The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a ...novel class of small molecules (1,2,3triazolo4,5-dpyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.
Infection with yellow fever virus (YFV), the prototypic mosquito-borne flavivirus, causes severe febrile disease with haemorrhage, multi-organ failure and a high mortality. Moreover, in recent years ...the Flavivirus genus has gained further attention due to re-emergence and increasing incidence of West Nile, dengue and Japanese encephalitis viruses. Potent and safe antivirals are urgently needed.
Starting from the crystal structure of the NS3 helicase from Kunjin virus (an Australian variant of West Nile virus), we identified a novel, unexploited protein site that might be involved in the helicase catalytic cycle and could thus in principle be targeted for enzyme inhibition. In silico docking of a library of small molecules allowed us to identify a few selected compounds with high predicted affinity for the new site. Their activity against helicases from several flaviviruses was confirmed in in vitro helicase/enzymatic assays. The effect on the in vitro replication of flaviviruses was then evaluated.
Ivermectin, a broadly used anti-helminthic drug, proved to be a highly potent inhibitor of YFV replication (EC₅₀ values in the sub-nanomolar range). Moreover, ivermectin inhibited, although less efficiently, the replication of several other flaviviruses, i.e. dengue fever, Japanese encephalitis and tick-borne encephalitis viruses. Ivermectin exerts its effect at a timepoint that coincides with the onset of intracellular viral RNA synthesis, as expected for a molecule that specifically targets the viral helicase.
The well-tolerated drug ivermectin may hold great potential for treatment of YFV infections. Furthermore, structure-based optimization may result in analogues exerting potent activity against flaviviruses other than YFV.
Objectives
In older adults, nutritional health is essential for good quality of life and living independently at home. Especially in cancer patients, malnutrition is common and known to complicate ...treatment. This study aims to evaluate the nutritional status and its associated factors in community-dwelling older adults with and without cancer.
Design
This is an observational study.
Setting
This study focuses on older community-dwelling people.
Participants
This study included older people with and without cancer (≥70 years). Cancer patients included patients with a new diagnosis of breast, lung, prostate, or colorectal cancer.
Measurements
Data collection included measures of nutritional status, quality of life, depression, fatigue, distress and functional status. We used multivariate logistic regression analysis to assess the association between personal characteristics and malnutrition.
Results
Data were available for 657 people; 383 people without cancer and 274 with a cancer diagnosis. Overall, malnutrition was detected in 245 (37.5%) people; in cancer patients this was 66.1%. Multivariate analysis showed that having cancer (OR 14.4, 95% CI: 8.01 - 23.3), being male (OR 2.38, 95% CI: 1.49–3.70), having depression (OR 13.5, 95% CI: 6.02-30.0), distress (OR 2.60, 95% CI: 1.55–4.37) and impaired instrumental activities of daily living (IADL) (OR 2.63, 95% CI: 1.63–4.24) were associated with a higher risk of malnutrition.
Conclusion
The prevalence of malnutrition in community-dwelling older people is high, particularly in patients with cancer. Benchmarking and routine screening of older patients may be helpful strategies to increase awareness of (risk of) malnutrition among professionals.
Abstract Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) is an important binding receptor for dengue virus (DENV) that recognizes N-glycosylation sites on ...the viral E-glycoprotein. DENV cannot bind nor infect the human B-cell line Raji/0. However, DENV productively infects Raji/DC-SIGN+ cells that constitutively express DC-SIGN on their surface. IL-4-treated monocytes, expressing high levels of DC-SIGN, are also susceptible for DENV infection. Several carbohydrate-binding agents (CBAs), such as the plant lectins HHA, GNA (mannose-specific) and UDA (N-acetylglucosamine-specific), inhibited dose-dependently the binding of DENV and subsequently viral replication in Raji/DC-SIGN+ cells (EC50 : 0.1–2.2 μM). These CBAs were clearly more active against DENV in IL-4-treated monocytes (EC50 : 4–56 nM). However, the CBAs were devoid of antiviral activity in DENV-susceptible Vero-B (DC-SIGN− ) cells, demonstrating cell type-dependent differences in viral entry mechanisms.
The aim of this paper was to describe the time trends in the prevalence of multimorbidity and polypharmacy in Flanders (Belgium) between 2000 and 2015, while controlling for age and sex.
Data were ...available from Intego, a Flemish-Belgian general practice-based morbidity registration network. The practice population between 2000 and 2015 was used as the denominator, representing a mean of 159,946 people per year. Age and gender-standardised prevalence rates were used for the trends of multimorbidity and polypharmacy in the total population and for subgroups. Joinpoint regression analyses were used to analyse the time trends and breaks in trends, for the entire population as well as for specific age and sex groups.
Overall, in 2015, 22.7% of the population had multimorbidity, while the overall prevalence of polypharmacy was 20%. Throughout the study period the standardised prevalence rate of multimorbidity rose for both sexes and in all age groups. The largest relative increase in multimorbidity was observed in the younger age groups (up to the age of 50 years). The prevalence of polypharmacy showed a significant increase between 2000 and 2015 for all age groups except the youngest (0-25 years).
For all adult age groups multimorbidity and polypharmacy are frequent, dynamic over time and increasing. This asks for both epidemiological and interventional studies to improve the management of the resulting complex care.
Inappropriate laboratory test ordering poses an important burden for healthcare. Clinical decision support systems (CDSS) have been cited as promising tools to improve laboratory test ordering ...behavior. The objectives of this study were to evaluate the effects of an intervention that integrated a clinical decision support service into a computerized physician order entry (CPOE) on the appropriateness and volume of laboratory test ordering, and on diagnostic error in primary care.
This study was a pragmatic, cluster randomized, open-label, controlled clinical trial.
Two hundred eighty general practitioners (GPs) from 72 primary care practices in Belgium.
Patients aged ≥ 18 years with a laboratory test order for at least one of 17 indications: cardiovascular disease management, hypertension, check-up, chronic kidney disease (CKD), thyroid disease, type 2 diabetes mellitus, fatigue, anemia, liver disease, gout, suspicion of acute coronary syndrome (ACS), suspicion of lung embolism, rheumatoid arthritis, sexually transmitted infections (STI), acute diarrhea, chronic diarrhea, and follow-up of medication.
The CDSS was integrated into a computerized physician order entry (CPOE) in the form of evidence-based order sets that suggested appropriate tests based on the indication provided by the general physician.
The primary outcome of the ELMO study was the proportion of appropriate tests over the total number of ordered tests and inappropriately not-requested tests. Secondary outcomes of the ELMO study included diagnostic error, test volume, and cascade activities.
CDSS increased the proportion of appropriate tests by 0.21 (95% CI 0.16-0.26, p < 0.0001) for all tests included in the study. GPs in the CDSS arm ordered 7 (7.15 (95% CI 3.37-10.93, p = 0.0002)) tests fewer per panel. CDSS did not increase diagnostic error. The absolute difference in proportions was a decrease of 0.66% (95% CI 1.4% decrease-0.05% increase) in possible diagnostic error.
A CDSS in the form of order sets, integrated within the CPOE improved appropriateness and decreased volume of laboratory test ordering without increasing diagnostic error.
ClinicalTrials.gov Identifier: NCT02950142 , registered on October 25, 2016.
This prospective cohort study identified risk factors for the development of caregiver burden and included older cancer survivors, middle-aged cancer survivors, older patients without cancer and ...their caregivers. Overall, more than 16 per cent of caregivers experienced high-to-severe burden at baseline. This proportion remained stable after 1 and 3 years. Caregivers who experienced increased caregiver burden at baseline were at higher risk maintaining their caregiver burden over the following years. Caregiver burden was not related to the cancer diagnosis but rather to the baseline psychosocial well-being of both the caregiver and patient and the physical condition of the patient.
Uncertainty is a central theme in the illness experiences of older cancer patients throughout their illness trajectory. Mishel’s popular theory on uncertainty during illness approaches uncertainty as ...an outcome and is characterized by the patient’s inability to find meaning in illness events. This study used the concepts of liminality and subjunctivity to explore uncertainty throughout the illness trajectory of cancer patients. We interviewed 18 older (age range = 57–92 years) patients with breast cancer or gastro-intestinal cancer 3 to 4 years post diagnosis. Our analysis is based on the QUAGOL guide that draws on elements of grounded theory such as constant comparison. We found that liminality and subjunctivity provide a useful frame for understanding uncertainty with a specific focus on its productive potential and meaning making. Health care professionals should be open to acquiring a complete picture of patients’ diverse and dynamic experiences of uncertainty in the different stages of their illness trajectory.
Background. Anti-cancer treatment and the cancer population have evolved since the last European Organisation for Research and Treatment of Cancer (EORTC) fungemia survey, and there are few recent ...large epidemiological studies. Methods. This was a prospective cohort study including 145 030 admissions of patients with cancer from 13 EORTC centers. Incidence, clinical characteristics, and outcome of fungemia were analyzed. Results. Fungemia occurred in 333 (0.23%; 95% confidence interval CI, .21–.26) patients, ranging from 0.15% in patients with solid tumors to 1.55% in hematopoietic stem cell transplantation recipients. In 297 evaluable patients age ranged from 17 to 88 years (median 56 years), 144 (48%) patients were female, 165 (56%) had solid tumors, and 140 (47%) had hematological malignancies. Fungemia including polymicrobial infection was due to: Candida spp. in 267 (90%), C. albicans in 128 (48%), and other Candida spp. in 145 (54%) patients. Favorable overall response was achieved in 113 (46.5%) patients by week 2. After 4 weeks, the survival rate was 64% (95% CI, 59%–70%) and was not significantly different between Candida spp. Multivariable logistic regression identified baseline septic shock (odds ratio OR 3.04, 95% CI, 1.22–7.58) and tachypnoea as poor prognostic factors (OR 2.95, 95% CI, 1.66–5.24), while antifungal prophylaxis prior to fungemia (OR 0.20, 95% CI, .06–.62) and remission of underlying cancer (OR, 0.18; 95% CI, .06–.50) were protective. Conclusions. Fungemia, mostly due to Candida spp., was rare in cancer patients from EORTC centers but was associated with substantial mortality. Antifungal prophylaxis and remission of cancer predicted better survival.
PDF
