Utilization of Romosozumab in Primary Care.

Objective: The objective of the study is to highlight the role and safety of romosozumab in patients at high risk of fractures in primary care. Data Sources: A systemic database search of PubMed/MEDLINE, ClinicalTrials.gov, and Cochrane Library was conducted for articles with keywords romosozumab, osteoporosis, and safety between inception and July 2022. Study Selection and Data Extraction: Phase 3 trials in patients with osteoporosis were included. Data results from these trials were utilized for assessment. Data Synthesis: Romosozumab decreased vertebral fracture incidence by 73% at 12 months (P < 0.001) in osteoporotic postmenopausal women compared with placebo. In an active-controlled fracture study in postmenopausal women with osteoporosis at high risk of fracture, a 48% lower risk of new vertebral fracture was observed at 24 months in the romosozumab-alendronate group (P < 0.001) compared with alendronate group. In a study comparing romosozumab with teriparatide in postmenopausal women with osteoporosis at high risk of fracture, 2.6% of the mean percentage change from baseline in the total hip (TH) areal bone mineral density (BMD) was observed with romosozumab, while teriparatide led -0.6% of change (P < 0.0001). Romosozumab significantly increased the mean percentage change from baseline in the lumbar spine (LS) and total hip (TH) BMD than placebo in men with osteoporosis (LS, 12.1% vs 1.2%; TH, 2.5% vs -0.5%; P < 0.001). Serious cardiovascular events were observed in the romosozumab compared with alendronate (2.5% vs 1.9%; odds ratio [OR] = 1.31; 95% confidence interval [CI] = 0.85-2.00) in postmenopausal women, and placebo (4.9% vs 2.5%) in men with osteoporosis. Relevance to Patient Care and Clinical Practice: This review discusses the role of romosozumab in patients with high fracture risk and its safety in primary care. Conclusions: Primary care physicians should consider romosozumab for patients at high fracture risk who are intolerant or have not responded to other pharmacological treatment. Further studies are needed to clarify the safety of cardiovascular events.

COVID-19 biomarkers and their overlap with comorbidities in a disease biomarker data model.

In response to the COVID-19 outbreak, scientists and medical researchers are capturing a wide range of host responses, symptoms and lingering postrecovery problems within the human population. These variable clinical manifestations suggest differences in influential factors, such as innate and adaptive host immunity, existing or underlying health conditions, comorbidities, genetics and other factors-compounding the complexity of COVID-19 pathobiology and potential biomarkers associated with the disease, as they become available. The heterogeneous data pose challenges for efficient extrapolation of information into clinical applications. We have curated 145 COVID-19 biomarkers by developing a novel cross-cutting disease biomarker data model that allows integration and evaluation of biomarkers in patients with comorbidities. Most biomarkers are related to the immune (SAA, TNF-∝ and IP-10) or coagulation (D-dimer, antithrombin and VWF) cascades, suggesting complex vascular pathobiology of the disease. Furthermore, we observe commonality with established cancer biomarkers (ACE2, IL-6, IL-4 and IL-2) as well as biomarkers for metabolic syndrome and diabetes (CRP, NLR and LDL). We explore these trends as we put forth a COVID-19 biomarker resource (https://data.oncomx.org/covid19) that will help researchers and diagnosticians alike.

Outcomes Associated With Rural Emergency Department Provider-to-Provider Telehealth for Sepsis Care: A Multicenter Cohort Study.

STUDY OBJECTIVE: To test the hypothesis that provider-to-provider tele-emergency department care is associated with more 28-day hospital-free days and improved Surviving Sepsis Campaign (SSC) guideline adherence in rural emergency departments (EDs). METHODS: Multicenter (n=23), propensity-matched, cohort study using medical records of patients with sepsis from rural hospitals in an established, on-demand, rural video tele-ED network in the upper Midwest between August 2016 and June 2019. The primary outcome was 28-day hospital-free days, with secondary outcomes of 28-day inhospital mortality and SSC guideline adherence. RESULTS: A total of 1,191 patients were included in the analysis, with tele-ED used for 326 (27%). Tele-ED cases were more likely to be transferred to another hospital (88% versus 8%, difference 79%, 95% confidence interval [CI] 75% to 83%). After matching and regression adjustment, tele-ED cases did not have more 28-day hospital-free days (difference 0.07 days more for tele-ED, 95% CI -0.04 to 0.17) or 28-day inhospital mortality (adjusted odds ratio [aOR] 0.51, 95% CI 0.16 to 1.60). Adherence with both the SSC 3-hour bundle (aOR 0.59, 95% CI 0.28 to 1.22) and complete bundle (aOR 0.45, 95% CI 0.02 to 11.60) were similar. An a priori-defined subgroup of patients treated by advanced practice providers suggested that the mortality was lower in the cohort with tele-ED use (aOR 0.11, 95% CI 0.02 to 0.73) despite no significant difference in complete SSC bundle adherence (aOR 2.88, 95% CI 0.52 to 15.86). CONCLUSION: Rural emergency department patients treated with provider-to-provider tele-ED care in a mature network appear to have similar clinical outcomes to those treated without.

How medical learners and educators decide what counts as mistreatment: A qualitative study.

INTRODUCTION: The mistreatment or abuse (maltreatment) of medical learners by their peers and supervisors has been documented globally for decades, and there is significant research about the prevalence, sequelae and strategies for intervention. However, there is evidence that learners experience maltreatment as being less clear cut than do researchers, educators and administrators. This definitional ambiguity creates problems for understanding and addressing this issue. The objective of this study was to understand how medical learners and educators make sense of less-than-ideal interactions in the clinical learning environment, and to describe which factors influenced their perception that the encounter constituted maltreatment. METHODS: Using constructivist grounded theory, we interviewed 16 medical students, 15 residents or fellows, and 18 educators associated with a single medical school (n = 49). Data collection began with the most junior learners, iterating with analysis as we progressed through the project. Constant comparative analysis was used to gather and compare stories of 'definitely', 'maybe' and 'definitely not' maltreatment across a variety of axes including experience level, clinical setting and type of interaction. RESULTS: Our data show that learners and educators have difficulty classifying their experiences of negative interpersonal interaction, except in the most severe and concrete cases. While there was tremendous variation in the way they categorised similar experiences, there was consistency in the elements drawn upon to make sense of those experiences. Participants interpreted negative interpersonal interactions on an individual basis by considering factors related to the interaction, initiator and recipient. CONCLUSIONS: Only the most negative behaviour is consistently understood as maltreatment; a complex process of individual sense-making is required to determine the acceptability of each interaction. The differences between how individuals judge these interactions highlight an opportunity for administrative, research and faculty development intervention.

Modeling and integration of N-glycan biomarkers in a comprehensive biomarker data model.

Molecular biomarkers measure discrete components of biological processes that can contribute to disorders when impaired. Great interest exists in discovering early cancer biomarkers to improve outcomes. Biomarkers represented in a standardized data model, integrated with multi-omics data, may improve the understanding and use of novel biomarkers such as glycans and glycoconjugates. Among altered components in tumorigenesis, N-glycans exhibit substantial biomarker potential, when analyzed with their protein carriers. However, such data are distributed across publications and databases of diverse formats, which hamper their use in research and clinical application. Mass spectrometry measures of 50 N-glycans on 7 serum proteins in liver disease were integrated (as a panel) into a cancer biomarker data model, providing a unique identifier, standard nomenclature, links to glycan resources, and accession and ontology annotations to standard protein, gene, disease, and biomarker information. Data provenance was documented with a standardized United States Food and Drug Administration-supported BioCompute Object. Using the biomarker data model allows the capture of granular information, such as glycans with different levels of abundance in cirrhosis, hepatocellular carcinoma, and transplant groups. Such representation in a standardized data model harmonizes glycomics data in a unified framework, making glycan-protein biomarker data exploration more available to investigators and to other data resources. The biomarker data model we describe can be used by researchers to describe their novel glycan and glycoconjugate biomarkers; it can integrate N-glycan biomarker data with multi-source biomedical data and can foster discovery and insight within a unified data framework for glycan biomarker representation, thereby making the data FAIR (Findable, Accessible, Interoperable, Reusable) (https://www.go-fair.org/fair-principles/).

Intrathecal amyloid-beta oligomer administration increases tau phosphorylation in the medial temporal lobe in the African green monkey: A nonhuman primate model of Alzheimer's disease.

AIMS: An obstacle to developing new treatment strategies for Alzheimer's disease (AD) has been the inadequate translation of findings in current AD transgenic rodent models to the prediction of clinical outcomes. By contrast, nonhuman primates (NHPs) share a close neurobiology with humans in virtually all aspects relevant to developing a translational AD model. The present investigation used African green monkeys (AGMs) to refine an inducible NHP model of AD based on the administration of amyloid-beta oligomers (AßOs), a key upstream initiator of AD pathology. METHODS: AßOs or vehicle were repeatedly delivered over 4 weeks to age-matched young adult AGMs by intracerebroventricular (ICV) or intrathecal (IT) injections. Induction of AD-like pathology was assessed in subregions of the medial temporal lobe (MTL) by quantitative immunohistochemistry (IHC) using the AT8 antibody to detect hyperphosphorylated tau. Hippocampal volume was measured by magnetic resonance imaging (MRI) scans prior to, and after, intrathecal injections. RESULTS: IT administration of AßOs in young adult AGMs revealed an elevation of tau phosphorylation in the MTL cortical memory circuit compared with controls. The largest increases were detected in the entorhinal cortex that persisted for at least 12 weeks after dosing. MRI scans showed a reduction in hippocampal volume following AßO injections. CONCLUSIONS: Repeated IT delivery of AßOs in young adult AGMs led to an accelerated AD-like neuropathology in MTL, similar to human AD, supporting the value of this translational model to de-risk the clinical trial of diagnostic and therapeutic strategies.

Thioether-Based Polymeric Micelles with Fine-Tuned Oxidation Sensitivities for Chemotherapeutic Drug Delivery.

Oxidation-sensitive drug delivery systems (DDSs) have attracted attention due to the potential to improve efficacy and safety of chemotherapeutics. These systems are designed to release the payload in response to oxidative stress conditions, which are associated with many types of cancer. Despite extensive research on the development of oxidation-sensitive DDS, the lack of selectivity toward cancer cells over healthy cells remains a challenge. Here, we report the design and characterization of polymeric micelles containing thioether groups with varying oxidation sensitivities within the micellar core, which become hydrophilic upon thioether oxidation, leading to destabilization of the micellar structure. We first used the thioether model compounds, 3-methylthiopropylamide (TPAM), thiomorpholine amide (TMAM), and 4-(methylthio)benzylamide (TPhAM) to investigate the effect of the chemical structures of the thioethers on the oxidation by hydrogen peroxide (H2O2). TPAM shows the fastest oxidation, followed by TMAM and TPhAM, showing that the oxidation reaction of thioethers can be modulated by changing the substituent groups bound to the sulfur atom. We next prepared micelles containing these different thioether groups within the core (TP, TM, and TPh micelles). The micelles containing the thioether groups with a higher oxidation sensitivity were destabilized by H2O2 at a lower concentration. Micelle destabilization was also tested in human liver cancer (HepG2) cells and human umbilical vein endothelial cells (HUVECs). The TP micelles having the highest oxidation sensitivity were destabilized in both HepG2 cells and HUVECs, while the TPh micelles, which showed the lowest reactivity toward H2O2, were stable in these cell lines. The TM micelles possessing a moderate oxidation sensitivity were destabilized in HepG2 cells but were stable in HUVECs. Furthermore, the micelles were loaded with doxorubicin (Dox) to evaluate their potential in drug delivery applications. Among the micelles, the TM micelles loaded with Dox showed the enhanced relative toxicity in HepG2 cells over HUVECs. Therefore, our approach to fine-tune the oxidation sensitivity of the micelles has potential for improving therapeutic efficacy and safety of drugs in cancer treatment.

Enabling precision medicine via standard communication of HTS provenance, analysis, and results.

A personalized approach based on a patient's or pathogen's unique genomic sequence is the foundation of precision medicine. Genomic findings must be robust and reproducible, and experimental data capture should adhere to findable, accessible, interoperable, and reusable (FAIR) guiding principles. Moreover, effective precision medicine requires standardized reporting that extends beyond wet-lab procedures to computational methods. The BioCompute framework (https://w3id.org/biocompute/1.3.0) enables standardized reporting of genomic sequence data provenance, including provenance domain, usability domain, execution domain, verification kit, and error domain. This framework facilitates communication and promotes interoperability. Bioinformatics computation instances that employ the BioCompute framework are easily relayed, repeated if needed, and compared by scientists, regulators, test developers, and clinicians. Easing the burden of performing the aforementioned tasks greatly extends the range of practical application. Large clinical trials, precision medicine, and regulatory submissions require a set of agreed upon standards that ensures efficient communication and documentation of genomic analyses. The BioCompute paradigm and the resulting BioCompute Objects (BCOs) offer that standard and are freely accessible as a GitHub organization (https://github.com/biocompute-objects) following the "Open-Stand.org principles for collaborative open standards development." With high-throughput sequencing (HTS) studies communicated using a BCO, regulatory agencies (e.g., Food and Drug Administration [FDA]), diagnostic test developers, researchers, and clinicians can expand collaboration to drive innovation in precision medicine, potentially decreasing the time and cost associated with next-generation sequencing workflow exchange, reporting, and regulatory reviews.

Why do few medical students report their experiences of mistreatment to administration?

INTRODUCTION: Over 50% of medical students worldwide report experiencing mistreatment and abuse during their clinical education, yet only a small proportion of students report these concerns to administration. It is unknown how medical students make sense of their experiences of mistreatment and come to decide whether to formally report these experiences. Improved understanding of this phenomenon will facilitate changes at the administrative and institutional levels to better support students. METHODS: Using Constructivist Grounded Theory, we interviewed 19 current and former medical students from one institution about their experiences with mistreatment and reporting. Data were analysed in an iterative fashion, using focused and theoretical forms of coding. RESULTS: The decision of whether to report mistreatment is only one phase in the process that students report experiencing when encountering mistreatment. This process can be understood as a journey consisting of five phases: Situating, Experiencing and Appraising, Reacting, Deciding and Moving Forward. Students move through these phases as they come to understand their position as medical learners and their ability to trust and be safe within this institution. Each experience of mistreatment causes students to react to what has happened to them, decide if they will share their experiences and reach out for support. They choose if they are going to report the mistreatment, at what cost and for what outcomes. Students continue through their training while incorporating their experiences into their understanding of the culture in which they are learning and continually resituating themselves within the institution. DISCUSSION: Student perceptions of trust or mistrust in their educational institution are highly influential when it comes to reporting mistreatment. Interventions designed to support students and decrease exposure to mistreatment may be best focused on increasing organisational trust between students and the medical school.

Real-Time Learning Through Telemedicine Enhances Professional Training in Rural Emergency Departments.

Background: The low volume and the intermittent nature of serious emergencies presenting to rural emergency departments (EDs) make it difficult to plan and deliver pertinent professional training. Telemedicine provides multiple avenues for training rural ED clinicians. This study examines how telemedicine contributes to professional training in rural EDs through both structured and unstructured approaches. Methods: This qualitative study examined training experiences in 18 hospitals located in 6 Midwest states in the United States, which participated in a single hub-and-spoke telemedicine network. Twenty-eight interviews were conducted with 7 physicians, 10 advanced practice providers, and 11 nurses. Standard, inductive qualitative analysis was used to identify key themes related to experiences with telemedicine-based training and its impact on rural ED practice. Results: For structured formal training, rural ED clinicians used asynchronous sessions more often than live sessions. It was reported that the formal training program may not have been fully utilized due to time and workload constraints. Rural clinicians strongly valued unstructured real-time training during telemedicine consultations. It was perceived consistently across professional groups that real-time training occurred frequently and its spontaneous nature was beneficial. Hub providers offering suggestions respectfully and explaining the rationale behind recommendations facilitated real-time learning. Rural providers and nurses perceived several effects of real-time training, including keeping rural practice up to date, instilling confidence, and improving performance. Discussion: Our research shows that telemedicine provided rural ED providers and nurses both formal training and real-time training opportunities. Real-time training occurred frequently, complemented formal training, and was perceived to have many advantages.

Telemedicine Is Associated with Faster Diagnostic Imaging in Stroke Patients: A Cohort Study.

BACKGROUND: Meeting time goals for patients with time-sensitive conditions can be challenging in rural emergency departments (EDs), and adopting policies is critical. ED-based telemedicine has been proposed to improve quality and timeliness of care in rural EDs. INTRODUCTION: The objective of this study was to test the hypothesis that diagnostic testing in telemedicine-supplemented ED care for patients with myocardial infarction (MI) and stroke would be faster than nontelemedicine care in rural EDs. MATERIALS AND METHODS: This observational cohort study included all ED patients with MI or stroke in 19 rural critical access hospitals served by a single real-time contract-based telemedicine provider in the upper Midwest (2007-2015). The primary outcome for the MI cohort was time-to-electrocardiogram (EKG) and for the stroke cohort was time-to-head computed tomography (CT) interpretation. To measure the relationship between telemedicine and timeliness parameters, generalized estimating equations models were used, clustering on presenting hospital. RESULTS: Of participating ED visits, 756 were included in the MI cohort (29% used telemedicine) and 140 were included in the stroke cohort (30% used telemedicine). Time-to-EKG did not differ when telemedicine was used (1% faster, 95% confidence interval [CI] -4% to 7%), or after telemedicine was implemented (4% faster, 95% CI -3% to 10%). Head CT interpretation was faster for telemedicine cases (15% faster, 95% CI 4-26%). No differences were observed in time to reperfusion therapy. CONCLUSIONS: Telemedicine implementation was associated with more timely head CT interpretation for rural patients with stroke, but no difference in early MI care. Future work will focus on the specific manner in which telemedicine changes ED care processes and ongoing professional education.

Emergency Department Telemedicine Shortens Rural Time-To-Provider and Emergency Department Transfer Times.

BACKGROUND: Emergency department (ED)-based telemedicine has been implemented in many rural hospitals to provide specialty care and expertise to patients with critical time-sensitive conditions. INTRODUCTION: The purpose of this study was to measure the impact of ED-based telemedicine on timeliness of care in participating rural hospitals. MATERIALS AND METHODS: Matched cohort study of patients seen in 1 of 14 rural hospitals in a large Midwestern telemedicine network. Telemedicine cases were matched 2:1 with controls based on age, diagnosis, and hospital. The primary outcome was door-to-provider time, and secondary outcomes included ED length-of-stay (LOS) and time-to-transfer in those transferred to other hospitals. RESULTS: Of 127,928 qualifying ED encounters, 2,857 consulted telemedicine and were matched with nontelemedicine controls. Door-to-provider time was shorter in telemedicine patients by 6.0 min (95% confidence interval [CI] 4.3-7.8 min). The first provider seeing the patient was a telemedicine provider in 41.7% of telemedicine encounters, and in these cases, telemedicine was 14.7 min earlier than local providers. ED LOS was 22.1 min shorter (95% CI 3.1-41.2) among transferred patients, but total ED LOS was longer (40.2 min, 95% CI 30.8-49.6 min) for all telemedicine patients. CONCLUSIONS: Telemedicine decreases ED door-to-provider time, most commonly because the telemedicine provider was the first provider seeing a patient. Among transferred patients, ED LOS at the first hospital was shorter in patients who had telemedicine consulted. Future work will focus on the clinical impact of more timely rural ED care.

Telemedicine Use Decreases Rural Emergency Department Length of Stay for Transferred North Dakota Trauma Patients.

BACKGROUND: Telemedicine has been proposed as one strategy to improve local trauma care and decrease disparities between rural and urban trauma outcomes. OBJECTIVES: This study was conducted to describe the effect of telemedicine on management and clinical outcomes for trauma patients in North Dakota. METHODS: Cohort study of adult (age ≥18 years) trauma patients treated in North Dakota Critical Access Hospital (CAH) Emergency Departments (EDs) from 2008 to 2014. Records were linked to a telemedicine network's call records, indicating whether telemedicine was available and/or used at the institution at the time of the care. Multivariable generalized estimating equations were developed to identify associations between telemedicine consultation and availability and outcomes such as transfer, timeliness of care, trauma imaging, and mortality. RESULTS: Of the 7,500 North Dakota trauma patients seen in CAH, telemedicine was consulted for 11% of patients in telemedicine-capable EDs and 4% of total trauma patients. Telemedicine utilization was independently associated with decreased initial ED length of stay (LOS) (30 min, 95% confidence interval [CI] 14-45 min) for transferred patients. Telemedicine availability was associated with an increase in the probability of interhospital transfer (adjusted odds ratio [aOR] 1.2, 95% CI 1.1-1.4). Telemedicine availability was associated with increased total ED LOS (15 min, 95% CI 10-21 min), and computed tomography scans (aOR 1.6, 95% CI 1.3-1.9). CONCLUSIONS: ED-based telemedicine consultation is requested for the most severely injured rural trauma patients. Telemedicine consultation was associated with more rapid interhospital transfer, and telemedicine availability is associated with increased radiography use and transfer. Future work should evaluate how telemedicine could target patients likely to benefit from telemedicine consultation.

Severe Ankyrin-R deficiency results in impaired surface retention and lysosomal degradation of RhAG in human erythroblasts.

Ankyrin-R provides a key link between band 3 and the spectrin cytoskeleton that helps to maintain the highly specialized erythrocyte biconcave shape. Ankyrin deficiency results in fragile spherocytic erythrocytes with reduced band 3 and protein 4.2 expression. We use in vitro differentiation of erythroblasts transduced with shRNAs targeting ANK1 to generate erythroblasts and reticulocytes with a novel ankyrin-R 'near null' human phenotype with less than 5% of normal ankyrin expression. Using this model, we demonstrate that absence of ankyrin negatively impacts the reticulocyte expression of a variety of proteins, including band 3, glycophorin A, spectrin, adducin and, more strikingly, protein 4.2, CD44, CD47 and Rh/RhAG. Loss of band 3, which fails to form tetrameric complexes in the absence of ankyrin, alongside GPA, occurs due to reduced retention within the reticulocyte membrane during erythroblast enucleation. However, loss of RhAG is temporally and mechanistically distinct, occurring predominantly as a result of instability at the plasma membrane and lysosomal degradation prior to enucleation. Loss of Rh/RhAG was identified as common to erythrocytes with naturally occurring ankyrin deficiency and demonstrated to occur prior to enucleation in cultures of erythroblasts from a hereditary spherocytosis patient with severe ankyrin deficiency but not in those exhibiting milder reductions in expression. The identification of prominently reduced surface expression of Rh/RhAG in combination with direct evaluation of ankyrin expression using flow cytometry provides an efficient and rapid approach for the categorization of hereditary spherocytosis arising from ankyrin deficiency.

The cytoskeletal binding domain of band 3 is required for multiprotein complex formation and retention during erythropoiesis.

Band 3 is the most abundant protein in the erythrocyte membrane and forms the core of a major multiprotein complex. The absence of band 3 in human erythrocytes has only been reported once, in the homozygous band 3 Coimbra patient. We used in vitro culture of erythroblasts derived from this patient, and separately short hairpin RNA-mediated depletion of band 3, to investigate the development of a band 3-deficient erythrocyte membrane and to specifically assess the stability and retention of band 3 dependent proteins in the absence of this core protein during terminal erythroid differentiation. Further, using lentiviral transduction of N-terminally green fluorescent protein-tagged band 3, we demonstrated the ability to restore expression of band 3 to normal levels and to rescue secondary deficiencies of key proteins including glycophorin A, protein 4.2, CD47 and Rh proteins arising from the absence of band 3 in this patient. By transducing band 3-deficient erythroblasts from this patient with band 3 mutants with absent or impaired ability to associate with the cytoskeleton we also demonstrated the importance of cytoskeletal connectivity for retention both of band 3 and of its associated dependent proteins within the reticulocyte membrane during the process of erythroblast enucleation.

The Business Case for Tele-emergency.

BACKGROUND: Tele-emergency is an expanding telehealth service that provides real-time audio/visual consultation delivered by an emergency medicine team to a remote, often rural, emergency department (ED). Financial analyses of tele-emergency in the literature are limited. This article expands the tele-emergency literature to describe the business case for tele-emergency. "Business case" is defined as a reasoned argument, supported by objective data and/or qualitative judgment, to implement or continue a service or product. MATERIALS AND METHODS: To evaluate tele-emergency financing from the perspective of a critical access hospital (CAH), 10 financial analysis categories were defined. Telephone interviews, site visits, and financial data from the eEmergency program of Avera Health (Sioux Falls, SD) were used to populate the categories. Avera Health information was augmented with national data where available. Three financial scenarios were then analyzed for CAH profit/loss associated with tele-emergency. RESULTS: Tele-emergency financial analysis demonstrated an $187,614 profit in a high revenue/low expense scenario, $49,841 profit in a midrange scenario, and $69,588 loss in a low revenue/high expense scenario. CONCLUSIONS: Tele-emergency may be a profitable rural hospital service line if the participating hospital adjusts ED processes to take advantage of increased revenue/savings opportunities afforded by tele-emergency. Savings due to tele-emergency primarily accrue when physician ED backup and physician ED staffing costs are substituted.

An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease.

Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3ß, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3ß using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies.

Massive hemoptysis with end stage renal disease (ESRD): An initial symptom of rare disease.

Microscopic polyangiitis is a rare autoimmune vasculitis, that could present with renal-pulmonary symptoms, posing diagnostic challenges in patients with preexisting kidney disease. Timely diagnosis is crucial to improve patient outcomes.