Anti-thymocyte globulin with CsA and MMF as GVHD prophylaxis in nonmyeloablative HLA-mismatched allogeneic HCT

Nonmyeloablative regimens are used for allogeneic hematopoietic cell transplantation (HCT) of older or medically unfit patients, but successful outcome is still hindered by graft-versus-host disease (GVHD), especially in the setting of HLA-mismatched HCT. New GVHD prophylaxis strategies are emerging, including the triple drug strategy, that improve the GVHD-free and relapse-free survival (GRFS). Because the impact of ATG in HLA-mismatched Flu-TBI-based nonmyeloablative HCT has not been investigated, we did a retrospective analysis in three Dutch centers. 67 patients were evaluable, with a median age of 56 years. Overall survival, relapse-free survival and GRFS at 4 years were 52%, 43%, and 38%, respectively. NRM findings and cumulative incidence of relapse at 4 years were 26% and 31%, respectively. At 1-year grade II-IV had occurred in 40% of the patients, and the incidence of moderate-severe chronic GVHD incidence was 16%. Acknowledging the limitations of retrospective analyses, we conclude that the use of ATG for HLA-mismatched truly nonmyeloablative Flu-TBI HCT is feasible and results in acceptable long term outcomes, especially with regards to GRFS. We consider ATG in combination with cyclosporin and mycophenolate mofetil as an alternative for the triple drug strategy that uses sirolimus for GVHD prophylaxis in this particular setting

Depression and related factors after oral oncological treatment: a 5-year prospective cohort study

PURPOSES: Being diagnosed with oral cancer is a life-threatening life event. It often induces social, emotional and psychological consequences and may cause depressive disorders. The primary aim of this study was to identify and quantify the personal and clinical characteristics involved in depression for patients who have been treated for oral cavity malignancies, with a 5-year follow-up period after treatment. The secondary aim of this study was to identify the clinical factors that increase a patient's risk of experiencing depression 5 years after treatment. METHODS: Patients with primary oral cancer were assessed for up to 5 years after primary treatment. A mixed-model analysis was performed, with depression measured by the Center for Epidemiologic Studies Depression Scale as outcome measure. RESULTS: A total of 141 patients were included in the study. Factors associated with depression were gender, tumour location and having an emotion-oriented coping style. The occurrence of depression within 5 years after treatment could be reliably predicted by a patient's gender, the location of their tumour and the extent to which they had an emotion-oriented coping style. CONCLUSIONS: This study revealed that being female, having a maxillary tumour and having an emotion-oriented coping style are associated with higher levels of depressive symptoms in patients treated for oral cancer up to 5 years post-treatment. A substantial proportion of the patients with oral cancer experienced high levels of depression both before and after their treatment, suggesting that adequate diagnostics and care are needed to try to prevent severe depression in these patients

Swallowing after Oral Oncological Treatment: A Five-Year Prospective Study

BACKGROUND: Swallowing rehabilitation in curative treated patients with oral cancer is still a challenge. Different factors may influence these patients' swallowing function. The aim of this study was to identify factors associated with swallowing function up to 5 years after cancer treatment. METHODS: Swallowing duration and frequency of 5 mL water and 15 mL applesauce were measured in 123 patients treated for oral cancer. Mixed model analyses were performed to identify associated factors. RESULTS: Age influenced all measured swallowing outcomes. Assessment moment, gender, tumor location, maximum tongue force, and tactile sensory function of the tongue were associated with both water and applesauce swallowing duration, tumor classification was associated with water swallowing duration, and alcohol consumption was associated with applesauce swallowing duration. Assessment moment, cancer treatment, maximum tongue force, and tactile sensory function of the tongue were associated with water and applesauce swallowing frequency. CONCLUSION: Patients who are older at diagnosis, women, and patients who regularly consume alcohol before their treatment may have poorer swallow functioning after curative oral cancer treatment. Patients that fit these criteria should have their swallowing evaluated during clinical follow-ups and sent to swallowing therapy when needed. During this therapy, optimizing tongue function needs attention to maintain an optimal swallowing function

Association Between Seizures and Neurodevelopmental Outcome at Two and Five Years in Asphyxiated Newborns With Therapeutic Hypothermia

OBJECTIVE: To investigate the association between the presence and severity of seizures in asphyxiated newborns and their neurodevelopmental outcome at ages two and five years. METHODS: Retrospective data analysis from a prospectively collected multicenter cohort of 186 term-born asphyxiated newborns undergoing therapeutic hypothermia (TH) in 11 centers in the Netherlands and Belgium. Seizures were diagnosed by amplitude-integrated electroencephalography (EEG) and raw EEG signal reading up to 48 hours after rewarming. Neurodevelopmental outcome was assessed by standardized testing at age two and five years. Primary outcome was death or long-term neurodevelopmental impairment (NDI) including cerebral palsy. Associations were calculated using univariate and multivariate logistic regression analyses adjusting for Thompson score and a validated brain magnetic resonance imaging (MRI) score. RESULTS: Seventy infants (38%) had seizures during TH or rewarming, and 44 (63%) of these needed two or more antiseizure medications (ASMs). Overall mortality was 21%. Follow-up data from 147 survivors were available for 137 infants (93%) at two and for 94 of 116 infants (81%) at five years. NDI was present in 26% at two and five years. Univariate analyses showed a significant association between seizures and death or NDI, but this was no longer significant after adjusting for Thompson and MRI score in the multivariate analysis; this was also true for severe seizures (need for two or more ASMs) or seizures starting during rewarming. CONCLUSION: The presence or severity of seizures in newborns undergoing TH for hypoxic-ischemic encephalopathy was not independently associated with death or NDI up to age five years after adjusting for several confounders

Neural Representation of Motor Output, Context and Behavioral Adaptation in Rat Medial Prefrontal Cortex During Learned Behavior

Selecting behavioral outputs in a dynamic environment is the outcome of integrating multiple information streams and weighing possible action outcomes with their value. Integration depends on the medial prefrontal cortex (mPFC), but how mPFC neurons encode information necessary for appropriate behavioral adaptation is poorly understood. To identify spiking patterns of mPFC during learned behavior, we extracellularly recorded neuronal action potential firing in the mPFC of rats performing a whisker-based “Go”/“No-go” object localization task. First, we identify three functional groups of neurons, which show different degrees of spiking modulation during task performance. One group increased spiking activity during correct “Go” behavior (positively modulated), the second group decreased spiking (negatively modulated) and one group did not change spiking. Second, the relative change in spiking was context-dependent and largest when motor output had contextual value. Third, the negatively modulated population spiked more when rats updated behavior following an error compared to trials without integration of error information. Finally, insufficient spiking in the positively modulated population predicted erroneous behavior under dynamic “No-go” conditions. Thus, mPFC neuronal populations with opposite spike modulation characteristics differentially encode context and behavioral updating and enable flexible integration of error corrections in future actions

First principles investigation of exchange interactions in quasi-one-dimensional antiferromagnet CaV2O4

The effect of orbital degrees of freedom on the exchange interactions in the spin-1 quasi-one-dimensional antiferromagnet CaV2O4 is systematically studied. For this purpose a realistic low-energy model with the parameters derived from the first-principles calculations is constructed. The exchange interactions are calculated using both the theory of infinitesimal spin rotations near the mean-field ground state and the superexchange model, which provide a consistent description. The obtained behaviour of exchange interactions substantially differs from the previously proposed phenomenological picture based on the magnetic measurements and structural considerations, namely: (i) Despite quasi-one-dimensional character of the crystal structure, consisting of the zigzag chains of edge-sharing VO6 octahedra, the electronic structure is essentially three-dimensional, that leads to finite interactions between the chains; (ii) The exchange interactions along the legs of the chains appear to dominate; and (iii) There is a substantial difference of exchange interactions in two crystallographically inequivalent chains. The combination of these three factors successfully reproduces the behaviour of experimental magnetic susceptibility.Comment: 15 pages, 6 figures, supplementary materia

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia

Aims: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. Methods: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400–600 mg*h/L was used as target range. Results: Sixteen patients received vancomycin (median gestational age: 41 [range: 38–42] weeks, postnatal age: 4.4 [2.5–5.5] days, birth weight: 3.5 [2.3–4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20–0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. Conclusion: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.</p

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T.MIC) (for efficacy purposes and 100% T.4×MIC and 100% T.5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T.MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T.MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T.4×MIC and 100% T.5×MIC are desired.</p

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia

Aims: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. Methods: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400–600 mg*h/L was used as target range. Results: Sixteen patients received vancomycin (median gestational age: 41 [range: 38–42] weeks, postnatal age: 4.4 [2.5–5.5] days, birth weight: 3.5 [2.3–4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20–0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. Conclusion: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.</p

Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia

Background:Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH.Methods:The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed.Results:The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters.Conclusions:The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.</p