Neuraminidase Inhibitor Resistance in Influenza: Assessing the Danger of Its Generation and Spread

Neuraminidase Inhibitors (NI) are currently the most effective drugs against influenza. Recent cases of NI resistance are a cause for concern. To assess the danger of NI resistance, a number of studies have reported the fraction of treated patients from which resistant strains could be isolated. Unfortunately, those results strongly depend on the details of the experimental protocol. Additionally, knowing the fraction of patients harboring resistance is not too useful by itself. Instead, we want to know how likely it is that an infected patient can generate a resistant infection in a secondary host, and how likely it is that the resistant strain subsequently spreads. While estimates for these parameters can often be obtained from epidemiological data, such data is lacking for NI resistance in influenza. Here, we use an approach that does not rely on epidemiological data. Instead, we combine data from influenza infections of human volunteers with a mathematical framework that allows estimation of the parameters that govern the initial generation and subsequent spread of resistance. We show how these parameters are influenced by changes in drug efficacy, timing of treatment, fitness of the resistant strain, and details of virus and immune system dynamics. Our study provides estimates for parameters that can be directly used in mathematical and computational models to study how NI usage might lead to the emergence and spread of resistance in the population. We find that the initial generation of resistant cases is most likely lower than the fraction of resistant cases reported. However, we also show that the results depend strongly on the details of the within-host dynamics of influenza infections, and most importantly, the role the immune system plays. Better knowledge of the quantitative dynamics of the immune response during influenza infections will be crucial to further improve the results

The real effects of borrower-based macroprudential policy:Evidence from administrative household-level data

We analyze the effects of borrower-based macroprudential policy at the household level. We exploit administrative Dutch tax and housing records in conjunction with the introduction of a mortgage loan-to-value (LTV) limit. We find that the regulation sharply reduces mortgage leverage with bunching at the LTV limit. While (regulation) affected households reduce total leverage and interest expenses, they also decrease cash balances to satisfy the LTV limit, generating an important solvency-liquidity trade-off. Nevertheless, affected households experience less financial distress after the introduction of the LTV regulation. Moreover, these households experience better liquidity management and smoother consumption following income loss. Overall, our results highlight the key financial stability and real effects of borrower-based macroprudential policy.</p

Mechanism of killing by virus-induced cytotoxic T lymphocytes elicited in vivo

The mechanism of lysis by in vivo-induced cytotoxic T lymphocytes (CTL) was examined with virus-specific CTL from mice infected with lymphocytic choriomeningitis virus (LCMV). LCMV-induced T cells were shown to have greater than 10 times the serine esterase activity of T cells from normal mice, and high levels of serine esterase were located in the LCMV-induced CD8+ cell population. Serine esterase was also induced in purified T-cell preparations isolated from mice infected with other viruses (mouse hepatitis, Pichinde, and vaccinia). In contrast, the interferon inducer poly(I.C) only marginally enhanced serine esterase in T cells. Serine esterase activity was released from the LCMV-induced T cells upon incubation with syngeneic but not allogeneic LCMV-infected target cells. Both cytotoxicity and the release of serine esterase were calcium dependent. Serine esterase released from disrupted LCMV-induced T cells was in the form of the fast-sedimenting particles, suggesting its inclusion in granules. Competitive substrates for serine esterase blocked killing by LCMV-specific CTL, but serine esterase-containing granules isolated from LCMV-induced CTL, in contrast to granules isolated from a rat natural killer cell tumor line, did not display detectable hemolytic activity. Fragmentation of target cell DNA was observed during the lytic process mediated by LCMV-specific CTL, and the release of the DNA label [125I]iododeoxyuridine from target cells and the accompanying fragmentation of DNA also were calcium dependent. These data support the hypothesis that the mechanism of killing by in vivo-induced T cells involves a calcium-dependent secretion of serine esterase-containing granules and a target cell death by a process involving nuclear degradation and DNA fragmentation

Nurses’ perceptions of and satisfaction with the use of automated dispensing cabinets at the Heart and Cancer Centers in Qatar: a cross-sectional study

Background Automated dispensing cabinets (ADCs) were introduced in 2010 and 2012 at the Heart Hospital (HH) and National Center for Cancer Care and Research (NCCCR), both run by Hamad Medical Corporation in Qatar. These medication distribution systems provide computer-controlled storage, dispensing, and tracking of drugs at the point of care in patient care units. The purpose of this study was to assess nurses’ perceptions of and satisfaction with the use of ADCs at HH and NCCCR. Methods A cross-sectional study was conducted in the two institutions in May and November 2012 using a piloted, validated, online, and anonymous questionnaire. The questionnaire consisted of four parts: nurses’ sociodemographic and practice characteristics, 21 questions about their perceptions, one question about their overall satisfaction, and one about the system’s ease of use. The self-administered survey was distributed to 503 nurses working at HH and NCCCR over three weeks using Survey Monkey®. Results The survey response rate was 80 % (n = 403). No significant difference was found in perception scores between the two institutions (p = 0.06). Ninety-four percent (n = 378) of nurses agreed that the medication delivery system allowed them to do their job more safely, and 90 % (n = 363) nurses agreed that they now spent less time waiting for medication from the pharmacy than they did before the ADC system was introduced. Eighty seven percent (n = 349) nurses agreed that they were able to administer medication more efficiently with the ADC system. The overall satisfaction rate (either “very satisfied” or “satisfied”) for the two hospitals was 91 %. Conclusions The nurses’ perceptions of and levels of satisfaction with the ADC system were very good over the 6 months after complete implementation and integration at HH and NCCCR. ADCs appear to increase efficiency in the medication process and should therefore improve the quality of care

Prospective Study of Antibiotic Prophylaxis for Prostate Biopsy Involving >1100 Men

We aimed to compare infection rates for two 3-day antibiotic prophylaxis regimens for transrectal ultrasound-guided prostate biopsy (TRUSgbp) and demonstrate local microbiological trends. In 2008, 558 men and, in 2009, 625 men had TRUSgpb. Regimen 1 (2008) comprised 400 mg Ofloxacin immediately before biopsy and 200 mg 12-hourly for 3 days. Regimen 2 (2009) comprised Ofloxacin 200 mg 12-hourly for 3 days commencing 24 hours before biopsy. 20/558 (3.6%) men had febrile episodes with regimen 1 and 10/625 (1.6%) men with regimen 2 (P = 0.03). E. coli was the most frequently isolated organism. Overall, 7/13 (54%) of positive urine cultures were quinolone resistant and (5/13) 40% were multidrug resistant. Overall, 5/9 (56%) patients with septicaemia were quinolone resistant. All patients were sensitive to Meropenem. There was 1 (0.2%) death with regimen 1. Commencing Ofloxacin 24 hours before TRUSgpb reduced the incidence of febrile episodes significantly. We observed the emergence of quinolone and multidrug-resistant E. coli. Meropenem should be considered for unresolving sepsis

Estimating the Precursor Frequency of Naive Antigen-specific CD8 T Cells

The constraint of fitting a diverse repertoire of antigen specificities in a limited total population of lymphocytes results in the frequency of naive cells specific for any given antigen (defined as the precursor frequency) being below the limit of detection by direct measurement. We have estimated this precursor frequency by titrating a known quantity of antigen-specific cells into naive recipients. Adoptive transfer of naive antigen-specific T cell receptor transgenic cells into syngeneic nontransgenic recipients, followed by stimulation with specific antigen, results in activation and expansion of both donor and endogenous antigen-specific cells in a dose-dependent manner. The precursor frequency is equal to the number of transferred cells when the transgenic and endogenous responses are of equal magnitude. Using this method we have estimated the precursor frequency of naive CD8 T cells specific for the H-2Db–restricted GP33–41 epitope of LCMV to be 1 in 2 × 105. Thus, in an uninfected mouse containing ∼2-4 × 107 naive CD8 T cells we estimate there to be 100–200 epitope-specific cells. After LCMV infection these 100–200 GP33-specific naive CD8 T cells divide >14 times in 1 wk to reach a total of ∼107 cells. Approximately 5% of these activated GP33-specific effector CD8 T cells survive to generate a memory pool consisting of ∼5 × 105 cells. Thus, an acute LCMV infection results in a >1,000-fold increase in precursor frequency of DbGP33-specific CD8 T cells from 2 × 102 naive cells in uninfected mice to 5 × 105 memory cells in immunized mice

A training model for relatives and friends in cognitive behaviour therapy (CBT) informed care for psychosis

Relatives and close friends provide life-long support as informal carers to those living with psychosis. We introduce a model for training informal carers in cognitive behaviour therapy (CBT) for psychosis, called Psychosis Recovery by Enabling Adult Carers at Home (Psychosis REACH). The model aims to address the carers’ own emotional needs and at the same time build their capabilities of promoting the recovery trajectory of the person they care for. We delivered two- and five-day workshops, underpinned by the Psychosis REACH model, to a cohort of 95 self-identified carers recruited via a charitable organisation in Canada. In a single-group before-and-after design, carers’ anxiety, depression and mental well-being significantly improved within a few days. A handful of carers who returned data for their cared-for-person after the end of training, observed either no change or a positive change in functioning. Our findings generated hypotheses that deserve further research to test whether training large groups of relatives and friends in CBT-informed care for psychosis can improve their anxiety, depression and mental well-being in the context of their caring role, as well as improve the functioning of those they care for

Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response

Dramatic rise of mutators has been found to accompany adaptation of bacteria in response to many kinds of stress. Two views on the evolutionary origin of this phenomenon emerged: the pleiotropic hypothesis positing that it is a byproduct of environmental stress or other specific stress response mechanisms and the second order selection which states that mutators hitchhike to fixation with unrelated beneficial alleles. Conventional population genetics models could not fully resolve this controversy because they are based on certain assumptions about fitness landscape. Here we address this problem using a microscopic multiscale model, which couples physically realistic molecular descriptions of proteins and their interactions with population genetics of carrier organisms without assuming any a priori fitness landscape. We found that both pleiotropy and second order selection play a crucial role at different stages of adaptation: the supply of mutators is provided through destabilization of error correction complexes or fluctuations of production levels of prototypic mismatch repair proteins (pleiotropic effects), while rise and fixation of mutators occur when there is a sufficient supply of beneficial mutations in replication-controlling genes. This general mechanism assures a robust and reliable adaptation of organisms to unforeseen challenges. This study highlights physical principles underlying physical biological mechanisms of stress response and adaptation

Laser Vaporization of Mouth Lesions, an Overview

Lasers are utilized in dentistry as a therapeutic tool or as an auxiliary tool. The major purpose of employing lasers in dentistry is to overcome the difficulties that are currently observed in traditional dental treatment treatments. The laser is used in hard tissue applications such as caries prevention, bleaching, restorative removal and curing, cavity preparation, dentinal hypersensitivity, growth modulation, and diagnostics, whereas soft tissue applications include wound healing, removal of hyperplastic tissue to uncover impacted or partially erupted teeth, photodynamic therapy for malignancies, and photo-stimulation of herpetic lesions. Lasers' capacity to perform minimally invasive operations with minimum patient discomfort has proven effective in the patient delivery system in dentistry practice. The availability of lasers with various wavelengths has produced a surgical panacea, and laser technology has replaced traditional surgical techniques in many oral surgical operations