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Objective. To determine the prevalence and causes of vision loss and calculate the effective cataract surgery coverage (eCSC) in adults aged 60 years and older in Latin America and the Caribbean in 2020. Methods. The International Agency for the Prevention of Blindness Vision Atlas and the Rapid Assessment of Avoidable Blindness databases were used as data source. The collected data were used to estimate the prevalence and causes of vision loss in people aged 60 years and older, and to determine the eCSC. Results. The overall prevalence of moderate to severe vision impairment (MSVI) and blindness in Latin America and the Caribbean were 14.14% and 2.94%, respectively. Tropical Latin America was the subregion with the highest prevalence of blindness (3.89%) while Southern Latin America had the lowest (0.96%). For both MSVI and blindness, cataract was the main cause of vision loss. The eCSC rates showed great variation, ranging from 4.0% in Guatemala to 75.2% in Suriname. Conclusions. The prevalence of vision loss in adults aged 60 years and older in Latin America and the Caribbean was higher than previous estimates on younger groups. Cataract was the main cause of blindness, and the eCSC indicates that the outcomes from cataract surgery should be improved. Specific actions associated with improving access, integrating eye assessment with primary care programs, expanding the use of telemedicine, and improving data quality should be taken by public health authorities aiming to address vision loss in this group.

Background: In responding to the global problems facing humankind, there is great value in equipping science and engineering students with skills to function well in multidisciplinary teams. Little attention has been paid into the factors that influence multidisciplinary collaboration and teamwork of science and engineering students. Purpose: This research describes multidisciplinary teamwork of applied physics and mechanical engineering students in a challenge-based learning (CBL) course. The study aimed to: a) identify the facilitators and barriers to multidisciplinary teamwork and b) explore learning outcomes connected to working in multidisciplinary teams. Sample: 30 students registered to the course, two teachers, and three tutors participated in this research. Design and Methods: An instrumental case study was conducted in the context of a pilot CBL course. Data included interviews, reflection reports, observations, and design posters. Transcribed video recordings were searched in an attempt to demonstrate the codes revealed with the qualitative content analysis of interview transcripts and reflection reports. Results: The results indicated knowledge acquisition, application, and an awareness of other disciplinary approaches as the learning outcomes with some differences for engineering and physics students. The findings also yielded individual (e.g. knowledge of control theory), team (e.g. disciplinary perspectives), and course factors (e.g. disciplinary connections to the challenge) that influenced multidisciplinary teamwork. Conclusion: Multidisciplinary teamwork is supported by the unique ways of thinking and approaching problems of the two disciplines. Implications contribute to future research and thinking for similar learning environments while improving student learning in multidisciplinary teams.

Higher engineering education programmes increasingly include courses characterised by real-world problems and student collaboration in multidisciplinary teams. Research findings demonstrate that students remain limited in perceiving and meaningfully bridging disciplinary differences in these course contexts. Drawing on the literature on boundaries and boundary interactions, this study sought to investigate how applied physics and mechanical engineering students managed their disciplinary differences in a challenge-based learning course. Using a qualitative, case study methodology, data from two multidisciplinary student teams (n = 12) were collected through reflective journals, individual interviews, and observations of team meetings. The findings confirm the value of disciplinary boundaries in creating new learning opportunities. The students coordinated their disciplinary differences during discussions in team meetings, preparations for the project plan and the stakeholder pitch, and test sessions in the lab. Results provide insights for designing similar courses and for future research.

Abstract Anthropogenic deoxygenation of the Baltic Sea caused major declines in demersal and benthic habitat quality with consequent impacts on biodiversity and ecosystem services. Using Baltic cod otolith chemical proxies of hypoxia, salinity, and fish metabolic status and growth, we tracked changes from baseline conditions in the late Neolithic (4500 BP) and early twentieth century to the present, in order to understand how recent, accelerating climate change has affected this key species. Otolith hypoxia proxies (Mn:Mg) increased with expanding anoxic water volumes, but decreased with increasing salinity indexed by otolith Sr:Ca. Metabolic status proxied by otolith Mg:Ca and reconstructed growth were positively related to dissolved oxygen percent saturation, with particularly severe declines since 2010. This long-term record of otolith indicators provides further evidence of a profound state change in oxygen for the worse, in one of the world’s largest inland seas. Spreading hypoxia due to climate warming will likely impair fish populations globally and evidence can be tracked with otolith chemical biomarkers.

Data supporting the clinical utility of multi-target stool DNA (mt-sDNA) at the guideline-recommended 3-year interval have not been reported.Between April 2015 and July 2016, candidates for colorectal cancer screening whose providers prescribed the mt-sDNA test were enrolled. Participants with a positive baseline test were recommended for colonoscopy and completed the study. Those with a negative baseline test were followed annually for 3 years. In year 3, the mt-sDNA test was repeated and colonoscopy was recommended independent of results. Data were analyzed using the Predictive Summary Index (PSI), a measure of the gain in certainty for dichotomous diagnostic tests (where a positive value indicates a net gain), and by comparing observed versus expected colorectal cancers and advanced precancerous lesions.Of 2,404 enrolled subjects, 2,044 (85%) had a valid baseline mt-sDNA result [284 (13.9%) positive and 1,760 (86.1%) negative]. Following participant attrition, the year 3 intention to screen cohort included 591 of 1,760 (33.6%) subjects with valid mt-sDNA and colonoscopy results, with no colorectal cancers and 63 advanced precancerous lesions [22 (34.9%) detected by mt-sDNA] and respective PSI values of 0% (P = 1) and 9.3% (P = 0.01). The observed 3-year colorectal cancer yield was lower than expected (one-sided P = 0.09), while that for advanced precancerous lesions was higher than expected (two-sided P = 0.009).Repeat mt-sDNA screening at a 3-year interval resulted in a statistically significant gain in detection of advanced precancerous lesions. Due to absence of year 3 colorectal cancers, the PSI estimate for colorectal cancer was underpowered and could not be reliably quantified. Larger studies are required to assess the colorectal cancer study findings.Prevention relevanceUnderstanding the 3-year yield of mt-sDNA for colorectal cancer and advanced precancerous polyps is required to ensure the clinical appropriateness of the 3-year interval and to optimize mt-sDNA's screening effectiveness.

Abstract Background Good vision highly depends on the transparency of the cornea, which is the “windscreen” of the eye. In fact, corneal blindness due to transparency loss is the second most common cause of blindness worldwide, and corneal transplantation is the main cure. Importantly, the cornea is normally avascular but can secondarily be invaded by pathological (blood and lymphatic) vessels due to severe inflammation, and the survival prognosis of a corneal graft mainly depends on the preoperative vascular condition of the recipient’s cornea. Whereas transplants placed into avascular recipient beds enjoy long-term survival rates of > 90%, survival rates significantly decrease in pathologically pre-vascularized, so-called high-risk recipients, which account for around 10% of all performed transplants in Germany and > 75% in lower and middle-income countries worldwide. Methods This parallel-grouped, open-randomized, multicenter, prospective controlled exploratory investigator-initiated trial (IIT) intends to improve graft survival by preconditioning pathologically vascularized recipient corneas by (lymph)angioregressive treatment before high-risk corneal transplantation. For this purpose, corneal crosslinking (CXL) will be used, which has been shown to potently regress corneal blood and lymphatic vessels. Prior to transplantation, patients will be randomized into 2 groups: (1) CXL (intervention) or (2) no pretreatment (control). CXL will be repeated once if insufficient reduction of corneal neovascularization should be observed. All patients (both groups) will then undergo corneal transplantation. In the intervention group, remaining blood vessels will be additionally regressed using fine needle diathermy (on the day of transplantation). Afterwards, the incidence of graft rejection episodes will be evaluated for 24 months (primary endpoint). Overall graft survival, as well as regression of corneal vessels and/or recurrence, among other factors, will be analyzed (secondary endpoints). Discussion Based on preclinical and early pilot clinical evidence, we want to test the novel concept of temporary (lymph)angioregressive pretreatment of high-risk eyes by CXL to promote subsequent corneal graft survival. So far, there is no evidence-based approach to reliably improve graft survival in the high-risk corneal transplantation setting available in clinical routine. If successful, this approach will be the first to promote graft survival in high-risk transplants. It will significantly improve vision and quality of life in patients suffering from corneal blindness. Trial registration ClinicalTrials.gov NCT05870566. Registered on 22 May 2023.

Introduction Currently, the majority of women worldwide with threatened preterm birth are treated with tocolytics. Although tocolytics can effectively delay birth for 48 hours, no tocolytic drug has convincingly been shown to improve neonatal outcomes and effects on long-term child development are unknown. The aim of this follow-up study of a placebo controlled randomised trial is to investigate the long-term effects of atosiban administration in case of threatened preterm birth on child’s neurodevelopment and behaviour development, overall health and mortality.Methods and analysis This protocol concerns a follow-up study of the multicentre randomised double-blind placebo controlled APOSTEL 8 trial (NL61439.018.17, EudraCT-number 2017-001007-72). In this trial, women with threatened preterm birth (between 30 and 34 weeks of gestation) defined as uterine contractions with (1) a cervical length of

Background and Aims: The multitarget stool DNA (mt-sDNA) assay is a noninvasive average-risk colorectal cancer (CRC) screening test. A new biomarker panel was developed for a next-generation test to improve specificity while maintaining/increasing sensitivity. We aimed first to establish an algorithm and cutoff for the next-generation mt-sDNA test and then to validate it using archived samples from the pivotal DeeP-C study (NCT01397747) of the first-generation test. Methods: Algorithm development and cross-validation included 3011 samples from 2 specimen collection studies (NCT03821948 and NCT03789162). The algorithm and cutoff were locked before validation. Validation test set samples included 57 CRC, 583 advanced precancerous lesions (APLs), and 7022 samples negative for CRC or APLs from the DeeP-C study, which prospectively enrolled average-risk, asymptomatic adults aged 50–84 years before screening colonoscopy. Next-generation biomarkers included methylated DNA markers ceramide synthase 4 gene, leucine-rich repeat-containing protein 4 gene, serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform gene, and zinc finger DHHC-type containing 1 gene (reference marker), and fecal hemoglobin. Primary validation end points were CRC sensitivity and specificity for the absence of advanced neoplasia. Secondary end points included APL sensitivity and specificity for non-neoplastic findings or negative colonoscopy. Results: Cross-validation and best-fit results from algorithm development closely matched, confirming algorithm reliability and reproducibility. For the test set, next-generation mt-sDNA test sensitivity was 93.0% (95% confidence interval [CI], 83.0%–98.1%) for CRC and 48.4% (95% CI, 44.2%–52.5%) for APLs. Specificity was 88.5% (95% CI, 87.7%–89.2%) for the absence of advanced neoplasia and 90.4% (95% CI, 89.5%–91.2%) for the combination of non-neoplastic findings or negative colonoscopy. Conclusion: Based on archived samples, the next-generation mt-sDNA test demonstrated promising CRC screening performance characteristics that will be further assessed in a prospective clinical validation study (BLUE-C; NCT04144738).

Background and Aims: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration–approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. Methods: Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. Results: A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib. Conclusion: These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.gov NCT02273362).

Ocean acidification is spreading globally as a result of anthropogenic CO2 emissions, but the Baltic Sea has until recently been thought to be relatively well-buffered by terrigenous inputs of alkalinity from its watershed. We discovered a 3- to 5-fold decline in boron (as B : Ca) in otoliths of eastern Baltic cod (EBC) between the late 1990s and 2021. Examining a time series of EBC otoliths, we found varying levels of B : Ca starting in the 1980s, with the most recent years showing an all-time low for this period. This trend correlates with declines in pH and dissolved oxygen but not with changes in salinity. We examined possible physiological influences on B : Ca by including a collection of Icelandic cod as an “out-group”. Icelandic cod otoliths showed strongly positive correlations of B : Ca with physiologically regulated P : Ca; this was not the case for EBC. Finally, B : Ca in EBC otoliths is negatively correlated, to some extent, with Mn : Mg, a proposed proxy for hypoxia exposure. This negative relationship is hypothesized to reflect the dual phenomena of hypoxia and acidification as a result of decomposition of large algal blooms. Taken together, the otolith biomarkers Mn : Mg and B : Ca in cod suggest a general increase in both hypoxia and acidification within the Baltic intermediate and deep waters in the last decade.

The Rapid Assessment of Avoidable Blindness (RAAB) is a population-based cross-sectional survey methodology used to collect data on the prevalence of vision impairment and its causes and eye care service indicators among the population 50 years and older. RAAB has been used for over 20 years with modifications to the protocol over time reflected in changing version numbers; this paper describes the latest version of the methodology–RAAB7. RAAB7 is a collaborative project between the International Centre for Eye Health and Peek Vision with guidance from a steering group of global eye health stakeholders. We have fully digitised RAAB, allowing for fast, accurate and secure data collection. A bespoke Android mobile application automatically synchronises data to a secure Amazon Web Services virtual private cloud when devices are online so users can monitor data collection in real-time. Vision is screened using Peek Vision’s digital visual acuity test for mobile devices and uncorrected, corrected and pinhole visual acuity are collected. An optional module on Disability is available. We have rebuilt the RAAB data repository as the end point of RAAB7’s digital data workflow, including a front-end website to access the past 20 years of RAAB surveys worldwide. This website (https://www.raab.world) hosts open access RAAB data to support the advocacy and research efforts of the global eye health community. Active research sub-projects are finalising three new components in 2024-2025: 1) Near vision screening to address data gaps on near vision impairment and effective refractive error coverage; 2) an optional Health Economics module to assess the affordability of eye care services and productivity losses associated with vision impairment; 3) an optional Health Systems data collection module to support RAAB’s primary aim to inform eye health service planning by supporting users to integrate eye care facility data with population data.

Objective: To evaluate the effect of hemorrhoids on noninvasive stool test performance for colorectal cancer (CRC) screening. Patients and Methods: We conducted a retrospective cohort study of test characteristics for the fecal immunochemical test (FIT) and the multitarget stool DNA (mt-sDNA) test, on the basis of hemorrhoid status, recorded at the time of colonoscopy, among patients enrolled in the pivotal prospective study for mt-sDNA that was conducted from June 2011, to May 2013. Test characteristics (sensitivity, specificity, positive, and negative predictive values) for FIT and mt-sDNA (performed < 90 days before colonoscopy) were stratified by the presence of hemorrhoids and compared. Results: Hemorrhoids were found in 51.7% (5163 of 9989) of the study cohort. Across all test characteristics, there were no statistically significant differences for FIT or mt-sDNA when stratified by hemorrhoid status. Analysis revealed mt-sDNA sensitivity of 44% and 41% for advanced precancerous lesions in nonhemorrhoidal and hemorrhoid patients, respectively (P=.41). The FIT sensitivity among the same lesion category was 24.9% in patients without hemorrhoids and 22.8% in those with hemorrhoids (P=.48). The mt-sDNA specificity was 86.4% in patients without hemorrhoids vs 87.7% in those with hemorrhoids (P=.67), although FIT specificity was 95.0% among patients without hemorrhoids vs 94.7% in those with hemorrhoids (P=.44). Conclusion: The presence of asymptomatic hemorrhoids did not adversely affect test performance in this large clinical study. These findings suggest that in the absence of overt gastrointestinal bleeding, FIT and mt-sDNA are options for CRC screening, irrespective of hemorrhoid status. Trial Registration: clinicaltrials.gov Identifier: NCT01397747

Examinations of ovarian cancer cells require the ability to identify tumor cells. Array-based comparative genome hybridization (aCGH) on 30 ovarian carcinomas (OC) identified three genomic loci (8q24.23; 17p12; 18q22.3) over- or under-represented in OC. A fluorescence in situ hybridization (FISH) probe of these three loci is intended to identify tumor cells by their signal pattern deviating from a diploid pattern. Human DNA from these three loci is isolated from bacterial artificial chromosomes (BAC), amplified and labeled with fluorescent dyes. After a standard FISH procedure, 71 OC suspensions from primary tumors, three OC cell lines, three lymphocyte suspensions, and one mesenchymal cell line LP-3 are analyzed with a fluorescence microscope. On average, 15% of the lymphocytes deviate from the expected diploid signal pattern, giving a cut-off of 36%. If this value is exceeded, tumor cells are detected. The mesenchymal cell line LP-3 shows only 21% as a negative control. The OC cell lines as positive controls exceed this value at 38%, 67%, and 54%. Of the 71 OC primary cultures, four cases fell below this cut-off as false negatives. In the two-sample t-test, the percentages of conspicuous signal patterns differ significantly.

AIM: To review existing data for the prevalence of corrected, uncorrected, and inadequately corrected refractive errors and spectacle wear in Hungary. METHODS: Data from two nationwide cross-sectional studies were analysed. The Rapid Assessment of Avoidable Blindness study collected population-based representative national data on the prevalence of visual impairment due to uncorrected refractive errors and spectacle coverage in 3523 people aged ≥50y (Group I). The Comprehensive Health Test Program of Hungary provided data on the use of spectacles in 80 290 people aged ≥18y (Group II). RESULTS: In Group I, almost half of the survey population showed refractive errors for distant vision, about 10% of which were uncorrected (3.2% of all male participants and 5.0% of females). The distance spectacle coverage was 90.7% (91.9% in males; 90.2% in females). The proportion of inadequate distance spectacles was found to be 33.1%. Uncorrected presbyopia was found in 15.7% of participants. In all age groups (Group II), 65.4% of females and 56.0% of males used distance spectacles, and approximately 28.9% of these spectacles were found to be inappropriate for dioptric power (with 0.5 dioptres or more). The prevalence of inaccurate distance spectacles was significantly higher in older age groups (71y and above) in both sexes. CONCLUSION: According to this population-based data, uncorrected refractive errors are not rare in Hungary. Despite recent national initiatives, further steps are required to reduce uncorrected refractive errors and associated negative effects on vision, such as avoidable visual impairment.

Abstract Background To assess patient and primary care provider (PCP) factors associated with adherence to American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF) guidelines for average risk colorectal cancer (CRC) screening. Methods Retrospective case-control study of medical and pharmacy claims from the Optum Research Database from 01/01/2014 − 12/31/2018. Enrollee sample was adults aged 50 − 75 years with ≥ 24 months continuous health plan enrollment. Provider sample was PCPs listed on the claims of average-risk patients in the enrollee sample. Enrollee-level screening opportunities were based on their exposure to the healthcare system during the baseline year. Screening adherence, calculated at the PCP level, was the percent of average-risk patients up to date with screening recommendations each year. Logistic regression modelling was used to examine the association between receipt of screening and enrollee and PCP characteristics. An ordinary least squares model was used to determine the association between screening adherence among the PCP’s panel of patients and patient characteristics. Results Among patients with a PCP, adherence to ACS and USPSTF screening guidelines ranged from 69 to 80% depending on PCP specialty and type. The greatest enrollee-level predictors for CRC screening were having a primary/preventive care visit (OR = 4.47, p

Abstract The use of species distribution models has proliferated, providing insights for sustainable management of migratory species in a globally changing environment. However, many of these models are based on statistical relationships developed from historical conditions that may not perform well under changing or even analogous conditions caused by climate change. In this paper, we used a mechanistic species distribution model called GR3D (Global Repositioning Dynamics for Diadromous Fish Distribution) to examine the integrated dynamics of American shad (Alosa sapidissima) populations across their native range along the Eastern U.S. coast, where the species demonstrates latitudinal variations in life histories and reproductive strategies. The initial design of the model was adapted to incorporate region‐specific parameterization to fit the species ecology. Then, a sensitivity analysis was performed to test the influences of uncertain processes regarding American shad distribution at sea, straying and reproduction on key characteristics of the species distribution. The sensitivity analysis showed the influence of the Allee effect (i.e., “depensatory” process) and the homing rate (i.e., fidelity to the breeding sites) on the probability of presence and abundances among catchments and metapopulations estimated by the model. Contrary to the homing rate, the distance of straying did not change the estimated number of metapopulations or abundances. Homing strength, however, was quite influential. The integration of complex migration patterns during the marine phase (i.e., wintering and summering offshore areas) provided more likely estimates of the species' overall distribution. Overall, our study illustrated the utility of incorporating factors governing the large‐scale distribution of migratory species to improve local management.

Abstract Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles (Legionella pneumophila, Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, Streptococcus pneumoniae) and observed comparable NF-κB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for Klebsiella, E.coli and Salmonella OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free Clear coli OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion, Klebsiella, E.coli and Salmonella OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome. Video Abstract

We utilized the population-based New Hampshire Colonoscopy Registry to calculate false discovery rates (FDR) and positive predictive values (PPVs) using three ‘positive’ colonoscopy definitions. Understanding the frequency of meaningful ‘true positive’ mt-sDNA and Fecal Immunochemical Test (FIT) results can optimize the use of these colorectal cancer (CRC) screening tests. We calculated FDR (positive stool test followed by negative colonoscopy divided by all positive stool tests) and PPV for mt-sDNA and FIT cohorts using the following definitions:1) DeeP-C Study (CRC, adenomas/serrated polyps ≥ 1 cm, villous/High Grade Dysplasia);2) 1 cm, and 5–9 mm proximal HPs.The sample included 549 mt-sDNA + and 410 FIT + and patients (mean age 66.4, 43.0% male). Using the most limited definition of positive colonoscopy, DeeP-C, FDR was 71.9% for mt-sDNA + and 81.7% for FIT +. Using the USMSTF definition, FDR decreased substantially: mt-sDNA+:33.2% and FIT+:47.6%. Adding all CSSPs resulted in the lowest FDR: mt-sDNA+:32.2% and FIT+:47.1%. Decreasing FDRs corresponded to increasing PPVs: mt-sDNA+:28.1% and FIT+:18.3% (DeeP-C definition) and mt-sDNA+:67.8% and FIT+:52.9% (DeeP-C + USMSTF + CSSP) (Table 1).FDRs decreased substantially when the definition of positive exams included all significant precancerous findings. These data present a comprehensive understanding of false positive outcomes at colonoscopies following positive stool tests, which to our knowledge is the first such analysis.

Abstract Purpose To inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening for prostate cancer in adults aged 18 years and older in primary care. This protocol outlines the planned scope and methods for a series of systematic reviews. Methods Updates of two systematic reviews and a de novo review will be conducted to synthesize the evidence on the benefits and harms of screening for prostate cancer with a prostate-specific antigen (PSA) and/or digital rectal examination (DRE) (with or without additional information) and patient values and preferences. Outcomes for the benefits of screening include reduced prostate cancer mortality, all-cause mortality, and incidence of metastatic prostate cancer. Outcomes for the harms of screening include false-positive screening tests, overdiagnosis, complications due to biopsy, and complications of treatment including incontinence (urinary or bowel), and erectile dysfunction. The quality of life or functioning (overall and disease-specific) and psychological effects outcomes are considered as a possible benefit or harm. Outcomes for the values and preferences review include quantitative or qualitative information regarding the choice to screen or intention to undergo screening. For the reviews on benefits or harms, we will search for randomized controlled trials, quasi-randomized, and controlled studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. For the review on values and preferences, we will search for experimental or observational studies in MEDLINE, Embase, and PsycInfo. For all reviews, we will also search websites of relevant organizations, gray literature, and reference lists of included studies. Title and abstract screening, full-text review, data extraction, and risk of bias assessments will be completed independently by pairs of reviewers with any disagreements resolved by consensus or by consulting with a third reviewer. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach will be used to assess the certainty of the evidence for each outcome. Discussion The series of systematic reviews will be used by the Canadian Task Force on Preventive Health Care to update their 2014 guideline on screening for prostate cancer in adults aged 18 years and older. Systematic review registration This review has been registered with PROSPERO (CRD42022314407) and is available on the Open Science Framework (osf.io/dm32k).

AIM: To examine the prevalence and composition of refractive errors in Hungary. METHODS: Nationwide cross-sectional data collected between 2014 and 2019 were analysed from the Comprehensive Health Screening Program of Hungary, which provided spectacle dioptric power and autorefractometry data for 68 227 people (35 850 women and 32 377 men). Their age distribution, 18-99y, was similar to the national demographic distributions. RESULTS: Of the total population, 16.50% of the refractive errors exhibited hyperopia, 40.05% emmetropia, and 43.45% myopia. Myopia was 3 times more frequent (58.7%) in younger ages (18-35y of age) compared to older age groups (19.4% of those 56-70y of age; P

Field surveys at four neighbouring but discrete sites in southern France revealed the presence of five ichneumonid parasitoids of the Lathyrus-feeding sterictiphorine argid sawfly Aprosthema tardum. Four of these parasitoids, Lathrolestes erythrocephalus, Ischyrocnemis goesi (both Ctenopelmatinae), Terozoa quadridens and Thibetoides aprosthemae (both Tryphoninae), could be identified and, by also incorporating laboratory studies, the developmental biology of each was elucidated and illustrated. A little supplementary information from a site in Italy is also presented. The fifth species was detected only once and failed to develop in its cocoon; it remains unidentified but the cephalic sclerites of its final instar larva are illustrated. The identified parasitoids are all more or less rare and little-known species and prior to this study only L. erythrocephalus had a known host; the others were biologically unknown even at the generic level and not recorded from France. The egg of L. erythrocephalus bears prominent hooked structures at its capital end, not reported in other studied Lathrolestes species. From its biology as an endoparasitoid of a sawfly and from larval characters, Ischyrocnemis is confidently assigned to Ctenopelmatinae. Both ctenopelmatines could successfully parasitise the host during any of its 2nd to 5th instars, but the tryphonines were less flexible. Terozoa monitors hosts until the moult to the final instar before ovipositing on them, usually affixing the egg to the head and often an eye (stemma), while Thibetoides parasitises much younger hosts, placing its strongly anchored egg behind a thoracic leg where it remains through successive host moults. Some characters used in the past to determine Terozoa species are discussed, and a new provisional key to the known species of Terozoa is presented. The very different developmental biology of Terozoa and Thibetoides may challenge views that they are closely related genera. Terozoa bituberculata (Constantineanu, 1973), stat. rev. is raised from synonymy with T. quadridens Perkins, 1962. Reinterpretations of several cephalic structures of final instar larvae as well as larval spiracles are discussed, and a new interpretation and terminology for describing the latter is introduced.

Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations.

**Background:** Gastroesophageal reflux disease (GERD) is a risk factor for Barrett’s esophagus (BE) and BE-related neoplasia (BERN). **Objectives:** This study aimed to evaluate healthcare resource utilization (HRU) and costs associated with GERD, BE, and BERN in the United States. **Methods:** Adult patients with GERD, nondysplastic BE (NDBE), and BERN (including indefinite for dysplasia \[IND\], low-grade dysplasia \[LGD\], high-grade dysplasia \[HGD\] or esophageal adenocarcinoma \[EAC\]), were identified from a large US administrative claims database, the IBM Truven Health MarketScan® databases (Q1/2015-Q4/2019). Patients were categorized into the corresponding mutually exclusive EAC-risk/diagnosis cohorts based on the most advanced stage from GERD to EAC using diagnosis codes in medical claims. Disease-related HRU and costs (2020 USD) were calculated for each cohort. **Results:** Patients were categorized into the following EAC-risk/diagnosis cohorts: 3 310 385 into GERD, 172 481 into NDBE, 11 516 into IND, 4332 into LGD, 1549 into HGD, and 11 676 into EAC. Disease-related annual mean number of inpatient admissions, office visits, and emergency department visits by cohort were 0.09, 1.45, and 0.19 for GERD; 0.08, 1.55, and 0.10 for NDBE; 0.10, 1.92, and 0.13 for IND; 0.09, 2.05, and 0.10 for LGD; 0.12, 2.16, and 0.14 for HGD; and 1.43, 6.27, and 0.87 for EAC. Disease-related annual mean total healthcare costs by cohort were $6955 for GERD, $8755 for NDBE, $9675 for IND, $12 241 for LGD, $24 239 for HGD, and $146 319 for EAC. **Discussion:** Patients with GERD, BE, and BERN had important HRU and costs, including inpatient admissions and office visits. As patients progressed to more advanced stages, there was substantially higher disease-related resource utilization, with associated costs being 16 times higher in patients with EAC than those with NDBE. **Conclusions:** Findings suggest the need for early identification of high-risk individuals prior to progression to EAC to potentially improve clinical and economic outcomes in this population.

Colorectal cancer screening rates are important metrics for public health and quality indicators for health care systems; however, published estimates of colorectal cancer screening rates often include both high-risk and average-risk patients, and the use of different epidemiologic methods makes between-study comparisons tenuous. The objective of this study was to measure the proportion of average-risk American adults who are up to date with colorectal cancer screening guidelines and examine the impact of evaluation methods on screening rate estimates. This repeated cross-sectional study used administrative claims to identify individuals aged 50–75 years between 2015 and 2018 with ≥ 1-year of continuous health plan enrollment. Sensitivity analyses to replicate prior studies in the literature included: 1) retrospective cohort study requiring ≥ 10 years of continuous enrollment to identify the most current screening rates (2018), and 2) inclusion of individuals with higher colorectal cancer risk. A total of 2,579,898; 2,948,064; 3,312,882; and 2,752,864 individuals were included in the 2015, 2016, 2017, and 2018 populations, respectively. In the cross-sectional sample, the proportion of individuals with up-to-date colorectal cancer screening was 51.8%, 51.3%, 51.0%, and 51.1% in 2015, 2016, 2017, and 2018, respectively. The inclusion of high-risk individuals increased estimates approximately 37%. Using a retrospective cohort design, 67.5% of average-risk individuals were up to date in 2018. This study demonstrated the impact of methodological differences on rate estimates. Efforts to track screening rates require transparency in measurement methods to accurately evaluate progress in improving rates.

Background and Aims: Approximately 20%–30% of colorectal cancers (CRCs) arise from the serrated polyp pathway. CRC screening options have differential sensitivity to detect sessile serrated polyps (SSPs). We used the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM) to assess how the detection of SSPs impacts predicted life years gained (LYG), CRC incidence, and CRC mortality with multitarget stool DNA (mt-sDNA) or fecal immunochemical test (FIT) screening. Methods: A simulated cohort of average-risk US individuals underwent triennial mt-sDNA or annual FIT screening between ages 45–75 years. SSP-attributed CRCs were modeled at 0% (base case), 14.3%, 20%, and 30%, in combination with 4 adherence & attendance scenarios: S1: 100% stool-screening adherence/100% follow-up colonoscopy attendance after a positive stool test; S2: reported stool-screening adherence (mt-sDNA = 71%; FIT = 43%)/100% follow-up colonoscopy attendance; S3: reported stool-screening adherence/reported follow-up colonoscopy attendance (mt-sDNA = 72%; FIT = 47%); and S4: reported stool-screening adherence/72% follow-up colonoscopy attendance. Outcomes were per 1000 individuals. Sensitivity analyses used ranges of stool-screening adherence or follow-up attendance. Results: At S1, S2, S3, and S4, LYG with FIT at the base case (0% SSP-attributed CRC) was 346.7, 279.3, 126.6, and 196.1, respectively, and with mt-sDNA was 324.6, 311.8, 215.8, and 215.8, respectively. Among the 4 adherence/attendance scenarios, modeling SSP-attributed CRCs decreased LYG by 4.9–20.9 with FIT and 2.0–5.1 with mt-sDNA. At S3 and 30% SSP-attributable CRCs, mt-sDNA had 95.1 more LYG, 21.5% greater CRC incidence reduction, and 22.2% greater CRC mortality reduction than FIT. Conclusion: Incorporating SSPs and real-world adherence into the CRC-AIM modeling analyses yielded more practice-relevant estimates of CRC screening outcomes and should be applied in future studies to afford more appropriate assessment of comparative effectiveness estimates between guideline-endorsed screening options.

Widely endorsed screening modalities for colorectal cancer (CRC) include structural visualization (e.g. colonoscopy) and stool-based tests including multitarget stool DNA (mt-sDNA), fecal immunochemical tests (FIT), or high-sensitivity guaiac-based fecal occult blood tests (gFOBT). However, CRC screenings are underutilized, hence understanding the screening utilization trends is important, particularly with respect to the newest guideline-endorsed option (mt-sDNA). The objective of this study was to assess patterns in overall CRC screenings following clinical availability of the mt-sDNA test among average-risk individuals in the Ascension Wisconsin healthcare system focusing primarily on individuals aged 50–75 years old. We also reported CRC screening behaviors among individuals 75 years old. Electronic medical records of individuals aged ≥ 40 years from 2015 to 2018 were reviewed to identify average-risk and screen-eligible members. For those with screening data available, we determined the proportion who were up-to-date with any United States Preventive Services Task Force (USPSTF) recommended screening strategy; the number of screening tests performed in the measurement year; and the distribution of screening modalities. Temporal trends were assessed using regression analysis, including subgroup analyses across age groups and screening modalities. A total of 172,045 unique patients aged ≥ 40 years were included, of which 115,708 individuals aged 50–75 years. When considering all individuals up-to-date and screened in the measurement year, overall adherence increased significantly over the 4-year study period, from 39,105 to 49,698 patients or 47 % to 59 % (p 75 years old. Growing adoption, higher preference, and the broad availability of mt-sDNA testing may be associated with an increase in overall CRC screening rates in the average-risk population, in parallel with a slight increase in the use of other non-invasive CRC screening tests.

Colorectal cancer (CRC) screening rates remain suboptimal in the US. We examined patient-focused concerns and influence of various factors (e.g., test attributes, provider recommendation) on CRC screening decision-making. We conducted a web survey with 1595 US adults aged 40–75 from a nationally representative panel in November 2019 (completion rate: 31.3 %). Analyses focused on individuals aged 45–75 years at average-risk for CRC (n = 1062). All participants rated their level of concern about various CRC screening test/procedure attributes. Participants who have screened previously designated the three most important attributes for choosing a screening method and rated how various factors influenced their decision to use a particular method. The top concern for participants who have not screened previously was having an invasive procedure (54.2 %) while the top concerns for participants who have screened previously were completing a colon prep (41.3 %) and test/procedure accuracy (41 %). Cost/insurance coverage was most frequently ranked among the most important attributes (48.5 %), followed by where the test can be taken (45.7 %) and test accuracy (43.6 %). Provider recommendation was reported as the major motivator across screening methods. Other factors that were frequently reported as very influential included convenience and comfort for the stool-based methods and scientific/clinical evidence and insurance coverage for colonoscopy. Variations by age, sex, and race/ethnicity were noted. Findings demonstrate that along with provider recommendation, patient preferences regarding test/procedure attributes and preparation requirements are influential in screening decision-making, highlighting the need for clinicians to involve patients in shared decision-making and incorporate patient needs and preferences in establishing screening strategies.

Colorectal cancer (CRC) is the third leading cause of cancer death in the US. Early detection improves CRC outcomes and multiple options are endorsed for CRC screening; however, adherence remains challenging. Among Medicaid enrollees, the fecal immunochemical test (FIT) is often used for average-risk CRC screening, with suboptimal adherence rates reported (12.3–23.2 %). The navigation-supported (personalized outreach by phone, mail, email and text), at home collection, multi-target stool DNA (mt-sDNA) test represents a relatively recent and broadly accessible option for average-risk CRC screening in Medicaid enrollees. We assessed cross-sectional mt-sDNA adherence in a national sample of Medicaid patients. Data from Exact Sciences Laboratories LLC (ESL; Madison, WI) were retrospectively analyzed. Participants included individuals 45 + years covered by Fee-For-Service (FFS)- or Managed-Medicaid. Primary analysis focused on the 50–74 age cohort and included those with valid mt-sDNA orders between January 1–December 31, 2018. Data from 25,794 individuals who received valid orders for mt-sDNA were included in analysis (61.2 % women; mean age at order 57.5 years). Overall adherence – completion of an ordered test – was 51.3 %. Adherence was 54.6 % in Managed-Medicaid and 38.9 % in FFS-Medicaid. Adherence by age was: 51.5 % for 50–64 years and 47.7 % for 65–74 years. Mt-sDNA tests ordered by gastroenterologists had higher adherence (60.5 %) compared with primary care clinicians (51.3 %). These data from a large, national sample of Medicaid-insured patients substantiate mt-sDNA testing as a viable patient-supported, home-based option to improve average-risk CRC screening participation in Medicaid enrollees.

Abstract Background Colorectal cancer (CRC) screening for average risk adults age 45 and older continues to be underutilized in the USA. One factor consistently associated with CRC screening completion is clinician recommendation. Understanding the barriers and facilitators of clinical adoption of emerging CRC screening strategies is important in developing effective intervention strategies to improve CRC screening rates. We aimed to develop a questionnaire based on the Theoretical Domains Framework (TDF) to assess determinants of clinical adoption of novel CRC screening strategies, using the multi-target stool DNA test (mt-sDNA; Cologuard®) as an example, and test the psychometric properties of this questionnaire on a sample of US clinicians. Methods A web survey was administered between November and December 2019 to a national panel of clinicians including primary care clinicians (PCCs) and gastroenterologists (GIs) to assess 10 TDF constructs with 55 items. Confirmatory factor analysis (CFA) was used to examine whether the a priori domain structure was supported by the data. Discriminant validity of domains was tested with Heterotrait-Monotrait ratio (HTMT). Internal consistency for each scale was assessed using Cronbach’s alpha. Criterion validity was assessed with self-reported mt-sDNA use and mt-sDNA recommendation as the outcomes. Results Complete surveys were received from 814 PCCs and 159 GIs (completion rate, 24.7% of 3299 PCCs and 29.6% of 538 GIs). Providers were excluded from analysis if they indicated not recommending CRC screening to average-risk patients (final N = 973). The final questionnaire consisted of 38 items covering 5 domains: (1) knowledge; (2) skills; (3) identity and social influence; (4) optimism, beliefs about consequences, and intentions; and (5) environmental context and resources. CFA results confirmed a reasonable fit (CFI = 0.948, SRMR = 0.057, RMSEA = 0.080). The domains showed sufficient discriminant validity (HTMT < 0.85), good internal consistency (McDonald’s omega > 0.76), and successfully differentiated providers who reported they had ordered mt-sDNA from those who never ordered mt-sDNA and differentiated providers who reported routinely recommending mt-sDNA from those who reported not recommending mt-sDNA. Conclusions Findings provide initial evidence for the validity and internal consistency of this TDF-based questionnaire in measuring potential determinants of mt-sDNA adoption for average-risk CRC screening. Further investigation of validity and reliability is needed when adapting this questionnaire to other novel CRC screening strategy contexts.

Software auf Basis Künstlicher Intelligenz aus dem Bereich des Natural Language Processing hat das Potenzial, wissenschaftliches Schreiben grundlegend zu verändern. Entsprechende Tools können bereits erstaunlich kohärente Texte in wissenschaftlichem Ton produzieren. Dies führt zu fundamentalen Fragen guter wissenschaftlicher Praxis und akademischer Kultur. Wir diskutieren diese Entwicklung vor dem Hintergrund einer Befragung deutscher Schreibdidaktiker:innen und arbeiten Fragen heraus, die im Zusammenhang mit KI-Schreibtools zukünftig von zentraler Bedeutung sein werden. Abschließend schlagen wir einen Passus für eine Selbstständigkeitserklärung vor, der den Entwicklungen Rechnung trägt.

Introduction The use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age.Methods and analysis This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design.Ethics and dissemination Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences.Trial registration number The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.

Abstract Background There is a need for the development of comprehensive, global, evidence‐based guidance for stakeholder engagement in guideline development. Stakeholders are any individual or group who is responsible for or affected by health‐ and healthcare‐related decisions. This includes patients, the public, providers of health care and policymakers for example. As part of the guidance development process, Multi‐Stakeholder Engagement (MuSE) Consortium set out to conduct four concurrent systematic reviews to summarise the evidence on: (1) existing guidance for stakeholder engagement in guideline development, (2) barriers and facilitators to stakeholder engagement in guideline development, (3) managing conflicts of interest in stakeholder engagement in guideline development and (4) measuring the impact of stakeholder engagement in guideline development. This protocol addresses the second systematic review in the series. Objectives The objective of this review is to identify and synthesise the existing evidence on barriers and facilitators to stakeholder engagement in health guideline development. We will address this objective through two research questions: (1) What are the barriers to multi‐stakeholder engagement in health guideline development across any of the 18 steps of the GIN‐McMaster checklist? (2) What are the facilitators to multi‐stakeholder engagement in health guideline development across any of the 18 steps of the GIN‐McMaster checklist? Search Methods A comprehensive search strategy will be developed and peer‐reviewed in consultation with a medical librarian. We will search the following databases: MEDLINE, Cumulative Index to Nursing & Allied Health Literature (CINAHL), EMBASE, PsycInfo, Scopus, and Sociological Abstracts. To identify grey literature, we will search the websites of agencies who actively engage stakeholder groups such as the AHRQ, Canadian Institutes of Health Research (CIHR) Strategy for Patient‐Oriented Research (SPOR), INVOLVE, the National Institute for Health and Care Excellence (NICE) and the PCORI. We will also search the websites of guideline‐producing agencies, such as the American Academy of Pediatrics, Australia's National Health Medical Research Council (NHMRC) and the WHO. We will invite members of the team to suggest grey literature sources and we plan to broaden the search by soliciting suggestions via social media, such as Twitter. Selection Criteria We will include empirical qualitative and mixed‐method primary research studies which qualitatively report on the barriers or facilitators to stakeholder engagement in health guideline development. The population of interest is stakeholders in health guideline development. Building on previous work, we have identified 13 types of stakeholders whose input can enhance the relevance and uptake of guidelines: Patients, caregivers and patient advocates; Public; Providers of health care; Payers of health services; Payers of research; Policy makers; Program managers; Product makers; Purchasers; Principal investigators and their research teams; and Peer‐review editors/publishers. Eligible studies must describe stakeholder engagement at any of the following steps of the GIN‐McMaster Checklist for Guideline Development. Data Collection and Analysis All identified citations from electronic databases will be imported into Covidence software for screening and selection. Documents identified through our grey literature search will be managed and screened using an Excel spreadsheet. A two‐part study selection process will be used for all identified citations: (1) a title and abstract review and (2) full‐text review. At each stage, teams of two review authors will independently assess all potential studies in duplicate using a priori inclusion and exclusion criteria. Data will be extracted by two review authors independently and in duplicate according to a standardised data extraction form. Main Results The results of this review will be used to inform the development of guidance for multi‐stakeholder engagement in guideline development and implementation. This guidance will be official GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group guidance. The GRADE system is internationally recognised as a standard for guideline development. The findings of this review will assist organisations who develop healthcare, public health and health policy guidelines, such as the World Health Organization, to involve multiple stakeholders in the guideline development process to ensure the development of relevant, high quality and transparent guidelines.

Abstract This is the protocol for a Campbell systematic review. The overall objective of this study is to gather and summarize the existing literature on conflict of interest issues when engaging stakeholders in guideline development.

Cholesteric liquid crystals (CLC) are molecules that can self-assemble into helicoidal superstructures exhibiting circularly polarized reflection. The facile self-assembly and resulting optical properties makes CLCs a promising technology for an array of industrial applications, including reflective displays, tunable mirror-less lasers, optical storage, tunable color filters, and smart windows. The helicoidal structure of CLC can be stabilized via in situ photopolymerization of liquid crystal monomers in a CLC mixture, resulting in polymer-stabilized CLCs (PSCLCs). PSCLCs exhibit a dynamic optical response that can be induced by external stimuli, including electric fields, heat, and light. In this review, we discuss the electro-optic response and potential mechanism of PSCLCs reported over the past decade. Multiple electro-optic responses in PSCLCs with negative or positive dielectric anisotropy have been identified, including bandwidth broadening, red and blue tuning, and switching the reflection notch when an electric field is applied. The reconfigurable optical response of PSCLCs with positive dielectric anisotropy is also discussed. That is, red tuning (or broadening) by applying a DC field and switching by applying an AC field were both observed for the first time in a PSCLC sample. Finally, we discuss the potential mechanism for the dynamic response in PSCLCs.