Search

Abstract Overly restrictive clinical trial eligibility criteria can reduce generalizability, slow enrollment, and disproportionately exclude historically underrepresented populations. The eligibility criteria for 196 Alzheimer’s Disease and Related Dementias (AD/ADRD) trials funded by the National Institute on Aging were analyzed to identify common criteria and their potential to disproportionately exclude participants by race/ethnicity. The trials were categorized by type (48 Phase I/II pharmacological, 7 Phase III/IV pharmacological, 128 non-pharmacological, 7 diagnostic, and 6 neuropsychiatric) and target population (51 AD/ADRD, 58 Mild Cognitive Impairment, 25 at-risk, and 62 cognitively normal). Eligibility criteria were coded into the following categories: Medical, Neurologic, Psychiatric, and Procedural. A literature search was conducted to describe the prevalence of disparities for eligibility criteria for African Americans/Black (AA/B), Hispanic/Latino (H/L), American Indian/Alaska Native (AI/AN) and Native Hawaiian/Pacific Islander (NH/PI) populations. The trials had a median of 15 criteria. The most frequent criterion were age cutoffs (87% of trials), specified neurologic (65%), and psychiatric disorders (61%). Underrepresented groups could be disproportionately excluded by 16 eligibility categories; 42% of trials specified English-speakers only in their criteria. Most trials (82%) contain poorly operationalized criteria (i.e., criteria not well defined that can have multiple interpretations/means of implementation) and criteria that may reduce racial/ethnic enrollment diversity.

Abstract There are two known mechanisms by which natural killer (NK) cells recognize and kill diseased targets: (i) direct killing and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated an indirect NK cell activation strategy for the enhancement of human NK cell killing function. We did this by leveraging the fact that toll-like receptor 9 (TLR9) agonism within pools of human peripheral blood mononuclear cells (PBMCs) results in a robust interferon signaling cascade that leads to NK cell activation. After TLR9 agonist stimulation, NK cells were enriched and incorporated into assays to assess their ability to kill tumor cell line targets. Notably, differential impacts of TLR9 agonism were observed—direct killing was enhanced while ADCC was not increased. To ensure that the observed differential effects were not attributable to differences between human donors, we recapitulated the observation using our Natural Killer—Simultaneous ADCC and Direct Killing Assay (NK-SADKA) that controls for human-to-human differences. Next, we observed a treatment-induced decrease in NK cell surface CD16—known to be shed by NK cells post-activation. Given the essential role of CD16 in ADCC, such shedding could account for the observed differential impact of TLR9 agonism on NK cell-mediated killing capacity.

Objective: This qualitative research project was undertaken to discover how students perceive the embedded librarian in their nursing class. The researchers determined how a required group research meeting was valued by students and whether that value warranted the necessary time and energy by an embedded librarian. Methods: Researchers conducted focus groups with twenty-three students from two different sections of the same nursing research methods undergraduate course. Students’ responses to a series of five questions were recorded within Zoom and supplemented by handwritten notes. Data was coded by hand and patterns that emerged from the five focus groups were analyzed. Results: Participants reported overall satisfaction with the embedded librarian and students felt they benefitted from the required research meeting with the librarian, which was part of the searching assignment rubric and closely tied to the assignment itself. Conclusion: Based on the data, a required research meeting with an embedded librarian, who is familiar with the course assignments, reinforces classroom instruction, point-of-need assistance with search strategies, and the opportunity to strengthen the relationship with the librarian for future research needs.

We present a genome assembly from an individual female thistle gall fly, Urophora cardui (Arthropoda; Insecta; Diptera; Tephritidae). The genome sequence has a total length of 837.80 megabases. Most of the assembly is scaffolded into 6 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 20.37 kilobases in length.

Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance use or a marker of the inclination to engage in such behavior. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1000 participants. Behaviors and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use.

BACKGROUND: Benign tracheal stenosis is relatively rare but remains a significant chronic disease due to its drastic symptoms including dyspnoea and inspiratory stridor, and consequent negative effect on quality of life. Traditionally, the surgical approach by resection of the stenotic tracheal segment has been the therapy of choice. However, endoscopic techniques have arisen and may offer a safe and less invasive alternative. OBJECTIVES: The aim of the retrospective study was to evaluate procedure-related safety and outcome of endoscopic treatment of benign tracheal stenosis at a single centre. METHODS: The study included all patients at our institution who between 2013 and 2022 had received endoscopic treatment of benign tracheal stenosis by rigid tracheoscopy, radial incision by electric papillotomy needle and dilation (endoscopic tracheoplasty) followed by triamcinolone acetonide as a local submucosal injection and additionally, from 2020, budesonide inhalation. RESULTS:A total of 22 patients were treated in a total of 38 interventions, each resulting in immediate improvement of symptoms. There were no peri-interventional complications or mortality. Of the 38 interventions, 11 received no triamcinolone acetonide administration, resulting in a 54.5% recurrence rate after an average of 21.1 (±18.0) months, while 27 had local triamcinolone acetonide, with a 37% recurrence rate. Since 2020, we additionally initiated post-interventional budesonide inhalation as recurrence prophylaxis for newly admitted patients and patients with recurrences(n = 8), of whom only one (12.5%) has to date experienced a recurrence. CONCLUSION: Our results indicate that endoscopic tracheoplasty offers a safe and successful, minimally invasive alternative to open surgery for patients with benign tracheal stenosis. We recommend local administration of triamcinolone into the mucosa as an additional treatment to decrease the risk of recurrence. However, given the uncontrolled study design and low sample size, safety and effectiveness cannot be conclusively demonstrated. Nonetheless, our findings suggest promising avenues for further investigation. Further studies on the additional benefit of inhaled corticosteroids are warranted.

Introduction Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4.Methods and analysis BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1–5/subject) and untreated prospective controls (≤30). Infants

Abstract Background The majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value. Methods We analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine. Results Lower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3+, CD4+, CD8+, and CD45+ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines. Conclusions Our results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.

Background The diagnosis of COPD requires the demonstration of non-fully reversible airflow limitation by spirometry in the appropriate clinical context. Yet, there are patients with symptoms and relevant exposures suggestive of COPD with either normal spirometry (pre-COPD) or preserved ratio but impaired spirometry (PRISm). Their prevalence, clinical characteristics and associated outcomes in a real-life setting are unclear. Methods To investigate them, we studied 3183 patients diagnosed with COPD by their attending physician included in the NOVELTY study (clinicaltrials.gov identifier NCT02760329), a global, 3-year, observational, real-life cohort that included patients recruited from both primary and specialist care clinics in 18 countries. Results We found that 1) approximately a quarter of patients diagnosed with (and treated for) COPD in real life did not fulfil the spirometric diagnostic criteria recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), and could be instead categorised as pre-COPD (13%) or PRISm (14%); 2) disease burden (symptoms and exacerbations) was highest in GOLD 3–4 patients (exacerbations per person-year (PPY) 0.82) and lower but similar in those in GOLD 1–2, pre-COPD and PRISm (exacerbations range 0.27–0.43 PPY); 3) lung function decline was highest in pre-COPD and GOLD 1–2, and much less pronounced in PRISm and GOLD 3-4; 4) PRISm and pre-COPD were not stable diagnostic categories and change substantially over time; and 5) all-cause mortality was highest in GOLD 3–4, lowest in pre-COPD, and intermediate and similar in GOLD 1–2 and PRISm. Conclusions Patients diagnosed COPD in a real-life clinical setting present great diversity in symptom burden, progression and survival, warranting medical attention.

To date, several types of airway stents are available to treat central airway obstructions. However, the ideal stent that can overcome anatomical, mechanical and microbiological issues is still awaited. In addition, therapeutic effect and self-elimination of these stents are desirable properties, which pose an additional challenge for development and manufacturing. We aimed to create a prototype bioresorbable tracheal stent with acceptable clinical tolerance, fit and biocompatibility, that could be tested in a rabbit model and in the future be further optimized to enable drug-elution and ensure local therapeutic effect. Twenty-one New Zealand White Rabbits received five different types of bioresorbable tracheal stents, 3D-printed from poly(D,L-lactide-co-ε-caprolactone) metacrylates. Various configurations were tested for their functionality and improved until the best performing prototype could undergo detailed in vivo assessment, regarding clinical tolerance, migration and biocompatibility. Previously tested types of 3D printed stents in our preliminary study required improvement due to several problems, mainly related to breakage, unreliable stability and/or migration within the trachea. Abandoned or refined pre-prototypes were not analyzed in a comparative way. The final best performing prototype stent (GSP2 (Group Stent Prototype 2), n = 8) allowed a transoral application mode and showed good clinical tolerance, minimal migration and acceptable biocompatibility. The good performance of stent type GSP2 was attributed to the helix-shaped surface structure, which was therefore regarded as a key-feature. This prototype stent offers the possibility for further research in a large animal model to confirm the promising data and assess other properties such as bioresorption.

An ongoing, severe outbreak of highly pathogenic avian influenza virus (HPAI) A H5N1 clade 2.3.4.4b has been circulating in wild and domestic bird populations throughout the world, reaching North America in 2021. This HPAI outbreak has exhibited unique characteristics when compared to previous outbreaks. The global distribution of disease, prolonged duration, extensive number of species and individual wild birds affected, and the large impact on the global poultry industry have all exceeded historical impacts of previous outbreaks in North America. In this study, we describe the results of HPAI surveillance conducted at The Raptor Center, a wildlife rehabilitation hospital at University of Minnesota (Saint Paul, MN, U.S.A.), from March 28th-December 31, 2022. All wild raptors admitted to the facility were tested for avian influenza viruses using polymerase chain reaction (PCR) testing. All non-negative samples were submitted to the United States Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) National Veterinary Services Laboratories for confirmatory HPAI testing and genetic sequencing. During the study period, 996 individual birds representing 20 different species were tested for avian influenza, and 213 birds were confirmed HPAI positive. Highly pathogenic avian influenza surveillance conducted at The Raptor Center contributed 75% of the HPAI positive raptor detections within the state of Minnesota, located within the Mississippi flyway, significantly augmenting state wildlife surveillance efforts. The viral genotypes observed in birds sampled at The Raptor Center were representative of what was seen in wild bird surveillance within the Mississippi flyway during the same time frame. Wildlife rehabilitation centers provide an opportune situation to augment disease surveillance at the human, wildlife and domestic animal interface during ongoing infectious disease outbreaks.

Abstract Purpose To evaluate the effectiveness of an erbium, chromium:yttrium–scandium–gallium–garnet (Er,Cr:YSGG) laser with side-firing tip in decontamination of titanium (Ti) disc. Methods In the first test series, 29 Ti-discs were contaminated with Staphylococcus aureus and treated as follows: positive control (no treatment); Perioflow; Laser A (0.75 W, 100 Hz), Laser B (1.5 W, 30 Hz); Laser C (no radiation, 60% water); and Laser D (no radiation, 50% water). For bacterial quantification, colony forming units (CFU, vital cells only) and quantitative PCR (qPCR, vital and devital cells) were performed. In a second test series, 92 Ti-discs were used, contaminated with in vivo-grown biofilm and treated as follows: positive control (no treatment); Perioflow; Laser E (1.5 W, 30 Hz), and Laser F (no radiation, 50% water). Considering the different and unknown culture conditions, quantification of bacteria was performed by broad-spectrum bacterial qPCR only. Based on the assumption that all cells of an organism contain an equivalent complement of genetic information, genome equivalent (GE) determination ensured the detection of the different intact and semi-intact genomes, regardless of type of bacterial species and vitality, circumvent the inherent bias of cultures. Results The GE values were significantly reduced by all interventions in both test series, compared to the positive control group (p

BackgroundUniversity Medical Centers (UMCs) must do their part for clinical trial transparency by fostering practices such as prospective registration, timely results reporting, and open access. However, research institutions are often unaware of their performance on these practices. Baseline assessments of these practices would highlight where there is room for change and empower UMCs to support improvement. We performed a status quo analysis of established clinical trial registration and reporting practices at German UMCs and developed a dashboard to communicate these baseline assessments with UMC leadership and the wider research community.Methods and findingsWe developed and applied a semiautomated approach to assess adherence to established transparency practices in a cohort of interventional trials and associated results publications. Trials were registered in ClinicalTrials.gov or the German Clinical Trials Register (DRKS), led by a German UMC, and reported as complete between 2009 and 2017. To assess adherence to transparency practices, we identified results publications associated to trials and applied automated methods at the level of registry data (e.g., prospective registration) and publications (e.g., open access). We also obtained summary results reporting rates of due trials registered in the EU Clinical Trials Register (EUCTR) and conducted at German UMCs from the EU Trials Tracker. We developed an interactive dashboard to display these results across all UMCs and at the level of single UMCs. Our study included and assessed 2,895 interventional trials led by 35 German UMCs. Across all UMCs, prospective registration increased from 33% (n = 58/178) to 75% (n = 144/193) for trials registered in ClinicalTrials.gov and from 0% (n = 0/44) to 79% (n = 19/24) for trials registered in DRKS over the period considered. Of trials with a results publication, 38% (n = 714/1,895) reported the trial registration number in the publication abstract. In turn, 58% (n = 861/1,493) of trials registered in ClinicalTrials.gov and 23% (n = 111/474) of trials registered in DRKS linked the publication in the registration. In contrast to recent increases in summary results reporting of drug trials in the EUCTR, 8% (n = 191/2,253) and 3% (n = 20/642) of due trials registered in ClinicalTrials.gov and DRKS, respectively, had summary results in the registry. Across trial completion years, timely results reporting (within 2 years of trial completion) as a manuscript publication or as summary results was 41% (n = 1,198/2,892). The proportion of openly accessible trial publications steadily increased from 42% (n = 16/38) to 74% (n = 72/97) over the period considered. A limitation of this study is that some of the methods used to assess the transparency practices in this dashboard rely on registry data being accurate and up-to-date.ConclusionsIn this study, we observed that it is feasible to assess and inform individual UMCs on their performance on clinical trial transparency in a reproducible and publicly accessible way. Beyond helping institutions assess how they perform in relation to mandates or their institutional policy, the dashboard may inform interventions to increase the uptake of clinical transparency practices and serve to evaluate the impact of these interventions.

Abstract To evaluate the impact of block sequential regularized expectation maximization (BSREM) reconstruction on quantitative and qualitative aspects of 2-[18F]FDG-avid pulmonary nodules compared to conventional ordered subset expectation maximization (OSEM) reconstruction method. Ninety-one patients with 144 2-[18F]FDG-avid pulmonary nodules (all ≤ 20 mm) undergoing PET/CT for oncological (re-)staging were retrospectively included. Quantitative parameters in BSREM and OSEM (including point spread function modelling) were measured, including maximum standardized uptake value (SUVmax). Nodule conspicuity in BSREM and OSEM images was evaluated by two readers. Wilcoxon matched pairs signed-rank test was used to compare quantitative and qualitative parameters in BSREM and OSEM. Pulmonary nodule SUVmax was significantly higher in BSREM images compared to OSEM images [BSREM 5.4 (1.2–20.7), OSEM 3.6 (0.7–17.4); p = 0.0001]. In a size-based analysis, the relative increase in SUVmax was more pronounced in smaller nodules (≤ 7 mm) as compared to larger nodules (8–10 mm, or > 10 mm). Lesion conspicuity was higher in BSREM than in OSEM (p

Objectives To evaluate the extent and quality of patient involvement reporting in examples of current practice in health research.Design Mixed-methods study. We used a targeted search strategy across three cohorts to identify health research publications that reported patient involvement: original research articles published in 2019 in the British Medical Journal (BMJ), articles listed in the Patient-Centered Outcomes Research Institute (PCORI) database (2019), and articles citing the GRIPP2 (Guidance for Reporting Involvement of Patients and Public) reporting checklist for patient involvement or a critical appraisal guideline for user involvement. Publications were coded according to three coding schemes: ‘phase of involvement’, the GRIPP2-Short Form (GRIPP2-SF) reporting checklist and the critical appraisal guideline.Outcome measures The phase of the study in which patients were actively involved. For the BMJ sample, the proportion of publications that reported patient involvement. The quality of reporting based on the GRIPP2-SF reporting guideline. The quality of patient involvement based on the critical appraisal guideline. Quantitative and qualitative results are reported.Results We included 86 publications that reported patient involvement. Patients were most frequently involved in study design (90% of publications, n=77), followed by study conduct (71%, n=61) and dissemination (42%, n=36). Reporting of patient involvement was often incomplete, for example, only 40% of publications (n=34) reported the aim of patient involvement. While the methods (57%, n=49) and results (59%, n=51) of involvement were reported more frequently, reporting was often unspecific and the influence of patients’ input remained vague. Therefore, a systematic assessment of the quality and impact of patient involvement according to the critical appraisal guideline was not feasible across samples.Conclusions As patient involvement is increasingly seen as an integral part of the research process and requested by funding bodies, it is essential that researchers receive specific guidance on how to report patient involvement activities. Complete reporting builds the foundation for assessing the quality of patient involvement and its impact on research.

BACKGROUND: Lung volume reduction, either by surgery or bronchoscopically by endobronchial valve treatment have been shown to be a cost-effective alternative compared with conservative therapy. However, there is no comparative analysis of lung volume reduction by surgery and bronchoscopic lung volume reduction using endobronchial valves. OBJECTIVES: The aim of this retrospective study was to provide a cost-effectiveness analysis of lung volume reduction by surgery compared with bronchoscopic lung volume reduction using endobronchial valves. METHODS: The effectiveness of lung volume reduction was assessed using forced expiratory volume in the first second (FEV1), residual volume (RV) and 6-minute walking distance (6MWD), measured at baseline and at 4 to 12 weeks. Cost unit accounting derived from SwissDRG was used as a surrogate of the costs from the payer’s perspective. RESULTS: In total, 67 patients (37 men and 30 women) with a mean age of 68.3 ± 7.4 years were included. Both clinical effectiveness and costs were comparable between surgical and bronchoscopic lung reduction. The incremental cost-effectiveness ratios (ICERs) for bronchoscopic compared with lung volume reduction by surgery for FEV1, RV and 6MWD were –101, 4 and 58, respectively. For RV and 6MWD, it could be shown that endobronchial valve treatment is justified as a probably cost-effective alternative to lung volume reduction by surgery. Endobronchial valve treatment resulted in an improvement of 0.25 quality-adjusted life years (QALYs) and an ICER of € 7657 per QALY gained. CONCLUSION: A robust statement on the superiority of one of the two procedures in terms of cost-effectiveness cannot be made from the present study. Therefore, the study is not suitable for resource allocation. Two upcoming trials comparing lung volume reduction surgery and endobronchial valve treatment may be able to answer this question.

Abstract Individuals with dyslexia present with reading-related deficits including inaccurate and/or less fluent word recognition and poor decoding abilities. Slow reading speed and worse text comprehension can occur as secondary consequences of these deficits. Reports of visual symptoms such as atypical eye movements during reading gave rise to a search for these deficits’ underlying mechanisms. This study sought to replicate established behavioral deficits in reading and cognitive processing speed while investigating their underlying mechanisms in more detail by developing a comprehensive profile of eye movements specific to reading in adult dyslexia. Using a validated standardized reading assessment, our findings confirm a reading speed deficit among adults with dyslexia. We observed different eye movements in readers with dyslexia across numerous eye movement metrics including the duration of a stop (i.e., fixation), the length of jumps (i.e., saccades), and the number of times a reader’s eyes expressed a jump atypical for reading. We conclude that individuals with dyslexia visually sample written information in a laborious and more effortful manner that is fundamentally different from those without dyslexia. Our findings suggest a mix of aberrant cognitive linguistic and oculomotor processes being present in adults with dyslexia.

Abstract Age-associated DNA methylation reflects aspect of biological aging—therefore epigenetic clocks for mice can elucidate how the aging process in this model organism is affected by specific treatments or genetic background. Initially, age-predictors for mice were trained for genome-wide DNA methylation profiles and we have recently described a targeted assay based on pyrosequencing of DNA methylation at only three age-associated genomic regions. Here, we established alternative approaches using droplet digital PCR (ddPCR) and barcoded bisulfite amplicon sequencing (BBA-seq). At individual CG dinucleotides (CpGs) the correlation of DNA methylation with chronological age was slightly higher for pyrosequencing and ddPCR as compared to BBA-seq. On the other hand, BBA-seq revealed that neighboring CpGs tend to be stochastically modified at murine age-associated regions. Furthermore, the binary sequel of methylated and non-methylated CpGs in individual reads can be used for single-read predictions, which may reflect heterogeneity in epigenetic aging. In comparison to C57BL/6 mice the single-read age-predictions using BBA-seq were also accelerated in the shorter-lived DBA/2 mice, and in C57BL/6 mice with a lifespan quantitative trait locus of DBA/2 mice. Taken together, we describe alternative targeted methods for epigenetic age predictions that provide new perspectives for aging-intervention studies in mice.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths in Switzerland. Despite this, there is no lung cancer screening program in the country. In the United States, low-dose computed tomography (LDCT) lung cancer screening is partially established and endorsed by guidelines. Moreover, evidence is growing that screening reduces lung cancer-related mortality and this was recently shown in a large European randomized controlled trial. Implementation of a lung cancer screening program, however, is challenging and depends on many country-specific factors. The goal of this article is to outline a potential Swiss lung cancer screening program. FRAMEWORK: An exhaustive literature review on international screening models as well as interviews and site visits with international experts were initiated. Furthermore, workshops and interviews with national experts and stakeholders were conducted to share experiences and to establish the basis for a national Swiss lung cancer screening program. SCREENING APPROACH: General practitioners, pulmonologists and the media should be part of the recruitment process. Decentralisation of the screening might lead to a higher adherence rate. To reduce stigmatisation, the screening should be integrated in a “lung health check”. Standardisation and a common quality level are mandatory. The PLCOm2012 risk calculation model with a threshold of 1.5% risk for developing cancer in the next six years should be used in addition to established inclusion criteria. Biennial screening is preferred. LUNG RADS and NELSON+ are applied as classification models for lung nodules. CONCLUSION: Based on data from recent studies, literature research, a health technology assessment, the information gained from this project and a pilot study the Swiss Interest Group for lung cancer screening (CH-LSIG) recommends the timely introduction of a systematic lung cancer screening program in Switzerland. The final decision is for the Swiss Cancer Screening Committee to make.

Abstract We report a case of primary malignant melanoma of the esophagus.

Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren’s syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways.

Cognitive psychology has a long history of using physiological measures, such as pupillometry. However, their susceptibility to confounds introduced by stimulus properties, such as color and luminance, has limited their application. Pupil size measurements, in particular, require sophisticated experimental designs to dissociate relatively small changes in pupil diameter due to cognitive responses from larger ones elicited by changes in stimulus properties or the experimental environment. Here, building on previous research, we present a pupillometry paradigm that adapts the pupil to stimulus properties during the baseline period without revealing stimulus meaning or context by using a pixel-scrambled image mask around an intact image. We demonstrate its robustness in the context of pupillary responses to branded product familiarity. Results show larger average and peak pupil dilation for passively viewed familiar product images and an extended later temporal component representing differences in familiarity across participants (starting around 1400 ms post-stimulus onset). These amplitude differences are present for almost all participants at the single-participant level, and vary somewhat by product category. However, amplitude differences were absent during the baseline period. These findings demonstrate that involuntary pupil size measurements combined with the presented paradigm are successful in dissociating cognitive effects of familiarity from physical stimulus confounds.

Cognitive psychology has a long history of using physiological measures, such as pupillometry. However, their susceptibility to confounds introduced by stimulus properties, such as color and luminance, has limited their application. Pupil size measurements, in particular, require sophisticated experimental designs to dissociate relatively small changes in pupil diameter due to cognitive responses from larger ones elicited by changes in stimulus properties or the experimental environment. Here, building on previous research, we present a pupillometry paradigm that adapts the pupil to stimulus properties during the baseline period without revealing stimulus meaning or context by using a pixel-scrambled image mask around an intact image. We demonstrate its robustness in the context of pupillary responses to branded product familiarity. Results show larger average and peak pupil dilation for passively viewed familiar product images and an extended later temporal component representing differences in familiarity across participants (starting around 1400 ms post-stimulus onset). These amplitude differences are present for almost all participants at the single-participant level, and vary somewhat by product category. However, amplitude differences were absent during the baseline period. These findings demonstrate that involuntary pupil size measurements combined with the presented paradigm are successful in dissociating cognitive effects of familiarity from physical stimulus confounds.

IntroductionUniversity students' psychological health is linked to their academic satisfaction. This study aimed to investigate students' psychological health and academic satisfaction in the context of COVID-19 and academic year-end stress.Materials and methodsStandardized self-filled scales for anxiety, depression, stress, psychological well-being, academic satisfaction (subjective assessment of students' quality of life in their educational setting), and an ad-hoc scale for stress on the learning experience due to COVID-19 were used in this cross-sectional study. Participants were first- to third-year students of eight different health-related tracks in Geneva, Switzerland. Descriptive statistics and hierarchical regression analyses were applied.ResultsIn June 2020, out of 2835 invited students, 433 (15%) completed the survey. Academic satisfaction was a stronger mental health predictor than COVID-19 stress on the learning experience, which mainly predicted stress and anxiety. Lower academic satisfaction scores were significantly associated with stress (β = -0.53, p < 0.001), depression (β = -0.26, p < 0.001), anxiety (β = -0.20, p < 0.001), while higher scores with psychological well-being (β = 0.48, p < 0.001). Identifying as female was strongly associated with anxiety and stress but not with depression or psychological well-being. Lower age was associated with stress only. The nature of the academic training had a lesser impact on mental health and the academic year had no impact.ConclusionsAcademic satisfaction plays a more substantial role than COVID-19 stress on the learning experience in predicting students' overall mental health status. Training institutions should address the underlying factors that can enhance students' academic satisfaction, especially during the COVID-19 period, in addition to ensuring that they have a continuous and adequate learning experience, as well as access to psychosocial services that help them cope with mental distress and enhance their psychological well-being.

Background: One-shot library sessions have numerous drawbacks; most notably, they rarely have a long-term impact on students' research behavior or skill sets. Library literature notes that when students interact with an embedded librarian, their skills improve. While close partnerships with subject faculty are important, librarians must also assess students’ skill sets to determine the impact of these teaching efforts. Case presentation: During the course, the embedded librarian used various activities and assignments to teach information-seeking skills, with the expected outcome of increased skill sets. This IRB-approved research project focused on measuring and assessing students’ information-seeking abilities before and after interacting with the embedded nursing librarian. Changes in students' information fluency skills were measured using pre- and post-tests. Conclusions:The study results provide evidence of the benefits of the embedded librarianship model. Continued measurement of students’ skills acquisition is important to enable librarians and library administrators to show the positive impacts the library has on student learning and success.

Abstract Background Differentiation of induced pluripotent stem cells (iPSCs) toward hematopoietic progenitor cells (HPCs) raises high hopes for disease modeling, drug screening, and cellular therapy. Various differentiation protocols have been established to generate iPSC-derived HPCs (iHPCs) that resemble their primary counterparts in morphology and immunophenotype, whereas a systematic epigenetic comparison was yet elusive. Results In this study, we compared genome-wide DNA methylation (DNAm) patterns of iHPCs with various different hematopoietic subsets. After 20 days of in vitro differentiation, cells revealed typical hematopoietic morphology, CD45 expression, and colony-forming unit (CFU) potential. DNAm changes were particularly observed in genes that are associated with hematopoietic differentiation. On the other hand, the epigenetic profiles of iHPCs remained overall distinct from natural HPCs. Furthermore, we analyzed if additional co-culture for 2 weeks with syngenic primary mesenchymal stromal cells (MSCs) or iPSC-derived MSCs (iMSCs) further supports epigenetic maturation toward the hematopoietic lineage. Proliferation of iHPCs and maintenance of CFU potential was enhanced upon co-culture. However, DNAm profiles support the notion that additional culture expansion with stromal support did not increase epigenetic maturation of iHPCs toward natural HPCs. Conclusion Differentiation of iPSCs toward the hematopoietic lineage remains epigenetically incomplete. These results substantiate the need to elaborate advanced differentiation regimen while DNAm profiles provide a suitable measure to track this process.

Introduction Second opinion programmes aim to support the patients’ decision-making process and to avoid treatments that are unnecessary from a medical perspective. The German second opinion directive, introduced in December 2018, constitutes a new legal framework in statutory health insurance for seeking second opinions for elective procedures and so far includes tonsillectomy, tonsillotomy, hysterectomy and shoulder arthroscopy. The directive mandates physicians who recommend one of the above-mentioned surgeries to inform their patients of their legal right to visit a certified second opinion provider. Since second opinion programmes are a fairly recent phenomenon in Germany, no comprehensive data are yet available on the degree of implementation, users, potential barriers and their effectiveness. We aim to examine the characteristics and the use of second opinion programmes as well as the needs and wishes from the perspective of (potential) users in Germany, with focus on the decision-making process, the patient–physician relationship and the motivation to seek a second opinion, as well as the role of health literacy.Methods and analysis Six substudies will include the following stakeholders: (1 and 2) patients with one of the four surgery-indications covered by the directive, (3) patients who electively sought an online-based second opinion, (4) patients with oncological diseases, (5) the general population and (6) medical specialists. A mixed-methods approach will be used, including questionnaires, interviews and focus groups. The data will be evaluated using quantitative descriptive analysis and qualitative content analysis. The integration of the results will take place in the form of a triangulation protocol.Ethics and dissemination The study protocol was approved by the Ethics Committee of the Brandenburg Medical School. The findings will be published in peer-reviewed journals and presented at scientific conferences.

In this paper we analyze panel data (N = 400) to investigate the change in attitudes towards the Covid-19 measures and the change in compliance behavior between the first and second lockdowns in a sample of young adults from the University of Bern, Switzerland. We find considerable fatigue. While respondents expressed high acceptance of and compliance with the Covid-19 measures during the first lockdown, both acceptance and compliance behavior decreased substantially during the second lockdown. Moreover, we show via a structural equation model that respondents' compliance behavior is largely driven by the perception of how others behave and by the acceptance of the Covid-19 measures. All other effects scrutinized e.g., individual and social risk perception, trust in politics, and pro-social orientations affect compliance behavior via the acceptance of Covid-19 measures. We also conduct two tests of causality of the estimated relation between attitudes towards the measures and social distancing behavior. The first test incorporates the effect of compliance behavior reported during the first lockdown on attitudes during the second lockdown. The second test involves estimating a first difference panel regression model of attitudes on compliance behavior. The results of both tests suggest that the effect of Covid-19 attitudes on social distancing behavior can be interpreted causally.

In this paper we analyze panel data (N = 400) to investigate the change in attitudes towards the Covid-19 measures and the change in compliance behavior between the first and second lockdowns in a sample of young adults from the University of Bern, Switzerland. We find considerable fatigue. While respondents expressed high acceptance of and compliance with the Covid-19 measures during the first lockdown, both acceptance and compliance behavior decreased substantially during the second lockdown. Moreover, we show via a structural equation model that respondents’ compliance behavior is largely driven by the perception of how others behave and by the acceptance of the Covid-19 measures. All other effects scrutinized e.g., individual and social risk perception, trust in politics, and pro-social orientations affect compliance behavior via the acceptance of Covid-19 measures. We also conduct two tests of causality of the estimated relation between attitudes towards the measures and social distancing behavior. The first test incorporates the effect of compliance behavior reported during the first lockdown on attitudes during the second lockdown. The second test involves estimating a first difference panel regression model of attitudes on compliance behavior. The results of both tests suggest that the effect of Covid-19 attitudes on social distancing behavior can be interpreted causally.

The health risk of the coronavirus pandemic is age-specific. The symptoms of a COVID-19 infection are usually mild in the healthy population below the age of 65; however, the measures laid down to prevent the spread of the virus apply typically to the whole population. Hence, those who have a low risk of severe symptoms face a social dilemma in cooperating and complying with the safety measures: Cooperating in preventing the spread of the disease is good for society but comes with individual costs. These costs provide an incentive not to cooperate with the safety measures. In this paper we analyze via structural equation modelling a sample of young adults (N = 510) who were surveyed right after the end of the first lockdown period in Switzerland. We investigate why and to what extent they cooperated in preventing the epidemic by following the recommendation to stay at home as much as possible. We hypothesize that those respondents who perceive themselves to be personally at risk, or who have relatives belonging to the risk group, complied more often with the safety measures as compared to those without severe risks. Cooperating should also be linked to individuals' pro-social orientation. Furthermore, we hypothesize that those who believe that the virus is dangerous for society or who have a personal interest in protection show higher support for the general safety measures. Our empirical results show that compliance with the coronavirus social distancing measures was generally very high during the first lockdown. Although young adults perceived themselves to be at low personal risk, they still believed that the virus is dangerous for society. Those who had a personal interest in staying at home because they had relatives belonging to the risk group complied more often with the safety measures. Overall, the results suggest that the support of the preventive measures is the most important promoter of cooperation to prevent the spread of COVID-19.

The rising numbers of residency applications along with fears of a constrained graduate medical education environment have created pressures on residency applicants. Anecdotal evidence suggests substantial challenges with the process of offering residency interviews. This narrative review is designed to identify and propose solutions for the current problems in the process of offering residency interviews. We used PubMed and web browser searches to identify relevant studies and reports. Materials were assessed for relevance to the current process of distributing residency interviews. There is limited relevant literature and the quality is poor overall. We were able to identify several key problem areas including uncertain timing of interview offers; disruption caused by the timing of interview offers; imbalance of interview offers and available positions; and a lack of clarity around waitlist and rejection status. In addition, the couples match and need for coordination of interviews creates a special case. Many of the problems related to residency interview offers are amenable to program-level interventions, which may serve as best practices for residency programs, focusing on clear communication of processes as well as attention to factors such as offer-timing and numbers. We provide potential strategies for programs as well as a call for additional research to better understand the problem and solutions.

Introduction: The average number of applications per allopathic applicant to emergency medicine (EM) residency programs in the United States (US) has increased significantly since 2014. This increase in applications has caused a significant burden on both programs and applicants. Our goal in this study was to investigate the drivers of this application increase so as to inform strategies to mitigate the surge. Methods: An expert panel designed an anonymous, web-based survey, which was distributed to US allopathic senior applicants in the 2017–2018 EM match cycle via the Council of Residency Directors in Emergency Medicine and the Emergency Medicine Residents Association listservs for completion between the rank list certification deadline and release of match results. The survey collected descriptive statistics and factors affecting application decisions. Results: A total of 532 of 1748 (30.4%) US allopathic seniors responded to the survey. Of these respondents, 47.3% felt they had applied to too many programs, 11.8% felt they had applied to too few, and 57.7% felt that their perception of their own competitiveness increased their number of applications. Application behavior of peers going into EM was identified as the largest external factor driving an increase in applications (61.1%), followed by US Medical Licensing Exam scores (46.9%) – the latter was most pronounced in applicants who self-perceived as “less competitive.” The most significant limiter of application numbers was the cost of using the Electronic Residency Application Service (34.3%). Conclusion: A substantial group of EM applicants identified that they were over-applying to residencies. The largest driver of this process was individual applicant response to the behavior of their peers who were also going into EM. Understanding these motivations may help inform solutions to overapplication.

Background: The widespread use of the JUUL™ device ignited a discussion about the effects these products have on harm reduction. Therefore, we conducted a study directly comparing the JUUL™ device with a cigarette, a heated tobacco product, and a nicotine-free e-cigarette to examine the acute effects on arterial stiffness. Methods: This crossover-designed study examines 20 occasional smokers (age 25.2 ± 2.5 years). Study participants used each of the four smoking devices for a duration of 5 min following a protocol. Peripheral blood pressure and parameters of arterial stiffness and endothelial vasodilator function such as the reactive hyperemia index and the augmentation index were measured using the EndoPAT™2000 before and after. Results: In addition to significant peripheral hemodynamic changes after 5 and 10 min (p < 0.05), the reactive hyperemia index showed a significant decrease for all devices 15 min after consumption and remained significantly decreased after 60 min (p < 0.01). The augmentation index adjusted for a heart rate of 75 bpm increased significantly for all devices 15 and 60 min after consumption (p < 0.01). Conclusions: In conclusion, the increases in blood pressure and arterial stiffness are similar after smoking, JUUL™ing, heating, and vaping. These changes may be associated with an increase in cardiovascular risks; however, an evaluation of the long-term effects of JUUL™ing, vaping and heating is needed.

Os saberes da docência são: a experiência, o conhecimento e os saberes pedagógicos (Pimenta, 2007). Todos estes saberes precisam ser mobilizados no curso de formação inicial, à medida que se constrói a identidade dos futuros professores. Neste artigo trazemos discussões referentes aos saberes docente do conhecimento, saber esse que se refere ao conhecimento produzido e ensinado tanto na universidade quanto na escola e seus questionamentos. São questionamentos como: ─ Qual é significado dos conceitos específicos – da ciência, por exemplo – no curso de formação inicial? ─ E, para a sociedade, o que significam? É importante o professor saber como, por que e para que esse conhecimento se constitui. Ao obter respostas a esses questionamentos, o professor tem disponíveis os aportes necessários para falar aos estudantes sobre determinado conteúdo e/ou conceito. Reflexões sobre o saber docente do conhecimento é o que apresentamos neste artigo, que está fundamentado em um relato de experiência, no qual discutimos com um grupo de professoras (curso de formação continuada), que atuam na educação infantil, o conteúdo “solo”. Nesta atividade fica evidente a falta de conhecimento das professoras sobre o assunto “solo”, bem como a pouca reflexão sobre ele. Ao que foi possível observar, as professoras apresentam aos estudantes o conceito de “solo” de maneira acrítica, sem uma reflexão do que significam os termos científicos envolvidos no conceito.

The coronavirus disease (COVID-19) pandemic has had a significant impact on undergraduate medical education with limitation of patient care activities and disruption to medical licensing examinations. In an effort to promote both safety and equity, the emergency medicine (EM) community has recommended no away rotations for EM applicants and entirely virtual interviews during this year’s residency application cycle. These changes affect the components of the EM residency application most highly regarded by program directors – Standardized Letters of Evaluation from EM rotations, board scores, and interactions during the interview. The Council of Residency Directors in Emergency Medicine Application Process Improvement Committee suggests solutions not only for the upcoming year but also to address longstanding difficulties within the process, encouraging residency programs to leverage these challenges as an opportunity for disruptive innovation.

Approximately 15 million children under age 6 are in childcare settings, offering childcare providers an opportunity to influence children’s dietary intake. Childcare settings vary in organizational structure – childcare centers (CCCs) vs. family childcare homes (FCCHs) – and in geographical location – urban vs. rural. Research on the nutrition-related best practices across these childcare settings is scarce. The objective of this study is to compare nutrition-related best practices of CCCs and FCCHs that participate in the Child and Adult Care Food Program (CACFP) in rural and urban Nebraska. Nebraska providers (urban n = 591; rural n = 579) reported implementation level, implementation difficulty and barriers to implementing evidence-informed food served and mealtime practices. Chi-square tests comparing CCCs and FCCHs in urban Nebraska and CCCs and FCCHs in rural Nebraska showed sub-optimal implementation for some practices across all groups, including limiting fried meats and high sugar/ high fat foods, using healthier foods or non-food treats for celebrations and serving meals family style. Significant differences (p

Abstract Background Transplantation of human hematopoietic stem cells into immunodeficient mice provides a powerful in vivo model system to gain functional insights into hematopoietic differentiation. So far, it remains unclear if epigenetic changes of normal human hematopoiesis are recapitulated upon engraftment into such “humanized mice.” Mice have a much shorter life expectancy than men, and therefore, we hypothesized that the xenogeneic environment might greatly accelerate the epigenetic clock. Results We demonstrate that genome-wide DNA methylation patterns of normal human hematopoietic development are indeed recapitulated upon engraftment in mice—particularly those of normal early B cell progenitor cells. Furthermore, we tested three epigenetic aging signatures, and none of them indicated that the murine environment accelerated age-associated DNA methylation changes. Conclusions Epigenetic changes of human hematopoietic development are recapitulated in the murine transplantation model, whereas epigenetic aging is not accelerated by the faster aging environment and seems to occur in the cell intrinsically.

Abstract Background SHOX2 and SEPT9 methylation in circulating cell-free DNA (ccfDNA) in blood are established powerful and clinically valuable biomarkers for diagnosis, staging, prognosis, and monitoring of cancer patients. The aim of the present study was to evaluate different quantification algorithms (relative quantification, absolute quantification, quasi-digital PCR) with regard to their clinical performance. Methods Methylation analyses were performed in a training cohort (141 patients with head and neck squamous cell carcinoma [HNSCC], 170 control cases) and a testing cohort (137 HNSCC cases, 102 controls). DNA was extracted from plasma samples, bisulfite-converted, and analyzed via quantitative real-time PCR. SHOX2 and SEPT9 methylations were assessed separately and as panel [mean SEPT9/SHOX2 ] using the ΔCT method for absolute quantification and the ΔΔCT-method for relative quantification. Quasi-digital PCR was defined as the number of amplification-positive PCR replicates. The diagnostic (sensitivity, specificity, area under the curve (AUC) of the receiver operating characteristic (ROC)) and prognostic accuracy (hazard ratio (HR) from Cox regression) were evaluated. Results Sporadic methylation in control samples necessitated the introduction of cutoffs resulting in 61–63% sensitivity/90–92% specificity (SEPT9/training), 53–57% sensitivity/87–90% specificity (SHOX2/training), and 64–65% sensitivity/90–91% specificity (mean SEPT9/SHOX2 /training). Results were confirmed in a testing cohort with 54–56% sensitivity/88–90% specificity (SEPT9/testing), 43–48% sensitivity/93–95% specificity (SHOX2/testing), and 49–58% sensitivity/88–94% specificity (mean SEPT9/SHOX2 /testing). All algorithms showed comparable cutoff-independent diagnostic accuracy with largely overlapping 95% confidence intervals (SEPT9: AUCtraining = 0.79–0.80; AUCtesting = 0.74–0.75; SHOX2: AUCtraining = 0.78–0.81, AUCtesting = 0.77–0.79; mean SEPT9/SHOX2 : AUCtraining = 0.81–0.84, AUCtesting = 0.80). The accurate prediction of overall survival was possible with all three algorithms (training cohort: HR SEPT9 = 1.23-1.90, HR SHOX2 = 1.14-1.85, HRmeanSEPT9/SHOX2 =1.19-1.89 ; testing cohort: HR SEPT9 =1.22-1.67, HR SHOX2 = 1.15-1.71, HRmeanSEPT9/SHOX2 = 1.12-1.77). Conclusion The concordant clinical performance based on different quantification algorithms allows for the application of various diagnostic platforms for the analysis of ccfDNA methylation biomarkers.

Abstract Culture medium of mesenchymal stromal cells (MSCs) is usually supplemented with either human platelet lysate (HPL) or fetal calf serum (FCS). Many studies have demonstrated that proliferation and cellular morphology are affected by these supplements – it is therefore important to determine if they favor outgrowth of different subpopulations and thereby impact on the heterogeneous composition of MSCs. We have isolated and expanded human bone marrow-derived MSCs in parallel with HPL or FCS and demonstrated that HPL significantly increases proliferation and leads to dramatic differences in cellular morphology. Remarkably, global DNA-methylation profiles did not reveal any significant differences. Even at the transcriptomic level, there were only moderate changes in pairwise comparison. Furthermore, the effects on proliferation, cytoskeletal organization, and focal adhesions were reversible by interchanging to opposite culture conditions. These results indicate that cultivation of MSCs with HPL or FCS has no systematic bias for specific cell types.

A presença de contaminantes emergentes em águas de superfície foi detectada em estudos realizados por pesquisadores de vários países. Neste estudo foram monitorados parâmetros fisiológicos de substratos contaminados pelos antibacterianos, nitrofurantoína (NTF), cloridrato de tetraciclina (CTC), cefalexina (CEF), amoxicilina (AMX), azitromicina (AZI) e norfloxacina (NOR) e pelos analgésicos, diclofenaco de sódio (DFS), dipirona monoidratada (DMH) e diclofenaco de potássio (DFP), em culturas de Lactuca spp. (alface) e de Saccharomyces cereviseae in vitro. Todas as substâncias avaliadas causam alterações metabólicas e fisiológicas na cultura de Lactuca spp., alterando a taxa de germinação, o comprimento de folhas, o comprimento de raízes e as taxas de clorofila alfa e de clorofila beta. No entanto apenas NOR, DFS e DMH causam alterações na concentração inibitória para a produção de espuma de S.cereviseae em concentrações ≤ 5000 ppm.

Introduction Poor access to quality healthcare is one of the most important reasons of high maternal and neonatal mortality in India, particularly in poorer states like Bihar. India has implemented initiatives to promote institutional maternal deliveries. It is important to ensure that health facilities are adequately equipped and staffed to provide quality care for mothers and newborns.Methods We conducted a cross-sectional study of 190 primary health centres (PHCs) and 36 district hospitals (DHs) across all districts in Bihar to assess the readiness of facilities to provide quality maternal and neonatal care. Infrastructure, equipment and supplies and staffing were assessed using the WHO service availability and readiness assessment and Indian public health standard guidelines. Additionally, we used household survey data to assess the quality of care reported by mothers delivering at study facilities.Results PHCs and DHs were found to have 61% and 67% of the mandated structural components to provide maternal and neonatal care, on average, respectively. DHs were, on average, slightly better equipped in terms of infrastructure, equipment and supplies by comparison to PHCs. DHs were found to be inadequately prepared to provide neonatal care. Lack of recommended handwashing stations and bins at both DHs and PHCs suggested low levels of hygiene. Only half of the essential drugs were available in both DHs and PHCs. While no association was revealed between structural capacity and patient-reported quality of care, adequacy of staffing was positively associated with the quality of care in DHs.Conclusion Examining all DHs and a representative sample of PHCs in Bihar, this study revealed the gaps in structural components that need to be filled to provide quality care to mothers and newborns. Access to quality care is essential if progress in reducing maternal and neonatal mortality is to be achieved in this high-burden state.

Introduction: Medical education is moving toward a competency-based framework with a focus on assessment using the Accreditation Council for Graduate Medical Education Milestones. Assessment of individual competencies through milestones can be challenging. While competencies describe characteristics of the person, the entrustable professional activities (EPAs) concept refers to work-related activities. EPAs would not replace the milestones but would be linked to them, integrating these frameworks. Many core specialties have already defined EPAs for resident trainees, but EPAs have not yet been created for emergency medicine (EM). This paper describes the development of milestone-linked EPAs for EM. Methods: Ten EM educators from across North America formed a consensus working group to draft EM EPAs, using a modified Glaser state-of-the-art approach. A reactor panel with EPA experts from the United States, Canada and the Netherlands was created, and an iterative process with multiple revisions was performed based on reactor panel input. Following this, the EPAs were sent to the Council of Residency Directors for EM (CORD-EM) listserv for additional feedback. Results: The product was 11 core EPAs that every trainee from every EM program should be able to perform independently by the time of graduation. Each EPA has associated knowledge, skills, attitudes and behaviors (KSAB), which are either milestones themselves or KSABs linked to individual milestones. We recognize that individual programs may have additional focus areas or work-based activities they want their trainees to achieve by graduation; therefore, programs are also encouraged to create additional program-specific EPAs. Conclusion: This set of 11 core, EM-resident EPAs can be used as an assessment tool by EM residency programs, allowing supervising physicians to document the multiple entrustment decisions they are already making during clinical shifts with trainees. The KSAB list within each EPA could assist supervisors in giving specific, actionable feedback to trainees and allow trainees to use this list as an assessment-for-learning tool. Linking each KSAB to individual EM milestones allows EPAs to directly inform milestone assessment for clinical competency committees. These EPAs serve as another option for workplace-based assessment, and are linked to the milestones to create an integrated framework.

Epigenetic clocks for mice were generated based on deep-sequencing analysis of the methylome. Here, we demonstrate that site-specific analysis of DNA methylation levels by pyrosequencing at only three CG dinucleotides (CpGs) in the genes Prima1, Hsf4, and Kcns1 facilitates precise estimation of chronological age in murine blood samples, too. DBA/2 mice revealed accelerated epigenetic aging as compared to C57BL6 mice, which is in line with their shorter life-expectancy. The three-CpG-predictor provides a simple and cost-effective biomarker to determine biological age in large intervention studies with mice.

Metastases of renal cell carcinoma (RCC) involving the parotid gland are very rare. We present to our knowledge the first case of a 74-year-old woman with metastases of an RCC which affected both parotid glands six and twelve years following curative therapy.