Evolutionary History and Attenuation of Myxoma Virus on Two Continents

The attenuation of myxoma virus (MYXV) following its introduction as a biological control into the European rabbit populations of Australia and Europe is the canonical study of the evolution of virulence. However, the evolutionary genetics of this profound change in host-pathogen relationship is unknown. We describe the genome-scale evolution of MYXV covering a range of virulence grades sampled over 49 years from the parallel Australian and European epidemics, including the high-virulence progenitor strains released in the early 1950s. MYXV evolved rapidly over the sampling period, exhibiting one of the highest nucleotide substitution rates ever reported for a double-stranded DNA virus, and indicative of a relatively high mutation rate and/or a continually changing selective environment. Our comparative sequence data reveal that changes in virulence involved multiple genes, likely losses of gene function due to insertion-deletion events, and no mutations common to specific virulence grades. Hence, despite the similarity in selection pressures there are multiple genetic routes to attain either highly virulent or attenuated phenotypes in MYXV, resulting in convergence for phenotype but not genotype. © 2012 Kerr et al

Superior Segment Facet Joint Violation During Instrumented Lumbar Fusion is Associated With Higher Reoperation Rates and Diminished Improvement in Quality of Life

Study Design: A retrospective cohort study at a single tertiary care center. Objective: To determine the impact of superior segment facet joint violation (FJV) during lumbar fusion on reoperation rates and quality of life (QOL). Summary of Background Data: Although lumbar fusion is an efficacious and durable treatment for numerous spinal pathologies, adjacent segment degeneration remains a serious complication. FJV has been suggested to alter load-bearing capability and potentially contribute to adjacent segment degeneration. Materials and Methods: Patients who underwent instrumented lumbar fusion surgery between 2009 and 2013 with postoperative computed tomography imaging were included. Patients were placed in the FJV group if either of the superior segment facet joints were compromised by the pedicle screw or rod. Patients with preserved facet joints were placed in the control group. Demographic, perioperative, QOL, and reoperation data were collected. QOL scores including the Pain Disability Questionnaire, Patient Health Questionnaire-9, and EuroQOL 5 Dimensions (EQ-5D) were acquired. Results: Of 240 patients included, 112 patients were found to have FJV and the remaining 128 patients were placed in the control group. One year following lumbar fusion, QOL outcomes and reoperation rates were similar between the FJV and control groups. At 2-year follow-up, patients in the FJV group were less likely to make a significant improvement in EQ-5D (P=0.041). Also, the reoperation rate in the FJV group was significantly higher than in the control group at 2 years (15.2% vs. 6.3%, respectively; P=0.024) and 3 years (19.6% vs. 9.4%, P=0.023). Multivariable logistic regression showed FJV to be an independent predictor of both (1) failing to make a significant improvement in EQ-5D (P=0.046) and (2) undergoing reoperation at both 2 and 3 years postoperatively (P=0.024 and 0.020, respectively). Conclusions: FJV was independently associated with a higher reoperation rate and diminished improvement in QOL

Cost analysis of centralized viral load testing for antiretroviral therapy monitoring in Nicaragua, a low-HIV prevalence, low-resource setting

<p>Abstract</p> <p>Background</p> <p>HIV viral load testing as a component of antiretroviral therapy monitoring is costly. Understanding the full costs and the major sources of inefficiency associated with viral load testing is critical for optimizing the systems and technologies that support the testing process. The objective of our study was to estimate the costs associated with viral load testing performed for antiretroviral therapy monitoring to both patients and the public healthcare system in a low-HIV prevalence, low-resource country.</p> <p>Methods</p> <p>A detailed cost analysis was performed to understand the costs involved in each step of performing a viral load test in Nicaragua, from initial specimen collection to communication of the test results to each patient's healthcare provider. Data were compiled and cross referenced from multiple information sources: laboratory records, regional surveillance centre records, and scheduled interviews with the key healthcare providers responsible for HIV patient care in five regions of the country.</p> <p>Results</p> <p>The total average cost of performing a viral load test in Nicaragua varied by region, ranging from US$99.01 to US$124.58, the majority of which was at the laboratory level: $88.73 to$97.15 per specimen, depending on batch size. The average cost to clinics at which specimens were collected ranged from $3.31 to$20.92, depending on the region. The average cost per patient for transportation, food, lodging and lost income ranged from $3.70 to$14.93.</p> <p>Conclusions</p> <p>The quantitative viral load test remains the single most expensive component of the process. For the patient, the distance of his or her residence from the specimen collection site is a large determinant of cost. Importantly, the efficiency of results reporting has a large impact on the cost per result delivered to the clinician and utility of the result for patient monitoring. Detailed cost analysis can identify opportunities for removing barriers to effective antiretroviral therapy monitoring programmes in limited-resource countries with low HIV prevalence.</p

Quality of life changes after lumbar decompression in patients with tandem spinal stenosis

Objective Tandem spinal stenosis (TSS) is a degenerative spinal condition characterized by spinal canal narrowing at 2 or more distinct spinal levels. It is an aging-related condition that is likely to increase as the population ages, but which remains poorly described in the literature. Here we sought to determine the impact of primary lumbar decompression on quality-of-life (QOL) outcomes in patients with symptomatic TSS. Patients and methods We retrospectively reviewed 803 patients with clinical and radiographic evidence of TSS treated between 2008 and 2014 with a minimum 2-year follow-up. The records of patients with clinical and radiographic evidence of concurrent cervical and lumbar stenosis were reviewed. Prospectively gathered QOL data, including the Pain Disability Questionnaire (PDQ), Patient Health Questionnaire-9 (PHQ-9), EuroQOL-5 Dimensions (EQ-5D), and Visual Analogue Scale (VAS) for low back pain, were assessed at the 6-month, 1-year, and 2-year follow-ups. Results Of 803 identified patients (mean age 66.2 years; 46.9% male), 19.6% underwent lumbar decompression only, 14.1% underwent cervical + lumbar decompression, and 66.4% underwent conservative management only. Baseline VAS scores were similar across all groups, but patients undergoing conservative management had better baseline QOL scores on all other measures. Both surgical cohorts experienced significant improvements in the VAS, PDQ, and EQ-5D at all time points; patients in the cervical + lumbar cohort also had significant improvement in the PHQ-9. Conservatively managed patients showed no significant improvement in QOL scores at any follow-up interval. Conclusion Lumbar decompression with or without cervical decompression improves low back pain and QOL outcomes in patients with TSS. The decision to prioritize lumbar decompression is therefore unlikely to adversely affect long-term quality-of-life improvements

Cancer Incidence among Pesticide Applicators Exposed to Cyanazine in the Agricultural Health Study

BACKGROUND: Cyanazine is a common pesticide used frequently in the United States during the 1980s and 1990s. Animal and human studies have suggested that triazines may be carcinogenic, but results have been mixed. We evaluated cancer incidence in cyanazine-exposed pesticide applicators among the 57,311 licensed pesticide applicators in the Agricultural Health Study (AHS). METHODS: We obtained detailed pesticide exposure information from a self-administered questionnaire completed at enrollment (1993–1997). Cancer incidence was followed through January 2002. Over half of cyanazine-exposed applicators had ≥ 6 years of exposure at enrollment, and approximately 85% had begun using cyanazine before the 1990s. We used adjusted Poisson regression to calculate rate ratios (RRs) and 95% confidence intervals (CIs) of multiple cancer sites among cyanazine-exposed applicators. We calculated p(trend) values, and all statistical tests were two-sided. Two exposure metrics were used: tertiles of lifetime days of exposure (LD) and intensity-weighted LD. RESULTS: A total of 20,824 cancer-free AHS applicators reported ever using cyanazine at enrollment. Cancer incidence comparisons between applicators with the lowest cyanazine exposure and those with the highest exposure yielded the following for the LD metric: all cancers, RR = 0.99 (95% CI, 0.80–1.24); prostate cancer, RR = 1.23 (95% CI, 0.87–1.70); all lymphohematopoietic cancers, RR = 0.92 (95% CI, 0.50–1.72); non-Hodgkin lymphoma, RR = 1.25 (95% CI, 0.47–3.35); lung cancer, RR = 0.52 (95% CI, 0.22–1.25). CONCLUSIONS: We did not find any clear, consistent associations between cyanazine exposure and any cancer analyzed. The number of sites was small for certain cancers, limiting any conclusion with regard to ovarian, breast, and some other cancers

Bleeding Risk and Antithrombotic Strategy in Patients With Sinus Rhythm and Heart Failure With Reduced Ejection Fraction Treated With Warfarin or Aspirin

We sought to assess the performance of existing bleeding risk scores, such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score or the Outpatient Bleeding Risk Index (OBRI), in patients with heart failure with reduced ejection fraction (HFrEF) in sinus rhythm (SR) treated with warfarin or aspirin. We calculated HAS-BLED and OBRI risk scores for 2,305 patients with HFrEF in SR enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. Proportional hazards models were used to test whether each score predicted major bleeding, and comparison of different risk scores was performed using Harell C-statistic and net reclassification improvement index. For the warfarin arm, both scores predicted bleeding risk, with OBRI having significantly greater C-statistic (0.72 vs 0.61; p = 0.03) compared to HAS-BLED, although the net reclassification improvement for comparing OBRI to HAS-BLED was not significant (0.32, 95% confidence interval [CI] −0.18 to 0.37). Performance of the OBRI and HAS-BLED risk scores was similar for the aspirin arm. For participants with OBRI scores of 0 to 1, warfarin compared with aspirin reduced ischemic stroke (hazard ratio [HR] 0.51, 95% CI 0.26 to 0.98, p = 0.042) without significantly increasing major bleeding (HR 1.24, 95% CI 0.66 to 2.30, p = 0.51). For those with OBRI score of ≥2, there was a trend for reduced ischemic stroke with warfarin compared to aspirin (HR 0.56, 95% CI 0.27 to 1.15, p = 0.12), but major bleeding was increased (HR 4.04, 95% CI 1.99 to 8.22, p <0.001). In conclusion, existing bleeding risk scores can identify bleeding risk in patients with HFrEF in SR and could be tested for potentially identifying patients with a favorable risk/benefit profile for antithrombotic therapy with warfarin

CHA2 DS2 -VASc score and adverse outcomes in patients with heart failure with reduced ejection fraction and sinus rhythm

AIMS: The aim of this study was to determine whether the CHA2 DS2 -VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure in sinus rhythm. METHODS AND RESULTS: CHA2 DS2 -VASc scores were calculated for 1101 patients randomized to warfarin and 1123 patients randomized to aspirin. Adverse outcomes were defined as death or ischaemic stroke, death alone, ischaemic stroke alone, and major haemorrhage. Using proportional hazards models, we found that each 1-point increase in the CHA2 DS2 -VASc score was associated with increased hazard of death or ischaemic stroke events [hazard ratio (HR) for the warfarin arm = 1.21, 95% confidence interval (CI) 1.13-1.30, P < 0.001; for aspirin, HR = 1.20, 95% CI 1.11-1.29, P < 0.001]. Similar increased hazards for higher CHA2 DS2 -VASc scores were observed for death alone, ischaemic stroke alone, and major haemorrhage. Overall performance of the CHA2 DS2 -VASc score was assessed using c-statistics for full models containing the risk score, treatment assignment, and score-treatment interaction, with the c-statistics for the full models ranging from 0.57 for death to 0.68 for major haemorrhage. CONCLUSIONS: The CHA2 DS2 -VASc score predicted adverse outcomes in patients with systolic heart failure in sinus rhythm, with modest prediction accuracy

Analysis of the expression of human tumor antigens in ovarian cancer tissues

Biomarkers for early detection of cancer have great clinical diagnostic potential. Numerous reports have documented the generation of humoral immune responses that are triggered in response to changes in protein expression patterns in tumor tissues and these biomarkers are referred to as tumor associated antigens (TAAs). Using a high-throughput technology, we previously identified 65 proteins as diagnostically useful TAAs by profiling the humoral immune responses in ovarian cancer (OVCA) patients. Here we determined the expression status of some of those TAAs in tissues from OVCA patients. The protein expression patterns of 4 of those 65 antigens, namely NASP, RCAS1, Nijmegen breakage syndrome1 (NBS1) and eIF5A, along with p53 and Her2 (known molecular prognosticators) and two proteins that interact with NBS1, MRE11 and RAD50, were assessed by immunohistochemistry (IHC). NASP and RCAS1 proteins were more frequently expressed in ovarian cancer tissues than with normal ovarian tissue and serous cystadenomas and MRE11 was less frequently expressed. When evaluated simultaneously, only NASP and MRE11 remained statistically significant with sensitivity of 66% and specificity of 89%. None of these proteins’ expression levels were prognostic for survival. Together, our results indicate that occurrence of humoral immune responses against some of these TAAs in OVCA patients is triggered by antigen protein overexpression