Comparing the teaching efficacy of a procedure-in-a-box toolkit to a live instructional workshop.

BACKGROUND: Emergency procedures have been traditionally taught in live "hands on" workshops, which are expensive (tuition, travel, hotel, and leaving one's practice idle). This study was conducted to compare the teaching efficacy of a traditional live workshop to a procedure-in-a-box toolkit (PBT) method which contains audiovisual instructions and props to practice the procedures. METHODS: Four procedures, zipper release, intraosseous needle placement, fishhook removal, and splinting, were taught to 32 physician volunteers, using both teaching methods. Each participant was asked to evaluate the teaching method after each session. RESULTS: The mean educational quality of each method were not significantly different from each other, but if given a choice study subjects preferred the live workshop more often. CONCLUSION: The live workshop is the preferable method for teaching procedures but when considering expenses, most of the subjects felt that the PBT method is an adequate substitute method for the live workshop

Incidence of Serious Bacterial Infections in Ex-premature Infants with a Postconceptional Age Less Than 48 Weeks Presenting to a Pediatric Emergency Department

Objectives: Premature infants are at higher risk of developing serious bacterial infections (SBI). However, the incidence of SBI in ex-premature infants presenting to the emergency department (ED) remains undetermined. The objective of this study is to examine the incidence of SBI in ex-premature infants with a postconceptional age of less than 48 weeks presenting to a pediatric ED.Methods: A retrospective medical record review was conducted on 141 ex-premature infants with a postconceptional age of less than 48 weeks who had a full or partial septic work up completed in a pediatric ED between January 1, 1998 and March 31, 2005.Results: The overall median gestational age at birth was 35 weeks (IQR 33-36 week) and the overall median postconceptional age at ED presentation was 40 weeks (IQR 37-42 weeks). Thirteen (9.2%) infants were found to have a SBI. Five subjects had pneumonia, four with bacteremia, two with pyelonephritis, and two with a concomitant infection of meningitis/pneumonia and bacteremia/pyelonephritis.Conclusion: The results of this study reveal that the incidence of SBI in ex-premature infants with a postconceptional age of less than 48 weeks is similar to in-term infants (9.2%) and is consistent with previously published incidence rates in-term infants (10%).[WestJEM. 2009;10:37-40.

Lessons learned from the history of postgraduate medical training in Japan: from disease-centred care to patient-centred care in an aging society.

BACKGROUND: Health workers, the core of health service delivery and a key driver of progress towards universal health coverage, must be available in sufficient numbers and distributed fairly to serve the entire population. In addition, the planning and management of the health workforce must be responsive to the changing needs of society, including changes in age structure and epidemiology. Considering these issues, this paper examines in historical perspective the evolution of postgraduate medical training and practice in Japan, from the late nineteenth century to the present. MAIN TEXT: When the first medical schools were established in the country towards the end of the nineteenth century, Japan was a largely agrarian society, with a population of about 30 million and an average life expectancy of 30-40 years. During the twentieth century, life expectancy and the national population continued to increase in a context of rapid economic growth. Since the 1980s, another demographic transition has occurred: low fertility rates and an aging society. As a result, the inputs and skills required from health professionals have changed considerably over time, posing new challenges to the national health sector and the management of human resources for health. CONCLUSIONS: The case of Japan offers valuable lessons for other countries experiencing a rapid epidemiological and demographic transition. To provide medical care that meets health priorities in the communities, we must consider not only the training of specialists, but also ensure the availability of a large cadre of physicians who possess basic skills and can provide patient-centred care. Furthermore, the Japanese experience shows that a highly hierarchical system and organisational culture are ill-suited to respond quickly to the changing demands of society

Phospholipase Cδ4 is required for Ca2+ mobilization essential for acrosome reaction in sperm

Zona pellucida (ZP)–induced acrosome reaction in sperm is a required step for mammalian fertilization. However, the precise mechanism of the acrosome reaction remains unclear. We previously reported that PLCδ4 is involved in the ZP-induced acrosome reaction in mouse sperm. Here we have monitored Ca2+ responses in single sperm, and we report that the [Ca2+]i increase in response to ZP, which is essential for driving the acrosome reaction in vivo, is absent in PLCδ4−/− sperm. Progesterone, another physiological inducer of the acrosome reaction, failed to induce sustained [Ca2+]i increases in PLCδ4−/− sperm, and consequently the acrosome reaction was partially inhibited. In addition, we observed oscillatory [Ca2+]i increases in wild-type sperm in response to these acrosome inducers. Calcium imaging studies revealed that the [Ca2+]i increases induced by exposure to ZP and progesterone started at different sites within the sperm head, indicating that these agonists induce the acrosome reaction via different Ca2+ mechanisms. Furthermore, store-operated channel (SOC) activity was severely impaired in PLCδ4−/− sperm. These results indicate that PLCδ4 is an important enzyme for intracellular [Ca2+]i mobilization in the ZP-induced acrosome reaction and for sustained [Ca2+]i increases through SOC induced by ZP and progesterone in sperm

Redox-sensitive transient receptor potential channels in oxygen sensing and adaptation

Regulation of ion channels is central to the mechanisms that underlie immediate acute physiological responses to changes in the availability of molecular oxygen (O2). A group of cation-permeable channels that are formed by transient receptor potential (TRP) proteins have been characterized as exquisite sensors of redox reactive species and as efficient actuators of electric/ionic signals in vivo. In this review, we first discuss how redox-sensitive TRP channels such as TRPA1 have recently emerged as sensors of the relatively inert oxidant O2. With regard to the physiological significance of O2 sensor TRP channels, vagal TRPA1 channels are mainly discussed with respect to their role in respiratory regulation in comparison with canonical pathways in glomus cells of the carotid body, which is a well-established O2-sensing organ. TRPM7 channels are discussed regarding hypoxia-sensing function in ischemic cell death. Also, ubiquitous expression of TRPA1 and TRPM7 together with their physiological relevance in the body is examined. Finally, based upon these studies on TRP channels, we propose a hypothesis of “O2 remodeling.” The hypothesis is that cells detect deviation of O2 availability from appropriate levels via sensors and adjust local O2 environments in vivo by controlling supply and consumption of O2 via pathways comprising cellular signals and transcription factors downstream of sensors, which consequently optimize physiological functions. This new insight into O2 adaptation through ion channels, particularly TRPs, may foster a paradigm shift in our understanding in the biological significance of O2

Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months;P < .001 and median OS, 17.4 vs 4.0 months;P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2

Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients

Total Synthesis of (±)-Phomoidride D

Described herein is a synthetic strategy for the total synthesis of (±)‐phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels–Alder cycloaddition. A subsequent SmI2‐mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion