Nevin Manimala

J Thromb Haemost. 2021 Feb 26. doi: 10.1111/jth.15277. Online ahead of print.

ABSTRACT

BACKGROUND: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules.

OBJECTIVES: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm. Patients/Methods A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies.

RESULTS: The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P<0.05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment.

CONCLUSIONS: Using a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.

PMID:33636042 | DOI:10.1111/jth.15277

Prostate. 2021 Feb 26. doi: 10.1002/pros.24110. Online ahead of print.

ABSTRACT

BACKGROUND: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival.

METHODS: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7-expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS).

RESULTS: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1-NR) in cohort 1 and 2.7 (95% CI: 2.1-5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8-7.5) in cohort 1 and 2.9 (95% CI: 1.3-5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%-45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%-52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5-10.4) in cohort 1 and 14.2 (95% CI: 8.5-NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11-0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06-0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03-0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47-13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels.

CONCLUSION: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, -7, and -17) may be prognostic for outcomes to immunotherapy.

PMID:33636027 | DOI:10.1002/pros.24110

Int J Clin Pract. 2021 Feb 26:e14115. doi: 10.1111/ijcp.14115. Online ahead of print.

ABSTRACT

AIMS: To evaluate the effect of pre-RIRS ESWL on the efficiency and safety of RIRS in the treatment of proximal ureter stones.

METHODS: The patients in the study population were divided into 2 groups. Group-1 was composed of patients who had undergone ESWL for proximal ureter stones before RIRS, and Group-2 was composed of patients who directly underwent RIRS without any prior ESWL. The clinical and demographic properties of the patients were analysed in the RIRSearch database. The operative outcomes, peroperative complications, postoperative complications, hospitalization time and the stone-free rates were compared between the groups.

RESULTS: There were 56 patients in Group-1 and 95 patients in Group-2. The demographic and clinical properties were similar between the groups. The stone-free rates, peroperative complications and postoperative complications were also similar between the groups; however, the fluoroscopy time was significantly higher in Group-1 (p=.043). The cut-off duration of 10 weeks between ESWL and RIRS had reasonable/favourable discriminating ability, with a 51% sensitivity and 88% specificity rate for stone-free status.

CONCLUSION: Performing ESWL on the proximal ureter stones before RIRS did not change the efficacy and safety of RIRS. The time between the patient’s last ESWL session and RIRS had a predictive value for stone-free status, but did not have any effect on complications.

PMID:33636023 | DOI:10.1111/ijcp.14115

Stapp Car Crash J. 2020 Nov;64:1-30.

ABSTRACT

The CORA rating metric is frequently used in the field of injury biomechanics to compare the similarity of response time histories. However, subjectivity exists within the CORA metric in the form of user-customizable parameters that give the metric the flexibility to be used for a variety of applications. How these parameters are customized is not always reported in the literature, and it is unknown how these customizations affect the CORA scores. Therefore, the purpose of this study was to evaluate how variations in the CORA parameters affect the resulting similarity scores. A literature review was conducted to determine how the CORA parameters are commonly customized within the literature. Then, CORA scores for two datasets were calculated using the most common parameter customizations and the default parameters. Differences between the CORA scores using customized and default parameters were statistically significant for all customizations. Furthermore, most customizations produced score increases relative to the default settings. The use of standard deviation corridors and exclusion of the corridor component were found to produce the largest score differences. The observed differences demonstrated the need for researchers to exercise transparency when using customized parameters in CORA analyses.

PMID:33636001

J Wildl Dis. 2021 Jan 6;57(1):242-245. doi: 10.7589/JWD-D-20-00095.

ABSTRACT

We determined venous blood gas, acid-base, and biochemical parameters for thirteen free-ranging Indian flying foxes (Pteropus giganteus) in Myanmar, using a handheld i-STAT analyzer with CG8+ and CHEM8 cartridges. For field-based projects, portable blood analyzers enable identification and management of electrolyte and acid-base imbalances and collection of physiologic data, but present logistical challenges.

PMID:33635999 | DOI:10.7589/JWD-D-20-00095

J Wildl Dis. 2021 Jan 6;57(1):60-70. doi: 10.7589/JWD-D-20-00011.

ABSTRACT

The warthog (Phacochoerus africanus) can be used as a model for investigating disease transmission at the human, wildlife, and livestock interface. An omnivore and scavenger, a warthog moves freely between natural ecotypes, farmland, and human communities and is susceptible to diseases of zoonotic, agricultural, and conservation concern. A retrospective study using 100 individual serum samples collected from May 1999 to August 2016 was performed to determine antibody prevalence to seven pathogens in warthogs from five locations in northeastern South Africa. Higher prevalence of antibodies to African swine fever virus and Mycobacterium bovis were detected in warthogs from the Greater Kruger National Park ecosystem in comparison to lower prevalence of antibodies to M. bovis and no antibodies to African swine fever virus in warthogs from uMhkuze Game Reserve. Low prevalence of antibodies to foot-and-mouth disease virus, Rift Valley fever virus, and influenza A virus was detected in all locations, and no antibodies against Brucella and Leptospira spp. were detected. No statistically significant difference in antibody prevalence was found between sexes for any disease. At the univariate analysis, M. bovis seropositivity was significantly different among age categories, with 49% (35/71) of adults found positive versus 29% (4/14) of juveniles and 9% (1/11) of sub-adults (Fisher’s exact test, P=0.020), and between the sampling locations (Fisher’s exact test, P=0.001). The multivariate model results indicated that juvenile warthogs had lower odds of testing positive to M. bovis antibodies than adults (juveniles’ odds ratio [OR]=0.17, 95% confidence interval [CI]: 0.02-1.0), although this result was not statistically significant at the 5% level (P=0.052). For warthogs sampled at Satara Buffalo Camp, the odds (OR=0.22, 95% CI: 0.035-0.96) of being M. bovis antibody positive were significantly lower (P=0.043) than for warthogs sampled at Skukuza. Of particular interest in this study was the detection of warthogs seropositive for influenza A virus.

PMID:33635986 | DOI:10.7589/JWD-D-20-00011

J Wildl Dis. 2021 Jan 6;57(1):104-115. doi: 10.7589/JWD-D-19-00001.

ABSTRACT

Canine distemper virus (CDV) has a broad mammalian host range. In Ontario, Canada, CDV is frequently encountered in wild carnivores and is the most common infectious cause of death for raccoons (Procyon lotor). The isolation of wild-type CDV strains genetically distinct from vaccine strains in North America has renewed interest in the epidemiological patterns of this virus. However, wildlife surveillance is challenging and often utilizes a combination of surveillance methods with aggregation of data from multiple sources. Our objective was to compare raccoon CDV data generated through two separate surveillance components operated by the Ontario-Nunavut node of the Canadian Wildlife Health Cooperative. The raw data generated by each component in addition to the results of multilevel logistic regression and spatial scan statistics, were compared between the datasets. A total of 498 raccoons obtained via passive surveillance between 2007 and 2017 and 887 raccoons obtained via enhanced-passive surveillance between 2014 and 2017, were tested for CDV. The number and geographic distribution of reports, proportion of yearly reports classified as CDV-positive, and characteristics of CDV-positive raccoons differed between passive and enhanced-passive surveillance components. Geographical data demonstrated that CDV infection was present throughout southern Ontario. The geographic area of both surveillance components combined was more representative than either passive or enhanced-passive surveillance in isolation; but was restricted compared to the overall distribution of raccoons in Ontario. Regression analyses produced statistically significant associations between the presence of CDV and host and environmental variables that were at times discordant between the two datasets. Studying the properties of these datasets will inform future passive wildlife surveillance strategies and highlights the impact that a surveillance strategy can have on the results of epidemiological analyses.

PMID:33635985 | DOI:10.7589/JWD-D-19-00001

J Wildl Dis. 2021 Jan 6;57(1):184-188. doi: 10.7589/JWD-D-20-00002.

ABSTRACT

Hunting activities are a potential risk factor for human infection with Leptospira spp. and, although wild boar seroprevalence has been studied, there are no concurrent serosurveys of wild boars (Sus scrofa), hunting dogs (Canis lupus familiaris), and hunters. The aim of our study was to assess the seroprevalence of Leptospira spp. antibodies in free-ranging wild boars, hunting dogs, and hunters, and risk factors associated with exposure in southern and central-western Brazil. Leptospira spp. antibodies were serologically detected using the microscopic agglutination test, with a total 30 serovars. Overall, 12.2% (9/74) of wild boars and 10.6% (16/170) of hunting dogs were seropositive for at least one serovar and all hunters 0.0% (0/49) were seronegative for Leptospira spp. Seropositivity was statistically higher in 42.1% (8/19) wild boars from natural areas when compared to 2.4% (1/41) from anthropized areas (P<0.001), with prevalence ratio of 17.14 (95% confidence interval: 2.29-128.36). Despite the limited sample size, our findings showed that hunters may be less exposed to Leptospira spp. than are wild boars, particularly in natural areas where Leptospira spp. may be maintained by wild reservoirs. In addition to acting as sentinels, hunting dogs may play a role in disease transmission of sylvatic leptospiral serovars.

PMID:33635982 | DOI:10.7589/JWD-D-20-00002

J Wildl Dis. 2021 Jan 6;57(1):194-198. doi: 10.7589/JWD-D-20-00007.

ABSTRACT

Chronic wasting disease (CWD) of white-tailed deer (Odocoileus virginianus) is a fatal neurologic disease that is spreading across North America. A common surveillance protocol for CWD currently involves screening with an enzyme-linked immunosorbent assay (ELISA) followed by confirmatory testing with immunohistochemistry (IHC). Medial retropharyngeal lymph nodes (MRPLN) are the tissue of choice to diagnose CWD in free-ranging white-tailed deer. We examined left and right MRPLN from 101 ELISA-positive deer harvested from 2015 to 2019 to determine the prevalence of cases in which prion protein was not detected by IHC as well as differences in IHC labeling between contralateral lymph nodes. Prion protein was not detected using IHC in either MRPLN in 5.9% (6/101) of cases. There was a significant but weak positive relationship between the number of IHC-positive follicles and ELISA optical density values (R2=0.08, P=0.039). Mean optical density values in IHC-positive MRPLN were higher than in IHC-negative MRPLN; however, this was not statistically significant (P=0.260). Failure to confirm ELISA diagnoses with IHC may have been because the methods tested different areas of MRPLN, or that there were differences in test sensitivity or antibody affinity. An additional 5.9% (6/101) of cases had one IHC-positive MRPLN, whereas the contralateral MRPLN was IHC negative. Therefore, testing a single MRPLN for CWD may lead to false-negative results, regardless of methodology, which highlights the importance of collecting and testing both MRPLN.

PMID:33635974 | DOI:10.7589/JWD-D-20-00007

Arch Pathol Lab Med. 2021 Feb 26. doi: 10.5858/arpa.2020-0441-OA. Online ahead of print.

ABSTRACT

CONTEXT.—: In laboratory testing for monoclonal gammopathies, paraproteins are identified via serum immunofixation or serum immunosubtraction and immunoturbidimetric quantitation of serum immunoglobulins is often used.

OBJECTIVE.—: To evaluate methodic differences between serum immunofixation and serum immunosubtraction as well as in the quantitation of serum immunoglobulins on different clinical chemical platforms.

DESIGN.—: Three hundred twenty-two unique routine patient samples were blinded and used for comparison between serum immunofixation on Sebia’s HYDRASIS 2 and serum immunosubtraction on Sebia’s CAPILLARYS 2 as well as between quantitation results of immunoglobulin A, G, and M on Abbott’s ARCHITECT c16000PLUS and Roche’s Cobas c 502 module. Microsoft Excel 2019 with the add-on Abacus 2.0 and MedCalc were used for statistical analysis and graphic depiction via bubble diagram, Passing-Bablok regressions, and Bland-Altman plots.

RESULTS.—: The median age of patients was 75 years and samples with paraproteinemia were nearly evenly split between sexes. Paraprotein identification differed remarkably between immunofixation and immunosubtraction. Quantitation of serum immunoglobulins showed higher values on Abbott’s ARCHITECT c16000PLUS when compared with Roche’s Cobas c 502 module.

CONCLUSIONS.—: Identification of paraproteins via serum immunosubtraction is inferior to serum immunofixation, which can have implications on the diagnosis and monitoring of patients with monoclonal gammopathy. If immunoturbidimetric quantitation of immunoglobulins is used for follow-up, the same clinical-chemical platform should be used consistently.

PMID:33635966 | DOI:10.5858/arpa.2020-0441-OA