Containing the burden of infectious diseases is everyone’s responsibility.:A call for an integrated strategy for developing and promoting hygiene behaviour change in home and everyday life

Across the world, health agencies recognize the profound impact of infectious disease on health and prosperity. Equally, they recognize that prevention is central to fighting infection, and that hygiene in home and everyday life (HEDL) is a key part of this. A current driver is the part that hygienei plays in tackling antibiotic resistance, but it also reflects growing numbers of people at greater risk of infection being cared for in the community. Sustaining the quality of state-funded healthcare requires that the public take greater responsibility for their own health, including protecting themselves and their families against infection. Hygiene must be must be everyone’s responsibility. However, if we are to be successful in promoting hygiene as part of public health, there are barriers which need to be overcome. A key issue is the need to balance evidence of the health benefits of hygiene against possible risks, such as environmental impacts and toxicity issues. Another issue is the role of microbes in human health and whether we have become “too clean”. Lack of a unified voice advocating for hygiene means these issues have tended to take precedence. Another barrier to change is public confusion about the need for hygiene and the difference between hygiene and cleanliness. To address this, we must work together to provide the public with a clear, consistent restatement of the importance of hygiene, and to change public perceptions about hygiene and good hygiene practice. This paper is unique because it examines these issues in an integrated manner and focuses on making achievable, constructive recommendations for developing an effective and sustainable approach. The paper lays out a risk management strategy for hygiene in home and everyday life which gives hygiene appropriate priority within the context of environmental and other health concerns. This “targeted hygiene” approach needs to be placed at the heart of a multimodal prevention strategy, alongside vaccination and other interventions. Based on the findings of this paper, we issue a call to action to national and international policy makers, health agencies and health professionals to recognize the need for an integrated, family-centredii approach to hygiene, and provide effective leadership to achieve this. This paper shows that many of the components of a behaviour change strategy are already in place, but need to be integrated rather than developed independently. We also issue a call to scientists, health professionals, environmental and regulatory agencies, immunologists, microbiomists, the private sector (hygiene appliance and product manufacturers) and the media to work together, through innovative research and communication policies. A collaborative effort is vital if we are to overcome barriers to change and action integrated behaviour change programmes that really work. The report represents the consensus views of an international, interdisciplinary group of experts in the field of infection prevention and hygiene. We recognise that this paper leaves many questions unanswered and would welcome further dialogue with stakeholders on how to develop policy. The aim of this paper is to provide a sound basis for such dialogue. At the 2016 launch of the European Human Biomonitoring Initiative, the EU commissioner for food safety said the followingiii which encapsulates the aim of this report. “We must collectively recognise that risk and uncertainty are part and parcel of every decision we take. We need to engage people in a serious and rational debate. But in this world of information overload – from old media and new – information, misinformation, opinions, prejudices, truths, half-truths and un-truths all compete for public attention. We need better communication of science so that people can be better informed about risk assessment and management decisions

Flaws in design, analysis and interpretation of Pfizer's antifungal trials of voriconazole and uncritical subsequent quotations

We have previously described how a series of trials sponsored by Pfizer of its antifungal drug, fluconazole, in cancer patients with neutropenia handicapped the control drug, amphotericin B, by flaws in design and analysis. We describe similar problems in two pivotal trials of Pfizer's new antifungal agent, voriconazole, published in a prestigious journal. In a non-inferiority trial, voriconazole was significantly inferior to liposomal amphothericin B, but the authors concluded that voriconazole was a suitable alternative. The second trial used amphothericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days. Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison. In a random sample of 50 references to these trials, we found that the unwarranted conclusions were mostly uncritically propagated. It was particularly surprising that relevant criticism raised by the FDA related to the first trial was only quoted once, and that none of the articles noted the obvious flaws in the design of the second trial. We suggest that editors ensure that the abstract reflects fairly on the remainder of the paper, and that journals do not impose any time limit for accepting letters that point out serious weaknesses in a study that have not been noted before

The origin of dust in galaxies revisited: the mechanism determining dust content

The origin of cosmic dust is a fundamental issue in planetary science. This paper revisits the origin of dust in galaxies, in particular, in the Milky Way, by using a chemical evolution model of a galaxy composed of stars, interstellar medium, metals (elements heavier than helium), and dust. We start from a review of time-evolutionary equations of the four components, and then, we present simple recipes for the stellar remnant mass and yields of metal and dust based on models of stellar nucleosynthesis and dust formation. After calibrating some model parameters with the data from the solar neighborhood, we have confirmed a shortage of the stellar dust production rate relative to the dust destruction rate by supernovae if the destruction efficiency suggested by theoretical works is correct. If the dust mass growth by material accretion in molecular clouds is active, the observed dust amount in the solar neighborhood is reproduced. We present a clear analytic explanation of the mechanism for determining dust content in galaxies after the activation of accretion growth: a balance between accretion growth and supernova destruction. Thus, the dust content is independent of the uncertainty of the stellar dust yield after the growth activation. The timing of the activation is determined by a critical metal mass fraction which depends on the growth and destruction efficiencies. The solar system formation seems to have occurred well after the activation and plenty of dust would have existed in the proto-solar nebula.Comment: 12 pages, 11 figure

Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment

Prostate cancer will develop chemoresistance following a period of chemotherapy. This is due, in part, to the acquisition of antiapoptotic properties by the cancer cells and, therefore, development of novel strategies for treatment is of critical need. Here, we attempt to clarify the role of the antiapoptotic molecule galectin-3 in prostate cancer cells using siRNA and antagonist approaches. The data showed that Gal-3 inhibition by siRNA or its antagonist GCS-100/modified citrus pectin (MCP) increased cisplatin-induced apoptosis of PC3 cells. Recent studies have indicated that cisplatin-induced apoptosis may be mediated by calpain, a calcium-dependent protease, as its activation leads to cleavage of androgen receptor into an androgen-independent isoform in prostate cancer cells. Thus, we examined whether calpain activation is associated with the Gal-3 function of regulating apoptosis. Here, we report that Gal-3 inhibition by siRNA or GCS-100/MCP enhances calpain activation, whereas Gal-3 overexpression inhibits it. Inhibition of calpain using its inhibitor and/or siRNA attenuated the proapoptotic effect of Gal-3 inhibition, suggesting that calpain activation may be a novel mechanism for the proapoptotic effect of Gal-3 inhibition. Thus, a paradigm shift for treating prostate cancer is suggested whereby a combination of a non-toxic anti-Gal-3 drug together with a toxic chemotherapeutic agent could serve as a novel therapeutic modality for chemoresistant prostate cancers

Soluble and Cell-Associated Insulin Receptor Dysfunction Correlates with Severity of HAND in HIV-Infected Women

Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population.To determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women.This is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (α) and full-length or intact (αβ)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry. HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND.This study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND

Injection therapy and denervation procedures for chronic low-back pain: a systematic review

Injection therapy and denervation procedures are commonly used in the management of chronic low-back pain (LBP) despite uncertainty regarding their effectiveness and safety. To provide an evaluation of the current evidence associated with the use of these procedures, a systematic review was performed. Existing systematic reviews were screened, and the Cochrane Back Review Group trial register was searched for randomized controlled trials (RCTs) fulfilling the inclusion criteria. Studies were included if they recruited adults with chronic LBP, evaluated the use of injection therapy or denervation procedures and measured at least one clinically relevant outcome (such as pain or functional status). Two review authors independently assessed studies for eligibility and risk of bias (RoB). A meta-analysis was performed with clinically homogeneous studies, and the GRADE approach was used to determine the quality of evidence. In total, 27 RCTs were included, 14 on injection therapy and 13 on denervation procedures. 18 (66%) of the studies were determined to have a low RoB. Because of clinical heterogeneity, only two comparisons could be pooled. Overall, there is only low to very low quality evidence to support the use of injection therapy and denervation procedures over placebo or other treatments for patients with chronic LBP. However, it cannot be ruled out that in carefully selected patients, some injection therapy or denervation procedures may be of benefit

Community mobilisation with women's groups facilitated by Accredited Social Health Activists (ASHAs) to improve maternal and newborn health in underserved areas of Jharkhand and Orissa: study protocol for a cluster-randomised controlled trial

Background: Around a quarter of the world's neonatal and maternal deaths occur in India. Morbidity and mortality are highest in rural areas and among the poorest wealth quintiles. Few interventions to improve maternal and newborn health outcomes with government-mandated community health workers have been rigorously evaluated at scale in this setting.The study aims to assess the impact of a community mobilisation intervention with women's groups facilitated by ASHAs to improve maternal and newborn health outcomes among rural tribal communities of Jharkhand and Orissa.Methods/design: The study is a cluster-randomised controlled trial and will be implemented in five districts, three in Jharkhand and two in Orissa. The unit of randomisation is a rural cluster of approximately 5000 population. We identified villages within rural, tribal areas of five districts, approached them for participation in the study and enrolled them into 30 clusters, with approximately 10 ASHAs per cluster. Within each district, 6 clusters were randomly allocated to receive the community intervention or to the control group, resulting in 15 intervention and 15 control clusters. Randomisation was carried out in the presence of local stakeholders who selected the cluster numbers and allocated them to intervention or control using a pre-generated random number sequence. The intervention is a participatory learning and action cycle where ASHAs support community women's groups through a four-phase process in which they identify and prioritise local maternal and newborn health problems, implement strategies to address these and evaluate the result. The cycle is designed to fit with the ASHAs' mandate to mobilise communities for health and to complement their other tasks, including increasing institutional delivery rates and providing home visits to mothers and newborns. The trial's primary endpoint is neonatal mortality during 24 months of intervention. Additional endpoints include home care practices and health care-seeking in the antenatal, delivery and postnatal period. The impact of the intervention will be measured through a prospective surveillance system implemented by the project team, through which mothers will be interviewed around six weeks after delivery. Cost data and qualitative data are collected for cost-effectiveness and process evaluations

The Interaction of LFA-1 on Mononuclear Cells and ICAM-1 on Tubular Epithelial Cells Accelerates TGF-β1-Induced Renal Epithelial-Mesenchymal Transition

The epithelial-mesenchymal transition (EMT) of renal epithelial cells (RTECs) has pivotal roles in the development of renal fibrosis. Although the interaction of lymphocyte function-associated antigen 1 (LFA-1) on leukocytes and its ligand, intracellular adhesion molecule 1 (ICAM-1), plays essential roles in most inflammatory reactions, its pathogenetic role in the EMT of RTECs remains to be clarified. In the present study, we investigated the effect of the interaction of LFA-1 on peripheral blood mononuclear cells (PBMCs) and ICAM-1 on HK-2 cells after stimulation with TGF-β1 on the EMT of RTECs. ICAM-1 was highly expressed in HK-2 cells. After TGF-β1 stimulation, the chemokines CCL3 and CXCL12 increased on HK-2 cells. After co-culture of PBMCs and HK-2 cells pre-stimulated with TGF-β1 (0.1 ng/ml) (HK-2-TGF-β1 (0.1)), the expression of the active form of LFA-1 increased on PBMCs; however, total LFA-1 expression did not change. The expression of the active form of LFA-1 on PBMCs did not increase after co-culture with not CCL3 but CXCL12 knockdown HK-2-TGF-β1 (0.1). The expression of epithelial cell junction markers (E-cadherin and occludin) further decreased and that of mesenchymal markers (vimentin and fibronectin) further increased in HK-2-TGF-β1 (0.1) after co-culture with PBMCs for 24 hrs (HK-2-TGF-β1 (0.1)-PBMCs). The phosphorylation of ERK 1/2 but not smad2 and smad3 increased in HK-2-TGF-β1 (0.1)-PBMCs. The snail and slug signaling did not increase HK-2-TGF-β1 (0.1)-PBMCs. Although the migration and invasion of HK-2 cells induced full EMT by a high dose (10.0 ng/ml) and long-term (72–96 hrs) TGF-β1 stimulation increased, that of HK-2-TGF-β1 (0.1)-PBMCs did not increase. These results suggested that HK-2 cells stimulated with TGF-β1 induced conformational activation of LFA-1 on PBMCs by increased CXCL12. Then, the direct interaction of LFA-1 on PBMCs and ICAM-1 on HK-2 cells activated ERK1/2 signaling to accelerate the part of EMT of HK-2 cells induced by TGF-β1