first estimate of visual acuity in Heliconius: from a behavioural optomotor assay, we found that mean visual acuity = 0.49 cycles-per-degree (cpd), with higher acuity in males than females. We also examined eye morphology and report more ommatidia in male eyes. Finally, we estimated how visual acuity affects Heliconius visual perception compared to a potential avian predator. Whereas the bird predator maintained high resolving power, Heliconius lost the ability to resolve detail at greater distances, though colours may remain salient. These results will inform future studies of Heliconius wing pattern evolution, as well as other aspects in these highly visual butterflies, which have emerged as an important system in studies of adaptation and speciation.

Oviposition behavior is not affected by ultraviolet light in a butterfly with sexually-dimorphic expression of a UV-sensitive opsin.

Animal vision is important for mediating multiple complex behaviors. In Heliconius butterflies, vision guides fundamental behaviors such as oviposition, foraging, and mate choice. Color vision in Heliconius involves ultraviolet (UV), blue and long-wavelength-sensitive photoreceptors (opsins). Additionally, Heliconius possess a duplicated UV opsin, and its expression varies widely within the genus. In Heliconius erato, opsin expression is sexually dimorphic; only females express both UV-sensitive opsins, enabling UV wavelength discrimination. However, the selective pressures responsible for sex-specific differences in opsin expression and visual perception remain unresolved. Female Heliconius invest heavily in finding suitable hostplants for oviposition, a behavior heavily dependent on visual cues. Here, we tested the hypothesis that UV vision is important for oviposition in H. erato and Heliconius himera females by manipulating the availability of UV in behavioral experiments under natural conditions. Our results indicate that UV does not influence the number of oviposition attempts or eggs laid, and the hostplant, Passiflora punctata, does not reflect UV wavelengths. Models of H. erato female vision suggest only minimal stimulation of the UV opsins. Overall, these findings suggest that UV wavelengths do not directly affect the ability of Heliconius females to find suitable oviposition sites. Alternatively, UV discrimination could be used in the context of foraging or mate choice, but this remains to be tested.

La visión animal cumple una función crucial guiando comportamientos complejos. Para las mariposas Heliconius, la visión juega un papel principal en comportamientos como la búsqueda de alimento, la elección de pareja y la ovoposición. La visión a color en Heliconius está compuesta por una combinación de fotoreceptores (opsinas) sensibles a rayos ultravioleta (UV), azul y ondas de longitud larga (verde­rojo). Adicionalmente, estas mariposas posen una segunda opsina sensible a rayos UV, generada por una duplicación. La expresión de estas dos opsinas UV varia ampliamente dentro del genero de Heliconius. En la especie Heliconius erato, la expresión de estas dos opsinas presenta un dimorfismo sexual donde únicamente las hembras expresan las dos opsinas sensibles a UV, lo que les permite la discriminación de ondas en el rango ultravioleta. Sin embargo, no se han estudiado las presiones ecológicas que han llevado a estas diferencias en la percepción visual entre ambos sexos. Las hembras de Heliconius invierten mucho tiempo buscando plantas hospederas para poner sus huevos y este comportamiento depende en gran medida de señales visuales. En este estudio, manipulamos la disponibilidad de rayos UV en condiciones naturales de luz, para evaluar si el comportamiento de ovoposición es guiado por la visión en UV en H. erato y su especie hermana Heliconius himera. Descubrimos que la presencia de rayos ultravioleta no influye en el número de intentos de ovoposición ni en la cantidad de huevos puestos. Además, la planta hospedera Passiflora puntata, presenta una escasa reflexión en las longitudes de onda UV. Así mismo, nuestros modelos de la visión de H. erato hembras, predicen solamente una estimulación mínima de las opsinas UV. En resumen, nuestros resultados sugieren que las ondas ultravioletas no afectan directamente la capacidad de las hembras Heliconius para encontrar sitios de oviposición adecuados. Alternativamente, la discriminación de ondas UV podría estar siendo utilizada en el contexto de la búsqueda de alimento o la elección de pareja, pero esta hipótesis sigue por ser evaluada.

A framework for understanding sources of bias in medication adherence research.

The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty-three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research.

Safety and immunogenicity of a ChAdOx1 vaccine against Rift Valley fever in UK adults: an open-label, non-randomised, first-in-human phase 1 clinical trial.

BACKGROUND: Rift Valley fever is a viral epidemic illness prevalent in Africa that can be fatal or result in debilitating sequelae in humans. No vaccines are available for human use. We aimed to evaluate the safety and immunogenicity of a non-replicating simian adenovirus-vectored Rift Valley fever (ChAdOx1 RVF) vaccine in humans. METHODS: We conducted a phase 1, first-in-human, open-label, dose-escalation trial in healthy adults aged 18-50 years at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Participants were required to have no serious comorbidities or previous history of receiving an adenovirus-based vaccine before enrolment. Participants were non-randomly allocated to receive a single ChAdOx1 RVF dose of either 5 × 109 virus particles (vp), 2·5 × 1010 vp, or 5 × 1010 vp administered intramuscularly into the deltoid of their non-dominant arm; enrolment was sequential and administration was staggered to allow for safety to be assessed before progression to the next dose. Primary outcome measures were assessment of adverse events and secondary outcome measures were Rift Valley fever neutralising antibody titres, Rift Valley fever GnGc-binding antibody titres (ELISA), and cellular response (ELISpot), analysed in all participants who received a vaccine. This trial is registered with ClinicalTrials.gov (NCT04754776). FINDINGS: Between June 11, 2021, and Jan 13, 2022, 15 volunteers received a single dose of either 5 × 109 vp (n=3), 2·5 × 1010 vp (n=6), or 5 × 1010 vp (n=6) ChAdOx1 RVF. Nine participants were female and six were male. 14 (93%) of 15 participants reported solicited local adverse reactions; injection-site pain was the most frequent (13 [87%] of 15). Ten (67%) of 15 participants (from the 2·5 × 1010 vp and 5 × 1010 vp groups only) reported systemic symptoms, which were mostly mild in intensity, the most common being headache (nine [60%] of 15) and fatigue (seven [47%]). All unsolicited adverse events reported within 28 days were either mild or moderate in severity; gastrointestinal symptoms were the most common reaction (at least possibly related to vaccination), occurring in four (27%) of 15 participants. Transient decreases in total white cell, lymphocyte, or neutrophil counts occurred at day 2 in some participants in the intermediate-dose and high-dose groups. Lymphopenia graded as severe occurred in two participants in the 5 × 1010 vp group at a single timepoint, but resolved at the subsequent follow-up visit. No serious adverse events occurred. Rift Valley fever neutralising antibodies were detectable across all dose groups, with all participants in the 5 × 1010 vp dose group having high neutralising antibody titres that peaked at day 28 after vaccination and persisted through the 3-month follow-up. High titres of binding IgG targeting Gc glycoprotein were detected whereas those targeting Gn were comparatively low. IFNγ cellular responses against Rift Valley fever Gn and Gc glycoproteins were observed in all participants except one in the 5 × 1010 vp dose group. These IFNγ responses peaked at 2 weeks after vaccination, were highest in the 5 × 1010 vp dose group, and tended to be more frequent against the Gn glycoprotein. INTERPRETATION: ChAdOx1 RVF was safe, well tolerated, and immunogenic when administered as a single dose in this study population. The data support further clinical development of ChAdOx1 RVF for human use. FUNDING: UK Department of Health and Social Care through the UK Vaccines Network, Oak Foundation, and the Wellcome Trust. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.

Identity resilience, science mistrust, COVID-19 risk and fear predictors of vaccine positivity and vaccination likelihood: A survey of UK and Portuguese samples.

Based on Identity Process Theory, we hypothesised that two elements of identity resilience (identity worth and identity continuity) differentially predict variance in COVID-19 fear and risk, science mistrust, vaccine positivity, and vaccination likelihood. Data from an online survey of 643 UK and 485 Portuguese adults collected during March 2021 showed the UK and Portuguese did not differ significantly on vaccination likelihood or identity resilience. UK respondents reported less science mistrust, COVID-19 risk, and fear, but higher vaccine positivity than the Portuguese. Identity worth and identity continuity differed between countries in their effects on science mistrust, COVID-19 fear, risk, vaccine positivity and vaccination likelihood. Science mistrust and COVID-19 fear proved key factors in predicting vaccine positivity and vaccination likelihood. We conclude the roles of discrete elements of identity resilience in health behaviour require further examination and action reducing prevalence of specific forms of science mistrust can improve vaccination likelihood.

A Contemporary Analysis of Closed Claims Related to Wrong-Site Surgery.

BACKGROUND: Wrong-site surgeries are considered "never events" and continue to occur despite the implementation of the Universal Protocol by The Joint Commission in 2003. METHODS: The authors reviewed closed claims data on wrong-site surgery between 2013 and 2020 from a medical malpractice company. The claims were classified by allegations made by claimants, the responsible services, the types of procedures, the injuries, and contributing factors. Researchers performed a descriptive analysis of the available variables and reviewed the clinical summary of each case. RESULTS: Between 2013 and 2020, there were 68 wrong-site closed claims cases. The mean age of the patients was 55.7 (standard deviation 16.21) years, and 51.5% were female. The services most frequently responsible for these were Orthopedic (35.3%), Neurosurgery (22.1%), and Urology (8.8%). The most common types of procedures were spine and intervertebral disc surgery (22.1%), arthroscopy (14.7%), and surgery on muscles/tendons (11.8%). The severity of claims was higher in the inpatient setting compared to the ambulatory setting. The most common alleged injuries included the need for additional surgery (45.6%), pain (33.8%), mobility dysfunction (10.3%), worsened injury (8.8%), death (7.4%), and total loss (7.4%). The top contributing factors to wrong-site surgery were failure to follow policy/protocol (83.8%) and failure to review the medical records (41.2%). The mean closed claim value was $136,452.84, and 60.3% of cases were settled. CONCLUSION: The risk of wrong-site surgeries is increased with spine surgeries, likely due to unique technical challenges. Further research is required to identify effective methods of prevention of these events.