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PURPOSE: VitreoDx is an experimental device enabling push-button collection of a neat vitreous liquid biopsy incidental to an intravitreal injection. We explored the ability of the device to collect a sample usable for proteomic biomarker discovery and testing. DESIGN: Pilot study using ex vivo human eyes. METHODS: Non-vitrectomized, human eyes from nine donors 75-91 years of age were refrigerated in BSS and used within 5 days of death. Four VitreoDx devices fitted with 25G needles, and four staked needle insulin syringes with 30G needles, were inserted at equal intervals through the pars plana of each eye and held in place by a fixture. The sampling mode of each VitreoDx device was triggered to attempt to acquire a liquid biopsy up to 70 μL. The plunger of each insulin syringe was retracted to attempt to obtain a liquid biopsy with a maximum volume of 50 μL. Samples acquired with the VitreoDx were extracted to polypropylene cryovials, refrigerated to -80 ºC, and sent for offsite proteomic analysis by proximity extension assay with a focus on panels containing approved and pipelined drug targets for neovascular disease and inflammatory factors. RESULTS: Of the attempted liquid biopsies with the novel 25G VitreoDx, 92% (66 of 72) resulted in successful acquisition (>25 μL) while 89% (64 of 72) attempted by a traditional 30G needle resulted in a successful acquisition. Sample volume sufficient for proteomics array analysis was acquired by the VitreoDx for every eye. Detectable protein was found for 151 of 166 unique proteins assayed in at least 25% of eyes sampled by VitreoDx. CONCLUSIONS: The high acquisition rate achieved by the prototype was similar to that achieved in previous clinical studies where a standard syringe was used with a 25G needle to biopsy vitreous fluid directly prior to standard intravitreal injection. Successful aspiration rates were likewise high for 30G needles. Together, these suggest that it is possible to routinely acquire liquid vitreous biopsies from patients who typically receive intravitreal injections with an injection device using a standard size needle without a vitreous cutter. Protein analysis shows that proteins of interest survive the sampling mechanism and may have potential to direct care in the future.

For dogs with oral tumors, cervical lymph node (LN) metastasis alters treatment and prognosis. It is therefore prudent to make an accurate determination of the clinical presence (cN+ neck) or absence (cN0 neck) of metastasis prior to treatment. Currently, surgical LN extirpation with histopathology is the gold standard for a diagnosis of metastasis. Yet, recommendations to perform elective neck dissection (END) for staging are rare due to morbidity. Sentinel lymph node (SLN) mapping with indirect computed tomography lymphangiography (ICTL) followed by targeted biopsy (SLNB) is an alternative option to END. In this prospective study, SLN mapping followed by bilateral END of all mandibular LNs (MLNs) and medial retropharyngeal LNs (MRLNs) was performed in 39 dogs with spontaneously occurring oral neoplasia. A SLN was identified by ICTL in 38 (97%) dogs. Lymphatic drainage patterns were variable although most often the SLN was identified as a single ipsilateral MLN. In the 13 dogs (33%) with histopathologically confirmed LN metastasis, ICTL correctly identified the draining lymphocentrum in all (100%). Metastasis was confined to the SLN in 11 dogs (85%); 2 dogs (15%) had metastasis beyond the SLN ipsilaterally. Contrast enhanced CT features had good accuracy in predicting metastasis, with short axis measurements less than 10.5 mm most predictive. ICTL imaging features alone were unable to predict metastasis. Cytologic or histopathologic SLN sampling is recommended prior to treatment to inform clinical decision-making. This is the largest study to show potential clinical utility of minimally invasive ICTL for cervical LN evaluation in canine oral tumors.

The use of publicly available sequencing datasets as controls (hereafter, "public controls") in studies of rare variant disease associations has great promise but can increase the risk of false-positive discovery. The specific factors that could contribute to inflated distribution of test statistics have not been systematically examined. Here, we leveraged both public controls, gnomAD v2.1 and several datasets sequenced in our laboratory to systematically investigate factors that could contribute to the false-positive discovery, as measured by λΔ95, a measure to quantify the degree of inflation in statistical significance. Analyses of datasets in this investigation found that 1) the significantly inflated distribution of test statistics decreased substantially when the same variant caller and filtering pipelines were employed, 2) differences in library prep kits and sequencers did not affect the false-positive discovery rate and, 3) joint vs. separate variant-calling of cases and controls did not contribute to the inflation of test statistics. Currently available methods do not adequately adjust for the high false-positive discovery. These results, especially if replicated, emphasize the risks of using public controls for rare-variant association tests in which individual-level data and the computational pipeline are not readily accessible, which prevents the use of the same variant-calling and filtering pipelines on both cases and controls. A plausible solution exists with the emergence of cloud-based computing, which can make it possible to bring containerized analytical pipelines to the data (rather than the data to the pipeline) and could avert or minimize these issues. It is suggested that future reports account for this issue and provide this as a limitation in reporting new findings based on studies that cannot practically analyze all data on a single pipeline.

This study examined differences in alcohol use by sexual and gender identities during the COVID-19 pandemic, and assessed whether variation between groups was explained by pandemic-related stressors and minority stress. Data from 2,429 partnered adults in the National Couples' Health and Time Use Study (n = 3,593) collected from September 2020 to April 2021 were used to model drinking patterns (frequency, amount, and drinking to cope) by sexual and gender identities, COVID-19 stress and disruption, microaggressions, and supportive climate. Regression models indicated differences in drinking by gender and sexual identities, even controlling for demographic and socioeconomic factors. Gay, lesbian, and bisexual people had higher odds of drinking to cope with the pandemic than did heterosexual people, and cisgender men had higher odds than did cisgender women. Gay and lesbian people drank more regularly than did heterosexual people, as did cisgender men in relation to cisgender women. Exclusively bisexual people drank significantly more drinks than exclusively heterosexual people, and cisgender men drank significantly more drinks than did cisgender women and those who identified as trans/another gender identity. COVID-19 stress and minority stress were associated with greater alcohol consumption, but they did not account for these differentials. Moving forward, researchers will need to continuously assess these associations, as sources of discrimination and stress will persist beyond the pandemic. Although LGBTQ+ people have disproportionate sources of stress, they varied in how they used alcohol to cope. Potential sources of resilience among sexual and gender diverse individuals should be explored.

The incidence of mental health problems is increasing in the United Kingdom and may be associated with lower dietary quality. Food expenditure is a marker of food insecurity with potential implications for mental health. This analysis considers data collected as part of the United Kingdom Household Longitudinal Survey (UKHLS), also known as 'Understanding Society' (2009-2021) (N = 388,944) to determine the extent to which food expenditure within and outside the household, is associated with mental health, whilst controlling for demographic factors. Mental health was measured using the General Health Questionnaire (GHQ-12) for which responses were on a 4-point scale and reverse-scored so that a higher score represented more favourable mental health. Household food expenditure and food expenditure outside the home were the outcomes. Controlling for socioeconomic and demographic factors, fixed-effects models indicated that better mental health was associated with greater household food expenditure and with greater food expenditure outside the home and that this association persisted post-lockdown. Among those on lower incomes better mental health was associated with lower food expenditure. When people who identified as white and non-white were modelled separately, better mental health was associated with lower food expenditure within and beyond the household only in those who identified as white. These findings imply that the mental health of people residing in the UK, particularly those on lower incomes and those who identify as white, may benefit from spending less of the household budget on food. In achieving United Nations General Assembly (2012) Sustainable Development Goals related to poverty, hunger and in promoting mental health, policies are needed to render food more affordable and to reduce other aspects of expenditure that impact upon food budgeting.

Providing consumers with product-specific environmental impact information for food products (ecolabels) may promote more sustainable purchasing, needed to meet global environmental targets. This UK study (N = 1051 participants) investigated the effectiveness of different ecolabels using an experimental online supermarket platform, comparing three labels against control (no label). Significant reductions were found in the environmental impact score (EIS) for all labels compared to control (labels presented: values for four environmental indicators [-3.9 percentiles, 95%CIs: -5.3, -2.6]; a composite score [taking values from A to E; -3.9, 95%CIs: -5.2,-2.5]; or both together [-3.2, 95%CIs: -4.5, -1.9]). Providing ecolabels is a promising intervention to promote the selection of more sustainable products.

Pre-exposure prophylaxis (PrEP) is being scaled up to prevent HIV acquisition among adolescent girls and young women (AGYW) in Eastern and Southern Africa. In a prior study more than one-third of AGYW 'mystery shoppers' stated they would not return to care based on interactions with health providers. We examined the experiences of AGYW in this study to identify main barriers to effective PrEP services. Unannounced patient actors (USP/'mystery shoppers') posed as AGYWs seeking PrEP using standardized scenarios 8 months after providers had received training to improve PrEP services. We conducted targeted debriefings using open-ended questions to assess PrEP service provision and counseling quality with USPs immediately following their visit. Debriefings were audio-recorded and transcribed. Transcripts were analyzed using thematic analysis to explore why USPs reported either positive or negative encounters. We conducted 91 USP debriefings at 24 facilities and identified three primary influences on PrEP service experiences: 1) Privacy improved likelihood of continuing care, 2) respectful attitudes created a safe environment for USPs, and 3) patient-centered communication improved the experience and increased confidence for PrEP initiation among USPs. Privacy and provider attitudes were primary drivers that influenced decision-making around PrEP in USP debriefs. Access to privacy and improving provider attitudes is important for scale-up of PrEP to AGYW.

BackgroundIsoniazid preventive therapy (IPT) decreases risk of tuberculosis (TB) disease; impact on long-term infant growth is unknown. In a recent randomized trial (RCT), we assessed IPT effects on infant growth without known TB exposure.MethodsThe infant TB Infection Prevention Study (iTIPS) trial was a non-blinded RCT among HIV-exposed uninfected (HEU) infants in Kenya. Inclusion criteria included age 6-10 weeks, birthweight ≥2.5 kg, and gestation ≥37 weeks. Infants in the IPT arm received 10 mg/kg isoniazid daily for 12 months, while the control trial received no intervention; post-trial observational follow-up continued through 24 months of age. We used intent-to-treat linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) between trial arms.ResultsAmong 298 infants, 150 were randomized to IPT, 47.6% were females, median birthweight was 3.4 kg (interquartile range [IQR] 3.0-3.7), and 98.3% were breastfed. During the 12-month intervention period and 12-month post-RCT follow-up, WAZ and HAZ declined significantly in all children, with more HAZ decline in male infants. There were no growth differences between trial arms, including in sex-stratified analyses. In longitudinal linear analysis, mean WAZ (β = 0.04 [95% CI:-0.14, 0.22]), HAZ (β = 0.14 [95% CI:-0.06, 0.34]), and WHZ [β = -0.07 [95% CI:-0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants randomized to IPT had higher monthly WHZ increase (β to 24 months 0.02 [95% CI:0.01, 0.04]) than the no-IPT arm.ConclusionIPT administered to HEU infants did not significantly impact growth outcomes in the first two years of life.

ObjectiveTo compare preferences, uptake, and cofactors for unassisted home-based oral self-testing (HB-HIVST) versus clinic-based rapid diagnostic blood tests (CB-RDT) for maternal HIV retesting.DesignProspective cohort.MethodsBetween November 2017 and June 2019, HIV-negative pregnant Kenyan women receiving antenatal care were enrolled and given a choice to retest with HB-HIVST or CB-RDT. Women were asked to retest between 36 weeks gestation and 1-week post-delivery if the last HIV test was ResultsOverall, 994 women enrolled and 33% (n = 330) selected HB-HIVST. HB-HIVST was selected because it was private (n = 224, 68%), convenient (n = 211, 63%), and offered flexibility in the timing of retesting (n = 207, 63%), whereas CB-RDT was selected due to the trust of providers to administer the test (n = 510, 77%) and convenience of clinic testing (n = 423, 64%). Among 905 women who reported retesting at follow-up, 135 (15%) used HB-HIVST. Most (n = 595, 94%) who selected CB-RDT retested with this strategy, compared to 39% (n = 120) who selected HB-HIVST retesting with HB-HIVST. HB-HIVST retesting was more common among women with higher household income and those who may have been unable to test during pregnancy (both retested postpartum and delivered ConclusionsWhile most women preferred CB-RDT for maternal retesting, HB-HIVST was acceptable and feasible and could be used to expand HIV retesting options.

This study sought to develop a user-friendly decision-making tool to explore country-specific estimates for costs and economic consequences of different options for scaling screening and psychosocial interventions for women with common perinatal mental health problems in Malawi. We developed a simple simulation model using a structure and parameter estimates that were established iteratively with experts, based on published trials, international databases and resources, statistical data, best practice guidance and intervention manuals. The model projects annual costs and returns to investment from 2022 to 2026. The study perspective is societal, including health expenditure and productivity losses. Outcomes in the form of health-related quality of life are measured in Disability Adjusted Life Years, which were converted into monetary values. Economic consequences include those that occur in the year in which the intervention takes place. Results suggest that the net benefit is relatively small at the beginning but increases over time as learning effects lead to a higher number of women being identified and receiving (cost‑)effective treatment. For a scenario in which screening is first provided by health professionals (such as midwives) and a second screening and the intervention are provided by trained and supervised volunteers to equal proportions in group and individual sessions, as well as in clinic versus community setting, total costs in 2022 amount to US$ 0.66 million and health benefits to US$ 0.36 million. Costs increase to US$ 1.03 million and health benefits to US$ 0.93 million in 2026. Net benefits increase from US$ 35,000 in 2022 to US$ 0.52 million in 2026, and return-on-investment ratios from 1.05 to 1.45. Results from sensitivity analysis suggest that positive net benefit results are highly sensitive to an increase in staff salaries. This study demonstrates the feasibility of developing an economic decision-making tool that can be used by local policy makers and influencers to inform investments in maternal mental health.

Mechanistic investigation of host-microbe interactions in the human gut are hindered by difficulty of co-culturing microbes with intestinal epithelial cells. On one hand the gut bacteria are a mix of facultative, aerotolerant or obligate anaerobes, while the intestinal epithelium requires oxygen for growth and function. Thus, a coculture system that can recreate these contrasting oxygen requirements is critical step towards our understanding microbial-host interactions in the human gut. Here, we demonstrate Intestinal Organoid Physoxic Coculture (IOPC) system, a simple and cost-effective method for coculturing anaerobic intestinal bacteria with human intestinal organoids (HIOs). Using commensal anaerobes with varying degrees of oxygen tolerance, such as nano-aerobe Bacteroides thetaiotaomicron and strict anaerobe Blautia sp., we demonstrate that IOPC can successfully support 24-48 hours HIO-microbe coculture. The IOPC recapitulates the contrasting oxygen conditions across the intestinal epithelium seen in vivo. The IOPC cultured HIOs showed increased barrier integrity, and induced expression of immunomodulatory genes. A transcriptomic analysis suggests that HIOs from different donors show differences in the magnitude of their response to coculture with anaerobic bacteria. Thus, the IOPC system provides a robust coculture setup for investigating host-microbe interactions in complex, patient-derived intestinal tissues, that can facilitate the study of mechanisms underlying the role of the microbiome in health and disease.

[This corrects the article DOI: 10.1371/journal.pone.0262402.].

[This corrects the article DOI: 10.1371/journal.pone.0267881.].

Introduction and objectiveThe commitment of pharmacy graduates to patient care and research is crucial to advancing pharmaceutical science and practice. Consequently, the value of involving undergraduate pharmacy students in research has been increasingly recognized. Given that the College of Pharmacy at Qatar University offers two undergraduate pharmacy research courses, it is relevant to explore the perception of faculty members of the delivery, impact, facilitators, barriers, and suggested improvements in these courses. This exploration will help to improve the existing curriculum and to highlight the prospective impact of student involvement in undergraduate pharmacy research courses on the personal and professional growth of students, as well as on the progressive evolution of the pharmacy profession.MethodsA qualitative exploratory case study was performed in which five virtual focus groups were conducted. All eligible faculty members from the clinical pharmacy and pharmaceutical science departments with experience supervising students who had taken one or two undergraduate pharmacy research courses were invited to participate. The focus group questions were based on the Theoretical domain framework of behavioral determinants. Verbatim transcription was performed, and the collected data were thematically analyzed using the computer-assisted coding software NVivo®.ResultsOf the 26 eligible faculty members, 21 participated in this study. Five deductive themes were identified: social professional role and influences, beliefs about capabilities, skills, beliefs about consequences and goals, and environmental resources and behavioral regulations. Overall, faculty members identified themselves as assessors and mentors. Participants expected students to possess independence, responsibility, and motivation. They believed that students generally required more practical research skills. Several benefits of incorporating students into undergraduate research have been highlighted, including increased publication productivity and quality. However, several hurdles to undergraduate research in pharmacy have been identified, including limited resources, limited timeframes, and sometimes delayed ethical approval.ConclusionFaculty members expressed optimism regarding the undergraduate research courses. However, some logistical concerns, including the lengthy ethical approval process and resource availability, must be addressed to optimize the effectiveness of these courses.

IntroductionUganda has a high demand for neurosurgical and neurological care. 78% of the over 50 million population reside in rural and remote communities where access to neurosurgical and neurological services is lacking. This study aimed to determine the feasibility, appropriateness, and usability of mobile neuro clinics (MNCs) in providing neurological care to rural and remote Ugandan populations.MethodsNeurosurgery, neurology, and mobile health clinic providers participated in an education and interview session to assess the feasibility, appropriateness, and usability of the MNC intervention. A qualitative analysis of the interview responses using the constructs in the updated Consolidated Framework for Implementation Research was performed. Providers' opinions were weighted using average sentiment scores on a novel sentiment-weighted scale adapted from the CFIR. A stakeholder analysis was also performed to assess the power and interest of the actors described by the participants.ResultsTwenty-one healthcare providers completed the study. Participants discussed the potential benefits and concerns of MNCs as well as potential barriers and critical incidents that could jeopardize the intervention. Of the five CFIR domains evaluated, variables in the implementation process domain showed the highest average sentiment scores, followed by the implementation climate constructs, inner setting, innovation, and outer setting domains. Furthermore, many interested stakeholders were identified with diverse roles and responsibilities for implementing MNCs. These findings demonstrate that MNC innovation is feasible, appropriate, and usable.ConclusionThe findings of this study support the feasibility, appropriateness, and usability of MNCs in Uganda. However, integration of this innovation requires careful planning and stakeholder engagement at all levels to ensure the best possible outcomes.

The human smile can convey both rewarding and affiliative social intent and thus has significant utility in politics, where the ability to bond with and reassure voters is vital to electoral success. We examine experimental evidence from the 2019 UK general election to investigate the influence of a politician's reward or affiliative smile on voter emotions. It was hypothesised that the winner's affiliative smile would engender positive affect across all partisan groups compared to the winner's reward smile display. Participants from a nationally representative sample were shown campaign footage containing both types of smiles from the leaders of the main competing political parties both before and after the election. Increases in happiness and affinity were revealed across all partisan groups when shown footage of the eventual winner's affiliative smile; at the same time, supporters of losing parties indicated a decrease in negative affect. Affinity has been shown to increase civic engagement. Thus, we conclude that affiliative smiles displayed by leading candidates during the campaign likely acted as a mechanism to align voter behaviour with the dominant political message.

Former United States President Ronald Reagan's use of media and his charismatic connection with viewers earned him the moniker "the great communicator". One aspect of his charisma, the influence of elicited laughter, during a highly critical 5-minute news story by CBS reporter Leslie Stahl during the 1984 US presidential election is examined here. Two experiments examining the effects of audience laughter on perceptions of charismatic leadership are reported. In the first experiment the effects of audience laughter in response to Reagan's comments were investigated. Here, Reagan's perceived warmth as an effective leader significantly diminished when strong laughter is removed, whereas perceptions of competence remained unaffected. The second study carried out on an older cohort replicated and extended the first in a pre-registered design by considering the perception of trait charisma. Here, the presence or absence of audience laughter did not affect judgements of charisma. Additionally, the affective response before, and then after, the presentation of the news story was measured. Emotions associated with a positive appraisal all decreased after being shown the news story while emotions associated negative appraisal all increased. However, only participant anger was significantly increased when audience laughter was removed. Taken together the findings of both studies converge on the fact that subtle changes in media presentation of political leaders can have a significant effect on viewers. The findings show that even after 40 years in office the social psychological effects of presidential charisma can still influence observers.

A hearing aid or a contralateral routing of signal device are options for unilateral cochlear implant listeners with limited hearing in the unimplanted ear; however, it is uncertain which device provides greater benefit beyond unilateral listening alone. Eighteen unilateral cochlear implant listeners participated in this prospective, within-participants, repeated measures study. Participants were tested with the cochlear implant alone, cochlear implant + hearing aid, and cochlear implant + contralateral routing of signal device configurations with a one-month take-home period between each in-person visit. Audiograms, speech perception in noise, and lateralization were evaluated. Subjective feedback was obtained via questionnaires. Marked improvement in speech in noise and non-implanted ear lateralization accuracy were observed with the addition of a contralateral hearing aid. There were no significant differences in speech recognition between listening configurations. However, the chronic device use questionnaires and the final device selection showed a clear preference for the hearing aid in spatial awareness and communication domains. Individuals with limited hearing in their unimplanted ears demonstrate significant improvement with the addition of a contralateral device. Subjective questionnaires somewhat contrast with clinic-based outcome measures, highlighting the delicate decision-making process involved in clinically advising one device or another to maximize communication benefits.

IntroductionAdolescents with HIV in sub-Saharan Africa face challenges transitioning to adult HIV care, which can affect long-term HIV care adherence and retention. An adolescent transition package (ATP) focused on transition tools can improve post-transition clinical outcomes, but its implementation costs are unknown.MethodsWe estimated the average cost per patient of an HIV care visit and ATP provision to adolescents. Data was collected from 13 HIV clinics involved in a randomized clinical trial evaluating ATP in western Kenya. We conducted a micro-costing and activity-driven time estimation to assess costs from the provider perspective. We developed a flow-map, conducted staff interviews, and completed time and motion observation. ATP costs were estimated as the difference in average cost for an HIV care transition visit in the intervention compared to control facilities. We assessed uncertainty in costing estimates via Monte Carlo simulations.ResultsThe average cost of an adolescent HIV care visit was 29.8USD (95%CI 27.5, 33.4) in the standard of care arm and 32.9USD (95%CI 30.5, 36.8) in the ATP intervention arm, yielding an incremental cost of 3.1USD (95%CI 3.0, 3.4) for the ATP intervention. The majority of the intervention cost (2.8USD) was due ATP booklet discussion with the adolescent.ConclusionThe ATP can be feasibly implemented in HIV care clinics at a modest increase in overall clinic visit cost. Our cost estimates can be used to inform economic evaluations or budgetary planning of adolescent HIV care interventions in Kenya.

ObjectivesThe post-medieval period in Europe saw a dramatic increase in metabolic bone disease related to vitamin D deficiency (VDD). Recent paleopathological work has utilized interglobular dentin (IGD) as a proxy for poor vitamin D status during development, while enamel peptide analysis allows the identification of chromosomal sex in non-adult remains. Here we explore the relationship between sex, the presence of IGD, and macroscopic markers of VDD in an industrial era assemblage from Northeast England.Materials and methods25 individuals (9 females, 9 males, 9 unknown sex) from the cemetery site at Coach Lane, North Shields (1711-1857) were selected for paleopathological analysis, histological assessment of IGD, and enamel peptide determination of chromosomal sex.ResultsGround tooth sections from 21 individuals were of suitable quality for detection of IGD, and enamel peptide analysis confirmed the chromosomal sex of ten individuals. Sixteen individuals (76.1%) exhibited ≥1 episode of IGD. Nine of these (42.8%) exhibited >1 episode and four (19%) exhibited ≥4 episodes in regular intervals. Male sex was significantly associated with the presence of IGD (p = 0.0351; 100% males vs. 54.5% females). Females were more likely to exhibit macroscopic evidence of VDD (45.5% females vs 30% males) but this was not statistically significant.Discussion and conclusionsPeriods of poor mineral metabolism during childhood appear much more prevalent at Coach Lane than macroscopic evidence suggests. Evidence of seasonal IGD episodes indicates that northern latitude played a major role in poor VD status in the Northeast of England. The significant association of IGD with male sex may be due to sex-related differences in dentinal mineralization or a higher risk of poor VD status in males aged

PurposeVitreoDx is an experimental device enabling push-button collection of a neat vitreous liquid biopsy incidental to an intravitreal injection. We explored the ability of the device to collect a sample usable for proteomic biomarker discovery and testing.DesignPilot study using ex vivo human eyes.MethodsNon-vitrectomized, human eyes from nine donors 75-91 years of age were refrigerated in BSS and used within 5 days of death. Four VitreoDx devices fitted with 25G needles, and four staked needle insulin syringes with 30G needles, were inserted at equal intervals through the pars plana of each eye and held in place by a fixture. The sampling mode of each VitreoDx device was triggered to attempt to acquire a liquid biopsy up to 70 μL. The plunger of each insulin syringe was retracted to attempt to obtain a liquid biopsy with a maximum volume of 50 μL. Samples acquired with the VitreoDx were extracted to polypropylene cryovials, refrigerated to -80 ºC, and sent for offsite proteomic analysis by proximity extension assay with a focus on panels containing approved and pipelined drug targets for neovascular disease and inflammatory factors.ResultsOf the attempted liquid biopsies with the novel 25G VitreoDx, 92% (66 of 72) resulted in successful acquisition (>25 μL) while 89% (64 of 72) attempted by a traditional 30G needle resulted in a successful acquisition. Sample volume sufficient for proteomics array analysis was acquired by the VitreoDx for every eye. Detectable protein was found for 151 of 166 unique proteins assayed in at least 25% of eyes sampled by VitreoDx.ConclusionsThe high acquisition rate achieved by the prototype was similar to that achieved in previous clinical studies where a standard syringe was used with a 25G needle to biopsy vitreous fluid directly prior to standard intravitreal injection. Successful aspiration rates were likewise high for 30G needles. Together, these suggest that it is possible to routinely acquire liquid vitreous biopsies from patients who typically receive intravitreal injections with an injection device using a standard size needle without a vitreous cutter. Protein analysis shows that proteins of interest survive the sampling mechanism and may have potential to direct care in the future.

Stable isotope analysis is an increasingly used molecular tool to reconstruct the diet and ecology of elusive primates such as unhabituated chimpanzees. The consumption of C4 plant feeding termites by chimpanzees may partly explain the relatively high carbon isotope values reported for some chimpanzee communities. However, the modest availability of termite isotope data as well as the diversity and cryptic ecology of termites potentially consumed by chimpanzees obscures our ability to assess the plausibility of these termites as a C4 resource. Here we report the carbon and nitrogen isotope values from 79 Macrotermes termite samples from six savanna woodland chimpanzee research sites across equatorial Africa. Using mixing models, we estimated the proportion of Macrotermes C4 plant consumption across savanna woodland sites. Additionally, we tested for isotopic differences between termite colonies in different vegetation types and between the social castes within the same colony in a subset of 47 samples from 12 mounds. We found that Macrotermes carbon isotope values were indistinguishable from those of C3 plants. Only 5 to 15% of Macrotermes diets were comprised of C4 plants across sites, suggesting that they cannot be considered a C4 food resource substantially influencing the isotope signatures of consumers. In the Macrotermes subsample, vegetation type and caste were significantly correlated with termite carbon values, but not with nitrogen isotope values. Large Macrotermes soldiers, preferentially consumed by chimpanzees, had comparably low carbon isotope values relative to other termite castes. We conclude that Macrotermes consumption is unlikely to result in high carbon isotope values in either extant chimpanzees or fossil hominins.

BackgroundInsomnia may be a risk factor for cardiovascular disease in HIV (HIV-CVD); however, mechanisms have yet to be elucidated.MethodsWe examined cross-sectional associations of insomnia symptoms with biological mechanisms of HIV-CVD (immune activation, systemic inflammation, and coagulation) among 1,542 people with HIV from the Veterans Aging Cohort Study (VACS) Biomarker Cohort. Past-month insomnia symptoms were assessed by the item, "Difficulty falling or staying asleep?," with the following response options: "I do not have this symptom" or "I have this symptom and…" "it doesn't bother me," "it bothers me a little," "it bothers me," "it bothers me a lot." Circulating levels of the monocyte activation marker soluble CD14 (sCD14), inflammatory marker interleukin-6 (IL-6), and coagulation marker D-dimer were determined from blood specimens. Demographic- and fully-adjusted (CVD risk factors, potential confounders, HIV-related factors) regression models were constructed, with log-transformed biomarker variables as the outcomes. We present the exponentiated regression coefficient (exp[b]) and its 95% confidence interval (CI).ResultsWe observed no significant associations between insomnia symptoms and sCD14 or IL-6. For D-dimer, veterans in the "Bothers a Lot" group had, on average, 17% higher D-dimer than veterans in the "No Difficulty Falling or Staying Asleep" group in the demographic-adjusted model (exp[b] = 1.17, 95%CI = 1.01-1.37, p = .04). This association was nonsignificant in the fully-adjusted model (exp[b] = 1.09, 95%CI = 0.94-1.26, p = .27).ConclusionWe observed little evidence of relationships between insomnia symptoms and markers of biological mechanisms of HIV-CVD. Other mechanisms may be responsible for the insomnia-CVD relationship in HIV; however, future studies with comprehensive assessments of insomnia symptoms are warranted.

PurposeTo investigate any associations between cigarette smoking and retinal microvascular changes in diabetic patients without visible retinopathy.DesignRetrospective, cross-sectional study.Participants1099 eyes from 1099 diabetic patients with no clinical evidence of diabetic retinopathy (DR) were included in this study.MethodsDiabetic patients underwent optical coherence tomography angiography (OCTA) scanning at Zuckerberg San Francisco General Hospital and Trauma Center between April 2018 and September 2019. Patient demographic and clinical information was collected. Standard bivariate statistics and multivariate linear regression were performed.Main outcome measuresOCTA parameters included metrics related to the foveal avascular zone (FAZ; area, perimeter, circularity), perfusion density (PD; full, center, inner), and vessel length density (VLD; full, center, inner).ResultsThe study population included 750 non-smokers and 349 smokers. FAZ perimeter was the only OCTA parameter that was significantly different between the two groups on uncontrolled analysis (P = 0.033). Multivariate regression analyses revealed significant associations between lower VLD full (β = -0.31, P = 0.048), lower VLD inner (β = -0.35, P = 0.046) and a history of smoking. No significant associations between cigarette smoking and either FAZ or PD were detected.ConclusionsOur results suggest that smoking is likely associated with deleterious changes in the retinal microvasculature of patients with a history of diabetes and no visible DR. Based on these findings, diabetic patients with a history of smoking may benefit from higher prioritization in terms of ophthalmic screening.

PurposeThe purpose of this study was to examine whether racial and ethnic differences in retinal microvasculature are detectable with quantitative measures derived from optical coherence tomography angiography (OCTA).MethodsOCTA scans and fundus photography were obtained in 447 eyes from 271 patients with and without diabetes between April and October 2018. Fundus photos were graded by the hospital reading center for diabetic retinopathy (DR) severity. Eight OCTA parameters relating to the foveal avascular zone (FAZ), superficial vascular perfusion, and deep vascular perfusion were analyzed for significant differences between race and ethnicity groups, self-reported by patients and organized according to National Center for Health Statistics groupings. Multiple regression was then used to adjust estimates for possible confounding by age, gender, hypertension, and last hemoglobin A1c level.ResultsSignificant differences in FAZ area were found between white and non-white patients. After adjustment, the differences between white and all non-white groups were statistically significant (p

INTRODUCTION: Sea-level rise is a consequence of climate change that can impact the ecological and physiological changes of coastal, ground-dwelling species. Sea-level rise has a potential to inundate birds, rodents, spiders, and insects that live on the ground in coastal areas. Yet, there is still much to be learned concerning the specifics of these impacts. The red imported fire ant Solenopsis invicta (Buren) excavates soil for its home and is capable of surviving flooding. Because of their ground-dwelling life history and rapid reproduction, fire ants make an ideal model for discovery and prediction of changes that may be due to sea-level rise. There are up to 500,000 individuals in a colony, and these invasive ants naturally have a painful sting. However, observations suggest that colonies of fire ants that dwell in tidally-influenced areas are more aggressive with more frequent stings and more venom injected per sting (behavioral and physiological changes) than those located inland. This may be an adaption to sea-level rise. Therefore, the objective of this study is to elucidate differences in inland and coastal defensiveness via micro-dissection and comparison of head width, head length, stinger length, and venom sac volume. But first because fire ants ability to raft on brackish tidal water is unknown, it had to be determined if fire ants could indeed raft in brackish water and examine the behavior differences between those flooded with freshwater vs. saltwater. METHODS: To test the coastal-aggression hypothesis, inland colonies and coastal colonies, which experience relatively greater amounts of flooding, specifically regular tidal and windblown water and oscillations (i.e. El Nińo Southern Oscillation) from the Gulf of Mexico, were collected. To mimic sea-level rise, the colonies were flooded in salinities that correspond to both their collection site and conditions found in a variety of locales and situations (such as storm surge from a tropical storm). Individual ants were immediately taken from each colony for dissection before flooding, 1-hour into flooding, and 24-hours into flooding. RESULTS AND DISCUSSION: Fire ants use their venom to defend themselves and to communicate alarm or aggression. Dissections and measurement of heads, venom sacs, and stingers revealed both coastal and inland colonies experience an increase in venom sac volume after 24 hours; in fact coastal colonies increased their venom volume by 75% after 24 h of flooding Whether this venom sac enlargement is due to diffusion of water or venom sac production is unknown. These ground-dwelling ants exhibit physiological and behavioral adaptations to ongoing sea-level rise possibly indicating that they are responding to increased flooding. Fire ants will raft on high-salinity water; and sea-level rise may cause stings by flooded ants to be more severe because of increased venom volume.

PurposeTo compare quantitative changes in macular parameters in diabetic patients detected by two optical coherence tomography angiography (OCTA) instruments.Methods80 phakic eyes were classified as no diabetes, diabetes without diabetic retinopathy (DR), mild non-proliferative diabetic retinopathy (NPDR), and severe NPDR or proliferative DR (PDR). OCTA was performed using devices from two manufacturers (Zeiss and Heidelberg). Superficial and deeper vascular skeleton density (SVSD, DVSD), superficial and deeper vessel area density (SVAD, DVAD), choriocapillaris flow voids (CCFV), and choroidal flow voids (CFV) were calculated. Inter-device comparisons were performed using the size comparison index (SCI) and the discrepancy index (DI).ResultsThe two devices were inconsistent in SVSD, DVSD, DVAD, CCFV and CFV parameters (all P < 0.05). In addition, the SCI was positive for DVAD (all P < 0.001) and negative for SVSD, DVSD, CCFV and CFV in all groups (all P 0.05). The mean DI of CCFV was statistically different between the four groups (P < 0.001).ConclusionsThe two instruments were largely inconsistent in the measurement of macular parameters relevant to DR. The choice of imaging device can impact OCTA analytics and should be taken into account when drawing conclusions about DR-related changes.

ObjectivesAdapt a cognitive-behavioral stress management program (Nuevo Amanecer or NA) to be generalizable to rural, low literacy Spanish-speaking Latinas with breast cancer survivors at all phases of survivorship.MethodsApply the Transcreation Framework, a community-engaged translational model, to develop the adapted program (Nuevo Amanecer or NA-II), design a randomized controlled trial for community settings, identify recruiters and interventionists, and recruit participants into the trial.ResultsAdaptations included expanding the program from eight to ten weeks, simplifying materials, and increasing skills practice. We added stress management videos, healthy lifestyles information, and survivorship information. Interventionists were trained Latina breast cancer survivors. All core components of NA were retained in NA-II including managing the impact of cancer, information on breast cancer and its treatment, finding cancer information, getting support, managing thoughts, stress management techniques, and setting goals. Participants receive a program manual. Each session includes a review of that week’s content using the manual, practicing a stress-management skill, setting a specific goal, and reviewing videos. Spanish-speaking Latinas with non-metastatic breast cancer were recruited by community recruiters. Of 231 women approached, 24% refused, 10% were ineligible, and 153 (66%) were randomized to the intervention or a wait-list control group. The sample was vulnerable: 69% had < high school education, more than half had only Medicaid or no insurance, 91% was foreign born, and 48% reported financial hardship in the past year.ConclusionsApplying the Transcreation Framework to engage stakeholders in designing community-based RCTs enhanced congruence with community contexts and recruitment of this vulnerable population.

BackgroundIn high-income countries, individual- and community-level factors are associated with increased contact with the criminal justice system. However, little is known about how these factors contribute to the risk of arrest in South Africa, which has one of the highest rates of arrests globally. We examine both individual- and community-level factors associated with arrests among young men living in the townships of Cape Town.MethodsData were collected from a stratified community sample of 906 young men aged 18-29 years old living in 18 township neighborhoods. Communities with high and low rates of arrest were identified. Logistic regression models were used to assess which individual-level (such as substance use and mental health status) and community-level (such as infrastructure and presence of bars and gangs) factors predict arrests.ResultsSignificant predictors of arrests were substance use, gang activity, being older, more stressed, and less educated. Living in communities with better infrastructure and in more recently established communities populated by recent immigrants was associated with having a history of arrests.ConclusionsWhen considering both individual- and community-level factors, substance use and gang violence are the strongest predictors of arrests among young men in South Africa. Unexpectedly, communities with better infrastructure have higher arrest rates. Community programs are needed to combat substance use and gang activity as a pathway out of risk among South African young men.Trial registrationClinicalTrials.gov registration #NCT02358226, registered Nov 24, 2014.

In the eastern Pacific Ocean, the tropical tuna purse-seine fishery incidentally captures high numbers of five mobulid bycatch species; all of which are classified as mortalities by the Inter-American Tropical Tuna Commission due to uncertainties in post-release mortality rates. To date, the factors (operational or environmental) leading to the capture of these species by the fishery have not been well studied. Here, we developed Generalized Additive Models for fisheries observer data to analyze the relationships between the presence/absence of Mobula mobular bycatch and oceanographic conditions, the spatial and temporal variability in fishing location, and the set type (associated with dolphins, free-swimming tuna schools or floating objects). Our results suggest that chlorophyll concentration and sea surface height are the most important variables to describe the presence of M. mobular in conjunction with geographic location (latitude and longitude) and set type. Presence of the species was predicted in waters with chlorophyll concentrations between 0.5-1 mg·m-3 and with sea surface height values close to 0; which indicates direct relationships with productive upwelling systems. Seasonally, M. mobular was observed more frequently during December-January and August-September. We also found the highest probability of presence observed in School sets, followed by Dolphin sets. Three areas were observed as important hotspots: the area close to the coastal upwelling of northern Peru, the area west to Islands Colon Archipelago (Galapagos) and the area close to the Costa Rica Dome. This information is crucial to identify the mobulids habitat and hotspots that could be managed and protected under dynamic spatial management measures to reduce the mortality of mobulid rays in the eastern Pacific purse-seine fishery and, hence, ensure the sustainability of the populations of these iconic species.

A recent global trend toward retirement of farmland presents opportunities to reclaim habitat for threatened and endangered species. We examine habitat restoration opportunities in one of the world's most converted landscapes, California's San Joaquin Desert (SJD). Despite the presence of 35 threatened and endangered species, agricultural expansion continues to drive habitat loss in the SJD, even as marginal farmland is retired. Over the next decades a combination of factors, including salinization, climate change, and historical groundwater overdraft, are projected to lead to the retirement of more than 2,000 km2 of farmland in the SJD. To promote strategic habitat protection and restoration, we conducted a quantitative assessment of habitat loss and fragmentation, habitat suitability, climatic niche stability, climate change impacts, habitat protection, and reintroduction opportunities for an umbrella species of the SJD, the endangered blunt-nosed leopard lizard (Gambelia sila). We use our suitability models, in conjunction with modern and historical land use maps, to estimate the historical and modern rate of habitat loss to development. The estimated amount of habitat lost since the species became protected under endangered species law in 1967 is greater than the total amount of habitat currently protected through public ownership and conservation easement. We document climatic niche contraction and associated range contraction away from the more mesic margins of the species' historical distribution, driven by the anthropogenic introduction of exotic grasses and forbs. The impact of exotic species on G. sila range dynamics appears to be still unfolding. Finally, we use NASA fallowed area maps to identify 610 km2 of fallowed or retired agricultural land with high potential to again serve as habitat. We discuss conservation strategies in light of the potential for habitat restoration and multiple drivers of ongoing and historical habitat loss.

Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.

BackgroundPatient and public involvement (PPI) in trials aims to enhance research by improving its relevance and transparency. Planning for statistical analysis begins at the design stage of a trial within the protocol and is refined and detailed in a Statistical Analysis Plan (SAP). While PPI is common in design and protocol development it is less common within SAPs. This study aimed to reach consensus on the most important and relevant statistical analysis items within an SAP to involve patients and the public.MethodsWe developed a UK-based, two-round Delphi survey through an iterative consultation with public partners, statisticians, and trialists. The consultation process started with 55 items from international guidance for statistical analysis plans. We aimed to recruit at least 20 participants per key stakeholder group for inclusion in the final analysis of the Delphi survey. Participants were asked to vote on each item using a Likert scale from 1 to 9, where a rating of 1 to 3 was labelled as having 'limited importance'; 4 to 6 as 'important but not critical' and 7 to 9 as 'critical' to involve patients and the public. Results from the second round determined consensus on critical items for PPI.ResultsThe consultation exercise led to the inclusion of 15 statistical items in the Delphi survey. We recruited 179 participants, of whom 72% (129: 36 statisticians, 29 patients or public partners, 25 clinical researchers or methodologists, 27 trial managers, and 12 PPI coordinators) completed both rounds. Participants were on average 48 years old, 60% were female, 84% were White, 64% were based in England and 84% had at least five years' experience in trials. Four items reached consensus regarding critical importance for patient and public involvement: presentation of results to trial participants; summary and presentation of harms; interpretation and presentation of findings in an academic setting; factors impacting how well a treatment works. No consensus was reached for the remaining 11 items. In general, the results were consistent across stakeholder groups.DiscussionWe identified four critical items to involve patients and the public in statistical analysis plans. The remaining 11 items did not reach consensus and need to be considered in a case-by-case basis with most responders considering patient and public involvement important (but not critical). Our research provides a platform to enable focused future efforts to improve patient and public involvement in trials and enhance the relevance of statistical analyses to patients and the public.

IntroductionNatural language processing (NLP) uses various computational methods to analyse and understand human language, and has been applied to data acquired at Emergency Department (ED) triage to predict various outcomes. The objective of this scoping review is to evaluate how NLP has been applied to data acquired at ED triage, assess if NLP based models outperform humans or current risk stratification techniques when predicting outcomes, and assess if incorporating free-text improve predictive performance of models when compared to predictive models that use only structured data.MethodsAll English language peer-reviewed research that applied an NLP technique to free-text obtained at ED triage was eligible for inclusion. We excluded studies focusing solely on disease surveillance, and studies that used information obtained after triage. We searched the electronic databases MEDLINE, Embase, Cochrane Database of Systematic Reviews, Web of Science, and Scopus for medical subject headings and text keywords related to NLP and triage. Databases were last searched on 01/01/2022. Risk of bias in studies was assessed using the Prediction model Risk of Bias Assessment Tool (PROBAST). Due to the high level of heterogeneity between studies and high risk of bias, a metanalysis was not conducted. Instead, a narrative synthesis is provided.ResultsIn total, 3730 studies were screened, and 20 studies were included. The population size varied greatly between studies ranging from 1.8 million patients to 598 triage notes. The most common outcomes assessed were prediction of triage score, prediction of admission, and prediction of critical illness. NLP models achieved high accuracy in predicting need for admission, triage score, critical illness, and mapping free-text chief complaints to structured fields. Incorporating both structured data and free-text data improved results when compared to models that used only structured data. However, the majority of studies (80%) were assessed to have a high risk of bias, and only one study reported the deployment of an NLP model into clinical practice.ConclusionUnstructured free-text triage notes have been used by NLP models to predict clinically relevant outcomes. However, the majority of studies have a high risk of bias, most research is retrospective, and there are few examples of implementation into clinical practice. Future work is needed to prospectively assess if applying NLP to data acquired at ED triage improves ED outcomes when compared to usual clinical practice.

Malawi has a population of around 20 million people and is one of the world's most economically deprived nations. Severe mental illness (largely comprising psychoses and severe mood disorders) is managed by a very small number of staff in four tertiary facilities, aided by clinical officers and nurses in general hospitals and clinics. Given these constraints, psychosis is largely undetected and untreated, with a median duration of untreated psychosis (DUP) of around six years. Our aim is to work with people with lived experience (PWLE), caregivers, local communities and health leaders to develop acceptable and sustainable psychosis detection and management systems to increase psychosis awareness, reduce DUP, and to improve the health and lives of people with psychosis in Malawi. We will use the UK Medical Research Council guidance for developing and evaluating complex interventions, including qualitative work to explore diverse perspectives around psychosis detection, management, and outcomes, augmented by co-design with PWLE, and underpinned by a Theory of Change. Planned deliverables include a readily usable management blueprint encompassing education and community supports, with an integrated care pathway that includes Primary Health Centre clinics and District Mental Health Teams. PWLE and caregivers will be closely involved throughout to ensure that the interventions are shaped by the communities concerned. The effect of the interventions will be assessed with a quasi-experimental sequential implementation in three regions, in terms of DUP reduction, symptom remission, functional recovery and PWLE / caregiver impact, with quality of life as the primary outcome. As the study team is focused on long-term impact, we recognise the importance of having embedded, robust evaluation of the programme as a whole. We will therefore evaluate implementation processes and outcomes, and cost-effectiveness, to demonstrate the value of this approach to the Ministry of Health, and to encourage longer-term adoption across Malawi.

BackgroundWhile self-rated health (SRH) is a well-validated indicator, its alignment with objective health is inconsistent, particularly among women and older adults. This may reflect group-based differences in characteristics considered when rating health. Using a combination of SRH and satisfaction with health (SH) could capture lived realities for all, thus enabling a more accurate search for predictors of subjective health. With the combined measure of SRH and SH as the outcome we explore a range of characteristics that predict high SRH/SH compared with predictors of a low rating for either SRH or SH.MethodsData were from the Canadian General Social Survey 2016 which includes participants 15 years of age and older. We performed classification and regression tree (CRT) analyses to identify the best combination of socioeconomic, behavioural, and mental health predictors of good SRH and health satisfaction.ResultsAlmost 85% of the population rated their health as good; however, 19% of those had low SH. Conversely, about 20% of those reporting poor SRH were, none-the-less, satisfied. CRT identified healthy eating, absence of a psychological disability, no work disability from long-term illness, and high resilience as the main predictors of good SRH/SH. Living with a spouse or children, higher social class and healthy behaviours also aligned with high scores in both self-perceived health measures. Sex was not a predictor.ConclusionsCombining SRH and SH eliminated sex as a predictor of subjective health, and identified characteristics, particularly resilience, that align with high health and well-being and that are malleable.

BackgroundTreatment of cardiovascular diseases (CVD) is a substantial burden to healthcare systems worldwide. New tools are needed to improve precision of treatment by optimizing the balance between efficacy, safety, and cost. We developed a high-throughput multi-marker decision support instrument which simultaneously quantifies proteins associated with CVD.Methods and findingsCandidate proteins independently associated with different clinical outcomes were selected from clinical studies by the screening of 368 circulating biomarkers. We then custom-designed a quantitative PEA-panel with 21 proteins (CVD-21) by including recombinant antigens as calibrator samples for normalization and absolute quantification of the proteins. The utility of the CVD-21 tool was evaluated in plasma samples from a case-control cohort of 4224 patients with chronic coronary syndrome (CCS) using multivariable Cox regression analyses and machine learning techniques. The assays in the CVD-21 tool gave good precision and high sensitivity with lower level of determination (LOD) between 0.03-0.7 pg/ml for five of the biomarkers. The dynamic range for the assays was sufficient to accurately quantify the biomarkers in the validation study except for troponin I, which in the modeling was replaced by high-sensitive cardiac troponin T (hs-TnT). We created seven different multimarker models, including a reference model with NT-proBNP, hs-TnT, GDF-15, IL-6, and cystatin C and one model with only clinical variables, for the comparison of the discriminative value of the CVD-21 tool. All models with biomarkers including hs-TnT provided similar discrimination for all outcomes, e.g. c-index between 0.68-0.86 and outperformed models using only clinical variables. Most important prognostic biomarkers were MMP-12, U-PAR, REN, VEGF-D, FGF-23, TFF3, ADM, and SCF.ConclusionsThe CVD-21 tool is the very first instrument which with PEA simultaneously quantifies 21 proteins with associations to different CVD. Novel pathophysiologic and prognostic information beyond that of established biomarkers were identified by a number of proteins.

BackgroundMaternal folic acid supplementation is protective against the development of neural tube defects (NTDs) in babies. However, recent public-facing communications have raised concerns about a causal relationship between folic acid supplementation, particularly after the first trimester, and ankyloglossia (tongue-tie) in infants. Non-evidence-based communications are potentially harmful because they could adversely affect adherence to folic acid supplementation, increasing NTD occurrence. This study aimed to review evidence on the relationships between maternal folic acid supplementation during preconception and/or pregnancy and the risk of ankyloglossia in infants.MethodsWe searched the databases MEDLINE, EMBASE, Cochrane CENTRAL, and Scopus. We searched for observational, and interventional studies, and systematic reviews investigating the effect of maternal folic acid supplementation during preconception or pregnancy on the occurrence of ankyloglossia in offspring. The search was registered on PROSPERO on 01/12/2022, ID: CRD42022375862.ResultsThe database searches yielded 93 articles. After removing duplicates and screening titles and abstracts, 26 remained. One article was judged relevant for inclusion in analyses; a case-control study that directly mentions the relationship between folic acid supplementation and ankyloglossia. This study reported that regular intake of folic acid supplements was higher in women with infants with ankyloglossia. However, this study has limitations regarding design, selection bias, and confounding, calling the findings into question.ConclusionsInsufficient evidence exists for a relationship between folic acid supplementation and ankyloglossia. Currently, the benefits of folic acid supplementation far outweigh the risks. This must be clearly communicated to patients by their clinicians during preconception and antenatal care.

There is growing evidence that music can induce a wide range of visual imagery. To date, however, there have been few thorough investigations into the specific content of music-induced visual imagery, and whether listeners exhibit consistency within themselves and with one another regarding their visual imagery content. We recruited an online sample (N = 353) who listened to three orchestral film music excerpts representing happy, tender, and fearful emotions. For each excerpt, listeners rated how much visual imagery they were experiencing and how vivid it was, their liking of and felt emotional intensity in response to the excerpt, and, finally, described the content of any visual imagery they may have been experiencing. Further, they completed items assessing a number of individual differences including musical training and general visual imagery ability. Of the initial sample, 254 respondents completed the survey again three weeks later. A thematic analysis of the content descriptions revealed three higher-order themes of prominent visual imagery experiences: Storytelling (imagined locations, characters, actions, etc.), Associations (emotional experiences, abstract thoughts, and memories), and References (origins of the visual imagery, e.g., film and TV). Although listeners demonstrated relatively low visual imagery consistency with each other, levels were higher when considering visual imagery content within individuals across timepoints. Our findings corroborate past literature regarding music's capacity to encourage narrative engagement. It, however, extends it (a) to show that such engagement is highly visual and contains other types of imagery to a lesser extent, (b) to indicate the idiosyncratic tendencies of listeners' imagery consistency, and (c) to reveal key factors influencing consistency levels (e.g., vividness of visual imagery and emotional intensity ratings in response to music). Further implications are discussed in relation to visual imagery's purported involvement in music-induced emotions and aesthetic appeal.

BackgroundRegular physical activity is important for arthritis self-management and could be promoted through tailoring community leisure and fitness centers' customer-relationship management (CRM) strategies.ObjectivesThis study investigates the influence of two CRM strategies on individuals with arthritis reaching or maintaining two moderate-to-vigorous physical activity (MVPA) thresholds (≥150 and ≥45 minutes/week) from baseline-to-12 months and 12-to-24 months as well as mean changes in total minutes/week of MVPA. It also explores time-dependent variations in the influence of socio-cognitive variables on MVPA outcomes.MethodsSurvey data from 374 participants with arthritis in a two-year randomized controlled trial (control versus two CRM strategies: IncentiveOnly and Incentive+Support) were used. Participants reported measures of physical activity participation, socio-cognitive decision-making, mental and physical wellbeing, friendship, community connectedness, sense of trust in others, and demographics.Findings/discussionReceiving the Incentive+Support CRM strategy (versus control) increased participants' likelihood of reaching/maintaining both physical activity thresholds from 12-to-24 months (≥150 MVPA minutes/week, p < .001; ≥45 MVPA minutes/week, p < .032) but not from baseline-to-12 months. However, receiving the IncentiveOnly CRM strategy (versus control) did not predict reaching/maintaining these thresholds. Importantly, socio-cognitive decision-making variables' influence on reaching/maintaining these MVPA thresholds varied over time, suggesting CRM strategies may require further tailoring based on time-specific profiles. Perhaps because of new facility induced excitement, the mean change in total MVPA minutes/week for the control group significantly increased (26.8 minute/week, p = .014, 95% CI [5.5, 48.0]) from baseline-to-12 months, but subsequently declined by 11.4 minute/week from 12-to-24 months (p = .296, 95% CI [-32.7, 9.9]). Mean changes in total MVPA minutes/week were non-significant for those receiving IncentiveOnly content but significant for those receiving Incentive+Support content: baseline-to-12 months (38.2 minute/week increase, p = .023, 95% CI [4.9, 71.4]) and baseline-to-24-months (45.9 minute/week increase, p = .007, 95% CI [12.7, 79.1]).

Introducing SimpliPyTEM, a Python library and accompanying GUI that simplifies the post-acquisition evaluation of transmission electron microscopy (TEM) images, helping streamline the workflow. After an imaging session, a folder of image and/or video files, typically containing low contrast and large file size 32-bit images, can be quickly processed via SimpliPyTEM into high-quality, high-contrast.jpg images with suitably sized scale bars. The app can also generate HTML or PDF files containing the processed images for easy viewing and sharing. Additionally, SimpliPyTEM specifically focuses on in situ TEM videos, an emerging field of EM involving the study of dynamic processes whilst imaging. The package allows fast data processing into preview movies, averages, image series, or motion-corrected averages. The accompanying Python library offers many standard image processing methods, all simplified to a single command, plus a module to analyse particle morphology and population. This latter application is particularly useful for life sciences investigations. User-friendly tutorials and clear documentation are included to help guide users through the processing and analysis. We invite the EM community to contribute to and further develop this open-source package.

BackgroundMultimorbidity is one of the greatest challenges facing health and social care systems globally. It is associated with high rates of health service use, adverse healthcare events, and premature death. Despite its importance, little is known about the effects of contextual determinants such as household and area characteristics on health and care outcomes for people with multimorbidity. This study protocol presents a plan for the examination of associations between individual, household, and area characteristics with important health and social care outcomes.MethodsThe study will use a cross-section of data from the SAIL Databank on 01 January 2019 and include all people alive and registered with a Welsh GP. The cohort will be stratified according to the presence or absence of multimorbidity, defined as two or more long-term conditions. Multilevel models will be used to examine covariates measured for individuals, households, and areas to account for social processes operating at different levels. The intra-class correlation coefficient will be calculated to determine the strength of association at each level of the hierarchy. Model outcomes will be any emergency department attendance, emergency hospital or care home admission, or mortality, within the study follow-up period.DiscussionHousehold and area characteristics might act as protective or risk factors for health and care outcomes for people with multimorbidity, in which case results of the analyses can be used to guide clinical and policy responses for effective targeting of limited resources.