Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients.

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Quantitative investigation of dose accumulation errors from intra-fraction motion in MRgRT for prostate cancer.

Accurate spatial dose delivery in radiotherapy is frequently complicated due to changes in the patient's internal anatomy during and in-between therapy segments. The recent introduction of hybrid MRI radiotherapy systems allows unequaled soft-tissue visualization during radiation delivery and can be used for dose reconstruction to quantify the impact of motion. To this end, knowledge of anatomical deformations obtained from continuous monitoring during treatment has to be combined with information on the spatio-temporal dose delivery to perform motion-compensated dose accumulation (MCDA). Here, the influence of the choice of deformable image registration algorithm, dose warping strategy, and magnetic resonance image resolution and signal-to-noise-ratio on the resulting MCDA is investigated. For a quantitative investigation, four 4D MRI-datasets representing typical patient observed motion patterns are generated using finite element modeling and serve as a gold standard. Energy delivery is simulated intra-fractionally in the deformed image space and, subsequently, MCDA-processed. Finally, the results are substantiated by comparing MCDA strategies on clinically acquired patient data. It is shown that MCDA is needed for correct quantitative dose reconstruction. For prostate treatments, using the energy per mass transfer dose warping strategy has the largest influence on decreasing dose estimation errors.

Detecting clinically-relevant changes in progressive multiple sclerosis.

OBJECTIVE: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS). METHODS: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy's Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS. RESULTS: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW. CONCLUSION: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS.

Proxy measurements in multiple sclerosis: agreement on different patient-reported outcome scales.

BACKGROUND: Patient-reported outcome (PRO) scales are often used in multiple sclerosis (MS) research. Full understanding of items can be influenced by disease worsening, mood disturbances and cognitive problems of the MS patient. Earlier research with the Multiple Sclerosis Impact Scale (MSIS-29) showed that proxy respondents (i.e. partners of patients) can provide useful information. OBJECTIVE: To determine agreement between patients and proxy respondents on different MS PRO scales. METHODS: 139 Patients and partners completed the MSIS-29 (Physical and Psychological scale), Multiple Sclerosis Walking Scale (MSWS-12), Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) and Guy's Neurological Disability Scale (GNDS). We calculated the mean difference and intra-class correlation coefficients (ICC) on scale level and weighted kappas (κ(w)) on item level. RESULTS: On all scales, except MSNQ, the partner score was higher. ICCs were good for MSWS, GNDS and MSIS Physical, and moderate for MSNQ and MSIS Psychological. κ(w) was excellent for MSWS items, fair to good for GNDS, MSIS Physical and MSIS Psychological items, and poor for MSNQ items. CONCLUSION: Partners of patients with MS can be a useful source of information for several PRO scales, especially when the focus is on physical functioning. For psychological functioning this seems to be less reliable.

Progression on the Multiple Sclerosis Functional Composite in multiple sclerosis: what is the optimal cut-off for the three components?

For the Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT), components of the Multiple Sclerosis Functional Composite (MSFC), cut-off points of 20% change have previously been defined as meaningful endpoints of functional decline. Recently, however, a 15% change of MSFC components was introduced. The objective of this study was to determine optimal cut-offs for all MSFC components to indicate clinical disease progression in a primary progressive (PP) multiple sclerosis (MS) population. T25FW, 9HPT and the Paced Auditory Serial Addition Test (PASAT) were performed in 161 patients with PPMS with a 2-year interval. Absolute and relative differences in test scores were calculated. For each cut-off point of relative change, proportions of patients who progressed (deterioration beyond cut-off value) and improved (improvement beyond cut-off value) were calculated. Further, we calculated the ratio of 'improved' versus 'progressed' patients. Line graphs were created indicating: percentage progressed patients, percentage improved patients, and ratio of improved versus progressed patients. The optimal cut-off was determined by searching the cut-off point with the lowest ratio of improved versus progressed patients, while at the same time capturing a substantial amount of progression. For both T25FW and 9HPT, the ratio between patients that improved and worsened clearly decreased between the cut-offs of 15% and 20%. For the PASAT, the ratio between patients improved and worsened was persistently poor. In conclusion, a cut-off of 20% for both T25FW and 9HPT has a better signal-to-noise ratio than lower values (e.g. 15%) and is therefore preferable for the assessment of disease progression. No satisfactory cut-off point for the PASAT could be determined.

The search for responsive clinical endpoints in primary progressive multiple sclerosis.

OBJECTIVE: To determine whether in primary progressive multiple sclerosis (PPMS) combining scores of Expanded Disability Status Scale (EDSS) with data from Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT) would produce a clinical endpoint that has a higher event rate than EDSS alone. METHODS: In a group of 161 PPMS patients, EDSS, T25FW, and 9HPT were performed at three time points over 2 years. We calculated how many patients showed clinically meaningful deterioration (or improvement) on individual and combined scales. We defined improvements on one scale with deterioration on the other as "opposing changes." We investigated the possible effect of baseline disability on the definition of our endpoint by dividing the population into two subsets of patients determined by baseline EDSS level. RESULTS: On individual scales, event rates were highest on T25FW: 34% and 46% 1 year and 2 years after baseline. On a combination of two scales, at 1 year the event rate was highest on T25FW/9HPT (46%; with a high rate of opposing changes) and at 2 years on T25FW/EDSS (57%; with a lower rate of opposing changes). In both subsets, event rates were highest on T25FW and (at 2 years) on the combination of T25FW/EDSS. CONCLUSIONS: T25FW has the highest event rate as a single scale, independent of baseline disability level. A term of 2 years turned out to be more meaningful to observe than 1 year. "Worsening on either T25FW or EDSS" is the most appropriate composite endpoint in this patient group.

[Intakes for (day) clinical psychotherapy. A cohort study]. / Intakes voor (deeltijd) klinische psychotherapie. Een cohortonderzoek.

Little is known about the type of patient who is referred for clinical psychotherapy. A descriptive, retrospective cohort study was performed involving 100 patients who attended a (day) clinic for personality, anxiety and eating disorders. Sociodemographic and clinical characteristics of these patients are described. Most of the patients had multiple disorders of a serious nature, displayed a high degree of functional impairment and were relatively treatment-resistant. Of the 70% who were diagnosed as requiring treatment, 79% agreed to have the treatment that was offered.

The Minnesota DARE PLUS Project: creating community partnerships to prevent drug use and violence.

The research community has criticized Drug Abuse Resistance Education (D.A.R.E.) because the extant literature indicates a lack of evidence that the elementary school program prevents drug use. Yet D.A.R.E. continues to be the most widely implemented drug use prevention program in the United States and has considerable community support. To date, the junior high D.A.R.E. program has not been evaluated. The Minnesota DARE PLUS Project is a randomized trial of 24 schools and communities. During 1999-2001, students in eight schools will receive the junior high D.A.R.E. curriculum in 7th grade; eight schools also will receive the curriculum as well as additional parent involvement, peer leadership, and community components in the 7th and 8th grades; and eight schools will serve as controls. This article describes the background and conceptualization, the curriculum and additional intervention components, and the evaluation methods of the DARE PLUS Project.

Hemolytic anemia caused by Babesia gibsoni infection in dogs.

Babesia gibsoni caused severe hemolytic anemia in 11 dogs from southern California. The most common clinical signs of B gibsoni infection were lethargy, anorexia, anemia, and thrombocytopenia. Acute infection with B gibsoni may be misdiagnosed as autoimmune hemolytic anemia. Diagnosis was most reliably determined by identification of the intraerythrocytic parasites on Giemsa-stained blood smears. The pathogenicity of B gibsoni, difficulties in diagnosis, the parasite's resistance to treatment with available drugs, and frequent interstate movement of dogs indicate that this disease may be a serious threat to dogs throughout the United States.