•Influenza infections unseasonably low during May to July 2020 in Cambodia.•Outbreak of influenza A (H3N2) virus infection occurred in a pagoda in August 2020.•Mask use and social distancing were ...infrequent and inconsistent in this population.•Measures to prevent COVID-19 spread may have delayed the influenza season.•Ongoing influenza surveillance and vaccination are priorities.
Global influenza virus circulation decreased during the COVID-19 pandemic, possibly due to widespread community mitigation measures. Cambodia eased some COVID-19 mitigation measures in June and July 2020. On 20 August a cluster of respiratory illnesses occurred among residents of a pagoda, including people who tested positive for influenza A but none who were positive for SARS-CoV-2.
A response team was deployed on 25 August 2020. People with influenza-like illness (ILI) were asked questions regarding demographics, illness, personal prevention measures, and residential arrangements. Respiratory swabs were tested for influenza and SARS-Cov-2 by real-time reverse transcription PCR, and viruses were sequenced. Sentinel surveillance data were analyzed to assess recent trends in influenza circulation in the community.
Influenza A (H3N2) viruses were identified during sentinel surveillance in Cambodia in July 2020 prior to the reported pagoda outbreak. Among the 362 pagoda residents, 73 (20.2%) ILI cases were identified and 40 were tested, where 33/40 (82.5%) confirmed positive for influenza A (H3N2). All 40 were negative for SARS-CoV-2. Among the 73 residents with ILI, none were vaccinated against influenza, 47 (64%) clustered in 3/8 sleeping quarters, 20 (27%) reported often wearing a mask, 27 (36%) reported often washing hands, and 11 (15%) reported practicing social distancing. All viruses clustered within clade 3c2.A1 close to strains circulating in Australia in 2020.
Circulation of influenza viruses began in the community following the relaxation of national COVID-19 mitigation measures, and prior to the outbreak in a pagoda with limited social distancing. Continued surveillance and influenza vaccination are required to limit the impact of influenza globally.
Antibodies to CD44 have been used to successfully ameliorate murine models of autoimmune disease. The most often studied disease model has been murine inflammatory arthritis, where a clear mechanism ...for the efficacy of CD44 antibodies has not been established. We have recently shown in a murine passive-model of the autoimmune disease immune thrombocytopenia (ITP) that some CD44 antibodies themselves can induce thrombocytopenia in mice, and the CD44 antibody causing the most severe thrombocytopenia (IM7), also is known to be highly effective in ameliorating murine models of arthritis. Recent work in the K/BxN serum-induced model of arthritis demonstrated that antibody-induced thrombocytopenia reduced arthritis, causing us to question whether CD44 antibodies might primarily ameliorate arthritis through their thrombocytopenic effect. We evaluated IM7, IRAWB14.4, 5035-41.1D, KM201, KM114, and KM81, and found that while all could induce thrombocytopenia, the degree of protection against serum-induced arthritis was not closely related to the length or severity of the thrombocytopenia. CD44 antibody treatment was also able to reverse established inflammation, while thrombocytopenia induced by an anti-platelet antibody targeting the GPIIbIIIa platelet antigen, could not mediate this effect. While CD44 antibody-induced thrombocytopenia may contribute to some of its therapeutic effect against the initiation of arthritis, for established disease there are likely other mechanisms contributing to its efficacy. Humans are not known to express CD44 on platelets, and are therefore unlikely to develop thrombocytopenia after CD44 antibody treatment. An understanding of the relationship between arthritis, thrombocytopenia, and CD44 antibody treatment remains critical for continued development of CD44 antibody therapeutics.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis through its cognate receptors death receptor 4 (DR4) and death receptor 5 (DR5), preferentially in malignant cells. ...However, many malignant cells remain resistant to TRAIL cytotoxicity by poorly characterized mechanisms. Here, using cholangiocarcinoma cells, as a model for TRAIL resistance, we identified a role for the oncogenic Hedgehog (Hh)-GLI pathway in the regulation of TRAIL cytotoxicity. Blockade of Hh using pharmacological and genetic tools sensitizes the cells to TRAIL cytotoxicity. Restoration of apoptosis sensitivity coincided with upregulation of DR4 expression, while expression of other death effector proteins remained unaltered. Knockdown of DR4 mimics Hh-mediated resistance to TRAIL cytotoxicity. Hh regulates the expression of DR4 by modulating the activity of its promoter. Luciferase, chromatin immunoprecipitation and expression assays show that the transcription factor GLI3 binds to the DR4 promoter and Hh requires an intact GLI3-repression activity to silence DR4 expression. Finally, small interfering RNA (siRNA)-targeted knockdown of GLI3, but not GLI1 or GLI2, restores DR4 expression and TRAIL sensitivity, indicating that the Hh effect is exclusively mediated by this transcription factor. In conclusion, these data provide evidence of a regulatory mechanism, which modulates TRAIL signaling in cancer cells and suggest new therapeutic approaches for TRAIL-resistant neoplasms.
Immunization with a recombinant form of the protective antigen (rPA) from Bacillus anthracis has been carried out with rhesus macaques. Rhesus macaques immunized with 25 microg or more of B. ...subtilis-expressed rPA bound to alhydrogel had a significantly increased immunoglobulin G (IgG) response to rPA compared with macaques receiving the existing licensed vaccine from the United Kingdom (anthrax vaccine precipitated AVP), although the isotype profile was unchanged, with bias towards the IgG1 and IgG2 subclasses. Immune macaque sera from all immunized groups contained toxin-neutralizing antibody and recognized all the domains of PA. While the recognition of the N terminus of PA (domains 1 to 3) was predominant in macaques immunized with the existing vaccines (AVP and the U.S. vaccine anthrax vaccine adsorbed), macaques immunized with rPA recognized the N- and C-terminal domains of PA. Antiserum derived from immunized macaques protected macrophages in vitro against the cytotoxic effects of lethal toxin. Passive transfer of IgG purified from immune macaque serum into naive A/J mice conferred protection against challenge with B. anthracis in a dose-related manner. The protection conferred by passive transfer of 500 microg macaque IgG correlated significantly (P = 0.003; r = 0.4) with the titers of neutralizing antibody in donor macaques. Subsequently, a separate group of rhesus macaques immunized with 50 microg of Escherichia coli-derived rPA adsorbed to alhydrogel was fully protected against a target dose of 200 50% lethal doses of aerosolized B. anthracis. These data provide some preliminary evidence for the existence of immune correlates of protection against anthrax infection in rhesus macaques immunized with rPA.
Discrete choice experiments (DCEs) are commonly used to elicit patient preferences as marginal rates of substitution (MRSs) between treatment or health service attributes. Because these studies are ...increasing in importance, it is vital that uncertainty around MRS estimates is reported.
To review recently published DCE studies that elicit patient preferences in relation to MRS reporting and to explore the accuracy of using other reported information to estimate the uncertainty of the MRSs.
A systematic literature review of DCEs conducted with patients between 2014 and July 2019 was performed. The number of studies reporting coefficients, MRSs, standard errors (SEs), and confidence intervals was recorded. If all information was reported, studies were included in an analysis to determine the impact of estimating the SEs of MRSs using coefficients and assuming zero covariance, to determine the impact of this assumption.
Two hundred and thirty-two patient DCEs were identified in the review; 34.1% (n = 79) reported 1 or more MRS and, of these, only 62.0% (n = 49) provided an estimate of the uncertainty. Of these studies, 16 contained enough information for inclusion in the analysis, providing 116 datapoints. Actual SEs were smaller than estimated SEs in 75.0% of cases (n = 87), and estimated SEs were within 25% of the actual SE in 59.5% of cases (n = 69).
Uncertainty of MRS estimates is unreported in a substantial proportion of recently published DCE studies. Estimating the SE of a MRS by solely using the SEs of the utility coefficients is likely to lead to biased estimates of the precision of patient trade-offs.
•Discrete choice experiments (DCEs) that elicit patient preferences are increasingly being conducted, and their role in decision making is increasing. One of the key outputs of a DCE is the marginal rate of substitution (MRS), but it has been suggested in the literature that reporting of uncertainty around MRSs is inadequate.•In this study, a systematic literature review was conducted to determine the frequency with which DCE studies that elicit patient preferences reported MRS without information on the degree of uncertainty. An analysis was also conducted to determine how standard errors (SEs) of MRSs calculated using commonly reported information compare with the actual SEs.•The degree of uncertainty around MRS estimates was not reported in over one-third of patient preference DCE studies that reported MRS. The analysis indicated that estimates of SEs calculated using commonly reported information are often significantly biased when covariances (typically not reported) are not included in calculations. Thus, it is crucial that researchers calculate and report SEs of MRSs.
The aim of this study was to examine the association between body mass index (BMI) and asthma incidence. Data from the baseline examination conducted during 1971-1975, and the first follow-up ...conducted during 1982-1984, of the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (a cohort study) was used. Asthma was self-reported or reported by proxies. BMI was calculated from measured height and weight obtained during the baseline examination. Among 9,456 participants aged 25-74 yrs who were free of asthma at baseline, 317 participants reported a diagnosis of asthma during the follow-up interview. Compared with participants with a BMI of 18.5-<25.0 kg.m(-2), the odds ratio (OR) for those with a BMI of > or =35 kg x m(-2) was 1.87 (95% confidence interval (CI) 1.12-3.13). ORs were similar for males and females. However, only 125 of the 298 participants who recalled a date of onset reported a diagnosis that occurred after their baseline examination. Among this group of participants, BMI was not significantly associated with asthma incidence (OR 1.52, 95% CI 0.62-3.77). In conclusion, although obese people reported more "incident" asthma during follow-up, it remains unclear whether this represents reactivation of previously diagnosed asthma or the onset of new cases, and whether these new cases actually represent true asthma or respiratory symptoms misdiagnosed as asthma.
Objectives
Preference information is increasingly being elicited to support decision-making. Although discrete choice experiments (DCEs) are commonly used, little is known about how respondents’ ...relative experience of a health issue, and its treatment, might impact the results of preference studies. The aim of this study was to explore how preferences differ between groups of individuals with varying levels of experience of a health issue and its treatment, using a weight loss maintenance (WLM) programme as a case study.
Methods
An online DCE survey was provided to four groups, each differing in their level of experience with weight loss and WLM programmes. One group was recruited from a randomised controlled trial of a WLM programme (ISRCTN14657176) and the other three from an online panel. Choice data were analysed using mixed logit models. Relative attribute importance scores and willingness-to-pay (WTP) estimates were estimated to enable comparisons between groups.
Results
Preferences differed between the groups across different attributes. The largest differences related to the outcome (weight re-gain) and cost attributes, resulting in WTP estimates that were statistically significantly different. The most experienced group was willing to pay £0.35 (95% CI: £0.28, £0.42) to avoid a percentage point increase in weight re-gain, compared with £0.12 (95% CI: £0.08, £0.16) for the least experienced group.
Conclusion
This study provides evidence in a public health setting to suggest that preferences differ based on respondent experience of the health issue and its treatment. Health preference researchers should therefore carefully consider the appropriate composition of their study samples.
Activation of the unfolded protein response sensor PKR-like endoplasmic reticulum kinase (Perk) attenuates endoplasmic reticulum (ER) stress levels. Conversantly, if the damage is too severe and ER ...function cannot be restored, this signaling branch triggers apoptosis. Bcl-2 homology 3-only family member Bim is essential for ER stress-induced apoptosis. However, the regulatory mechanisms controlling Bim activation under ER stress conditions are not well understood. Here, we show that downregulation of the miR-106b-25 cluster contributes to ER stress-induced apoptosis and the upregulation of Bim. Hypericin-mediated photo-oxidative ER damage induced Perk-dependent cell death and led to a significant decrease in the levels of miRNAs belonging to miR-106b-25 cluster in wild-type (WT) but not in Perk⁻/⁻ MEFs. Further, we show that expression of miR-106b-25 and Mcm-7 (host gene of miR-106b-25) is co-regulated through the transcription factors Atf4 (activating transcription factor 4) and Nrf2 (nuclear factor-erythroid-2-related factor 2). ER stress increased the activity of WT Bim 3'UTR (untranslated region) construct but not the miR-106b-25 recognition site-mutated Bim 3'UTR construct. Overexpression of miR-106b-25 cluster inhibits ER stress-induced cell death in WT but did not confer any further protection in Bim-knockdown cells. Further, we show downregulation in the levels of miR-106b-25 cluster in the symptomatic SOD1(G86R) transgenic mice. Our results suggest a molecular mechanism whereby repression of miR-106b-25 cluster has an important role in ER stress-mediated increase in Bim and apoptosis.
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