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Multimodal MRI staging for tracking progression and clinical-imaging correlation in sporadic Creutzfeldt-Jakob disease

Neuroimage Clin. 2020 Dec 11;30:102523. doi: 10.1016/j.nicl.2020.102523. Online ahead of print.

ABSTRACT

Diffusion imaging is very useful for the diagnosis of sporadic Creutzfeldt-Jakob disease, but it has limitations in tracking disease progression as mean diffusivity changes non-linearly across the disease course. We previously showed that mean diffusivity changes across the disease course follow a quasi J-shaped curve, characterized by decreased values in earlier phases and increasing values later in the disease course. Understanding how MRI metrics change over-time, as well as their correlations with clinical deficits are crucial steps in developing radiological biomarkers for trials. Specifically, as mean diffusivity does not change linearly and atrophy mainly occurs in later stages, neither alone is likely to be a sufficient biomarker throughout the disease course. We therefore developed a model combining mean diffusivity and Volume loss (MRI Disease-Staging) to take into account mean diffusivity’s non-linearity. We then assessed the associations between clinical outcomes and mean diffusivity alone, Volume alone and finally MRI Disease-Staging. In 37 sporadic Creutzfeldt-Jakob disease subjects and 30 age- and sex-matched healthy controls, high angular resolution diffusion and high-resolution T1 imaging was performed cross-sectionally to compute z-scores for mean diffusivity (MD) and Volume. Average MD and Volume were extracted from 41 GM volume of interest (VOI) per hemisphere, within the images registered to the Montreal Neurological Institute (MNI) space. Each subject’s volume of interest was classified as either “involved” or “not involved” using a statistical threshold of ± 2 standard deviation (SD) for mean diffusivity changes and/or -2 SD for Volume. Volumes of interest were MRI Disease-Staged as: 0 = no abnormalities; 1 = decreased mean diffusivity only; 2 = decreased mean diffusivity and Volume; 3 = normal (“pseudo-normalized”) mean diffusivity, reduced Volume; 4 = increased mean diffusivity, reduced Volume. We correlated Volume, MD and MRI Disease-Staging with several clinical outcomes (scales, score and symptoms) using 4 major regions of interest (Total, Cortical, Subcortical and Cerebellar gray matter) or smaller regions pre-specified based on known neuroanatomical correlates. Volume and MD z-scores correlated inversely with each other in all four major ROIs (cortical, subcortical, cerebellar and total) highlighting that ROIs with lower Volumes had higher MD and vice-versa. Regarding correlations with symptoms and scores, higher MD correlated with worse Mini-Mental State Examination and Barthel scores in cortical and cerebellar gray matter, but subjects with cortical sensory deficits showed lower MD in the primary sensory cortex. Volume loss correlated with lower Mini-Mental State Examination, Barthel scores and pyramidal signs. Interestingly, for both Volume and MD, changes within the cerebellar ROI showed strong correlations with both MMSE and Barthel. Supporting using a combination of MD and Volume to track sCJD progression, MRI Disease-Staging showed correlations with more clinical outcomes than Volume or MD alone, specifically with Mini-Mental State Examination, Barthel score, pyramidal signs, higher cortical sensory deficits, as well as executive and visual-spatial deficits. Additionally, when subjects in the cohort were subdivided into tertiles based on their Barthel scores and their percentile of disease duration/course (“Time-Ratio”), subjects in the lowest (most impaired) Barthel tertile showed a much greater proportion of more advanced MRI Disease-Stages than the those in the highest tertile. Similarly, subjects in the last Time-Ratio tertile (last tertile of disease) showed a much greater proportion of more advanced MRI Disease-Stages than the earliest tertile. Therefore, in later disease stages, as measured by time or Barthel, there is overall more Volume loss and increasing MD. A combined multiparametric quantitative MRI Disease-Staging is a useful tool to track sporadic Creutzfeldt-Jakob- disease progression radiologically.

PMID:33636540 | DOI:10.1016/j.nicl.2020.102523

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A concordance study determining language dominance between navigated transcranial magnetic stimulation and the Wada test in patients with drug-resistant epilepsy

Epilepsy Behav. 2021 Feb 23;117:107711. doi: 10.1016/j.yebeh.2020.107711. Online ahead of print.

ABSTRACT

OBJECTIVE: It remains unclear whether transcranial magnetic stimulation (TMS) can replace the Wada test to determine language hemisphere dominance (HD). Using the Wada test as the gold standard, this study aimed to investigate the accuracy of navigated TMS (nTMS) in determining language HD.

METHODS: This study enrolled nine right-handed patients with drug-resistant epilepsy. We hypothesized that application of nTMS to language-related areas of the language-dominant hemisphere would induce positive manifestation of language dysfunction (LD). To test our hypothesis, the patients were instructed to perform a visual object-naming task while nTMS was applied to the anterior (e.g., Broca’s area) and posterior (e.g., Wernicke’s area) regions, which are closely related to language processing. The Wada test result was used as the gold standard, and the diagnostic value of nTMS was assessed using the Kappa consistency test.

RESULTS: The nTMS-induced LD positive rate for the bilateral anterior language areas (85.7%) was higher than that for the posterior language areas (57.1%). There was high consistency between nTMS stimulation of the left anterior and posterior language areas and the Wada test results for determining language HD. In contrast, the consistency of stimulation of the right anterior and posterior transfer sites was moderate (Kappa value = 0.545, P = 0.171) and low, respectively. For the latter, no statistical calculation was performed because stimulation of the right posterior speech area was negative in all patients compared with the Wada test results.

CONCLUSIONS: Our findings revealed that using nTMS to stimulate language-related left anterior and posterior areas could predict language HD with high accuracy. When the stimulation performance of these areas is positive, nTMS and the Wada test are equally accurate. Observing only negative performance may indicate that language HD has been transferred to the right side.

PMID:33636527 | DOI:10.1016/j.yebeh.2020.107711

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The psychosocial impact of COVID-19 within the first six months of the pandemic on youth with epilepsy and their caregivers

Epilepsy Behav. 2021 Feb 12;117:107855. doi: 10.1016/j.yebeh.2021.107855. Online ahead of print.

ABSTRACT

OBJECTIVES: We assessed the impact of COVID-19 on children with epilepsy and their families, focusing on epilepsy management, family routines, learning, and adherence to Centers for Disease Control and Prevention (CDC) pandemic guidelines (e.g., social distancing, mask wearing) within the first six months of the pandemic. Group differences in COVID-19 impact on families were also examined based on race and ethnicity, being medically and/or geographically underserved, and insurance status.

METHODS: Participants (n = 131) included children with epilepsy and their families from two clinical trials. The Impact of COVID-19 on Pediatric Epilepsy Management (ICPEM) measure was developed and administered to caregivers online from April 2020 to September 2020 across four large pediatric hospitals. Administration of the ICPEM occurred both during routine study assessments and an additional acute time point to obtain information early in the pandemic (e.g., April and May 2020). Descriptive statistics and t-tests were used for analyses.

RESULTS: Data indicate minor to moderate impact of COVID-19 on pediatric epilepsy management. Caregivers of children with epilepsy reported the most impact on education and social functioning. Adherence to CDC guidelines was reported to be high. Those having public insurance reported greater difficulties obtaining daily anti-seizure medications compared to those with private insurance.

CONCLUSIONS: This study presents important initial data regarding the impact of COVID-19 epilepsy management and daily functioning in children with epilepsy and their families. While the acute impact of COVID-19 restrictions appear to be mild to moderate, it is unclear what the long-term impact of the pandemic will be on families of children with epilepsy.

PMID:33636530 | DOI:10.1016/j.yebeh.2021.107855

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The Wellness Quest: A health literacy and self-advocacy tool developed by youth for youth mental health

Health Expect. 2021 Feb 26. doi: 10.1111/hex.13214. Online ahead of print.

ABSTRACT

BACKGROUND: Less than 20% of youth who experience mental health difficulties access and receive appropriate treatment. This is exacerbated by barriers such as stigma, confidentiality concerns and lack of mental health literacy. A youth team developed the Wellness Quest: a health literacy tool to enable help-seeking youth to advocate for themselves.

OBJECTIVE: To evaluate the content, presentation and utility of the Wellness Quest tool among youth.

PARTICIPANTS: Participants aged 14 to 26.

METHODS: A youth research team conducted five focus groups and one online survey to evaluate the Wellness Quest tool. Thematic analysis was used to analyse the qualitative data, and descriptive statistics were used to explore the survey results.

MAIN RESULTS: Overall evaluations of the Wellness Quest were positive: participants felt it would be useful during their mental health help-seeking journey. Participants expressed the need for information about services for specific populations, such as Indigenous, immigrants, refugees and 2SLGBTQ + youth. They expressed that the tool should be available in complementary online and print versions.

DISCUSSION: Improving mental health literacy may improve mental health by enabling youth and those who support them to recognize and respond to signs of distress and understanding where and how to get help. The Wellness Quest tool may equip youth with the knowledge to make informed decisions and advocate for their own mental health, thereby facilitating help-seeking among youth.

PATIENT OR PUBLIC CONTRIBUTION: Youth as service users led all stages of the project, from designing and conducting the study and analysing the data to writing the manuscript.

PMID:33636052 | DOI:10.1111/hex.13214

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Prognostic Value of Preoperative Inflammation Markers in Non-Muscle Invasıve Bladder Cancer

Int J Clin Pract. 2021 Feb 26:e14118. doi: 10.1111/ijcp.14118. Online ahead of print.

ABSTRACT

PURPOSE: To investigate the prediction values of the preoperative NLR, LMR, PLR, MPV, RDW for recurrence and progression of patients with non-muscle invasive bladder cancer (NMIBC).

METHODS: In this prospective study, 94 consecutive patients, newly diagnosed with NMIBC between July 2017 – August 2018 were included. The blood samples were collected from patients before transurethral resection of bladder tumor (TURB) and NLR, LMR, PLR, RDW, MPV values were calculated. The effect of these preoperative inflammatory parameters and other clinicopathological parameters on recurrence and progression rates were evaluated. Kaplan-Meier and multivariate Cox regression analyses were performed to identify significant prognostic variables.

RESULTS: The mean follow-up was 11 ± 6.4 months. Recurrence was observed in 35.1% and progression was detected in 7.4% of the patients. Neutrophil-lymphocyte ratio was statistically significantly associated with both recurrence (p = 0.01) and progression (p = 0.035) whereas lymphocyte-monocyte ratio was only associated with recurrence (p = 0.038). In the survival analyses, the relationship between recurrence and LMR was confirmed in both univariate (p = 0.021) and multivariate (p = 0.022) analyses. The relationship between NLR and recurrence was confirmed in univariate analysis (p = 0.019), however in multivariate analysis was found to be statistically insignificant (p = 0.051).

CONCLUSIONS: Lymphocyte-monocyte ratio might be an easy obtainable, non-invasive and cost-effective method for predicting recurrence of disease in patients with non-muscle invasive bladder cancer.

PMID:33636055 | DOI:10.1111/ijcp.14118

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Unsuspected femoral hernias diagnosed during endoscopic inguinal hernia repair

Adv Clin Exp Med. 2021 Feb 26. doi: 10.17219/acem/130357. Online ahead of print.

ABSTRACT

BACKGROUND: The laparoscopic totally extraperitoneal inguinal hernia repair (TEP), unlike the Lichtenstein tension-free mesh repair, allows for inspecting the femoral canal area for the presence of an occult femoral hernia.

OBJECTIVES: To determine the incidence of an unsuspected femoral hernia in patients undergoing TEP repair.

MATERIAL AND METHODS: Data was collected prospectively from 180 patients (23 women) who underwent hernia repair, including examination of the femoral canal, between November 2017 and March 2019, and the incidence of a femoral hernia was determined. Correlations between the incidence of a femoral hernia and sex, age and the type of inguinal hernia diagnosed in the patients (indirect, direct, both indirect and direct) were assessed.

RESULTS: Femoral hernias were found in 14 patients (7.77%). None of the hernias had previously been detected clinically. The incidence of a femoral hernia was higher in women (6/23, 26.07%) than in men (8/157, 5.09%). The incidence of a femoral hernia was higher in older patients: the average age of patients with a femoral hernia was 57.86 years (median: 60 years), whereas the average age of patients without a femoral hernia was 49.92 years (median: 49 years). However, the correlation was not statistically significant. No correlation was found between the incidence of a femoral hernia and the type of inguinal hernia diagnosed in the patients (direct, indirect, both indirect and direct).

CONCLUSIONS: The TEP repair allows for detecting and repairing an occult femoral hernia.

PMID:33636062 | DOI:10.17219/acem/130357

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Does Extracorporeal Shock Wave Lithotripsy Before Retrograde Intrarenal Surgery Complicate the Surgery for Upper Ureter Stone? The Results of RIRSearch Group

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

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Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial

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

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Pharmacokinetic Modeling and Simulation Support for Age- and Weight-Adjusted Dosing of Dabigatran Etexilate in Children with Venous Thromboembolism

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

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ANTIBODY PREVALENCE TO AFRICAN SWINE FEVER VIRUS, MYCOBACTERIUM BOVIS, FOOT-AND-MOUTH DISEASE VIRUS, RIFT VALLEY FEVER VIRUS, INFLUENZA A VIRUS, AND BRUCELLA AND LEPTOSPIRA SPP. IN FREE-RANGING WARTHOG (PHACOCHOERUS AFRICANUS) POPULATIONS IN SOUTH AFRICA

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