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Background: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. Methods: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. Results: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients. Conclusions: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients. This study shows that repeated intraperitoneal chemotherapy, regardless of method of administration, is a promising and safe treatment for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a selected subset of patients. [ABSTRACT FROM AUTHOR]

Aims: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side‐effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side‐effects and drug effectiveness. Methods: Twenty‐four children and adolescents (15 males, 9 females) aged 6–18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side‐effects and drug effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro‐aripiprazole concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed‐effects models. Results: For both aripiprazole and dehydro‐aripiprazole, one‐compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro‐aripiprazole) trough concentrations best predicted higher BMI z‐scores (P <.001) and higher Hb1Ac levels (P =.03) during follow‐up. No significant association was found between sum concentrations and effectiveness. Conclusions: Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems. [ABSTRACT FROM AUTHOR]

Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods: Forty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models. Results: A risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P <.001). Higher sum trough concentrations also predicted more sedation (P <.05), higher prolactin levels (P <.001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P <.01). Conclusion: Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems. [ABSTRACT FROM AUTHOR]

Quantification of tumor‐specific variants (TSVs) in cell‐free DNA is rapidly evolving as a prognostic and predictive tool in patients with cancer. Currently, both variant allele frequency (VAF) and number of mutant molecules per mL plasma are used as units of measurement to report those TSVs. However, it is unknown to what extent both units of measurement agree and what are the factors underlying an existing disagreement. To study the agreement between VAF and mutant molecules in current clinical studies, we analyzed 1116 TSVs from 338 patients identified with next‐generation sequencing (NGS) or digital droplet PCR (ddPCR). On different study cohorts, a Deming regression analysis was performed and its 95% prediction interval was used as surrogate for the limits of agreement between VAF and number of mutant molecules per mL and to identify outliers. VAF and number of mutant molecules per mL plasma yielded greater agreement when using ddPCR than NGS. In case of discordance between VAF and number of mutant molecules per mL, insufficient molecular coverage in NGS and high cell‐free DNA concentration were the main responsible factors. We propose several optimization steps needed to bring monitoring of TSVs in cell‐free DNA to its full potential. [ABSTRACT FROM AUTHOR]

Bleeding is a common adverse event following ibrutinib monotherapy. However, it remains unclear how hemostasis is affected by venetoclax in combination with ibrutinib. Here we investigated hemostasis in patients with chronic lymphocytic leukemia (CLL) at baseline, during ibrutinib monotherapy, and during venetoclax and ibrutinib combination therapy or venetoclax monotherapy. Primary hemostasis, assessed by Multiplate using adenosine diphosphate (ADP), arachidonic acid (AA), and thrombin receptor agonist peptide (TRAP-6), was impaired in all CLL patients at baseline, remained unchanged upon ibrutinib monotherapy, and improved significantly following venetoclax added to ibrutinib or as monotherapy. Secondary hemostasis assessed by thromboelastography (TEG) was normal and unchanged throughout treatment. The frequency of clinical bleeding events was the highest during ibrutinib monotherapy, in line with the demonstrated improved primary hemostasis upon addition of venetoclax, thus pointing toward a treatment option for CLL patients with increased bleeding risk. [ABSTRACT FROM AUTHOR]

Cystic fibrosis is a chronic lung disease requiring frequent lung-function monitoring to track acute respiratory events (pulmonary exacerbations). The association between lung-function trajectory and time-to-first exacerbation can be characterized using joint longitudinal-survival modeling. Joint models specified through the shared parameter framework quantify the strength of association between such outcomes but do not incorporate latent sub-populations reflective of heterogeneous disease progression. Conversely, latent class joint models explicitly postulate the existence of sub-populations but do not directly quantify the strength of association. Furthermore, choosing the optimal number of classes using established metrics like deviance information criterion is computationally intensive in complex models. To overcome these limitations, we integrate latent classes in the shared parameter joint model through a fully Bayesian approach. To choose the optimal number of classes, we construct a mixture model assuming more latent classes than present in the data, thereby asymptotically "emptying" superfluous latent classes, provided the Dirichlet prior on class proportions is sufficiently uninformative. Model properties are evaluated in simulation studies. Application to data from the US Cystic Fibrosis Registry supports the existence of three sub-populations corresponding to lung-function trajectories with high initial forced expiratory volume in 1 s (FEV1), rapid FEV1 decline, and low but steady FEV1 progression. The association between FEV1 and hazard of exacerbation was negative in each class, but magnitude varied. [ABSTRACT FROM AUTHOR]

Objective: To investigate the variance in reported prevalence rates of permanent neonatal hearing impairment (HI) worldwide. Design: A systematic review and meta-analysis was performed on reported prevalence rates of sensorineural and permanent conductive or mixed HI worse than 40 dB in neonates, detected as a result of a screening programme or audiometric study. Study sample: For meta-analysis, 35 articles were selected, 25 from high-income countries and 10 from middle-income countries according to the world bank classification system. Results: The prevalence rate of permanent uni- and bilateral HI worse than 40 dB in neonates varied from 1 to 6 per 1000, the overall prevalence was 2.21 per 1000 [1.71, 2.8]. In NICU populations the prevalence rate was higher with a larger fraction of bilateral cases. Although not significant, prevalence rates were slightly higher in Asia compared to Europe and the number of infants lost to follow-up appeared higher in countries with lower gross national income. Conclusion: Substantial variations exist in prevalence rates of neonatal permanent HI across countries and regions. There is a strong need for more data from low-income countries to identify demographic factors that account for this variability in reported prevalence rates. Reporting these data in a uniform way is advocated. [ABSTRACT FROM AUTHOR]

Molecular profiling of tumor derived cell free DNA (cfDNA) is gaining ground as a prognostic and predictive biomarker. However to what extent cfDNA reflects the full metastatic landscape as currently determined by tumor tissue analysis remains controversial. Though technically challenging, whole exome sequencing (WES) of cfDNA enables thorough evaluation of somatic alterations. Here, we review the feasibility of WES of cfDNA and determine the sensitivity of WES-detected single nucleotide variants (SNVs) in cfDNA on individual patient data level using paired tumor tissue as reference x 100%). The pooled sensitivity was 50% (95% credible interval (Cl): 29-72%). The tissue mutant allele frequency (MAF) of variants exclusively identified in tissue was significantly lower (12.5%, range: 0.5-18%) than the tissue MAF of variants identified in both tissue and cfDNA (23.9%, range: 17-38%), p = 0.004. The overall agreement (* "1"J™ x 100%)between SNVs in cfDNA and tumor tissue was 31% (95% Cl: 15-49%). The number of detected SNVs was positively correlated with circulating tumor DNA (ctDNA) fraction (p = 0.015). A sub analysis of samples with ctDNA fractions a 25% improved the sensitivity to 69% (95% Cl: 46-89%) and agreement to 46% (95% Cl: 36-59%), suggesting that WES is mainly feasible for patients with high ctDNA fractions. Pre- and post-analytical procedures were highly variable between studies rendering comparisons problematic. In conclusion, various aspects of WES of cfDNA are largely in its investigative phase, standardization of methodologies is highly needed to bring this promising technique to its clinical potential. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate in vivo T2 mapping as quantitative, imaging-based biomarker for meniscal degeneration in humans, by studying the correlation between T2 relaxation time and degree of histological degeneration as reference standard.Methods: In this prospective validation study, 13 menisci from seven patients with radiographic knee osteoarthritis (median age 67 years, three males) were included. Menisci were obtained during total knee replacement surgery. All patients underwent pre-operative magnetic resonance imaging using a 3-T MR scanner which included a T2 mapping pulse sequence with multiple echoes. Histological analysis of the collected menisci was performed using the Pauli score, involving surface integrity, cellularity, matrix organization, and staining intensity. Mean T2 relaxation times were calculated in meniscal regions of interest corresponding with the areas scored histologically, using a multi-slice multi-echo postprocessing algorithm. Correlation between T2 mapping and histology was assessed using a generalized least squares model fit by maximum likelihood.Results: The mean T2 relaxation time was 22.4 ± 2.7 ms (range 18.5-27). The median histological score was 10, IQR 7-11 (range 4-13). A strong correlation between T2 relaxation time and histological score was found (rs = 0.84, CI 95% 0.64-0.93).Conclusion: In vivo T2 mapping of the human meniscus correlates strongly with histological degeneration, suggesting that T2 mapping enables the detection and quantification of early compositional changes of the meniscus in knee OA.Key Points: • Prospective histology-based study showed that in vivo T 2 mapping of the human meniscus correlates strongly with histological degeneration. • Meniscal T 2 mapping allows detection and quantifying of compositional changes, without need for contrast or special MRI hardware. • Meniscal T 2 mapping provides a biomarker for early OA, potentially allowing early treatment strategies and prevention of OA progression. [ABSTRACT FROM AUTHOR]

Antithrombin deficiency is a strong risk factor for venous thromboembolism (VTE), but the absolute risk of the first and recurrent VTE is unclear. The objective of this paper is to establish the absolute risks of the first and recurrent VTE and mortality in individuals with antithrombin deficiency. The databases Embase, Medline Ovid, Web of Science, the Cochrane Library, and Google Scholar were systematically searched for case-control and cohort studies. Bayesian random-effects meta-analysis was used to calculate odds ratios (ORs), absolute risks, and probabilities of ORs being above thresholds. Thirty-five publications were included in the systematic review and meta-analysis. Based on 19 studies, OR estimates for the first VTE showed a strongly increased risk for antithrombin deficient individuals, OR 14.0; 95% credible interval (CrI), 5.5 to 29.0. Based on 10 studies, meta analysis showed that the annual VTE risk was significantly higher in antithrombin-deficient than in non-antithrombin-deficient individuals: 1.2% (95% CrI, 0.8-1.7) versus 0.07% (95% CrI, 0.01-0.14). In prospective studies, the annual VTE risk in antithrombin deficient individuals was as high as 2.3%; 95% CrI, 0.2-6.5%. Data on antithrombin deficiency subtypes are very limited for reliable risk-differentiation. The OR for recurrent VTE based on 10 studies was 2.1; 95% CrI, 0.2 to 4.0. The annual recurrence risk without long-term anticoagulant therapy based on 4 studies was 8.8% (95% CrI, 4.6-14.1) for antithrombin-deficient and 4.3% (95% CrI, 1.5-7.9) for non-antithrombin-deficient VTE patients. The probability of the recurrence risk being higher in antithrombin-deficient patients was 95%. The authors conclude that antithrombin deficient individuals have a high annual VTE risk, and a high annual recurrence risk. Antithrombin deficient patients with VTE require long-term anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Identifying the number of classes in Bayesian finite mixture models is a challenging problem. Several criteria have been proposed, such as adaptations of the deviance information criterion, marginal likelihoods, Bayes factors, and reversible jump MCMC techniques. It was recently shown that in overfitted mixture models, the overfitted latent classes will asymptotically become empty under specific conditions for the prior of the class proportions. This result may be used to construct a criterion for finding the true number of latent classes, based on the removal of latent classes that have negligible proportions. Unlike some alternative criteria, this criterion can easily be implemented in complex statistical models such as latent class mixed-effects models and multivariate mixture models using standard Bayesian software. We performed an extensive simulation study to develop practical guidelines to determine the appropriate number of latent classes based on the posterior distribution of the class proportions, and to compare this criterion with alternative criteria. The performance of the proposed criterion is illustrated using a data set of repeatedly measured hemoglobin values of blood donors. [ABSTRACT FROM AUTHOR]

Aim: Children born preterm often have neurodevelopmental problems later in life. Abnormal maturation of the auditory brainstem in the presence of normal hearing might be a marker for these problems. We conducted a meta-analysis of auditory brainstem response (ABR) latencies at term age to describe differences in auditory brainstem maturation between normal-hearing preterm and term-born infants.Method: Computerized databases were searched for studies published between 1995 and 2014 that reported ABR measurements at term age in infants born preterm in a case-control design. Five peaks reflect the conduction of a neural signal along the brainstem auditory pathway. We collected I to V interpeak latency data, and III to V interpeak latency data, which refers to the more central part of the pathway.Results: Preterm-born infants' III to V interval is significantly longer compared to infants born at term (0.081ms, effect-size=0.974), which also reflects on the I to V interval. Moreover, significantly increased ABR interpeak latencies of infants born preterm are related to lower gestational age and the need for neonatal intensive care treatment.Interpretation: The delayed conduction time towards and into the auditory brainstem at term age suggests atypical maturation of the brainstem in normal-hearing infants born preterm. Both the duration of gestation and the consequences of the preterm birth (intensive care needed) negatively affect maturation of the auditory brainstem, which may influence later development. [ABSTRACT FROM AUTHOR]

Blood donors experience a temporary reduction in their hemoglobin (Hb) value after donation. At each visit, the Hb value is measured, and a too low Hb value leads to a deferral for donation. Because of the recovery process after each donation as well as state dependence and unobserved heterogeneity, longitudinal data of Hb values of blood donors provide unique statistical challenges. To estimate the shape and duration of the recovery process and to predict future Hb values, we employed three models for the Hb value: (i) a mixed-effects models; (ii) a latent-class mixed-effects model; and (iii) a latent-class mixed-effects transition model. In each model, a flexible function was used to model the recovery process after donation. The latent classes identify groups of donors with fast or slow recovery times and donors whose recovery time increases with the number of donations. The transition effect accounts for possible state dependence in the observed data. All models were estimated in a Bayesian way, using data of new entrant donors from the Donor InSight study. Informative priors were used for parameters of the recovery process that were not identified using the observed data, based on results from the clinical literature. The results show that the latent-class mixed-effects transition model fits the data best, which illustrates the importance of modeling state dependence, unobserved heterogeneity, and the recovery process after donation. The estimated recovery time is much longer than the current minimum interval between donations, suggesting that an increase of this interval may be warranted. [ABSTRACT FROM AUTHOR]

Introduction: Preterm infants are born during critical stages of brain development, in which the adaptive capacity of the fetus to extra-uterine environment is limited. Inadequate brain perfusion has been directly linked to preterm brain damage. Advanced high-frequency ultrasound probes and processing algorithms allow visualization of microvessels and depiction of regional variation. To assess whether visualization and flow velocity estimates of preterm cerebral perfusion using Doppler techniques are accurate,we conducted an in vitro experiment using a microvessel flow phantom. Materials and Methods: An in-house developed flow phantom containing two microvessels (inner diameter 200 and 700mm) with attached syringe pumps, filled with bloodmimicking fluid, was used to generate non-pulsatile perfusion of variable flow. Measurements were performed using an Esaote MyLab70 scanner. Results: Microvessel mimicking catheters with velocities as low as 1 cm/s were adequately visualized with a linear ultrasound probe. With a convex probe, velocities <2 cm/s could not be depicted. Within settings, velocity and diameter measurements were highly reproducible [intra-class correlation 0.997 (95% CI 0.996-0.998) and 0.914 (0.864-0.946)]. Overall, mean velocity was overestimated up to threefold, especially in high velocity ranges. Significant differences were seen in velocity measurements when using steer angle correction and in vessel diameter estimation (p <0.05). Conclusion: Visualization of microvessel-size catheters mimicking small brain vessels is feasible. Reproducible velocity and diameter results can be obtained, although important overestimation of the values is observed. Before velocity estimates of microcirculation can find its use in clinical practice, calibration of the ultrasound machine for any specific Doppler purpose is essential. The ultimate goal is to develop a sonographic tool that can be used for objective study of regional perfusion in routine practice. [ABSTRACT FROM AUTHOR]

Background: To optimize the planning of blood donations but also to continue motivating the volunteers it is important to streamline the practical organization of the timing of donations. While donors are asked to return for donation after a suitable period, still a relevant proportion of blood donors is deferred from donation each year due to a too low hemoglobin level. Rejection of donation may demotivate the candidate donor and implies an inefficient planning of the donation process. Hence, it is important to predict the future hemoglobin level to improve the planning of donors' visits to the blood bank. Methods: The development of the hemoglobin prediction rule is based on longitudinal (panel) data from blood donations collected by Sanquin (the only blood product collecting and supplying organization in the Netherlands). We explored and contrasted two popular statistical models, i.e. the transition (autoregressive)model and the mixed effects model as plausible models to account for the dependence among subsequent hemoglobin levels within a donor. Results: The predictors of the future hemoglobin level are age, season, hemoglobin levels at the previous visits, and a binary variable indicating whether a donation was made at the previous visit. Based on cross-validation, the areas under the receiver operating characteristic curve (AUCs) for male donors are 0.83 and 0.81 for the transition model and the mixed effects model, respectively; for female donors we obtained AUC values of 0.73 and 0.72 for the transition model and the mixed effects model, respectively. Conclusion: We showed that the transition models and the mixed effects models provide a much better prediction compared to a multiple linear regression model. In general, the transition model provides a somewhat better prediction than the mixed effects model, especially at high visit numbers. In addition, the transition model offers a better trade-off between sensitivity and specificity when varying the cut-off values for eligibility in predicted values. Hence transition models make the prediction of hemoglobin level more precise and may lead to less deferral from donation in the future. [ABSTRACT FROM AUTHOR]

Background Numbers of blood leukocyte subsets are highly dynamic in childhood and differ greatly between subjects. Interindividual variation is only partly accounted for by genetic factors. Objective We sought to determine which nongenetic factors affect the dynamics of innate leukocytes and naive and memory lymphocyte subsets. Methods We performed 6-color flow cytometry and linear mixed-effects modeling to define the dynamics of 62 leukocyte subsets from birth to 6 years of age in 1182 children, with 1 to 5 measurements per subject. Subsequently, we defined the effect of prenatal maternal lifestyle-related or immune-mediated determinants, birth characteristics, and bacterial/viral exposure–related determinants on leukocyte subset dynamics. Results Functionally similar leukocyte populations were grouped by using unbiased hierarchical clustering of patterns of age-related leukocyte dynamics. Innate leukocyte numbers were high at birth and predominantly affected by maternal low education level. Naive lymphocyte counts peaked around 1 year, whereas most memory lymphocyte subsets more gradually increased during the first 4 years of life. Dynamics of CD4 + T cells were predominantly associated with sex, birth characteristics, and persistent infections with cytomegalovirus (CMV) or EBV. CD8 + T cells were predominantly associated with CMV and EBV infections, and T-cell receptor γδ + T cells were predominantly associated with premature rupture of membranes and CMV infection. B-cell subsets were predominantly associated with sex, breast-feeding, and Helicobacter pylori carriership. Conclusions Our study identifies specific dynamic patterns of leukocyte subset numbers, as well as nongenetic determinants that affect these patterns, thereby providing new insights into the shaping of the childhood immune system. [ABSTRACT FROM AUTHOR]