Multiscale model for the effects of adaptive immunity suppression on the viral therapy of cancer

Oncolytic virotherapy - the use of viruses that specifically kill tumor cells - is an innovative and highly promising route for treating cancer. However, its therapeutic outcomes are mainly impaired by the host immune response to the viral infection. In the present work, we propose a multiscale mathematical model to study how the immune response interferes with the viral oncolytic activity. The model assumes that cytotoxic T cells can induce apoptosis in infected cancer cells and that free viruses can be inactivated by neutralizing antibodies or cleared at a constant rate by the innate immune response. Our simulations suggest that reprogramming the immune microenvironment in tumors could substantially enhance the oncolytic virotherapy in immune-competent hosts. Viable routes to such reprogramming are either in situ virus-mediated impairing of CD$8^+$ T cells motility or blockade of B and T lymphocytes recruitment. Our theoretical results can shed light on the design of viral vectors or new protocols with neat potential impacts on the clinical practice.Comment: 14 pages, 4 figure

In vitro micrografting for production of Indian citrus ringspot virus (ICRSV)-free plants of kinnow mandarin (Citrus nobilis Lour X C. deliciosa Tenora)

Production of Indian citrus ringspot virus (ICRSV)-free plants from an infected plant of kinnow mandarin (Citrus nobilis Lour 9 C. deliciosa Tenora) is reported. The shoot apices of different sizes (0.2-1.0 mm) excised from the ICRSV-infected plant were micrografted onto decapitated rootstock seedlings of rough lemon (C. jambhiri). Micrograft survival depended on the size of shoot apex and the sucrose concentration of the culture medium. Increase in scion size from 0.2 to 0.7 mm resulted in an increase in micrografting success rate from 30.55 to 51.88%. Further, micrograft survival obtained with 0.2 mm was improved from 30.55 to 38.88% by increasing sucrose concentration in the culture media from 5 to 7.5%. The micrografted plants were tested for ICRSV using ELISA and RT-PCR. All plants raised from 0.2-mm scion were found negative with both ELISA and RT-PCR whereas only 20% of the ELISA negative plants raised from 0.3-mm scion were found negative for ICRSV with RT-PCR. The outcome of this research is the successful establishment, acclimatization and virus testing of micrografted plants

MDRD or CKD-EPI study equations for estimating prevalence of stage 3 CKD in epidemiological studies: which difference? Is this difference relevant?

Background: Prevalence of stage 3 chronic kidney disease (CKD) is increasing according to the NHANES study. Prevalence has been calculated using the MDRD study equation for estimating glomerular filtration rate (GFR). Recently, a new estimator based on creatinine, the CKD-EPI equation, has been proposed which is presumed to better perform in normal GFR ranges. The aim of the study was to measure the difference in prevalence of stage 3 CKD in a population using either the MDRD or the CKD-EPI study equations. Methods: CKDscreening is organized in the Province of Liège, Belgium. On a voluntary basis, people aged between 45 and 75 years are invited to be screened. GFR is estimated by the MDRD study equation and by the "new" CKD-EPI equations. Results: The population screened consisted in 1992 people (47% of men). Mean serum creatinine was 0.86 ± 0.20 mg/dl. The prevalence of stage 3 CKD in this population using the MDRD or the CKD-EPI equations was 11.04 and 7.98%, respectively. The prevalence of stage 3 CKD is significantly higher with the MDRD study equation (p <0,0012). Conclusions: Prevalence of stage 3 CKDvaries strongly following the method used for estimating GFR, MDRD or CKDEPI study equations. Such discrepancies are of importance and must be confirmed and explained by additional studies using GFR measured with a reference method

Nucleotide analysis of pome fruit virus isolates detected in apple and pear samples from Italy and India

In the framework of a joint research project between Italy and India field surveys were done in different pear and apple growing areas of North of India and Central and Southern Italy. Samples were collected from plants belonging to common and local varieties and molecularly analyzed for the detection of the main pome fruit viruses (Apple stem pitting virus, Apple stem groving virus, Apple chlorotic leaf spot virus, Apple mosaic virus) by using harmonized diagnostic protocols.The sequence homology was evaluated and a phylogenetic tree was built, on the basis of which, the Indian isolate of ASGV showed maximum sequence identity at a nucleotide level to Italian isolates when analyzed by BLAST (http://blast.ncbi.nlm.nih.gov/Blast.cgi). Similarly, a maximum identity, ranging from 90-93%, was found for the Italian isolates of ASPV and pear and apple isolates from Poland, while a sequence homology ranging from 83 to86% was observed within the Indian isolates of ASPV. Multiple alignment of the Indian pome ACLSV-isolates indicate maximum variability in the middle portion while the first 140 nucleotides are maximally conserved and shared a percent identity at nucleotide level of 86-100% with the Italian isolates.The ApMV Indian isolates showed maximum (92-99%) sequence homology to the Korean isolate (AY125977) from apple. However, a comparison with other isolates from different host plant species revealed a clustering of Indian isolates with a Czech isolate from pear and a sequence homology of 84 to 98%. Phylogenetic analysis showed that sequence variability was independent to the geographical origin or the host for all the investigated viruses.Keywords: ACLSV, ASPV, ASGV, ApMV, sequences analysis, Italy, India

History of Foot Ulcer Increases Mortality Among Individuals With Diabetes: Ten-year follow-up of the Nord-Trøndelag Health Study, Norway

OBJECTIVE To compare mortality rates for individuals with diabetes with and without a history of foot ulcer (HFU) and with that for the nondiabetic population. RESEARCH DESIGN AND METHODS This population-based study included 155 diabetic individuals with an HFU, 1,339 diabetic individuals without an HFU, and 63,632 nondiabetic individuals who were all followed for 10 years with mortality as the end point. RESULTS During the follow-up period, a total of 49.0% of diabetic individuals with an HFU died, compared with 35.2% of diabetic individuals without an HFU and 10.5% of those without diabetes. In Cox regression analyses adjusted for age, sex, education, current smoking, and waist circumference, having an HFU was associated with more than a twofold (2.29 [95% CI 1.82–2.88]) hazard risk for mortality compared with that of the nondiabetic group. In corresponding analyses comparing diabetic individuals with and without an HFU, an HFU was associated with 47% increased mortality (1.47 [1.14–1.89]). Significant covariates were older age, male sex, and current smoking. After inclusion of A1C, insulin use, microalbuminuria, cardiovascular disease, and depression scores in the model, each was significantly related to life expectancy. CONCLUSIONS AN HFU increased mortality risk among community-dwelling adults and elderly individuals with diabetes. The excess risk persisted after adjustment for comorbidity and depression scores, indicating that close clinical monitoring might be warranted among individuals with an HFU, who may be particularly vulnerable to adverse outcomes. Hospital-based studies have shown that mortality rates in individuals with diabetic foot ulcers are about twice those observed in individuals with diabetes without foot ulcers (1,2). A diabetic foot ulcer reflects the presence of underlying pathological conditions, and the risk of recurrent ulcers is high (3,4). It has been suggested that the elevated mortality rate among individuals with diabetic foot ulcers is related to comorbid disease such as cardiovascular disease and nephropathy (5) or to psychological factors including depression (6). Although the mortality rate in individuals with diabetes is high, no large population-based studies have examined the impact on mortality of a history of foot ulcers (HFU) among individuals with diabetes. The purpose of this study was to compare mortality rates for individuals with diabetes reporting an HFU with those for individuals without an HFU and the nondiabetic population. These issues were investigated in the Nord-Trøndelag Health Study (HUNT 2), which includes a very large population-based sample of men and women from a well-defined geographic area. Participants with self-reported diabetes were well characterized with regard to their diabetes, and information on demographics, lifestyle, and prevalent disease including depression was available

The rise in road traffic injuries in Lilongwe, Malawi: A snapshot of the growing epidemic of trauma in low income countries

Introduction: Road traffic injuries (RTIs) and death are a major public health issue worldwide. Unless appropriate action is taken urgently, the burden of RTIs will continue to increase globally. This will be particularly pronounced in developing countries where rapid motorization is likely to continue over the next decades. Malawi is one of these countries with a population of 17.2 million and a Gross National Income per capita of 340 US$. The impact of the rising burden of injury on the health sector is considerable. However, data to demonstrate this development is lacking. Methods: This study is an analysis of data from the Kamuzu Central Hospital (KCH) Trauma Registry. KCH is a 900-bed tertiary care public hospital in Lilongwe, the capital city of Malawi. The KCH Trauma Registry was established to collect patient demographic information, clinical characteristics, and outcome data for all patients presenting to the emergency department with injuries. All patients who presented to the emergency department with injuries between January 2009 and December 2015 were included in the study. Results: A 96,967 patients with injuries between 2009 and 2015 were registered in the KCH Trauma Registry. The mean age of these patients was 23.3 years and 36.8% were children younger than 18 years. 25,193 (26.2%) patients had road traffic related injuries, of these 19,244 (76.4%) were men. There was a 62.4% rise in the number of RTI victims treated at KCH from 2447 in 2009–3975 in 2015. If this trend continues, 7997 patients will be expected to need treatment for RTIs at KCH in 2030, doubling the numbers seen in 2015 in just 15 years. The highest number of injuries occurred in pedestrians (32.3%) and cyclists (28.2%) and continually rose over the years studied. The length of hospital stay for RTIs increased from 6.4 ± 9.1days in 2009 to 15.0 ± 19.4 in 2015. Discussion: There was a rapidly growing burden of RTIs at KCH in Lilongwe, Malawi, between 2009 and 2015, and projections based on our data show that this burden will double by 2030. It is essential that surgical trauma services are scaled up to meet this challenge in Malawi. There is also a large potential for prevention of injuries involving vulnerable road users. Road traffic campaigns should focus on improved driver training, use of lights, pedestrian and cyclist visibility, and vehicle fitness. Standards should include physical separation of pedestrians and vehicles, through raised pavements or separate walk and cycle ways. The absence of a clear strategy to meet the growing epidemic of injuries in Malawi will come at a huge cost to an already strained economy, and the largest portion of the burden of injury will continue to be borne by the poorest segment of the population

Translating chronic kidney disease epidemiology into patient care—the individual/public health risk paradox

Background Applying the Kidney Disease Outcomes Quality Initiative definitions of chronic kidney disease (CKD), it appears that CKD is common. The increased recognition of CKD has brought with it the clinical challenge of translating into practice the implications for the patient and for service planning. To understand the clinical relevance and translate that into information to support individual patient care and service planning, we explored clinical outcomes in a large British CKD cohort, identified through routine opportunistic testing, with a 6-year follow-up (∼13 000 patient-years). Methods A cohort had previously been identified with CKD—sustained reduced eGFR over at least 3 months and case note review. Six-year (13 339 patient-years) follow-up for renal replacement therapy (RRT) initiation and death was achieved through data linkage. Age- and sex-specific mortality rates were compared to the general population. Results Of 3414 individuals (most Stage 3b–5), median age 78.6 years, followed for 13 339 patient-years, 170 (5%) initiated RRT and 2024 (59%) died without initiating RRT. RRT initiation rates decreased with age from 14.33 to 0.65 per 100 patient-years among those aged 15–25 and 75–85 years at baseline but the actual numbers initiating RRT increased from 6 to 34, respectively. RRT initiation rates were lower for female sex, absence of macroalbuminuria and less advanced CKD stage. Mortality rates increased with age from 2 to 34 per 100 patient-years for those aged 15–45 and > 85 years at baseline, an excess of 2 and 17 per 100 patient-years over that of the general population, respectively. However, the increase in relative risk was 19-fold for those aged 15–45 years and just 2-fold in those > 85 years. These data have been converted into simple tools for considering individual patients' risk and informing service planning. Conclusions The contrast between relative and absolute risk for both RRT initiation and mortality by age group illustrates the difficulties for planning services. The challenge that now faces clinicians is how to appropriately identify which elderly patients with CKD are at high risk of poor outcome

Estimating measures of interaction on an additive scale for preventive exposures

Measures of interaction on an additive scale (relative excess risk due to interaction [RERI], attributable proportion [AP], synergy index [S]), were developed for risk factors rather than preventive factors. It has been suggested that preventive factors should be recoded to risk factors before calculating these measures. We aimed to show that these measures are problematic with preventive factors prior to recoding, and to clarify the recoding method to be used to circumvent these problems. Recoding of preventive factors should be done such that the stratum with the lowest risk becomes the reference category when both factors are considered jointly (rather than one at a time). We used data from a case-control study on the interaction between ACE inhibitors and the ACE gene on incident diabetes. Use of ACE inhibitors was a preventive factor and DD ACE genotype was a risk factor. Before recoding, the RERI, AP and S showed inconsistent results (RERI = 0.26 [95%CI: −0.30; 0.82], AP = 0.30 [95%CI: −0.28; 0.88], S = 0.35 [95%CI: 0.02; 7.38]), with the first two measures suggesting positive interaction and the third negative interaction. After recoding the use of ACE inhibitors, they showed consistent results (RERI = −0.37 [95%CI: −1.23; 0.49], AP = −0.29 [95%CI: −0.98; 0.40], S = 0.43 [95%CI: 0.07; 2.60]), all indicating negative interaction. Preventive factors should not be used to calculate measures of interaction on an additive scale without recoding

Impact of hip arthroplasty registers on orthopaedic practice and perspectives for the future

Total hip arthroplasty (THA) registers are established in several countries to collect data aiming to improve the results after THA. Monitoring of adverse outcomes after THA has focused mainly on revision surgery, but patient-reported outcomes have also been investigated.Several surgery-related factors influencing the survival of the THA have been thoroughly investigated and have changed clinical practice. These factors include surgical approach, specific implants, the size of the components, type of fixation and different bone cements.Register data have been used to examine the risk of venous thromboembolism and bleeding after THA. These investigations have resulted in shorter duration of thromboprophylaxis and a reduced frequency of blood transfusion.Registers may provide specific information to surgeons on the outcome of all THAs that they have performed with a detailed analysis of revisions rates and reasons for the revisions.A number of other stakeholders can use register data to provide benchmarks. The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man supplies data to the Orthopaedic Device Evaluation Panel (ODEP), which provides benchmarks at 3, 5, 7, 10, and 13 years graded from A*, A, B and C.Future perspectives: National registers have to play a major role in documenting the quality of THA in order to describe best practice and report implant outliers. The registers have to be used for research and post-market surveillance and register data may be a source for intelligent decision tools