Effects of Cetuximab and Erlotinib on the behaviour of cancer stem cells in head and neck squamous cell carcinoma.

The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies.This work was supported by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs, Grant number: NC/L00061X/1), by The São Paulo Research Foundation (FAPESP Grant numbers 2014/12658-3 and 2011/21395-8), and by the Barts and The London Charitable Foundation

A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma

Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses.A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.ClinicalTrials.gov NCT00626015

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

MODIS-Based Investigation of Flood Areas in Southern Cambodia from 2002–2013

In Cambodia and the Vietnamese Mekong Delta, floods commonly occur during the rainy season, and a better understanding of their spatio-temporal distribution is important for both disaster prevention and the improvement of agricultural production. This study investigated spatio-temporal flood inundation and land cover change from 2002 to 2013 in the southern part of Cambodia using Terra satellite on-board Moderate Resolution Imaging Spectroradiometer (MODIS) images. The algorithm for flood inundation detection, WFFI (Wavelet-based Filter for detecting spatio-temporal changes in Flood Inundation) was used, and the parameters were modified to fit the present study. The estimated inundation areas were validated using eight Landsat images. In a comparison between the original and modified WFFIs, the modified WFFI (70&#8722;96%) exhibited better accuracy than the original WFFI (30&#8722;70%). Overall, the temporal change in the flood inundation area presented a decreasing trend, and a link to the in-situ observed water level showed a decreasing trend during the rainy season. Furthermore, the estimated flood inundation exhibited a significant delay since 2008. Based on the yearly land cover MODIS product, the permanent water body and wetland areas decreased, whereas the cropland areas increased. This was as a result of increased agricultural productivity. However, water shortage was the major obstacle to increasing agricultural productivity, and it also had a negative impact on aquatic ecology, such as fish spawning grounds

Four-Year Trajectories of Health-Related Quality of Life in People Living with HIV: Impact of Unmet Basic Needs across Age Groups in Positive Spaces, Healthy Places

Despite significant advances in antiretroviral therapy, unmet basic needs can negatively impact health-related quality of life (HRQoL) in people living with HIV, especially as they age. We aimed to examine the effect of unmet basic needs across age groups on changes in HRQoL over a 4-year period in persons with HIV. Physical and mental HRQoL scores from the Positive Spaces, Healthy Spaces cohort interviewed in 2006 (n = 538), 2007 (n = 506), and 2009 (n = 406) were examined across three age groups according to their unmet needs for food, clothing, and housing. Individual growth curve model analyses were used to investigate changes over time, adjusting for demographics, employment, living conditions, social supports, HIV status, and health behavior risks. Low scores on physical and mental HRQoL were positively associated with higher number of unmet basic needs (&beta; = &minus;6.40, standard error (SE) = 0.87, p &lt; 0.001 and &beta; = &minus;7.39, SE = 1.00, p &lt; 0.001, respectively). There was a slight improvement in physical and mental HRQoL over 4 years in this HIV cohort, but the burden of unmet basic needs took its toll on those over 50 years of age. Regularly assessing unmet basic needs is recommended given the impact these can have on HRQOL for people living with HIV. Recognition of unmet needs is vital, as is the development of timely interventions

Four-Year Trajectories of Health-Related Quality of Life in People Living with HIV: Impact of Unmet Basic Needs across Age Groups in Positive Spaces, Healthy Places

Despite significant advances in antiretroviral therapy, unmet basic needs can negatively impact health-related quality of life (HRQoL) in people living with HIV, especially as they age. We aimed to examine the effect of unmet basic needs across age groups on changes in HRQoL over a 4-year period in persons with HIV. Physical and mental HRQoL scores from the Positive Spaces, Healthy Spaces cohort interviewed in 2006 (n = 538), 2007 (n = 506), and 2009 (n = 406) were examined across three age groups according to their unmet needs for food, clothing, and housing. Individual growth curve model analyses were used to investigate changes over time, adjusting for demographics, employment, living conditions, social supports, HIV status, and health behavior risks. Low scores on physical and mental HRQoL were positively associated with higher number of unmet basic needs (&beta; = &minus;6.40, standard error (SE) = 0.87, p &lt; 0.001 and &beta; = &minus;7.39, SE = 1.00, p &lt; 0.001, respectively). There was a slight improvement in physical and mental HRQoL over 4 years in this HIV cohort, but the burden of unmet basic needs took its toll on those over 50 years of age. Regularly assessing unmet basic needs is recommended given the impact these can have on HRQOL for people living with HIV. Recognition of unmet needs is vital, as is the development of timely interventions

Efficacy of Needle-Less Intradermal Vaccination against Porcine Epidemic Diarrhea Virus

To prevent diarrhea in suckling piglets infected by porcine epidemic diarrhea virus (PEDV), porcine epidemic diarrhea (PED) vaccines are administered mainly through intramuscular (IM) or oral routes. We found that growing pigs vaccinated with an inactivated PEDV vaccine via the intradermal (ID) route had higher neutralizing antibody titers and cytokine (IFN-γ, IL-4, and IL-10) levels than non-vaccinated pigs. In addition, suckling piglets acquired lactogenic immunity from pregnant sows inoculated with an ID PED vaccine. We evaluated the efficacy of vaccination via this route, along with subsequent protection against virulent PEDV. At six days post-challenge, the survival rate of suckling piglets exposed to virulent PEDV was 70% for the ID group and 0% for the mock group (no vaccine). At necropsy, villi length in the duodenum and ileum of piglets with lactogenic immunity provided by ID-vaccinated sows proved to be significant (p &lt; 0.05) when compared with those in piglets from mock group sows. Thus, vaccination using an inactivated PED vaccine via the ID route provides partial protection against infection by virulent PEDV

Pathogenicity and Genetic Characterization of Vietnamese Classical Swine Fever Virus: 2014–2018

Here, we examined the pathogenicity and genetic differences between classical swine fever viruses (CSFV) isolated on pig farms in North Vietnam from 2014&ndash;2018. Twenty CSFV strains from 16 pig farms were classified as genotype 2 (sub-genotypes 2.1b, 2.1c, and 2.2). The main sub-genotype, 2.1c, was classified phylogenetically as belonging to the same cluster as viruses isolated from the Guangdong region in South China. Strain HY58 (sub-genotype 2.1c), isolated from pigs in Vietnam, caused higher mortality (60%) than the Vietnamese ND20 strain (sub-genotype 2.2). The Vietnamese strain of sub-genotype 2.1b was estimated to have moderate virulence; indeed, genetic analysis revealed that it belongs to the same cluster as Korean CSFV sub-genotype 2.1b. Most CSFVs circulating in North Vietnam belong to sub-genotype 2.1c. Geographical proximity means that this genotype might continue to circulate in both North Vietnam and Southern China (Guangdong, Guangxi, and Hunan)

Unmet basic needs negatively affect health-related quality of life in people aging with HIV: results from the Positive Spaces, Healthy Places study

Abstract Background Basic needs (e.g., food security and stable housing) are important determinants of health and well-being, yet their impact on health-related quality of life (HRQoL) in the context of HIV and aging has not been systematically investigated. Methods Multiple linear regression models examined the relationship between unmet basic needs, and physical and mental HRQoL by age strata (20-34, 35-49 and 50+) in a cross-sectional sample of 496 people living with HIV in Ontario, Canada. Results An overwhelming majority of participants (87%) reported unmet needs related to food, clothing or housing. The prevalence of unmet basic needs in the two older groups appeared to be lower than among younger participants, but the difference did not reach statistical significance. The presence of unmet basic needs predicted substantially lower mean physical health and mental health summary scores in the two oldest groups. Notably, age moderated the influence of unmet basic needs on HRQoL. Conclusions The availability and accessibility of food security, appropriate clothing and stable housing for people living with HIV who are aging need to become a higher priority for program planners and decision makers