Description and evaluation of an EBM curriculum using a block rotation

BACKGROUND: While previous authors have emphasized the importance of integrating and reinforcing evidence-based medicine (EBM) skills in residency, there are few published examples of such curricula. We designed an EBM curriculum to train family practice interns in essential EBM skills for information mastery using clinical questions generated by the family practice inpatient service. We sought to evaluate the impact of this curriculum on interns, residents, and faculty. METHODS: Interns (n = 13) were asked to self-assess their level of confidence in basic EBM skills before and after their 2-week EBM rotation. Residents (n = 21) and faculty (n = 12) were asked to assess how often the answers provided by the EBM intern to the inpatient service changed medical care. In addition, residents were asked to report how often they used their EBM skills and how often EBM concepts and tools were used in teaching by senior residents and faculty. Faculty were asked if the EBM curriculum had increased their use of EBM in practice and in teaching. RESULTS: Interns significantly increased their confidence over the course of the rotation. Residents and faculty felt that the answers provided by the EBM intern provided useful information and led to changes in patient care. Faculty reported incorporating EBM into their teaching (92%) and practice (75%). Residents reported applying the EBM skills they learned to patient care (86%) and that these skills were reinforced in the teaching they received outside of the rotation (81%). All residents and 11 of 12 faculty felt that the EBM curriculum had improved patient care. CONCLUSIONS: To our knowledge, this is the first published EBM curriculum using an individual block rotation format. As such, it may provide an alternative model for teaching and incorporating EBM into a residency program

Impacts of climate change on plant diseases – opinions and trends

There has been a remarkable scientific output on the topic of how climate change is likely to affect plant diseases in the coming decades. This review addresses the need for review of this burgeoning literature by summarizing opinions of previous reviews and trends in recent studies on the impacts of climate change on plant health. Sudden Oak Death is used as an introductory case study: Californian forests could become even more susceptible to this emerging plant disease, if spring precipitations will be accompanied by warmer temperatures, although climate shifts may also affect the current synchronicity between host cambium activity and pathogen colonization rate. A summary of observed and predicted climate changes, as well as of direct effects of climate change on pathosystems, is provided. Prediction and management of climate change effects on plant health are complicated by indirect effects and the interactions with global change drivers. Uncertainty in models of plant disease development under climate change calls for a diversity of management strategies, from more participatory approaches to interdisciplinary science. Involvement of stakeholders and scientists from outside plant pathology shows the importance of trade-offs, for example in the land-sharing vs. sparing debate. Further research is needed on climate change and plant health in mountain, boreal, Mediterranean and tropical regions, with multiple climate change factors and scenarios (including our responses to it, e.g. the assisted migration of plants), in relation to endophytes, viruses and mycorrhiza, using long-term and large-scale datasets and considering various plant disease control methods

Tracing the role of human civilization in the globalization of plant pathogens

Acknowledgments. We apologize to all those colleagues whose work was not cited because of space restrictions.Peer reviewedPostprin

The burden of respiratory infections among older adults in long-term care:a systematic review

BACKGROUND: Respiratory infections among older adults in long-term care facilities (LTCFs) are a major global concern, yet a rigorous systematic synthesis of the literature on the burden of respiratory infections in the LTCF setting is lacking. To address the critical need for evidence regarding the global burden of respiratory infections in LTCFs, we assessed the burden of respiratory infections in LTCFs through a systematic review of the published literature. METHODS: We identified articles published between April 1964 and March 2019 through searches of PubMed (MEDLINE), EMBASE, and the Cochrane Library. Experimental and observational studies published in English that included adults aged ≥60 residing in LTCFs who were unvaccinated (to identify the natural infection burden), and that reported measures of occurrence for influenza, respiratory syncytial virus (RSV), or pneumonia were included. Disagreements about article inclusion were discussed and articles were included based on consensus. Data on study design, population, and findings were extracted from each article. Findings were synthesized qualitatively. RESULTS: A total of 1451 articles were screened for eligibility, 345 were selected for full-text review, and 26 were included. Study population mean ages ranged from 70.8 to 90.1 years. Three (12%) studies reported influenza estimates, 7 (27%) RSV, and 16 (62%) pneumonia. Eighteen (69%) studies reported incidence estimates, 7 (27%) prevalence estimates, and 1 (4%) both. Seven (27%) studies reported outbreaks. Respiratory infection incidence estimates ranged from 1.1 to 85.2% and prevalence estimates ranging from 1.4 to 55.8%. Influenza incidences ranged from 5.9 to 85.2%. RSV incidence proportions ranged from 1.1 to 13.5%. Pneumonia prevalence proportions ranged from 1.4 to 55.8% while incidence proportions ranged from 4.8 to 41.2%. CONCLUSIONS: The reported incidence and prevalence estimates of respiratory infections among older LTCF residents varied widely between published studies. The wide range of estimates offers little useful guidance for decision-making to decrease respiratory infection burden. Large, well-designed epidemiologic studies are therefore still necessary to credibly quantify the burden of respiratory infections among older adults in LTCFs, which will ultimately help inform future surveillance and intervention efforts

Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule

Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14–1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14–1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14–1 induced a dose- (IC50 = 10 μM) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14–1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14–1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27kip1, Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14–1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas

Spider Silk Constructs Enhance Axonal Regeneration and Remyelination in Long Nerve Defects in Sheep

BACKGROUND: Surgical reapposition of peripheral nerve results in some axonal regeneration and functional recovery, but the clinical outcome in long distance nerve defects is disappointing and research continues to utilize further interventional approaches to optimize functional recovery. We describe the use of nerve constructs consisting of decellularized vein grafts filled with spider silk fibers as a guiding material to bridge a 6.0 cm tibial nerve defect in adult sheep. METHODOLOGY/PRINCIPAL FINDINGS: The nerve constructs were compared to autologous nerve grafts. Regeneration was evaluated for clinical, electrophysiological and histological outcome. Electrophysiological recordings were obtained at 6 months and 10 months post surgery in each group. Ten months later, the nerves were removed and prepared for immunostaining, electrophysiological and electron microscopy. Immunostaining for sodium channel (NaV 1.6) was used to define nodes of Ranvier on regenerated axons in combination with anti-S100 and neurofilament. Anti-S100 was used to identify Schwann cells. Axons regenerated through the constructs and were myelinated indicating migration of Schwann cells into the constructs. Nodes of Ranvier between myelin segments were observed and identified by intense sodium channel (NaV 1.6) staining on the regenerated axons. There was no significant difference in electrophysiological results between control autologous experimental and construct implantation indicating that our construct are an effective alternative to autologous nerve transplantation. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that spider silk enhances Schwann cell migration, axonal regrowth and remyelination including electrophysiological recovery in a long-distance peripheral nerve gap model resulting in functional recovery. This improvement in nerve regeneration could have significant clinical implications for reconstructive nerve surgery

Dengue virus neutralizing antibody levels associated with protection from infection in Thai cluster studies

BACKGROUND: Long-term homologous and temporary heterologous protection from dengue virus (DENV) infection may be mediated by neutralizing antibodies. However, neutralizing antibody titers (NTs) have not been clearly associated with protection from infection. METHODOLOGY/PRINCIPAL FINDINGS: Data from two geographic cluster studies conducted in Kamphaeng Phet, Thailand were used for this analysis. In the first study (2004-2007), cluster investigations of 100-meter radius were triggered by DENV-infected index cases from a concurrent prospective cohort. Subjects between 6 months and 15 years old were evaluated for DENV infection at days 0 and 15 by DENV PCR and IgM ELISA. In the second study (2009-2012), clusters of 200-meter radius were triggered by DENV-infected index cases admitted to the provincial hospital. Subjects of any age 6 months and older were evaluated for DENV infection at days 0 and 14. In both studies, subjects who were DENV PCR positive at day 14/15 were considered to have been susceptible on day 0. Comparison subjects from houses in which someone had documented DENV infection, but the subject remained DENV negative at days 0 and 14/15, were considered non-susceptible. Day 0 samples were presumed to be from just before virus exposure, and underwent plaque reduction neutralization testing (PRNT). Seventeen susceptible (six DENV-1, five DENV-2, and six DENV-4), and 32 non-susceptible (13 exposed to DENV-1, 10 DENV-2, and 9 DENV-4) subjects were evaluated. Comparing subjects exposed to the same serotype, receiver operating characteristic (ROC) curves identified homotypic PRNT titers of 11, 323 and 16 for DENV-1, -2 and -4, respectively, to differentiate susceptible from non-susceptible subjects. CONCLUSIONS/SIGNIFICANCE: PRNT titers were associated with protection from infection by DENV-1, -2 and -4. Protective NTs appeared to be serotype-dependent and may be higher for DENV-2 than other serotypes. These findings are relevant for both dengue epidemiology studies and vaccine development efforts

A Novel Intracellular Isoform of Matrix Metalloproteinase-2 Induced by Oxidative Stress Activates Innate Immunity

Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress.Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M(77), thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes.A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure