Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks.

Metabolic diseases are often characterized by circadian misalignment in different tissues, yet how altered coordination and communication among tissue clocks relate to specific pathogenic mechanisms remains largely unknown. Applying an integrated systems biology approach, we performed 24-hr metabolomics profiling of eight mouse tissues simultaneously. We present a temporal and spatial atlas of circadian metabolism in the context of systemic energy balance and under chronic nutrient stress (high-fat diet [HFD]). Comparative analysis reveals how the repertoires of tissue metabolism are linked and gated to specific temporal windows and how this highly specialized communication and coherence among tissue clocks is rewired by nutrient challenge. Overall, we illustrate how dynamic metabolic relationships can be reconstructed across time and space and how integration of circadian metabolomics data from multiple tissues can improve our understanding of health and disease.

Deletion of IFT20 exclusively in the RPE ablates primary cilia and leads to retinal degeneration.

Vision impairment places a serious burden on the aging society, affecting the lives of millions of people. Many retinal diseases are of genetic origin, of which over 50% are due to mutations in cilia-associated genes. Most research on retinal degeneration has focused on the ciliated photoreceptor cells of the retina. However, the contribution of primary cilia in other ocular cell types has largely been ignored. The retinal pigment epithelium (RPE) is a monolayer epithelium at the back of the eye intricately associated with photoreceptors and essential for visual function. It is already known that primary cilia in the RPE are critical for its development and maturation; however, it remains unclear whether this affects RPE function and retinal tissue homeostasis. We generated a conditional knockout mouse model, in which IFT20 is exclusively deleted in the RPE, ablating primary cilia. This leads to defective RPE function, followed by photoreceptor degeneration and, ultimately, vision impairment. Transcriptomic analysis offers insights into mechanisms underlying pathogenic changes, which include transcripts related to epithelial homeostasis, the visual cycle, and phagocytosis. Due to the loss of cilia exclusively in the RPE, this mouse model enables us to tease out the functional role of RPE cilia and their contribution to retinal degeneration, providing a powerful tool for basic and translational research in syndromic and non-syndromic retinal degeneration. Non-ciliary mechanisms of IFT20 in the RPE may also contribute to pathogenesis and cannot be excluded, especially considering the increasing evidence of non-ciliary functions of ciliary proteins.

The Role of the Human Cerebellum for Learning from and Processing of External Feedback in Non-Motor Learning: A Systematic Review.

This review aimed to systematically identify and comprehensively review the role of the cerebellum in performance monitoring, focusing on learning from and on processing of external feedback in non-motor learning. While 1078 articles were screened for eligibility, ultimately 36 studies were included in which external feedback was delivered in cognitive tasks and which referenced the cerebellum. These included studies in patient populations with cerebellar damage and studies in healthy subjects applying neuroimaging. Learning performance in patients with different cerebellar diseases was heterogeneous, with only about half of all patients showing alterations. One patient study using EEG demonstrated that damage to the cerebellum was associated with altered neural processing of external feedback. Studies assessing brain activity with task-based fMRI or PET and one resting-state functional imaging study that investigated connectivity changes following feedback-based learning in healthy participants revealed involvement particularly of lateral and posterior cerebellar regions in processing of and learning from external feedback. Cerebellar involvement was found at different stages, e.g., during feedback anticipation and following the onset of the feedback stimuli, substantiating the cerebellum's relevance for different aspects of performance monitoring such as feedback prediction. Future research will need to further elucidate precisely how, where, and when the cerebellum modulates the prediction and processing of external feedback information, which cerebellar subregions are particularly relevant, and to what extent cerebellar diseases alter these processes.

An Outcome Comparison Between Geriatric and Nongeriatric Emergency Departments.

STUDY OBJECTIVE: We sought to describe diagnosis rates and compare common process outcomes between geriatric emergency departments (EDs) and nongeriatric EDs participating in the American College of Emergency Physicians Clinical Emergency Data Registry (CEDR). METHODS: We conducted an observational study of ED visits in calendar year 2021 within the CEDR by older adults. The analytic sample included 6,444,110 visits at 38 geriatric EDs and 152 matched nongeriatric EDs, with the geriatric ED status determined based on linkage to the American College of Emergency Physicians' Geriatric ED Accreditation program. Stratified by age, we assessed diagnosis rates (X/1000) for 4 common geriatric syndrome conditions and a set of common process outcomes including the ED length of stay, discharge rates, and 72-hour revisit rates. RESULTS: Across all age categories, geriatric EDs had higher diagnosis rates than nongeriatric EDs for 3 of the 4 following geriatric syndrome conditions of interest: urinary tract infection, dementia, and delirium/altered mental status. The median ED site-level length of stay for older adults was lower at geriatric EDs compared with that at nongeriatric EDs, whereas 72-hour revisit rates were similar across all age categories. Geriatric EDs exhibited a median discharge rate of 67.5% for adults aged 65 to 74 years, 60.8% for adults aged 75 to 84 years, and 55.6% for adults aged >85 years. Comparatively, the median discharge rate at nongeriatric ED sites was 69.0% for adults aged 65 to 74 years, 64.2% for adults aged 75 to 84 years, and 61.3% for adults aged >85 years. CONCLUSION: Geriatric EDs had higher geriatric syndrome diagnosis rates, lower ED lengths of stay, and similar discharge and 72-hour revisit rates when compared with nongeriatric EDs in the CEDR. These findings provide the first benchmarks for emergency care process outcomes in geriatric EDs compared with nongeriatric EDs.

Dysregulation of Wnt signaling in bone of type 2 diabetes mellitus and diabetic Charcot arthropathy.

BACKGROUND: Type 2 diabetes mellitus (T2DM) patients show a markedly higher fracture risk and impaired fracture healing when compared to non-diabetic patients. However in contrast to type 1 diabetes mellitus, bone mineral density in T2DM is known to be normal or even regionally elevated, also known as diabetic bone disease. Charcot arthropathy is a severe and challenging complication leading to bone destruction and mutilating bone deformities. Wnt signaling is involved in increasing bone mineral density, bone homeostasis and apoptotic processes. It has been shown that type 2 diabetes mellitus is strongly associated with gene variants of the Wnt signaling pathway, specifically polymorphisms of TCF7L2 (transcription factor 7 like 2), which is an effector transcription factor of this pathway. METHODS: Bone samples of 19 T2DM patients and 7 T2DM patients with additional Charcot arthropathy were compared to 19 non-diabetic controls. qPCR analysis for selected members of the Wnt-signaling pathway (WNT3A, WNT5A, catenin beta, TCF7L2) and bone gamma-carboxyglutamate (BGLAP, Osteocalcin) was performed and analyzed using the 2-ΔΔCt- Method. Statistical analysis comprised one-way analysis of variance (ANOVA). RESULTS: In T2DM patients who had developed Charcot arthropathy WNT3A and WNT5A gene expression was down-regulated by 89 and 58% compared to healthy controls (p < 0.0001). TCF7L2 gene expression showed a significant reduction by 63% (p < 0.0001) and 18% (p = 0.0136) in diabetic Charcot arthropathy. In all diabetic patients BGLAP (Osteocalcin) was significantly decreased by at least 59% (p = 0.0019). CONCLUSIONS: For the first time with this study downregulation of members of the Wnt-signaling pathway has been shown in the bone of diabetic patients with and without Charcot arthropathy. This may serve as future therapeutic target for this severe disease.

Tissue-dependent differences in Bardet-Biedl syndrome gene expression.

BACKGROUND INFORMATION: Primary cilia are highly conserved multifunctional cell organelles that extend from the cell membrane. A range of genetic disorders, collectively termed ciliopathies, is attributed to primary cilia dysfunction. The archetypical ciliopathy is the Bardet-Biedl syndrome (BBS), patients of which display virtually all symptoms associated with dysfunctional cilia. The primary cilium acts as a sensory organelle transmitting intra- and extracellular signals thereby transducing various signalling pathways facilitated by the BBS proteins. Growing evidence suggests that cilia proteins also have alternative functions in ciliary independent mechanisms, which might be contributing to disease etiology. RESULTS: In an attempt to gain more insight into possible differences in organ specific roles, we examined whether relative gene expression for individual Bbs genes was constant across different tissues in mouse, in order to distinguish possible differences in organ specific roles. All tested tissues show differentially expressed Bbs transcripts with some tissues showing a more similar stoichiometric composition of transcripts than others do.  However, loss of Bbs6 or Bbs8 affects expression of other Bbs transcripts in a tissue-dependent way. CONCLUSIONS AND SIGNIFICANCE: Our data support the hypothesis that in some organs, BBS proteins not only function in a complex but might also have alternative functions in a ciliary independent context. This significantly alters our understanding of disease pathogenesis and development of possible treatment strategies.

Cardiopulmonary resuscitation and skill retention in emergency physicians.

STUDY OBJECTIVES: The American Heart Association (AHA) recently established the Resuscitation Quality Improvement (RQI) program, which requires physicians to perform quarterly cardiopulmonary resuscitation (CPR) skill checks. The aim of this study was to determine if timing of last training impacted skill performance of emergency physicians. METHODS: A convenience sample of emergency medicine (EM) physicians was asked to complete a Basic Life Support (BLS) scenario on a manikin. Participants passed the scenario if they successfully performed high-quality CPR. Participants completed a survey to assess clinical experience and timing of prior BLS training. Outcomes were comparisons of skills check pass rates for physicians recently trained in BLS (≤90 days) and those trained >90 days ago and those trained >2 years ago. RESULTS: A total of 113 individuals were included in the study: 87 attending physicians and 26 residents. Overall 92.9% correctly performed CPR with the proper assessment, compression rate, compression depth and rescue breaths. There was no difference between success rates in EM physicians who had BLS training within 90 days (91.7%) and physicians who had not had BLS within 90 days, (93.1%). (p = 1.00) There was no difference in the pass rate of those trained within 90 days (91.7%) to those trained >2 years ago (90.9%) (95CI 0.088, 0.096). CONCLUSION: There was no difference between delivery of high-quality CPR in EM physicians who had recent BLS training and those who did not.

Bardet-Biedl Syndrome proteins regulate cilia disassembly during tissue maturation.

Primary cilia are conserved organelles that mediate cellular communication crucial for organogenesis and homeostasis in numerous tissues. The retinal pigment epithelium (RPE) is a ciliated monolayer in the eye that borders the retina and is vital for visual function. Maturation of the RPE is absolutely critical for visual function and the role of the primary cilium in this process has been largely ignored to date. We show that primary cilia are transiently present during RPE development and that as the RPE matures, primary cilia retract, and gene expression of ciliary disassembly components decline. We observe that ciliary-associated BBS proteins protect against HDAC6-mediated ciliary disassembly via their recruitment of Inversin to the base of the primary cilium. Inhibition of ciliary disassembly components was able to rescue ciliary length defects in BBS deficient cells. This consequently affects ciliary regulation of Wnt signaling. Our results shed light onto the mechanisms by which cilia-mediated signaling facilitates tissue maturation.

Unscheduled Procedural Sedation: A Multidisciplinary Consensus Practice Guideline.

The American College of Emergency Physicians (ACEP) organized a multidisciplinary effort to create a clinical practice guideline specific to unscheduled, time-sensitive procedural sedation, which differs in important ways from scheduled, elective procedural sedation. The purpose of this guideline is to serve as a resource for practitioners who perform unscheduled procedural sedation regardless of location or patient age. This document outlines the underlying background and rationale, and issues relating to staffing, practice, and quality improvement.

Predictors, Prevalence, and Outcomes of Early Crystalloid Responsiveness Among Initially Hypotensive Patients With Sepsis and Septic Shock.

OBJECTIVES: The prevalence of responsiveness to initial fluid challenge among hypotensive sepsis patients is unclear. To avoid fluid overload, and unnecessary treatment, it is important to differentiate these phenotypes. We aimed to 1) determine the proportion of hypotensive sepsis patients sustaining favorable hemodynamic response after initial fluid challenge, 2) determine demographic and clinical risk factors that predicted refractory hypotension, and 3) assess the association between timeliness of fluid resuscitation and refractoriness. DESIGN: Secondary analysis of a prospective, multisite, observational, consecutive-sample cohort. SETTING: Nine tertiary and community hospitals over 1.5 years. PATIENTS: Inclusion criteria 1) suspected or confirmed infection, 2) greater than or equal to two systemic inflammatory response syndrome criteria, 3) systolic blood pressure less than 90 mm Hg, greater than 40% decrease from baseline, or mean arterial pressure less than 65 mm Hg. MEASUREMENTS AND MAIN RESULTS: Sex, age, heart failure, renal failure, immunocompromise, source of infection, initial lactate, coagulopathy, temperature, altered mentation, altered gas exchange, and acute kidney injury were used to generate a risk score. The primary outcome was sustained normotension after fluid challenge without vasopressor titration. Among 3,686 patients, 2,350 (64%) were fluid responsive. Six candidate risk factors significantly predicted refractoriness in multivariable analysis: heart failure (odds ratio, 1.43; CI, 1.20-1.72), hypothermia (odds ratio, 1.37; 1.10-1.69), altered gas exchange (odds ratio, 1.33; 1.12-1.57), initial lactate greater than or equal to 4.0 mmol/L (odds ratio, 1.28; 1.08-1.52), immunocompromise (odds ratio, 1.23; 1.03-1.47), and coagulopathy (odds ratio, 1.23; 1.03-1.48). High-risk patients (≥ three risk factors) had 70% higher (CI, 48-96%) refractory risk (19% higher absolute risk; CI, 14-25%) versus low-risk (zero risk factors) patients. Initiating fluids in greater than 2 hours also predicted refractoriness (odds ratio, 1.96; CI, 1.49-2.58). Mortality was 15% higher (CI, 10-18%) for refractory patients. CONCLUSIONS: Two in three hypotensive sepsis patients were responsive to initial fluid resuscitation. Heart failure, hypothermia, immunocompromise, hyperlactemia, and coagulopathy were associated with the refractory phenotype. Fluid resuscitation initiated after the initial 2 hours more strongly predicted refractoriness than any patient factor tested.

Perceptions and attitudes regarding antibiotic resistance in Germany: a cross-sectoral survey amongst physicians, veterinarians, farmers and the general public.

Background: Drivers of antibiotic (AB) resistance (ABR) include outpatient treatment, hospital care and animal husbandry. During the first phase of the One Health project RAI (Responsible Antibiotic Use via Information and Communication) surveys were conducted in these sectors. Objectives: To compare perceptions and attitudes towards ABR among general practitioners (GPs), hospital physicians, veterinarians, pig farmers and the general public. Methods: Cross-sectional questions on AB use and ABR were integrated in group-specific surveys of GPs, hospital physicians, veterinarians, pig farmers and the German general population. Results: A total of 1789 participants (340 GPs, 170 hospital physicians, 215 pig farmers, 60 veterinarians and 1004 members of the public) responded. Each group tended to identify drivers of ABR as being from outside its own area of activity. Guidelines were shown to be an important information source for AB therapy for all prescriber groups, but the frequency of routine use differed (39% of GPs, 65% of hospital physicians and 53% of veterinarians). Regarding further information sources, hospital physicians preferred smartphone apps and e-learning, GPs preferred non-sponsored training and veterinarians preferred multidisciplinary networks and e-learning. Farmers were predominantly satisfied with existing solutions. Farmers had three times better basic knowledge of ABR and knew twice as many people with MDR organism problems than the general public. They also received information on ABR more often from their veterinarians than patients did from their doctors. Conclusions: This study reveals considerable differences in perceptions and attitudes to ABR among the groups investigated. The results can help to tailor future interventions. Furthermore, they promote mutual understanding and thus support the One Health approach.

Synthesis and Optical Properties of Phenanthroline-Derived Schiff Base-Like Dinuclear RuII -NiII Complexes.

Two phenanthroline-derived Schiff base-like ligands with a covalently linked ruthenium(II) phosphorescent unit were synthesised and converted into bimetallic RuII -NiII complexes. The optical properties were studied to examine a possible photoluminescence quenching through a nonradiative energy-transfer upon a coordination-induced spin-state switch (CISSS) at the nickel(II) centre. Therefore, the metalloligands and the nickel(II) complexes were studied using UV/Vis absorbance, steady-state, and time-resolved emission spectroscopy in solutions of MeCN and pyridine. It is demonstrated that the nature of the bridging ligand between the ruthenium(II) donor and the nickel(II) acceptor strongly influences the photophysical behaviour upon CISSS. For the complex with a phenazine bridge, photoluminescence quenching is observed in the presence of a paramagnetic nickel(II) centre.

Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care.

We provide recommendations for stocking of antidotes used in emergency departments (EDs). An expert panel representing diverse perspectives (clinical pharmacology, medical toxicology, critical care medicine, hematology/oncology, hospital pharmacy, emergency medicine, emergency medical services, pediatric emergency medicine, pediatric critical care medicine, poison centers, hospital administration, and public health) was formed to create recommendations for antidote stocking. Using a standardized summary of the medical literature, the primary reviewer for each antidote proposed guidelines for antidote stocking to the full panel. The panel used a formal iterative process to reach their recommendation for both the quantity of antidote that should be stocked and the acceptable timeframe for its delivery. The panel recommended consideration of 45 antidotes; 44 were recommended for stocking, of which 23 should be immediately available. In most hospitals, this timeframe requires that the antidote be stocked in a location that allows immediate availability. Another 14 antidotes were recommended for availability within 1 hour of the decision to administer, allowing the antidote to be stocked in the hospital pharmacy if the hospital has a mechanism for prompt delivery of antidotes. The panel recommended that each hospital perform a formal antidote hazard vulnerability assessment to determine its specific need for antidote stocking. Antidote administration is an important part of emergency care. These expert recommendations provide a tool for hospitals that offer emergency care to provide appropriate care of poisoned patients.

Antibiotic prescribing behavior among general practitioners - a questionnaire-based study in Germany.

BACKGROUND: This study investigates the barriers and facilitators of the use of antibiotics in acute respiratory tract infections by general practitioners (GPs) in Germany. METHODS: A multidisciplinary team designed and pre-tested a written questionnaire addressing the topics awareness of antimicrobial resistance (7 items), use of antibiotics (9 items), guidelines/sources of information (9 items) and sociodemographic factors (7 items), using a five-point-Likert-scale ("never" to "very often"). The questionnaire was mailed by postally to 987 GPs with registered practices in eastern Germany in May 2015. RESULTS: 34% (340/987) of the GPs responded to this survey. Most of the participants assumed a multifactorial origin for the rise of multidrug resistant organisms. In addition, 70.2% (239/340) believed that their own prescribing behavior influenced the drug-resistance situation in their area. GPs with longer work experience (> 25 years) assumed less individual influence on drug resistance than their colleagues with less than 7 years experience as practicing physicians (Odds Ratio [OR] 0.32, 95% Confidence Interval [CI] 0.17-0.62; P < 0.001). 99.1% (337/340) of participants were familiar with the "delayed prescription" strategy to reduce antibiotic prescriptions. However, only 29.4% (74/340) answered that they apply it "often" or "very often". GPs working in rural areas were less likely than those working in urban areas to apply delayed prescription. CONCLUSION: The knowledge on factors causing antimicrobial resistance in bacteria is good among GPs in eastern Germany. However measures to improve rational prescription are not widely implemented yet. Further efforts have to be made in order to improve rational prescription of antibiotic among GPs. Nevertheless, there is a strong awareness of antimicrobial resistance among the participating GPs.

Delayed Second Dose Antibiotics for Patients Admitted From the Emergency Department With Sepsis: Prevalence, Risk Factors, and Outcomes.

OBJECTIVE: 1) Determine frequency and magnitude of delays in second antibiotic administration among patients admitted with sepsis; 2) Identify risk factors for these delays; and 3) Exploratory: determine association between delays and patient-centered outcomes (mortality and mechanical ventilation after second dose). DESIGN: Retrospective, consecutive sample sepsis cohort over 10 months. SETTING: Single, tertiary, academic medical center. PATIENTS: All patients admitted from the emergency department with sepsis or septic shock (defined: infection, ≥ 2 systemic inflammatory response syndrome criteria, hypoperfusion/organ dysfunction) identified by a prospective quality initiative. EXCLUSIONS: less than 18 years old, not receiving initial antibiotics in the emergency department, death before antibiotic redosing, and patient refusing antibiotics. INTERVENTIONS: We determined first-to-second antibiotic time and delay frequency. We considered delay major for first-to-second dose time greater than or equal to 25% of the recommended interval. Factors of interest were demographics, recommended interval length, comorbidities, clinical presentation, location at second dose, initial resuscitative care, and antimicrobial activity mechanism. MEASUREMENTS AND MAIN RESULTS: Of 828 sepsis cases, 272 (33%) had delay greater than or equal to 25%. Delay frequency increased dose dependently with shorter recommended interval: 11 (4%) delays for 24-hour intervals (median time, 18.52 hr); 31 (26%) for 12-hour intervals (median, 10.58 hr); 117 (47%) for 8-hour intervals (median, 9.60 hr); and 113 (72%) for 6-hour intervals (median, 9.55 hr). In multivariable regression, interval length significantly predicted major delay (12 hr: odds ratio, 6.98; CI, 2.33-20.89; 8 hr: odds ratio, 23.70; CI, 8.13-69.11; 6 hr: odds ratio, 71.95; CI, 25.13-206.0). Additional independent risk factors were inpatient boarding in the emergency department (odds ratio, 2.67; CI, 1.74-4.09), initial 3-hour sepsis bundle compliance (odds ratio, 1.57; CI, 1.07-2.30), and older age (odds ratio, 1.16 per 10 yr, CI, 1.01-1.34). In the exploratory multivariable analysis, major delay was associated with increased hospital mortality (odds ratio, 1.61; CI, 1.01-2.57) and mechanical ventilation (odds ratio, 2.44; CI, 1.27-4.69). CONCLUSIONS: Major second dose delays were common, especially for patients given shorter half-life pharmacotherapies and who boarded in the emergency department. They were paradoxically more frequent for patients receiving compliant initial care. We observed association between major second dose delay and increased mortality, length of stay, and mechanical ventilation requirement.

[Antibiotic intake and resistance development - Knowledge, experience and behavior among the German general population]. / Antibiotikaeinnahme und Resistenzentwicklung - Wissen, Erfahrungen und Einnahmeverhalten innerhalb der deutschen Allgemeinbevölkerung.

BACKGROUND: The network project RAI (Rational Use of Antibiotics via Information and Communication) is aimed at developing tailored information and communication tools on the subject of antibiotic (AB) resistance for various stakeholder groups. During the preparation phase, a survey was performed addressing the German general population. OBJECTIVES: To gain insights into the knowledge, attitudes, and behavior of nonprescribers concerning AB and multidrug-resistant organisms (MDRO). METHODS: Using computer-assisted, telephone-based interviews a random sample of 1,004 persons aged 14 years and older was surveyed. Descriptive reporting of data and multivariate analysis were performed, including sociodemographic variables. RESULTS: Only 24 % of participants knew that bacteria (but not viruses or humans) could develop AB resistance. However, this knowledge did not influence the outcome of other questions. Regardless of knowledge, 71 % thought that the subject was important, but 58 % did not believe in the influence of their own behavior on MDRO development. When visiting a physician, patients were given an antibiotic three times as often as information on AB resistance. 17 % did not take the AB as prescribed and 20 % of all participants stated that they personally knew at least one person with MDRO problems. This personal involvement had a significant effect on the rating of self-influence, on the importance of the subject, on the interaction between patient and physician (more information, less AB), and on AB intake compliance (less frequent). DISCUSSION: We found considerable knowledge gaps, but this had no impact on the assessment of the subject. A starting point for an intervention could be patient-physician communication. This seems more effective and safer than a public campaign.

Status of estrogen receptor 1 (ESR1) gene in mastopathy predicts subsequent development of breast cancer.

Mastopathy is a common disease of the breast likely associated with elevated estrogen levels and a putative risk factor for breast cancer. The role of estrogen receptor alpha (ESR1) in mastopathy has not been investigated previously. Here, we investigated the prevalence of ESR1 gene amplification in mastopathy and its prediction for breast cancer. Paraffin-embedded tissues from 58 women with invasive breast cancer were analyzed. For all women, tissues with mastopathy taken at least 1.5 years before first diagnosis of breast cancer were available. Tissue from 46 women with mastopathy without a diagnosis of breast carcinoma in the observed time frame (12-18 years) was used as control. Fluorescence in situ hybridization analysis revealed that ESR1 was amplified in nine of 58 (15.5 %) breast cancers. All ESR1-amplified breast cancers were strongly positive for estrogen receptor with ER immunohistochemistry. Interestingly, in women with ESR1 amplification in breast cancer, the amplification was detectable in mastopathic tissues prior to the first diagnosis of breast cancer but was absent in tissues from women with mastopathy who did not develop breast cancer. Our study suggests that ESR1 gene amplification is an early event in breast pathology and might be a helpful predictive marker to identify patients at high risk of developing breast cancer.

Entropy: a conceptual approach to measuring situation-level workload within emergency care and its relationship to emergency department crowding.

BACKGROUND: Emergency department (ED) crowding correlates with patient safety. Difficulties quantifying crowding and providing solutions were highlighted in the recent Institute of Medicine (IOM) report calling for the application of advanced industrial engineering (IE) research techniques to evaluate ED crowding. ED personnel workload is a related concept, with potential reciprocal effects between the two. Collaboration between emergency medicine and IE is needed to address crowding and ED personnel workload. OBJECTIVE: We review ED crowding and workload literature, relationships between workload and ED crowding, and the potential application of information theory as implemented in IE frameworks entitled "entropy" in evaluating both topics. DISCUSSION: IE techniques have applications for emergency medicine and have been successful in helping improve ED operations. Lean and Six Sigma applications are some of these techniques. Existing ED workload measures don't account for all aspects of work in the ED (acuity, efficiency, tasks, etc.) Crowding scales, such as NEDOCS (National ED Overcrowding Study) and EDWIN (ED Work Index), fail to predict ED crowding. A new measurement "entropy" may provide a more comprehensive evaluation of ED workload and may predict work overload seen with crowding. Entropy measures task-based work and the information flow involved. By assigning an entropy value to patient type-specific tasks, we might predict when the ED is overwhelmed, and crowded. CONCLUSIONS: IE techniques provide solutions to the ED crowding problem and improve ED workload. We propose a technique novel to medicine: "Entropy," derived from information theory, which may provide insight into ED personnel workload, its potential for measuring ED crowding, and possibly, in predicting an overwhelming situation.

A Comprehensive Multi-Functional Approach for Measuring Parkinson's Disease Severity.

OBJECTIVES: This research study aims to advance the staging of Parkinson's disease (PD) by incorporating machine learning to assess and include a broader multi-functional spectrum of neurocognitive symptoms in the staging schemes beyond motor-centric assessments. Specifically, we provide a novel framework to modernize and personalize PD staging more objectively by proposing a hybrid feature scoring approach. METHODS: We recruited thirty-seven individuals diagnosed with PD, each of whom completed a series of tablet-based neurocognitive tests assessing motor, memory, speech, executive functions, and tasks ranging in complexity from single to multi-functional. Then, the collected data was used to develop a hybrid feature scoring system to calculate a weighted vector for each function. We evaluated current PD staging schemes and developed a new approach based on the features selected and extracted using Random Forest and Principal Component Analysis. RESULTS: Our findings indicate a substantial bias in current PD staging systems toward fine-motor skills, i.e., other neurological functions (memory, speech, executive function, etc.) do not map into current PD stages as well as fine-motor skills do. The results demonstrate that a more accurate and personalized assessment of PD severity could be achieved by including a more exhaustive range of neurocognitive functions in the staging systems either by involving multiple functions in a unified staging score or by designing a function-specific staging system. CONCLUSIONS: The proposed hybrid feature score approach provides a comprehensive understanding of PD by highlighting the need for a staging system that covers various neurocognitive functions. This approach could potentially lead to more effective, objective, and personalized treatment strategies. Further, this proposed methodology could be adapted to other neurodegenerative conditions such as Alzheimer's disease or ALS.