Residency Program Responses to Early COVID-19 Surges Highlight Tension as to Whether Residents Are Learners or Essential Workers.

PURPOSE: To quantify the extent to which internal medicine (IM) residents provided care for patients with COVID-19 and examine characteristics of residency programs with or without plans (at some point) to exclude residents from COVID-19 care during the first 6 months of the pandemic. METHOD: The authors used data from a nationally representative, annually recurring survey of U.S. IM program directors (PDs) to quantify early (March-August 2020) resident participation in COVID-19 care. The survey was fielded from August to December 2020. PDs reported whether they had planned to exclude residents from COVID-19 care (i.e., PTE status). PTE status was tested for association with program and COVID-19 temporal characteristics, resident schedule accommodations, and resident COVID-19 cases. RESULTS: The response rate was 61.5% (264/429). Nearly half of PDs (45.4%, 118/260) reported their program had planned at some point to exclude residents from COVID-19 care. Northeastern U.S. programs represented a smaller percentage of PTE than non-PTE programs (26.3% vs 36.6%; P = .050). PTE programs represented a higher percentage of programs with later surges than non-PTE programs (33.0% vs 13.6%, P = .048). Median percentage of residents involved in COVID-19 care was 75.0 (interquartile range [IQR]: 22.5-100.0) for PTE programs, compared with 95.0 (IQR: 60.0-100.0) for non-PTE programs ( P < .001). Residents participated most in intensive care units (87.6%, 227/259) and inpatient wards (80.8%, 210/260). Accommodations did not differ by PTE status. PTE programs reported fewer resident COVID-19 cases than non-PTE programs (median percentage = 2.7 [IQR: 0.0-8.6] vs 5.1 [IQR: 1.6-10.7]; P = .011). CONCLUSIONS: IM programs varied widely in their reported plans to exclude residents from COVID-19 care during the early pandemic. A high percentage of residents provided COVID-19 care, even in PTE programs. Thus, the pandemic highlighted the tension as to whether residents are learners or employees.

Infectious Complications in Injection Drug Use.

Introduction: The prevalence of opioid use disorder has increased steadily over the last decade (from 2.2 million in 2010 to 10.2 million in 2018) and with it, a surge in infectious complications associated with injection drug use (IDU). Trainees in internal medicine routinely diagnose, manage, and treat patients experiencing these infections in the hospital setting as well as screen for and immunize against other comorbid infections in the ambulatory setting. Methods: This 90-minute, case-based, interactive workshop was led by two facilitators, an infectious diseases specialist and a senior internal medicine resident. To evaluate its effectiveness, we used a pre- and postsession survey administered at the beginning and end of the workshop. Learners were asked to rate comfort level in recognizing, managing, and counseling about various IDU-related infections, as well as to answer specific, content-level questions. Result: Thirty of 42 participants who attended the workshop completed the evaluation. There was a statistically significant change in participants' comfort level with diagnosing and managing IDU-associated infections as well as ambulatory standards of care for people who inject drugs (PWID) from pre- to postworkshop. Discussion: Our workshop focused on the management and prevention of infections among PWID in both the inpatient and ambulatory settings. Learners demonstrated increased comfort in managing these conditions.

Assessing care models implemented in primary healthcare for persons with dementia: a mixed-methods study protocol.

INTRODUCTION: Dementia is on the rise in Canada and globally. Ensuring accessibility to diagnosis, treatment and management throughout the course of the disease is a very significant problem worldwide. In order to provide comprehensive care to patients and their caregivers, enhancing primary care-based dementia care is seen as the way forward. In many Canadian provinces various collaborative care models (collCMs) anchored in primary care to improve dementia care have been developed and implemented. The overall objective of our research programme is to identify key factors for the successful implementation of collCMs, and to facilitate dissemination and scale-up of dementia best practices. METHODS AND ANALYSIS: We will use a convergent mixed-methods design. An observational study using chart review (2014-2016) and questionnaires (2014-2018; repeated in 2020) will measure application of guidelines and implementation of collCMs. This study will be complemented with a qualitative descriptive study using interviews (2017-2020) conducted in parallel. Quantitative and qualitative results will be further integrated using a matrix representing sites and findings. An integrated knowledge exchange strategy will ensure uptake by principal stakeholders throughout the research. ETHICS AND DISSEMINATION: Our study has been approved by all relevant ethics committees. Our dissemination plan follows an integrated knowledge transfer strategy using provincial, national and international councils. We will present the results individually to the clinical sites and then to these councils. Our research will be the first provincial and cross jurisdictional evaluation of primary care models for patients living with dementia, providing evidence on the ongoing debate on the respective role of clinicians in primary care and specialists in caring for patients with dementia.

Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion.

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/- mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/- mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.

Student Learning in an Accelerated Introductory Biology Course Is Significantly Enhanced by a Flipped-Learning Environment.

A flipped-classroom environment generally strives to create more in-class time for activities that enhance student learning, while shifting some content delivery to outside the classroom through the use of short didactic videos. We compared a flipped-classroom setting with the traditional ("control") setting for an accelerated lower-division general biology course. Student self-reporting and video analytics functions showed ample and variable video viewing among individual students. Student learning was evaluated through quizzes administered after a set of concepts were covered (post 1) and at the end of the course (post 2). Students in the flipped sections had significantly higher quiz scores than students in the control sections for both post 1 and post 2. Analyses of variance analyzing the effect of and interactions between type of instruction, in-class activities, time, and Bloom's level of the quiz questions found significant differences in the overall model and all the factors, except for the presence and level of activities. Significant differences between students in the flipped and control sections were observed for low-level Bloom's questions only. Thus, the positive effect of the flipped-classroom approach on student learning may be due to improvements in recall of basic concepts and a better understanding of biology vocabulary in their first biology course.

Supervised Balance Training and Wii Fit-Based Exercises Lower Falls Risk in Older Adults With Type 2 Diabetes.

OBJECTIVES: This study examined the benefits of and differences between 12 weeks of thrice-weekly supervised balance training and an unsupervised at-home balance activity (using the Nintendo Wii Fit) for improving balance and reaction time and lowering falls risk in older individuals with type 2 diabetes mellitus (T2DM). DESIGN: Before-after trial. SETTING: University research laboratory, home environment. PARTICIPANTS: Sixty-five older adults with type 2 diabetes were recruited for this study. Participants were randomly allocated to either supervised balance training (mean age 67.8 ± 5.2) or unsupervised training using the Nintendo Wii Fit balance board (mean age 66.1 ± 5.6). INTERVENTION: The training period for both groups lasted for 12 weeks. Individuals were required to complete three 40-minute sessions per week for a total of 36 sessions. MEASUREMENT: The primary outcome measure was falls risk, which was as derived from the physiological profile assessment. In addition, measures of simple reaction time, lower limb proprioception, postural sway, knee flexion, and knee extension strength were also collected. Persons also self-reported any falls in the previous 6 months. RESULTS: Both training programs resulted in a significant lowering of falls risk (P < .05). The reduced risk was attributable to significant changes in reaction times for the hand (P < .05), foot (P < .01), lower-limb proprioception (P < .01), and postural sway (P < .05). CONCLUSIONS: Overall, training led to a decrease in falls risk, which was driven by improvements in reaction times, lower limb proprioception, and general balance ability. Interestingly, the reduced falls risk occurred without significant changes in leg strength, suggesting that interventions to reduce falls risk that target intrinsic risk factors related to balance control (over muscle strength) may have positive benefits for the older adult with T2DM at risk for falls.

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.

Calcific aortic valve disease (CAVD) is a major cause of morbidity in the aging population, but the underlying mechanisms of its progression remain poorly understood. Aortic valve calcification preferentially occurs on the fibrosa, which is subjected to disturbed flow. The side-specific progression of the disease is characterized by inflammation, calcific lesions, and extracellular matrix (ECM) degradation. Here, we explored the role of mechanosensitive microRNA-181b and its downstream targets in human aortic valve endothelial cells (HAVECs). Mechanistically, miR-181b is upregulated in OS and fibrosa, and it targets TIMP3, SIRT1, and GATA6, correlated with increased gelatinase/MMP activity. Overexpression of miR-181b led to decreased TIMP3 and exacerbated MMP activity as shown by gelatinase assay, and miR-181b inhibition decreased gelatinase activity through the repression of TIMP3 levels. Luciferase assay showed specific binding of miR-181b to the TIMP3 gene. Overexpression of miR-181b in HAVECs subjected to either LS or OS increased MMP activity, and miR-181b inhibition abrogated shear-sensitive MMP activity. These studies suggest that targeting this shear-dependent miRNA may provide a novel noninvasive treatment for CAVD.

Composite critical ratio functions for odontocete cetaceans.

Critical ratios (CRs) are useful for estimating detection thresholds of tonal signals when the spectral density of noise is known. In cetaceans, CRs have only been measured for a few animals representing four odontocete species. These data are sparse, particularly for lower frequencies where anthropogenic noise is concentrated. There is currently no systematic method for implementing CR predictions (e.g., a composite frequency-dependent CR function). The current study measures CRs for two bottlenose dolphins (Tursiops truncatus) and estimates composite CR functions. The composite models can aid in predicting and extrapolating auditory masking for a broad range of frequencies.

Omics-based approaches to understand mechanosensitive endothelial biology and atherosclerosis.

Atherosclerosis is a multifactorial disease that preferentially occurs in arterial regions exposed to d-flow can be used to indicate disturbed flow or disturbed blood flow. The mechanisms by which d-flow induces atherosclerosis involve changes in the transcriptome, methylome, proteome, and metabolome of multiple vascular cells, especially endothelial cells. Initially, we begin with the pathogenesis of atherosclerosis and the changes that occur at multiple levels owing to d-flow, especially in the endothelium. Also, there are a variety of strategies used for the global profiling of the genome, transcriptome, miRNA-ome, DNA methylome, and metabolome that are important to define the biological and pathophysiological mechanisms of endothelial dysfunction and atherosclerosis. Finally, systems biology can be used to integrate these 'omics' datasets, especially those that derive data based on a single animal model, in order to better understand the pathophysiology of atherosclerosis development in a holistic manner and how this integrative approach could be used to identify novel molecular diagnostics and therapeutic targets to prevent or treat atherosclerosis. WIREs Syst Biol Med 2016, 8:378-401. doi: 10.1002/wsbm.1344 For further resources related to this article, please visit the WIREs website.

The role of endothelial mechanosensitive genes in atherosclerosis and omics approaches.

Atherosclerosis is the leading cause of morbidity and mortality in the U.S., and is a multifactorial disease that preferentially occurs in regions of the arterial tree exposed to disturbed blood flow. The detailed mechanisms by which d-flow induces atherosclerosis involve changes in the expression of genes, epigenetic patterns, and metabolites of multiple vascular cells, especially endothelial cells. This review presents an overview of endothelial mechanobiology and its relation to the pathogenesis of atherosclerosis with special reference to the anatomy of the artery and the underlying fluid mechanics, followed by a discussion of a variety of experimental models to study the role of fluid mechanics and atherosclerosis. Various in vitro and in vivo models to study the role of flow in endothelial biology and pathobiology are discussed in this review. Furthermore, strategies used for the global profiling of the genome, transcriptome, miR-nome, DNA methylome, and metabolome, as they are important to define the biological and pathophysiological mechanisms of atherosclerosis. These "omics" approaches, especially those which derive data based on a single animal model, provide unprecedented opportunities to not only better understand the pathophysiology of atherosclerosis development in a holistic and integrative manner, but also to identify novel molecular and diagnostic targets.

The role of epigenetics in the endothelial cell shear stress response and atherosclerosis.

Currently in the field of vascular biology, the role of epigenetics in endothelial cell biology and vascular disease has attracted more in-depth study. Using both in vitro and in vivo models of blood flow, investigators have recently begun to reveal the underlying epigenetic regulation of endothelial gene expression. Recently, our group, along with two other independent groups, have demonstrated that blood flow controls endothelial gene expression by DNA methyltransferases (DNMT1 and 3A). Disturbed flow (d-flow), characterized by low and oscillating shear stress (OS), is pro-atherogenic and induces expression of DNMT1 both in vivo and in vitro. D-flow regulates genome-wide DNA methylation patterns in a DNMT-dependent manner. The DNMT inhibitor 5-Aza-2'deoxycytidine (5Aza) or DNMT1 siRNA reduces OS-induced endothelial inflammation. Moreover, 5Aza inhibits the development of atherosclerosis in ApoE(-/-) mice. Through a systems biological analysis of genome-wide DNA methylation patterns and gene expression data, we found 11 mechanosensitive genes which were suppressed by d-flow in vivo, experienced hypermethylation in their promoter region in response to d-flow, and were rescued by 5Aza treatment. Interestingly, among these mechanosensitive genes, the two transcription factors HoxA5 and Klf3 contain cAMP-response-elements (CRE), which may indicate that methylation of CRE sites could serve as a mechanosensitive master switch in gene expression. These findings provide new insight into the mechanism by which flow controls epigenetic DNA methylation patterns, which in turn alters endothelial gene expression, regulates vascular biology, and induces atherosclerosis. These novel findings have broad implications for understanding the biochemical mechanisms of atherogenesis and provide a basis for identifying potential therapeutic targets for atherosclerosis. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.

Identifying competencies required for medication prescribing for general practice residents: a nominal group technique study.

BACKGROUND: Teaching of medication prescribing is a specific challenge in general practice curriculum. The aim of this study was to identify and rank the competencies required for prescribing medication for general practice residents in France. METHODS: Qualitative consensus study using the nominal group technique. We invited different stakeholders of the general practice curriculum and medication use in primary care to a series of meetings. The nominal group technique allowed for the quick development of a list of consensual and ranked answers to the following question: "At the end of their general practice curriculum, in terms of medication prescribing, what should residents be able to do?". RESULTS: Four meetings were held that involved a total of 31 participants, enabling the creation of a final list of 29 ranked items, grouped in 4 domains. The four domains identified were 'pharmacology', 'regulatory standards', 'therapeutics', and 'communication (both with patients and healthcare professionals)'. Overall, the five items the most highly valued across the four meetings were: 'write a legible and understandable prescription', 'identify specific populations', 'prescribe the doses and durations following the indication', 'explain a lack of medication prescription to the patient', 'decline inappropriate medication request'. The 'communication skills' domain was the domain with the highest number of items (10 items), and with the most highly-valued items. CONCLUSION: The study results suggest a need for developing general practice residents' communication skills regarding medication prescribing.

Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs.

Atherosclerosis preferentially occurs in arterial regions exposed to disturbed flow, in part, due to alterations in gene expression. MicroRNAs (miRNAs) are small, noncoding genes that post-transcriptionally regulate gene expression by targeting messenger RNA transcripts. Emerging evidence indicates that alteration of flow conditions regulate expression of miRNAs in endothelial cells both in vitro and in vivo. These flow-sensitive miRNAs, known as mechano-miRs, regulate endothelial gene expression and can regulate endothelial dysfunction and atherosclerosis. MiRNAs such as, miR-10a, miR-19a, miR-23b, miR-17-92, miR-21, miR-663, miR-92a, miR-143/145, miR-101, miR-126, miR-712, miR-205, and miR-155, have been identified as mechano-miRs. Many of these miRNAs were initially identified as flow sensitive in vitro and were later found to play a critical role in endothelial function and atherosclerosis in vivo through either gain-of-function or loss-of-function approaches. The key signaling pathways that are targeted by these mechano-miRs include the endothelial cell cycle, inflammation, apoptosis, and nitric oxide signaling. Furthermore, we have recently shown that the miR-712/205 family, which is upregulated by disturbed flow, contributes to endothelial inflammation and vascular hyperpermeability by targeting tissue inhibitor of metalloproteinase-3, which regulates metalloproteinases and a disintegrin and metalloproteinases. The mechano-miRs that are implicated in atherosclerosis are termed as mechanosensitive athero-miRs and are potential therapeutic targets to prevent or treat atherosclerosis. This review summarizes the current knowledge of mechanosensitive athero-miRs and their role in vascular biology and atherosclerosis.

HIV-1 infection induces strong production of IP-10 through TLR7/9-dependent pathways.

OBJECTIVE: To study the cytokine/chemokine profiles in response to HIV-1 viremia, and elucidate the pathways leading to HIV-1-induced inflammation. DESIGN/METHODS: Plasma levels of 19 cytokines in individuals with early HIV-1 infection and individuals undergoing treatment interruptions were evaluated via multiplex assay. To investigate the cellular sources of relevant cytokines, sorted cells from HIV-1 infected individuals were assessed for mRNA expression. Relevant signaling pathways were assessed by comparing cytokine production patterns of peripheral blood mononuclear cells stimulated with intact HIV-1 or specific Toll-like receptor (TLR) stimulants with and without a TLR7/9 antagonist. RESULTS: IP-10 plasma concentration was most significantly associated with HIV-1 viral load and was the most significant contributor in a multivariate model. IP-10 mRNA was highly expressed in monocytes and mDCs and these cells were the dominant producers after in-vitro stimulation with TLR7/8 ligands (CL097 and ssRNAGag1166), AT-2 HIV-1, and HIV-1NL43 virus. Partial least square discriminant analysis of culture supernatants revealed distinct cytokine/chemokine secretion profiles associated with intact viruses compared with TLR7/8 ligands alone, with IP-10 production linked to the former. A TLR7/9 antagonist blocked IP-10 production following whole virus stimulation, suggesting the involvement of TLR7/9 in the recognition of HIV-1 by these cells. CONCLUSION: Monocytes and mDCs produce significant amounts of IP-10 in response to HIV-1 viremia and after in-vitro stimulation with HIV-1. Stimulation with HIV-1-derived TLR7/8-ligands versus HIV-1 resulted in distinct cytokine/chemokine profiles, indicating additional pathways other than TLR7/8 that lead to the activation of innate immune cells by HIV-1.

Induction of strong HIV-1-specific CD4+ T-cell responses using an HIV-1 gp120/NefTat vaccine adjuvanted with AS02A in antiretroviral-treated HIV-1-infected individuals.

BACKGROUND: Induction of HIV-1-specific CD4(+) T-cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1. METHODS: We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GlaxoSmithKline Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02(A) Adjuvant System in subjects with well-controlled chronic HIV-1 infection on highly active antiretroviral therapy. Ten individuals received the vaccine; whereas adjuvant alone or placebo was given to 5 subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and carboxyfluorescein succinimidyl ester-based proliferation assays. RESULTS: The vaccine was well tolerated with no related serious adverse events. Vaccine recipients had significantly stronger gp120-specific CD4(+) T-cell responses which persisted until week 48 and greater gp120-specific CD4(+) T-cell proliferation activity as compared with controls. In the vaccine group, the number of participants who demonstrated positive responses for both gp120-specific CD4(+) T-cell interleukin-2 production and gp120-specific CD8(+) T-cell proliferation were significantly higher at week 6. CONCLUSIONS: The gp120/NefTat/AS02(A) vaccine induced strong gp120-specific CD4(+) T-cell responses and a higher number of vaccinees developed both HIV-1-specific CD4(+) T-cell responses and CD8(+) T-cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control.

Changes in cytokine levels and NK cell activation associated with influenza.

Several studies have highlighted the important role played by murine natural killer (NK) cells in the control of influenza infection. However, human NK cell responses in acute influenza infection, including infection with the 2009 pandemic H1N1 influenza virus, are poorly documented. Here, we examined changes in NK cell phenotype and function and plasma cytokine levels associated with influenza infection and vaccination. We show that absolute numbers of peripheral blood NK cells, and particularly those of CD56(bright) NK cells, decreased upon acute influenza infection while this NK cell subset expanded following intramuscular influenza vaccination. NK cells exposed to influenza antigens were activated, with higher proportions of NK cells expressing CD69 in study subjects infected with seasonal influenza strains. Vaccination led to increased levels of CD25+ NK cells, and notably CD56(bright) CD25+ NK cells, whereas decreased amounts of this subset were present in the peripheral blood of influenza infected individuals, and predominantly in study subjects infected with the 2009 pandemic H1N1 influenza virus. Finally, acute influenza infection was associated with low plasma concentrations of inflammatory cytokines, including IFN-γ, MIP-1ß, IL-2 and IL-15, and high levels of the anti-inflammatory cytokines IL-10 and IL-1ra. Altogether, these data suggest a role for the CD56(bright) NK cell subset in the response to influenza, potentially involving their recruitment to infected tissues and a local production and/or uptake of inflammatory cytokines.