Zanamivir Conjugated to Poly-L-Glutamine is Much More Active Against Influenza Viruses in Mice and Ferrets Than the Drug Itself

Purpose: Previously, polymer-attached zanamivir had been found to inhibit influenza A viruses in vitro far better than did small-molecule zanamivir (1) itself. The aim of this study was to identify in vitro—using the plaque reduction assay—a highly potent 1-polymer conjugate, and subsequently test its antiviral efficacy in vivo. Methods: By examining the structure-activity relationship of 1-polymer conjugates in the plaque assay, we have determined that the most potent inhibitor against several representative influenza virus strains has a neutral high-molecular-weight backbone and a short alkyl linker. We have examined this optimal polymeric inhibitor for efficacy and immunogenicity in the mouse and ferret models of infection. Results: 1 attached to poly-L-glutamine is an effective therapeutic for established influenza infection in ferrets, reducing viral titers up to 30-fold for 6 days. There is also up to a 190-fold reduction in viral load when the drug is used as a combined prophylactic/therapeutic in mice. Additionally, we see no evidence that the drug conjugate stimulates an immune response in mice upon repeat administration. Conclusions: 1 attached to a neutral high-molecular-weight backbone through a short alkyl linker drastically reduced both in vitro and in vivo titers compared to those observed with 1 itself. Thus, further development of this polymeric zanamivir for the mitigation of influenza infection seems warranted.National Institutes of Health (U.S.) (Grant U01-AI074443

Drug allergy

Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. This type of adverse drug reaction (ADR) not only affects patient quality of life, but may also lead to delayed treatment, unnecessary investigations, and even mortality. Given the myriad of symptoms associated with the condition, diagnosis is often challenging. Therefore, referral to an allergist experienced in the identification, diagnosis and management of drug allergy is recommended if a drug-induced allergic reaction is suspected. Diagnosis relies on a careful history and physical examination. In some instances, skin testing, graded challenges and induction of drug tolerance procedures may be required

Evidence of superficial knowledge regarding antibiotics and their use: Results of two cross-sectional surveys in an urban informal settlement in Kenya

<div><p>We assessed knowledge and practices related to antibiotic use in Kibera, an urban informal settlement in Kenya. Surveys was employed at the beginning (entry) and again at the end (exit) of a 5-month longitudinal study of AMR. Two-hundred households were interviewed at entry, of which 149 were also interviewed at exit. The majority (>65%) of respondents in both surveys could name at least one antibiotic, with amoxicillin and cotrimoxazole jointly accounting for 85% and 77% of antibiotics mentioned during entry and exit, respectively. More than 80% of respondents felt antibiotics should not be shared or discontinued following the alleviation of symptoms. Nevertheless, 66% and 74% of respondents considered antibiotics effective for treating colds and flu in the entry and exit surveys, respectively. There was a high (87%, entry; 70% exit) level of reported antibiotic use (past 12 months) mainly for colds/flu, coughs and fever, with >80% of respondents obtaining antibiotics from health facilities and pharmacies. Less than half of respondents remembered getting information on the correct use of antibiotics, although 100% of those who did reported improved attitudes towards antibiotic use. Clinicians and community pharmacists were highly trusted information sources. Paired household responses (n = 149) generally showed improved knowledge and attitudes by the exit survey although practices were largely unchanged. Weak agreement (κ = -0.003 to 0.22) between survey responses suggest both that unintended learning had not occurred, and that participant responses were not based on established knowledge or behaviors. Targeted public education regarding antibiotics is needed to address this gap.</p></div

A Participatory Return-to-Work Program for Temporary Agency Workers and Unemployed Workers Sick-Listed Due to Musculoskeletal Disorders: a Process Evaluation Alongside a Randomized Controlled Trial

Introduction Beside (cost-)effectiveness, the feasibility of an intervention is important for successful implementation in daily practice. This study concerns the process evaluation of a newly developed participatory return-to-work (RTW) program for workers without an employment contract, sick-listed due to musculoskeletal disorders. The program consisted of a stepwise process, guided by an independent RTW coordinator, aimed at making a consensus-based RTW plan with the possibility of a temporary (therapeutic) workplace. The aims of this study were to describe the reach and extent of implementation of the new program, the satisfaction and experiences of all stakeholders, and the perceived barriers and facilitators for implementation of the program in daily practice. Methods Temporary agency workers and unemployed workers, sick-listed for 2–8 weeks due to musculoskeletal disorders were eligible for this study. Data were collected from the workers; their insurance physicians and labour experts at the Dutch Social Security Agency; RTW coordinators; and case managers from participating vocational rehabilitation agencies. Data collection took place using professionals’ reports, standardized matrices, questionnaires at baseline and at 3-month follow-up, and group interviews with the professionals. Results Of the 79 workers who were allocated to the participatory RTW program group, 72 workers actually started with the intervention. Overall, implementation of the program was performed according to protocol. However, offering of suitable temporary workplaces was delayed with 44.5 days. Results showed satisfaction with the RTW coordinator among the workers and three quarters of the labour experts experienced a minor or major contribution of the presence of the RTW coordinator. Several barriers for implementation were identified, such as the administrative time-investment, unclear information about the program, no timely offering of temporary (therapeutic) workplaces, and the need for additional support in case of complex health problems. Conclusions This study indicates overall feasibility for implementation of the participatory RTW program in daily practice. However, to overcome important barriers, more attention should be paid to improve timely offering of suitable temporary workplaces, to describe more clearly the program goals and the professional’s roles, and to offer additional support for workers suffering from complex multi-causal health problems. Trial registration NTR1047

Maternal Perception of Child Weight Among Mexicans in California and Mexico

The prevalence of childhood overweight is high in Mexican immigrant communities in the United States. Understanding mother’s perceptions of child weight in immigrants’ country of origin may help to understand this high prevalence. The goal of this study was to examine and compare mothers’ perception of weight in Mexico (MX) and in an immigrant community in California (CA). We assessed perceptions of child weight using a pictorial scale with 314 mothers of 5-year-old children in MX and 60 mothers of 5 year-old-children in CA. We compared maternal reports with children’s objectively measured weight. Using chi-square and Analysis of Variance, we investigated associations of maternal perception of and satisfaction with weight according to socio-demographic characteristics. Mothers were more likely to underestimate their children’s weight in CA than in MX. On average, CA mothers wanted their children to be smaller than they currently were and mothers in MX wanted their children to be bigger than they currently were. This differed by weight status in CA with mothers of normal weight and at-risk-for-overweight children wanting them to be bigger and mothers of overweight children wanting them to be smaller. In order for programs to be effective, mothers must be able to recognize their children as overweight and want to address it. Because underestimation of weight and a desire for a larger size is common in this population, programs to address overweight may be more effective if they focus on alternative benefits of weight control strategies, such as healthy child development

Association between depressive symptoms and incident cardiovascular diseases

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVD). Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. Design, setting and participants: A pooled analysis of individual-participant-data from the Emerging Risk Factors Collaboration (ERFC; 162,036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and UK Biobank (UKB; 401,219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline. Exposure: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Centre for Epidemiological Studies Depression scale (CES-D; range 0-60; ≥16 indicates possible depressive disorder). UKB recorded the Patient Health Questionnaire-2 (PHQ-2; range 0-6; ≥3 indicates possible depressive disorder). Main Outcomes and Measures: Primary outcomes were incident fatal/nonfatal coronary heart disease (CHD), stroke and CVD (composite of CHD and stroke). Hazard ratios (HRs) per 1-SD higher log-CES-D or PHQ-2 adjusted for age, sex, smoking and diabetes were reported. Results: Among 162,036 participants from the ERFC, 73% were female, mean (SD) age at baseline was 63 (9) years, and 5,078 CHD and 3,932 stroke events were recorded (median follow-up, 9.5-years). Associations with CHD, stroke and CVD were log-linear. HRs (95%CI) per 1SD higher depression score for CHD, stroke and CVD respectively were 1.07 (1.03-1.11), 1.05 (1.01-1.10), and 1.06 (1.04-1.08). This reflects, 36 versus 29 CHD events, 28 versus 25 stroke events, and 63 versus 54 CVD events per 1000 individuals over 10 years in the highest versus lowest quintile of CES-D (geometric mean CES-D score, 19 versus 1). Among 401,219 participants from the UKB, 55% were female, mean baseline age was 56 (8) years, and 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1-years). HRs per 1SD higher depression score for CHD, stroke and CVD respectively were 1.11 (1.08-1.14), 1.10 (1.06-1.14) and 1.10 (1.08-1.13). This reflects, 21 versus 14 CHD events, 15 versus 10 stroke events, and 36 versus 25 CVD events per 1000 individuals over 10 years in those with PHQ2 ≥4 versus 0. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. Conclusions and Relevance: In a pooled analysis of 563,255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels below the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.Lisa Pennells, Stephen Kaptoge and Sarah Spackman are funded by a British Heart Foundation Programme Grant (RG/18/13/33946). Steven Bell was funded by the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Tom Bolton is funded by the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Angela Wood is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). John Danesh holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award.* *The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care

Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child

Background: Countries worldwide recommend women planning pregnancy to use daily 400 mg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. Methodology/Principal Findings: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). Conclusions: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use

Induction of Tachykinin Production in Airway Epithelia in Response to Viral Infection

The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to lung challenge has been previously demonstrated but has been focused predominantly on the release of the tachykinins from nerves innervating the lung. We have previously demonstrated the most dramatic phenotype described for the substance P encoding gene preprotachykinin-A (PPT-A) to date in controlling the host immune response to the murine gammaherpesvirus 68, in the lung.In this study we have utilised transgenic mice engineered to co-ordinately express the beta-galactosidase marker gene along with PPT-A to facilitate the tracking of PPT-A expression. Using a combination of these mice and conventional immunohistology we now demonstrate that PPT-A gene expression and substance P peptide are induced in cells of the respiratory tract including tracheal, bronchiolar and alveolar epithelial cells and macrophages after viral infection. This induction was observed 24h post infection, prior to observable inflammation and the expression of pro-inflammatory chemokines in this model. Induced expression of the PPT-A gene and peptide persisted in the lower respiratory tract through day 7 post infection.Non-neuronal PPT-A expression early after infection may have important clinical implications for the progression or management of lung disease or infection aside from the well characterised later involvement of the tachykinins during the inflammatory response