PharmaMemory: an interactive, animated web application for learning autonomic physiology and pharmacology.

Medical students face challenging but important topics they must learn in short periods of time, such as autonomic pharmacology. Autonomic pharmacology is difficult in that it requires students to synthesize detailed anatomy, physiology, clinical reasoning, and pharmacology. The subject poses a challenge to learn as it is often introduced early in medical school curricula. To ease the difficulty of learning autonomic pharmacology, we created a free web application, PharmaMemory (www.pharmamemory.com), that interactively depicts the effects of high-yield autonomic drugs on the human body. PharmaMemory provides users with the opportunity to read and quiz themselves on the mechanisms, side effects, indications, and contraindications of these drugs while interacting with the application. We provided PharmaMemory to first-year medical students for three consecutive years of quality improvement and assessed the application's perceived effects on learning via user surveys. Survey feedback showed that users viewed PharmaMemory favorably and self-reported increased knowledge and confidence in the subject of autonomic pharmacology. Comments revealed that users liked the website's visuals, opportunity for challenged recall, and conciseness. PharmaMemory utilizes challenged recall, visual stimulation, and interactive learning to provide users with a multifaceted learning tool. Preliminary data suggest that students find this method of learning beneficial. Further studies are needed to assess PharmaMemory compared with more traditional learning methods such as PowerPoint or text-based learning. Additionally, further research is needed to quantitatively assess reduction in cognitive load.NEW & NOTEWORTHY PharmaMemory (www.pharmamemory.com) is a free web application that interactively depicts the effects of high-yield autonomic drugs on the human body.

COVID-19 Infection Control Measures in Long-Term Care Facility, Pennsylvania, USA.

Residents of long-term care facilities are at risk for coronavirus disease. We report a surveillance exercise at such a facility in Pennsylvania, USA. After introduction of a testing strategy and other measures, this facility had a 17-fold lower coronavirus disease case rate than neighboring facilities.

Pulmonary Embolism and Increased Levels of d-Dimer in Patients with Coronavirus Disease.

We report 3 patients with coronavirus disease who had a decline in respiratory status during their hospital course that responded well to intravenous steroids and interleukin-6 receptor antagonist therapy. These patients later showed development of persistent hypoxia with increased levels of d-dimer levels and were given a diagnosis of pulmonary embolisms.

Successfully transfected primary peripherally mobilized human CD34+ hematopoietic stem and progenitor cells (HSPCs) demonstrate increased susceptibility to retroviral infection.

Transfection, the process of introducing purified nucleic acids into cells, and viral transduction, viral-mediated nucleic acid transfer, are two commonly utilized techniques for gene delivery in the research setting. Transfection allows purified nucleic acid to be introduced into target cells through chemical-based techniques, nonchemical methods or particle-based methods, while viral transduction employs genomes or vectors based on adenoviruses, retroviruses (e.g. lentiviruses), adeno-associated viruses, or hybrid viruses. Transfected DNAs are often tested for potential effects on subsequent transduction, but it is not clear whether transfection itself rather than the particular nucleic acid being introduced might impact subsequent viral transfection. We observed a significant association between successfully transfected mobilized peripheral blood CD34+ human stem and progenitor cells (HSPCs) and permissiveness to subsequent lentiviral transduction, which was not evident in other cells such as 293 T cells and Jurkat cells. This association, apparently specific to CD34+ human stem and progenitor cells (HSPCs), is critical to both research and clinical applications as these cells are a frequent target of transfection and viral transduction owing to the durable nature of these cells in living systems. This finding may also present a significant opportunity to enhance the success of viral transduction for clinical applications.

Beyond eloquence and onto centrality: a new paradigm in planning supratentorial neurosurgery.

PURPOSE: Minimizing post-operational neurological deficits as a result of brain surgery has been one of the most pertinent endeavours of neurosurgical research. Studies have utilised fMRIs, EEGs and MEGs in order to delineate and establish eloquent areas, however, these methods have not been utilized by the wider neurosurgical community due to a lack of clinical endpoints. We sought to ascertain if there is a correlation between graph theory metrics and the neurosurgical notion of eloquent brain regions. We also wanted to establish which graph theory based nodal centrality measure performs the best in predicting eloquent areas. METHODS: We obtained diffusion neuroimaging data from the Human Connectome Project (HCP) and applied a parcellation scheme to it. This enabled us to construct a weighted adjacency matrix which we then analysed. Our analysis looked at the correlation between PageRank centrality and eloquent areas. We then compared PageRank centrality to eigenvector centrality and degree centrality to see what the best measure of empirical neurosurgical eloquence was. RESULTS: Areas that are considered neurosurgically eloquent tended to be predicted by high PageRank centrality. By using summary scores for the three nodal centrality measures we found that PageRank centrality best correlated to empirical neurosurgical eloquence. CONCLUSION: The notion of eloquent areas is important to neurosurgery and graph theory provides a mathematical framework to predict these areas. PageRank centrality is able to consistently find areas that we consider eloquent. It is able to do so better than eigenvector and degree central measures.

ANALYSIS OF PLASMODIUM LINEAGES IDENTIFIED IN CAPTIVE PENGUINS (SPHENISCIFORMES SPP.), EIDERS (SOMATERIA SPP.), AND INCA TERNS (LAROSTERNA INCA) IN A NORTH AMERICAN ZOOLOGICAL COLLECTION.

Vector-borne Plasmodium spp. infect a wide range of bird species. Although infections may be asymptomatic, certain genera, especially those that evolved in regions without endemic malaria, appear particularly susceptible to symptomatic disease, leading to morbidity and mortality. High mortalities associated with malaria infections have been documented in captive species of Sphenisciformes, Somateria, and Larosterna, all genera that evolved in climates with low mosquito exposure. To better characterize trends in Plasmodium-related mortality in a zoological collection in New York, necropsy reports for birds of all three genera that died between 1998 and February 2018 were analyzed; comparisons were made between birds that died with or without evidence of malaria infection. A seasonal peak in deaths was observed in birds regardless of their malaria status. There was no significant difference in the age of birds at death between malaria-positive and malaria-negative animals. These results suggest that age and season of death were not associated with malaria status. To investigate an association between parasite lineage and clinical outcome, polymerase chain reaction was used to identify parasite lineage in necropsied birds as well as healthy birds sampled as part of surveillance studies. Twelve different Plasmodium lineages were identified. The relative prevalence of parasite lineages was compared between necropsy and surveillance samples. A single parasite lineage, SGS1 (species: Plasmodium relictum), was significantly more likely to be found in surveillance samples; it was detected in a plurality of surveillance data but found in only one necropsy case. Other parasite lineages were more likely to be found in necropsies than in surveillance samples, most notably SEIAUR01 (species: Plasmodium cathemerium). These data may be consistent with a difference in virulence between parasite lineages. This investigation has implications for the monitoring and care of vulnerable avian species.

Lung Cancer in Non-Smokers.

Lung cancer is the leading cause of cancer death worldwide and the third most common cancer following breast and prostate.1 As expected, the primary factor leading to lung cancer is tobacco smoke, and as smoking rates have declined, we have also seen an overall decline in lung cancer rates.2 Despite the general reduction in lung cancer rates, the rate of lung cancer in non-smokers has been noted to be increasing.3-8.

In vivo model of human post-traumatic heterotopic ossification demonstrates early fibroproliferative signature.

BACKGROUND: The relationship between the tissue injury healing response and development of heterotopic ossification (HO) is poorly understood. Here we compare a rat blast model and human traumatized muscle from a blast injury to study the early signatures of osteogenesis and fibrosis during the formation of HO. METHODS: Rat and human tissues were characterized using histology, scanning electron microscopy, immunohistochemistry, as well as gene and protein expression analysis. Additionally, animals and humans were assessed radiographically for HO formation following injury. RESULTS: Markers of bone formation were dramatically increased in tissue samples from both humans and rats, and both displayed increased fibroproliferative regions within the injured tissues and elevated expression of markers of tissue fibrosis such as TGF-ß1, Fibronectin, SMAD3 and PAI-1. Markers of inflammation and fibrosis (ACTA, TNFα, BMP1 and BMP3) were elevated at the RNA level in both rat and human samples. By day 42, bone formation in the rat blast model appeared similar in radiographs compared to human patients who progressed to develop post-traumatic HO. CONCLUSIONS: Our data demonstrates that a similar early fibrotic response is evident in both the rat blast model and the human tissues following a traumatic injury and demonstrates the relevance of this animal model for future translational studies.

Rising synchrony controls western North American ecosystems.

Along the western margin of North America, the winter expression of the North Pacific High (NPH) strongly influences interannual variability in coastal upwelling, storm track position, precipitation, and river discharge. Coherence among these factors induces covariance among physical and biological processes across adjacent marine and terrestrial ecosystems. Here, we show that over the past century the degree and spatial extent of this covariance (synchrony) has substantially increased, and is coincident with rising variance in the winter NPH. Furthermore, centuries-long blue oak (Quercus douglasii) growth chronologies sensitive to the winter NPH provide robust evidence that modern levels of synchrony are among the highest observed in the context of the last 250 years. These trends may ultimately be linked to changing impacts of the El Niño Southern Oscillation on midlatitude ecosystems of North America. Such a rise in synchrony may destabilize ecosystems, expose populations to higher risks of extinction, and is thus a concern given the broad biological relevance of winter climate to biological systems.

Fascia iliaca blockade with the addition of liposomal bupivacaine vs. plain bupivacaine for perioperative pain management following hip arthroscopy.

PURPOSE: A newer formulation of bupivacaine, encapsulated within carrier molecules, has garnered attention for its role in providing extended post-operative analgesia. The purpose was to evaluate the addition of liposomal bupivacaine to fascia iliaca blockade during hip arthroscopy. METHODS: Retrospective cohort study of patients undergoing hip arthroscopy with a pre-operative fascia iliaca blockade with either liposomal bupivacaine (Group 1; 266mg + 20 cc 0.5% plain bupivacaine) or bupivacaine (Group 2; 40 cc 0.25% plain bupivacaine). All patients received standardized pre-operative oral pain medications. The primary outcome was the defense veteran pain rating scale (DVPRS). Secondary outcomes included duration of hospital admission, PACU opioid use, PACU pain scores, and duration of nerve blockade. RESULTS: Thirty-eight males and 30 females, mean age of 33 years (range 14-56). There was no difference in pre-operative DVPRS between the groups (n.s.). There was no difference in post-operative DVPRS pain scores at POD0 (3.7 vs. 3.9, n.s.), POD1 (4.2 vs. 3.8, n.s.), POD2 (4.2 vs. 3.7, n.s.), POD3 (3.9 vs. 3.7, n.s.) or POD14 (2.2 vs. 2.4, n.s.). Group 1 trended towards longer mean total hospital admission time (872 vs. 822 min, n.s.), and greater mean morphine equivalents administered in the PACU (33 vs. 29 mg, n.s.). 68% of patients in group 1 reported continued anterior thigh numbness at POD3, compared to 34% in group 2 (p = 0.008). CONCLUSIONS: Despite the advertised benefits of prolonged post-operative analgesia using liposomal bupivacaine, there were no significant differences in post-operative pain scores or PACU opioid consumption. Our results support that acceptable pain scores are successfully achieved at all time periods with the use of multimodal analgesia including fascia iliaca blockade despite the type of pain medication administered. LEVEL OF EVIDENCE: III.

Arctic shrub growth trajectories differ across soil moisture levels.

The circumpolar expansion of woody deciduous shrubs in arctic tundra alters key ecosystem properties including carbon balance and hydrology. However, landscape-scale patterns and drivers of shrub expansion remain poorly understood, inhibiting accurate incorporation of shrub effects into climate models. Here, we use dendroecology to elucidate the role of soil moisture in modifying the relationship between climate and growth for a dominant deciduous shrub, Salix pulchra, on the North Slope of Alaska, USA. We improve upon previous modeling approaches by using ecological theory to guide model selection for the relationship between climate and shrub growth. Finally, we present novel dendroecology-based estimates of shrub biomass change under a future climate regime, made possible by recently developed shrub allometry models. We find that S. pulchra growth has responded positively to mean June temperature over the past 2.5 decades at both a dry upland tundra site and an adjacent mesic riparian site. For the upland site, including a negative second-order term in the climate-growth model significantly improved explanatory power, matching theoretical predictions of diminishing growth returns to increasing temperature. A first-order linear model fit best at the riparian site, indicating consistent growth increases in response to sustained warming, possibly due to lack of temperature-induced moisture limitation in mesic habitats. These contrasting results indicate that S. pulchra in mesic habitats may respond positively to a wider range of temperature increase than S. pulchra in dry habitats. Lastly, we estimate that a 2°C increase in current mean June temperature will yield a 19% increase in aboveground S. pulchra biomass at the upland site and a 36% increase at the riparian site. Our method of biomass estimation provides an important link toward incorporating dendroecology data into coupled vegetation and climate models.

Restriction of HIV-1-based lentiviral vectors in adult primary marrow-derived and peripheral mobilized human CD34+ hematopoietic stem and progenitor cells occurs prior to viral DNA integration.

BACKGROUND: Gene therapy is currently being attempted using a number of delivery vehicles including lentiviral-based vectors. The delivery and insertion of a gene using lentiviral-based vectors involves multiple discrete steps, including reverse transcription of viral RNA into DNA, nuclear entry, integration of viral DNA into the host genome and expression of integrated genes. Transduction of murine stem cells by the murine leukemia viruses is inefficient because the expression of the integrated DNA is profoundly blocked. Transduction of human stem cells by lentivirus vectors is also inefficient, but the cause and specific part of the retroviral lifecycle where this block occurs is unknown. RESULTS: Here we demonstrate that the dominant point of restriction of an HIV-1-based lentiviral vector in adult human hematopoietic stem and progenitor cells (HSPCs) from bone marrow and also those obtained following peripheral mobilization is prior to viral DNA integration. We specifically show that restriction of HSPCs to an HIV-1-based lentiviral vector is prior to formation of nuclear DNA forms. CONCLUSIONS: Murine restriction of MLV and human cellular restriction of HIV-1 are fundamentally different. While murine restriction of MLV occurs post integration, human restriction of HIV-1 occurs before integration.

HIV-1 Is Restricted prior to Integration of Viral DNA in Primary Cord-Derived Human CD34+ Cells.

Certain cells have the ability to block retroviral infection at specific stages of the viral cycle by the activities of well-characterized factors and transcriptional silencing machinery. Infection of murine stem cells (MSCs) by the murine leukemia viruses (MLVs) is profoundly blocked postintegration by transcriptional silencing. Here, we show that a dominant point of restriction of HIV-1 in human CD34+ cells is prior to integration of viral DNA and that HIV-1 restriction by human CD34+ cells is fundamentally different from MLV restriction by mouse cells.

The value of crossdating to retain high-frequency variability, climate signals, and extreme events in environmental proxies.

High-resolution biogenic and geologic proxies in which one increment or layer is formed per year are crucial to describing natural ranges of environmental variability in Earth's physical and biological systems. However, dating controls are necessary to ensure temporal precision and accuracy; simple counts cannot ensure that all layers are placed correctly in time. Originally developed for tree-ring data, crossdating is the only such procedure that ensures all increments have been assigned the correct calendar year of formation. Here, we use growth-increment data from two tree species, two marine bivalve species, and a marine fish species to illustrate sensitivity of environmental signals to modest dating error rates. When falsely added or missed increments are induced at one and five percent rates, errors propagate back through time and eliminate high-frequency variability, climate signals, and evidence of extreme events while incorrectly dating and distorting major disturbances or other low-frequency processes. Our consecutive Monte Carlo experiments show that inaccuracies begin to accumulate in as little as two decades and can remove all but decadal-scale processes after as little as two centuries. Real-world scenarios may have even greater consequence in the absence of crossdating. Given this sensitivity to signal loss, the fundamental tenets of crossdating must be applied to fully resolve environmental signals, a point we underscore as the frontiers of growth-increment analysis continue to expand into tropical, freshwater, and marine environments.

Progesterone receptor membrane component-1 (PGRMC1) and PGRMC-2 interact to suppress entry into the cell cycle in spontaneously immortalized rat granulosa cells.

Progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 are expressed in rat granulosa cells and spontaneously immortalized granulosa cells (SIGCs) but their biological roles are not well defined. The present studies demonstrate that depleting either Pgrmc1 or Pgrmc2 in SIGCs increases entry into the cell cycle but does not increase cell proliferation. Rather, PGRMC1 and/or PGRMC2-deplete cells accumulate in metaphase and undergo apoptosis. Because both PGRMC1 and PGRMC2 localize to the mitotic spindle, their absence likely accounts for cells arresting in metaphase. Moreover, pull-down assays, colocalization studies and in situ proximity ligation assays (PLA) indicate that PGRMC1 binds PGRMC2. Disrupting the PGRMC1:PGRMC2 complex through the use of siRNA or the cytoplasmic delivery of a PGRMC2 antibody increases entry into the cell cycle. Conversely, overexpressing either PGRMC1-GFP or GFP-PGRMC2 fusion protein inhibits entry into the cell cycle. Subsequent studies reveal that depleting PGRMC1 and/or PGRMC2 reduces the percentage of cells in G0 and increases the percentage of cells in G1. These observations indicate that in addition to their role at metaphase, PGRMC1 and PGRMC2 are involved in regulating entry into the G1 stage of the cell cycle. Interestingly, both PGRMC1 and PGRMC2 bind GTPase-activating protein-binding protein 2 (G3BP2) as demonstrated by pull-down assays, colocalization assays, and PLAs. G3bp2 siRNA treatment also promotes entry into the G1 stage. This implies that dynamic changes in the interaction among PGRMC1, PGRMC2, and G3BP2 play an important protein regulating the rate at which SIGCs enter into the cell cycle.

Expression of progesterone receptor membrane component-2 within the immature rat ovary and its role in regulating mitosis and apoptosis of spontaneously immortalized granulosa cells.

Progesterone receptor membrane component 2 (Pgrmc2) mRNA was detected in the immature rat ovary. By 48 h after eCG, Pgrmc2 mRNA levels decreased by 40% and were maintained at 48 h post-hCG. Immunohistochemical studies detected PGRMC2 in oocytes and ovarian surface epithelial, interstitial, thecal, granulosa, and luteal cells. PGRMC2 was also present in spontaneously immortalized granulosa cells, localizing to the cytoplasm of interphase cells and apparently to the mitotic spindle of cells in metaphase. Interestingly, PGRMC2 levels appeared to decrease during the G1 stage of the cell cycle. Moreover, overexpression of PGRMC2 suppressed entry into the cell cycle, possibly by binding the p58 form of cyclin dependent kinase 11b. Conversely, Pgrmc2 small interfering RNA (siRNA) treatment increased the percentage of cells in G1 and M stage but did not increase the number of cells, which was likely due to an increase in apoptosis. Depleting PGRMC2 did not inhibit cellular (3)H-progesterone binding, but attenuated the ability of progesterone to suppress mitosis and apoptosis. Taken together these studies suggest that PGRMC2 affects granulosa cell mitosis by acting at two specific stages of the cell cycle. First, PGRMC2 regulates the progression from the G0 into the G1 stage of the cell cycle. Second, PGRMC2 appears to localize to the mitotic spindle, where it likely promotes the final stages of mitosis. Finally, siRNA knockdown studies indicate that PGRMC2 is required for progesterone to slow the rate of granulosa cell mitosis and apoptosis. These findings support a role for PGRMC2 in ovarian follicle development.

A 10-Step Process to Align Problem-Based Learning With Accreditation Expectations for Self-Directed and Lifelong Learning.

OBJECTIVE: Self-directed and lifelong learning (SDLL) skills are essential skillsets in both undergraduate and graduate medical education (UME and GME). Hence, medical schools' accreditation bodies emphasize the requirements to acquire these skills in their accreditation standards. For example, in the United States, the Liaison Committee on Medical Education (LCME) clearly defines the components of the SDLL process in Element 6.3 of Accreditation Standard Six. Among the active learning pedagogies, problem-based learning (PBL) provides ample learning opportunities where SDLL skills are effectively applied. The aim of this article is to streamline the process of developing, delivering, and evaluating PBL sessions in line with the SDLL accreditation requirements through a 10-step design and implementation process. METHODS: Our 10-step process, detailed in the article, starts with developing learning objectives that inform the content of the PBL case and the required embedded learning triggers. The process carefully addresses the components of the SDLL process and other aspects of the accreditation needs within the framework of PBL. The approach to implementation, feedback, assessment, and evaluation is explicitly described to meet the regulatory expectations. DISCUSSION: In addition to the essential role in UME and GME, SDLL skills are vital requisites for continuing medical education of all physicians. Instilling this skillset early in medical students helps to cultivate their ability to apply these skills in their future professional roles. Using accreditation standards as a foundation for creating learning experiences, for example, PBL, requires careful content development and sequencing. Such a process needs explicit standardized steps that should not only be feasible, but also transferable for usage by different medical schools. CONCLUSION: Our streamlined 10-step process of designing and delivering an SDLL-oriented PBL experience can easily be adopted by other medical schools to address the SDLL skills acquisition as well as meeting the accreditation requirements.

A dynamic systems theory of intrateam conflict contagion.

Recognizing the challenges that conflict poses, organizational researchers have invested considerable energy toward investigating the processes by which conflict occurs and spreads within a team. However, current theoretical frameworks of conflict contagion posit a static growth trajectory in which members become engaged in conflict and stay in conflict. While this trajectory is certainly possible, the broader conflict literature outside of the organizational sciences has shown evidence for a more varied set of potential trajectories of conflict contagion. To advance theory on team conflict, we integrate conflict research from micro-level (interpersonal) to macro-level (interstate) perspectives into a formal theory of intrateam conflict contagion. Drawing from conflict stage and social contagion theory, we theorize that team members move through three stages of conflict (disengaged, at-risk, engaged) at rates determined by four process mechanisms (faultlines, forgiveness, frustration, integration) such that disengaged individuals become at-risk of engaging in conflict, engage in conflict, then disengage, only to potentially become at risk of reengaging at a later point in time. Using computational modeling, we demonstrate the generative sufficiency of our theory to account for conflict trajectories observed in the broader conflict literature. To facilitate the interpretation of such trajectories, we present a typology of contagion trajectories, discuss the dynamic properties of these trajectories (e.g., stability, bifurcations), and provide implications for future theory building and practice. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

HIV-1 reverse transcriptase (RT) polymorphism 172K suppresses the effect of clinically relevant drug resistance mutations to both nucleoside and non-nucleoside RT inhibitors.

Polymorphisms have poorly understood effects on drug susceptibility and may affect the outcome of HIV treatment. We have discovered that an HIV-1 reverse transcriptase (RT) polymorphism (RT(172K)) is present in clinical samples and in widely used laboratory strains (BH10), and it profoundly affects HIV-1 susceptibility to both nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) when combined with certain mutations. Polymorphism 172K significantly suppressed zidovudine resistance caused by excision (e.g. thymidine-associated mutations) and not by discrimination mechanism mutations (e.g. Q151M complex). Moreover, it attenuated resistance to nevirapine or efavirenz imparted by NNRTI mutations. Although 172K favored RT-DNA binding at an excisable pre-translocation conformation, it decreased excision by thymidine-associated mutation-containing RT. 172K affected DNA handling and decreased RT processivity without significantly affecting the k(cat)/K(m) values for dNTP. Surface plasmon resonance experiments revealed that RT(172K) decreased DNA binding by increasing the dissociation rate. Hence, the increased zidovudine susceptibility of RT(172K) results from its increased dissociation from the chain-terminated DNA and reduced primer unblocking. We solved a high resolution (2.15 Å) crystal structure of RT mutated at 172 and compared crystal structures of RT(172R) and RT(172K) bound to NNRTIs or DNA/dNTP. Our structural analyses highlight differences in the interactions between α-helix E (where 172 resides) and the active site ß9-strand that involve the YMDD loop and the NNRTI binding pocket. Such changes may increase dissociation of DNA, thus suppressing excision-based NRTI resistance and also offset the effect of NNRTI resistance mutations thereby restoring NNRTI binding.