HL7 FHIR in Health Research: A FHIR Specification for Metadata in Clinical, Epidemiological, and Public Health Studies.

This work presents the Fast Healthcare Interoperability Resources (FHIR®) specification of the NFDI4Health Metadata schema based on FHIR Version 4: We created 16 profiles to facilitate the integration of clinical, epidemiological, and public health study data. Despite challenges arising from the extensive MDS as well as missing concepts in semantic standards, it marks a significant advance in applying information technology standards to health research.

Data for AI in Congenital Heart Defects: Systematic Review.

Congenital heart disease (CHD) represents a significant challenge in prenatal care due to low prenatal detection rates. Artificial Intelligence (AI) offers promising avenues for precise CHD prediction. In this study we conducted a systematic review according to the PRISMA guidelines, investigating the landscape of AI applications in prenatal CHD detection. Through searches on PubMed, Embase, and Web of Science, 621 articles were screened, yielding 28 relevant studies for analysis. Deep Learning (DL) emerged as the predominant AI approach. Data types were limited to ultrasound and MRI sequences mainly. This comprehensive analysis provides valuable insights for future research and clinical practice in CHD detection using AI applications.

Deciphering a Beetle Clock: Individual and Sex-Dependent Variation in Daily Activity Patterns.

Circadian clocks are inherent to most organisms, including cryptozoic animals that seldom encounter direct light, and regulate their daily activity cycles. A conserved suite of clock genes underpins these rhythms. In this study, we explore the circadian behaviors of the red flour beetle Tribolium castaneum, a significant pest impacting stored grain globally. We report on how daily light and temperature cues synchronize distinct activity patterns in these beetles, characterized by reduced morning activity and increased evening activity, anticipating the respective environmental transitions. Although less robust, rhythmicity in locomotor activity is maintained in constant dark and constant light conditions. Notably, we observed more robust rhythmic behaviors in males than females with individual variation exceeding those previously reported for other insect species. RNA interference targeting the Clock gene weakened locomotor activity rhythms. Our findings demonstrate the existence of a circadian clock and of clock-controlled behaviors in T. castaneum. Furthermore, they highlight substantial individual differences in circadian activity, laying the groundwork for future research on the relevance of individual variation in circadian rhythms in an ecological and evolutionary context.

Towards an Interoperability Landscape for a National Research Data Infrastructure for Personal Health Data.

The German initiative "National Research Data Infrastructure for Personal Health Data" (NFDI4Health) focuses on research data management in health research. It aims to foster and develop harmonized informatics standards for public health, epidemiological studies, and clinical trials, facilitating access to relevant data and metadata standards. This publication lists syntactic and semantic data standards of potential use for NFDI4Health and beyond, based on interdisciplinary meetings and workshops, mappings of study questionnaires and the NFDI4Health metadata schema, and literature search. Included are 7 syntactic, 32 semantic and 9 combined syntactic and semantic standards. In addition, 101 ISO Standards from ISO/TC 215 Health Informatics and ISO/TC 276 Biotechnology could be identified as being potentially relevant. The work emphasizes the utilization of standards for epidemiological and health research data ensuring interoperability as well as the compatibility to NFDI4Health, its use cases, and to (inter-)national efforts within these sectors. The goal is to foster collaborative and inter-sectoral work in health research and initiate a debate around the potential of using common standards.

Chiral Bay-Alkynylated Tetraazaperylenes: Photophysics and Chiroptical Properties.

Fully bay-alkynylated octaazaperopyrene dioxide (OAPPDO) derivatives were accessible through Stille cross coupling reaction of the corresponding bay-chlorinated derivatives. This steric congestion of the bay area led to helically chiral fluorophores, and chiral resolution of two derivatives allowed the investigation of their chiroptical properties as well as their kinetics of enantiomerization and the related thermodynamic parameters depending on the size of the terminal alkynyl substituent. An increase of the latter resulted in stable OAPPDO atropisomers at room temperature. The dynamics of the photoexcited states of two of the OAPPDO derivatives were investigated by transient absorption (TA) and time-resolved photoluminescence (tr-PL) spectroscopy.

Swift C-C bond insertion by a 12-electron palladium(0) surrogate.

The selective activation of C-C bonds holds vast promise for catalysis. So far, research has been primarily directed at rhodium and nickel under harsh reaction conditions. Herein, we report C-C insertion reactions of a 12-electron palladium(0) surrogate stabilized by a cyclic(alkyl)(amino) carbene (CAAC) ligand. Benzonitrile (1), biphenylene (2), benzocyclobutenone (3), and naphtho[b]cyclopropene (4) were studied. These substrates allow elucidation of the effect of ring strain as well as hybridization encompassing sp3, sp2 and sp hybridized carbon atoms. All reactions proceed quantitatively at or below room temperature. This work therefore outlines perspectives for mild C-C bond functionalization catalysis.

Artificial Intelligence Bias in Health Care: Web-Based Survey.

BACKGROUND: Resources are increasingly spent on artificial intelligence (AI) solutions for medical applications aiming to improve diagnosis, treatment, and prevention of diseases. While the need for transparency and reduction of bias in data and algorithm development has been addressed in past studies, little is known about the knowledge and perception of bias among AI developers. OBJECTIVE: This study's objective was to survey AI specialists in health care to investigate developers' perceptions of bias in AI algorithms for health care applications and their awareness and use of preventative measures. METHODS: A web-based survey was provided in both German and English language, comprising a maximum of 41 questions using branching logic within the REDCap web application. Only the results of participants with experience in the field of medical AI applications and complete questionnaires were included for analysis. Demographic data, technical expertise, and perceptions of fairness, as well as knowledge of biases in AI, were analyzed, and variations among gender, age, and work environment were assessed. RESULTS: A total of 151 AI specialists completed the web-based survey. The median age was 30 (IQR 26-39) years, and 67% (101/151) of respondents were male. One-third rated their AI development projects as fair (47/151, 31%) or moderately fair (51/151, 34%), 12% (18/151) reported their AI to be barely fair, and 1% (2/151) not fair at all. One participant identifying as diverse rated AI developments as barely fair, and among the 2 undefined gender participants, AI developments were rated as barely fair or moderately fair, respectively. Reasons for biases selected by respondents were lack of fair data (90/132, 68%), guidelines or recommendations (65/132, 49%), or knowledge (60/132, 45%). Half of the respondents worked with image data (83/151, 55%) from 1 center only (76/151, 50%), and 35% (53/151) worked with national data exclusively. CONCLUSIONS: This study shows that the perception of biases in AI overall is moderately fair. Gender minorities did not once rate their AI development as fair or very fair. Therefore, further studies need to focus on minorities and women and their perceptions of AI. The results highlight the need to strengthen knowledge about bias in AI and provide guidelines on preventing biases in AI health care applications.

Impact of social phone programs on loneliness and mood in older adults: a mixed methods systematic review protocol.

OBJECTIVE: The objective of this mixed methods review is to examine the effectiveness and experience of social phone programs on loneliness and/or mood in community-dwelling older adults. INTRODUCTION: There is a large and growing older adult population that is burdened with loneliness. Loneliness affects both physical and mental health, and it is, therefore, imperative to examine ways of mitigating experiences of loneliness. Social phone programs are being offered through multiple organizations as a way of increasing socialization and decreasing loneliness in older adults. There is a need to examine existing data on social phone programs to determine their effectiveness and optimize their implementation. INCLUSION CRITERIA: Included studies will be original qualitative, quantitative, or mixed methods research, along with gray literature, examining the use of social phone programs to address loneliness and/or mood in older adults. METHODS: A convergent segregated mixed methods approach will be used, in line with the JBI methodology for mixed methods reviews. Articles will be searched in selected databases, sources of clinical trials, and gray literature. No limits have been set for language or date of publication. Two team members will select studies through title and abstract screening and then full-text screening. Critical appraisal will be performed in accordance with the standard JBI critical assessment tools, although no articles will be excluded based on this appraisal. Quantitative articles will be synthesized using meta-analysis, while a process of meta-aggregation will be used for qualitative articles. The findings will be integrated into a final report. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42022335119.

Fast Healthcare Interoperability Resources (FHIR) for Interoperability in Health Research: Systematic Review.

BACKGROUND: The standard Fast Healthcare Interoperability Resources (FHIR) is widely used in health information technology. However, its use as a standard for health research is still less prevalent. To use existing data sources more efficiently for health research, data interoperability becomes increasingly important. FHIR provides solutions by offering resource domains such as "Public Health & Research" and "Evidence-Based Medicine" while using already established web technologies. Therefore, FHIR could help standardize data across different data sources and improve interoperability in health research. OBJECTIVE: The aim of our study was to provide a systematic review of existing literature and determine the current state of FHIR implementations in health research and possible future directions. METHODS: We searched the PubMed/MEDLINE, Embase, Web of Science, IEEE Xplore, and Cochrane Library databases for studies published from 2011 to 2022. Studies investigating the use of FHIR in health research were included. Articles published before 2011, abstracts, reviews, editorials, and expert opinions were excluded. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and registered this study with PROSPERO (CRD42021235393). Data synthesis was done in tables and figures. RESULTS: We identified a total of 998 studies, of which 49 studies were eligible for inclusion. Of the 49 studies, most (73%, n=36) covered the domain of clinical research, whereas the remaining studies focused on public health or epidemiology (6%, n=3) or did not specify their research domain (20%, n=10). Studies used FHIR for data capture (29%, n=14), standardization of data (41%, n=20), analysis (12%, n=6), recruitment (14%, n=7), and consent management (4%, n=2). Most (55%, 27/49) of the studies had a generic approach, and 55% (12/22) of the studies focusing on specific medical specialties (infectious disease, genomics, oncology, environmental health, imaging, and pulmonary hypertension) reported their solutions to be conferrable to other use cases. Most (63%, 31/49) of the studies reported using additional data models or terminologies: Systematized Nomenclature of Medicine Clinical Terms (29%, n=14), Logical Observation Identifiers Names and Codes (37%, n=18), International Classification of Diseases 10th Revision (18%, n=9), Observational Medical Outcomes Partnership common data model (12%, n=6), and others (43%, n=21). Only 4 (8%) studies used a FHIR resource from the domain "Public Health & Research." Limitations using FHIR included the possible change in the content of FHIR resources, safety, legal matters, and the need for a FHIR server. CONCLUSIONS: Our review found that FHIR can be implemented in health research, and the areas of application are broad and generalizable in most use cases. The implementation of international terminologies was common, and other standards such as the Observational Medical Outcomes Partnership common data model could be used as a complement to FHIR. Limitations such as the change of FHIR content, lack of FHIR implementation, safety, and legal matters need to be addressed in future releases to expand the use of FHIR and, therefore, interoperability in health research.

The Experience of Older Adults Socially Distancing during the Early Stages of the COVID-19 Pandemic.

During the early stages of the COVID-19 pandemic, individuals were asked to stay home and restrict outings to limit the spread of the virus. Physical isolation was particularly emphasized for older adults over the age of 60 who, because of their age and related medical conditions, were at increased risk of severe disease and death from the virus. This led to reduced spread of the virus but also to social and emotional health challenges for older adults. Protecting the physical health of older adults was of the utmost importance during the pandemic but supporting social and mental health must not be overlooked. This patient-oriented qualitative study involved 40 interviews with older adults, conducted in the early stages of the pandemic, followed by a thematic analysis. Three themes were derived from the findings: subverted life plan, emotional impacts, and creating a path forward. The findings from this study will help inform current physical and social distancing guidelines during the ongoing COVID-19 pandemic. Moreover, findings indicate that social and emotional challenges with ongoing physical and social isolation must be taken into consideration for future pandemics.

Development of a dynamic in vitro stretch model of the alveolar interface with aerosol delivery.

We describe the engineering design, computational modeling, and empirical performance of a moving air-liquid interface (MALI) bioreactor for the study of aerosol deposition on cells cultured on an elastic, porous membrane which mimics both air-liquid interface exposure conditions and mechanoelastic motion of lung tissue during breathing. The device consists of two chambers separated by a cell layer cultured on a porous, flexible membrane. The lower (basolateral) chamber is perfused with cell culture medium simulating blood circulation. The upper (apical) chamber representing the air compartment of the lung is interfaced to an aerosol generator and a pressure actuation system. By cycling the pressure in the apical chamber between 0 and 7 kPa, the membrane can mimic the periodic mechanical strain of the alveolar wall. Focusing on the engineering aspects of the system, we show that membrane strain can be monitored by measuring changes in pressure resulting from the movement of media in the basolateral chamber. Moreover, liquid aerosol deposition at a high dose delivery rate (>1 µl cm-2 min-1 ) is highly efficient (ca. 51.5%) and can be accurately modeled using finite element methods. Finally, we show that lung epithelial cells can be mechanically stimulated under air-liquid interface and stretch-conditions without loss of viability. The MALI bioreactor could be used to study the effects of aerosol on alveolar cells cultured at the air-liquid interface in a biodynamic environment or for toxicological or therapeutic applications.

Quartz crystal microbalances (QCM) are suitable for real-time dosimetry in nanotoxicological studies using VITROCELL®Cloud cell exposure systems.

BACKGROUND: Accurate knowledge of cell-/tissue-delivered dose plays a pivotal role in inhalation toxicology studies, since it is the key parameter for hazard assessment and translation of in vitro to in vivo dose-response. Traditionally, (nano-)particle toxicological studies with in vivo and in vitro models of the lung rely on in silio computational or off-line analytical methods for dosimetry. In contrast to traditional in vitro testing under submerged cell culture conditions, the more physiologic air-liquid interface (ALI) conditions offer the possibility for real-time dosimetry using quartz crystal microbalances (QCMs). However, it is unclear, if QCMs are sensitive enough for nanotoxicological studies. We investigated this issue for two commercially available VITROCELL®Cloud ALI exposure systems. RESULTS: Quantitative fluorescence spectroscopy of fluorescein-spiked saline aerosol was used to determine detection limit, precision and accuracy of the QCMs implemented in a VITROCELL®Cloud 6 and Cloud 12 system for dose-controlled ALI aerosol-cell exposure experiments. Both QCMs performed linearly over the entire investigated dose range (200 to 12,000 ng/cm2) with an accuracy of 3.4% (Cloud 6) and 3.8% (Cloud 12). Their precision (repeatability) decreased from 2.5% for large doses (> 9500 ng/cm2) to values of 10% and even 25% for doses of 1000 ng/cm2 and 200 ng/cm2, respectively. Their lower detection limit was 170 ng/cm2 and 169 ng/cm2 for the Cloud 6 and Cloud 12, respectively. Dose-response measurements with (NM110) ZnO nanoparticles revealed an onset dose of 3.3 µg/cm2 (or 0.39 cm2/cm2) for both cell viability (WST-1) and cytotoxicity (LDH) of A549 lung epithelial cells. CONCLUSIONS: The QCMs of the Cloud 6 and Cloud 12 systems show similar performance and are highly sensitive, accurate devices for (quasi-) real-time dosimetry of the cell-delivered particle dose in ALI cell exposure experiments, if operated according to manufacturer specifications. Comparison with in vitro onset doses from this and previously published ALI studies revealed that the detection limit of 170 ng/cm2 is sufficient for determination of toxicological onset doses for all particle types with low (e.g. polystyrene) or high mass-specific toxicity (e.g. ZnO and Ag) investigated here. Hence, in principle QCMs are suitable for in vitro nanotoxciological studies, but this should be investigated for each QCM and ALI exposure system under the specific exposure conditions as described in the present study.

Impact of computerized physician order entry on ED patient length of stay.

OBJECTIVES: We evaluated whether implementation of computerized physician order entry (CPOE) reduces length of stay (LOS) for discharged emergency department (ED) patients. METHODS: Emergency department LOS for discharged and admitted patients were analyzed in a university-affiliated ED before and after introduction of CPOE. Patient demographics and covariates that may affect LOS (mode of arrival, provider staffing, daily census, and admission rate) were measured. RESULTS: The study included 71,188 patients; 49,175 (69%) were discharged from the ED (28, 687 before and 20,488 after CPOE). Length of stay for discharged patients decreased from 198 to 168 minutes (difference of -30; 95% confidence interval [CI], -28 to -33), whereas LOS for admitted patients increased from 405 to 441 minutes (difference of +36; 95% CI, 26-46). After controlling for covariates, CPOE implementation was associated with a 23-minute decrease in LOS for discharged patients (ß = -23 [95% CI, -26 to -19]). CONCLUSION: Implementation of CPOE was associated with a clinically significant (23-minute) decrease in LOS among patients who were discharged from the ED.

Impact on length of stay after introduction of emergency department information system.

OBJECTIVE: An electronic emergency department information system (EDIS) can monitor the progress of a patient visit, facilitate computerized physician order entry, display test results and generate an electronic medical record. Ideally, use of an EDIS will increase overall emergency department (ED) efficiency. However, in academic settings where new interns rotate through the ED monthly, the "learning curve" experienced by the new EDIS user may slow down patient care. In this study, we measured the impact of the "intern learning curve" on patient length of stay (LOS). METHODS: We retrospectively analyzed one year of patient care data, generated by a comprehensive EDIS in a single, urban, university-affiliated ED. Intern rotations began on the 23rd of each month and ended on the 22nd of the next month. Interns received a 1.5-hour orientation to the EDIS prior to starting their rotation; none had prior experience using the electronic system. Mean LOS (± standard error of the mean) for all patients treated by an intern were calculated for each day of the month. Values for similar numerical days from each month were combined and averaged over the year resulting in 31 discrete mean LOS values. The mean LOS on the first day of the intern rotation was compared with the mean LOS on the last day, using Student's t-test. RESULTS: During the study period 9,780 patients were cared for by interns; of these, 7,616 (78%) were discharged from the ED and 2,164 (22%) were admitted to the hospital. The mean LOS for all patients on all days was 267 ± 1.8 minutes. There was no difference between the LOS on the first day of the rotation (263±9 minutes) and the last day of the rotation (276 ± 11 minutes, p > 0.9). In a multiple linear regression model, the day of the intern rotation was not associated with patient LOS, even after adjusting for the number of patients treated by interns and total ED census (ß = -0.34, p = 0.11). CONCLUSION: In this academic ED, where there is complete intern "turnover" every month, there was no discernible impact of the EDIS "learning curve" on patient LOS.

Soluble iron modulates iron oxide particle-induced inflammatory responses via prostaglandin E(2 )synthesis: In vitro and in vivo studies.

BACKGROUND: Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of PM-induced inflammation by leached off metals, we investigated intracellular solubility of radio-labeled iron oxide ((59)Fe(2)O(3)) particles of 0.5 and 1.5 mum geometric mean diameter. Fe(2)O(3 )particles were examined for the induction of the release of interleukin 6 (IL-6) as pro-inflammatory and prostaglandin E(2 )(PGE(2)) as anti-inflammatory markers in cultured alveolar macrophages (AM) from Wistar Kyoto (WKY) rats. In addition, we exposed male WKY rats to monodispersed Fe(2)O(3 )particles by intratracheal instillation (1.3 or 4.0 mg/kg body weight) to examine in vivo inflammation. RESULTS: Particles of both sizes are insoluble extracellularly in the media but moderately soluble in AM with an intracellular dissolution rate of 0.0037 +/- 0.0014 d(-1 )for 0.5 mum and 0.0016 +/- 0.0012 d(-1 )for 1.5 mum (59)Fe(2)O(3 )particles. AM exposed in vitro to 1.5 mum particles (10 mug/mL) for 24 h increased IL-6 release (1.8-fold; p < 0.05) and also PGE(2 )synthesis (1.9-fold; p < 0.01). By contrast, 0.5 mum particles did not enhance IL-6 release but strongly increased PGE(2 )synthesis (2.5-fold, p < 0.005). Inhibition of PGE(2 )synthesis by indomethacin caused a pro-inflammatory phenotype as noted by increased IL-6 release from AM exposed to 0.5 mum particles (up to 3-fold; p < 0.005). In the rat lungs, 1.5 but not 0.5 mum particles (4.0 mg/kg) induced neutrophil influx and increased vascular permeability. CONCLUSIONS: Fe(2)O(3 )particle-induced neutrophilic inflammatory response in vivo and pro-inflammatory cytokine release in vitro might be modulated by intracellular soluble iron via PGE(2 )synthesis. The suppressive effect of intracellular released soluble iron on particle-induced inflammation has implications on how ambient PM-associated but soluble metals influence pulmonary toxicity of ambient PM.

Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs.

Currently, translocation of inhaled insoluble nanoparticles (NP) across membranes like the air-blood barrier into secondary target organs (STOs) is debated. Of key interest are the involved biological mechanisms and NP parameters that determine the efficiency of translocation. We performed NP inhalation studies with rats to derive quantitative biodistribution data on the translocation of NP from lungs to blood circulation and STOs. The inhaled NP were chain aggregates (and agglomerates) of either iridium or carbon, with primary particle sizes of 2-4 nm (Ir) and 5-10 nm (C) and aggregate sizes (mean mobility diameters) between 20 and 80 nm. The carbon aggregates contained a small fraction ( < 1%) of Ir primary particles. The insoluble aggregates were radiolabeled with (192)Ir. During 1 h of inhalation, rats were intubated and ventilated to avoid extrathoracic NP deposition and to optimize deep lung NP deposition. After 24 h, (192)Ir fractions in the range between 0.001 and 0.01 were found in liver, spleen, kidneys, heart, and brain, and an even higher fraction (between 0.01 and 0.05) in the remaining carcass consisting of soft tissue and bone. The fractions of (192)Ir carried with the carbon NP retained in STOs, the skeleton, and soft tissue were significantly lower than with NP made from pure Ir. Furthermore, there was significantly less translocation and accumulation with 80-nm than with 20-nm NP aggregates of Ir. These studies show that both NP characteristics--the material and the size of the chain-type aggregates--determine translocation and accumulation in STOs, skeleton, and soft tissue.

Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent reentrainment onto airways epithelium.

BACKGROUND: There is ongoing discussion that inhaled nanoparticles (NPs, < 100 nm) may translocate from epithelial deposition sites of the lungs to systemic circulation. OBJECTIVES AND METHODS: We studied the disappearance of NPs from the epithelium by sequential lung retention and clearance and bronchoalveolar lavage (BAL) measurements in healthy adult Wistar Kyoto (WKY) rats at various times over 6 months after administration of a single 60- to 100-min intratracheal inhalation of iridium-192 ((192)Ir)-radiolabeled NPs. A complete (192)Ir balance of all organs, tissues, excretion, remaining carcass, and BAL was performed at each time point. RESULTS: Directly after inhalation we found free NPs in the BAL; later, NPs were predominantly associated with alveolar macropages (AMs). After 3 weeks, lavageable NP fractions decreased to 0.06 of the actual NP lung burden. This is in stark contrast to the AM-associated fraction of micron-sized particles reported in the literature. These particles remained constant at about 0.8 throughout a 6-month period. Three weeks after inhalation, 80% of the retained Ir NPs was translocated into epithelium and interstitium. CONCLUSION: There is a strong size-selective difference in particle immobilization. Furthermore, AM-mediated NP transport to the larynx originates not only from the NP fraction retained on the epithelium but also from NPs being reentrained from the interstitium to the luminal side of epithelium. We conclude that NPs are much less phagocytized by AMs than large particles but are effectively removed from the lung surface into the interstitium. Even from these interstitial sites, they undergo AM-mediated long-term NP clearance to the larynx.