First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. METHODS: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached). CONCLUSIONS: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

The "Unconventional" Effect of Cysteine on the In Vitro Synthesis of Melanin.

This report details some of our observations regarding the impact of cysteine on the air-mediated oxidation of catecholamines, particularly epinephrine. The intent was to synthesize light-colored, pheomelanin-like materials. Pheomelanin is commonly described as a material generated from a mixture of catecholamines and cysteine. However, we observed that (1) the presence of cysteine resulted in a concentration-dependent delay in the onset of color formation and (2) the presence of cysteine resulted in darker, more eumelanin-like materials. These effects were particularly impactful in the case of epinephrine. More elaborate studies involving other amino acids or scaled-up reactions were conducted with epinephrine as the precursor. These studies show that other amino acids, e.g., methionine or serine, could lead to darker materials, but none were as impactful as cysteine. Although our results are in contrast to typical descriptions regarding the impact of cysteine on the synthesis of melanin, they may reflect crucial differences between the in vitrovsin vivo synthesis of pheomelanin.

Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P < .001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.

Towards Equal Access to Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy and Survival in Patients with Isolated Colorectal Peritoneal Metastases: A Nationwide Population-Based Study.

BACKGROUND: Before 2016, patients with isolated synchronous colorectal peritoneal metastases (PMCRC) diagnosed in expert centers had a higher odds of undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) and better overall survival (OS) than those diagnosed in referring centers. Nationwide efforts were initiated to increase awareness and improve referral networks. METHODS: This nationwide study aimed to evaluate whether the between-center differences in odds of undergoing CRS-HIPEC and OS have reduced since these national efforts were initiated. All patients with isolated synchronous PMCRC diagnosed between 2009 and 2021 were identified from the Netherlands Cancer Registry. Associations between hospital of diagnosis and the odds of undergoing CRS-HIPEC, as well as OS, were assessed using multilevel multivariable regression analyses for two periods (2009-2015 and 2016-2021). RESULTS: In total, 3948 patients were included. The percentage of patients undergoing CRS-HIPEC increased from 17.2% in 2009-2015 (25.4% in expert centers, 16.5% in referring centers), to 23.4% in 2016-2021 (30.2% in expert centers, 22.6% in referring centers). In 2009-2015, compared with diagnosis in a referring center, diagnosis in a HIPEC center showed a higher odds of undergoing CRS-HIPEC (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02-2.67) and better survival (hazard ratio [HR] 0.80, 95% CI 0.66-0.96). In 2016-2021, there were no differences in the odds of undergoing CRS-HIPEC between patients diagnosed in HIPEC centers versus referring centers (OR 1.27, 95% CI 0.76-2.13) and survival (HR 1.00, 95% CI 0.76-1.32). CONCLUSION: Previously observed differences in odds of undergoing CRS-HIPEC were no longer present. Increased awareness and the harmonization of treatment for PMCRC may have contributed to equal access to care and a similar chance of survival at a national level.

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.

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.

Shifting Perspectives on the Challenges of Shared Decision Making in Mental Health Care.

Although shared decision making (SDM) has become the most preferable way in doctor-patient communication, it is not fully implemented in mental health care likely due to the complex nature of psychiatric syndromes and treatments. In this review we provide a systematic overview of all perceived and reported barriers to SDM in the literature, acknowledging field-specific challenges, and offering perspectives to promote its wider use. We conducted a systematic search of the wider literature in different databases and included all publications mentioning specified barriers to SDM in psychiatric care. Relevant data and opinions were categorised into micro-, meso- and macro-level themes and put into clinical perspective. We derived 20 barriers to SDM from 100 studies and reports. Eight were on micro-level care delivery, seven involved meso-level issues, five concerned macro-level themes. The multitude of perceived and actual barriers to SDM underline the challenges its implementation poses in mental health care, some of which can be resolved while others are inherent to the nature of the care, with its long-term relationships, complex dynamics, and social consequences, all requiring a flexible approach. We present four perspectives to help change views on the potential of SDM in mental health care.

Cerebral hemodynamics and oxygenation in adult patients with sickle cell disease after stem cell transplantation.

Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity-matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased (p < .01), while GM and WM CVR increased (p < .01) compared with the baseline measures. OEF and CMRO2 also increased towards levels in healthy controls (p < .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis (p < .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow-up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.

ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): ASL pipeline inventory.

PURPOSE: To create an inventory of image processing pipelines of arterial spin labeling (ASL) and list their main features, and to evaluate the capability, flexibility, and ease of use of publicly available pipelines to guide novice ASL users in selecting their optimal pipeline. METHODS: Developers self-assessed their pipelines using a questionnaire developed by the Task Force 1.1 of the ISMRM Open Science Initiative for Perfusion Imaging. Additionally, each publicly available pipeline was evaluated by two independent testers with basic ASL experience using a scoring system created for this purpose. RESULTS: The developers of 21 pipelines filled the questionnaire. Most pipelines are free for noncommercial use (n = 18) and work with the standard NIfTI (Neuroimaging Informatics Technology Initiative) data format (n = 15). All pipelines can process standard 3D single postlabeling delay pseudo-continuous ASL images and primarily differ in their support of advanced sequences and features. The publicly available pipelines (n = 9) were included in the independent testing, all of them being free for noncommercial use. The pipelines, in general, provided a trade-off between ease of use and flexibility for configuring advanced processing options. CONCLUSION: Although most ASL pipelines can process the common ASL data types, only some (namely, ASLPrep, ASLtbx, BASIL/Quantiphyse, ExploreASL, and MRICloud) are well-documented, publicly available, support multiple ASL types, have a user-friendly interface, and can provide a useful starting point for ASL processing. The choice of an optimal pipeline should be driven by specific data to be processed and user experience, and can be guided by the information provided in this ASL inventory.

Comparing patient reported abdominal pain between patients treated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) and primary colorectal cancer surgery.

Oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) is an emerging palliative treatment for patients with unresectable colorectal peritoneal metastases. Previously, our study group reported that patients experienced abdominal pain for several weeks after PIPAC-OX. However, it is unknown how this compares to abdominal pain after regular colorectal cancer surgery. To provide some perspective, this study compared the presence of abdominal pain after PIPAC-OX to the presence of abdominal pain after primary tumor surgery. Patient reported abdominal pain scores (EORTC QLQ-CR-29), from two prospective, Dutch cohorts were used in this study. Scores ranged from 0 to 100, a higher score represents more abdominal pain. Abdominal pain at baseline and at four weeks after treatment were compared between the two groups. Twenty patients who underwent PIPAC-OX and 322 patients who underwent primary tumor surgery were included in the analysis. At baseline, there were no differences in abdominal pain between both groups (mean 20 vs. 18, respectively; p = 0.688). Four weeks after treatment, abdominal pain was significantly worse in the PIPAC group (39 vs 15, respectively; p < 0.001; Cohen's d = 0.99). The differential effect over time for abdominal pain differed significantly between both groups (mean difference: 19 vs - 3, respectively; p = 0.004; Cohen's d = 0.88). PIPAC-OX resulted in significantly worse postoperative abdominal pain than primary tumor surgery. These results can be used for patient counseling and stress the need for adequate analgesia during and after PIPAC-OX. Further research is required to prevent or reduce abdominal pain after PIPAC-OX.Trial registration CRC-PIPAC: Clinicaltrails.gov NCT03246321 (01-10-2017).

Concurrent lithium and haemodialysis treatment: Clinical recommendations based on the literature and a multicentre survey.

INTRODUCTION: Lithium has an irreplaceable role in the treatment of severe mood disorders, but declining renal function associated with its use leads to clinical dilemmas. Although not often applied, and requiring close monitoring and multidisciplinary actions, concurrent lithium and haemodialysis treatment (CLHT) is a feasible option. To our knowledge, however, there are no detailed consensus- or evidence-based treatment guidelines or directives on its delivery. METHODS: To fill this gap, we reviewed the literature and surveyed psychiatrists and nephrologists with experience in CLHT using a self-designed questionnaire. Our goal was to form an integrated picture of the current knowledge and clinical practices of CLHT and formulate practical recommendations for colleagues being confronted with patients with renal dysfunction requiring lithium to help manage their mood disorder. RESULTS: We identified 14 case reports and case series describing CLHT and one systematic review concluding CLHT to be effective. Ten nephrologists and six psychiatrists practising in the Netherlands completed our questionnaire, providing details on collaboration, lithium dosing regimens, serum level evaluations and additional amenities and services they deemed necessary during CLHT delivery. DISCUSSION: We found that CLHT appears to be safe and effective and argue that delivery is a shared responsibility and needs continuous multidisciplinary finetuning. To facilitate delivery, we provide a flowchart for the initiation or reinstatement of lithium therapy in haemodialysis patients and a practical guide for CLHT, including an easy-to-use rule of thumb for calculating the lithium target dose.

Progressive Changes in Cerebral Apparent Diffusion Values in Fabry Disease: A 5-Year Follow-up MRI Study.

BACKGROUND AND PURPOSE: White matter lesions are commonly found in patients with Fabry disease. Existing studies have shown elevated diffusivity in healthy-appearing brain regions that are commonly associated with white matter lesions, suggesting that DWI could help detect white matter lesions at an earlier stage This study explores whether diffusivity changes precede white matter lesion formation in a cohort of patients with Fabry disease undergoing yearly MR imaging examinations during a 5-year period. MATERIALS AND METHODS: T1-weighted anatomic, FLAIR, and DWI scans of 48 patients with Fabry disease (23 women; median age, 44 years; range, 15-69 years) were retrospectively included. White matter lesions and tissue probability maps were segmented and, together with ADC maps, were transformed into standard space. ADC values were determined within lesions before and after detection on FLAIR images and compared with normal-appearing white matter ADC. By means of linear mixed-effects modeling, changes in ADC and ΔADC (relative to normal-appearing white matter) across time were investigated. RESULTS: ADC was significantly higher within white matter lesions compared with normal-appearing white matter (P < .01), even before detection on FLAIR images. ADC and ΔADC were significantly affected by sex, showing higher values in men (60.1 [95% CI, 23.8-96.3] ×10-6mm2/s and 35.1 [95% CI, 6.0-64.2] ×10-6mm2/s), respectively. ΔADC increased faster in men compared with women (0.99 [95% CI, 0.27-1.71] ×10-6mm2/s/month). ΔADC increased with time even when only considering data from before detection (0.57 [95% CI, 0.01-1.14] ×10-6mm2/s/month). CONCLUSIONS: Our results indicate that in Fabry disease, changes in diffusion precede the formation of white matter lesions and that microstructural changes progress faster in men compared with women. These findings suggest that DWI may be of predictive value for white matter lesion formation in Fabry disease.

Primary tumor resection or systemic treatment as palliative treatment for patients with isolated synchronous colorectal cancer peritoneal metastases in a nationwide cohort study.

Limited data are available to guide the decision-making process for clinicians and their patients regarding palliative treatment options for patients with isolated synchronous colorectal cancer peritoneal metastases (CRC-PM). Therefore, the aim of this study is to analyze the outcome of the different palliative treatments for these patients. All patients diagnosed with isolated synchronous CRC-PM between 2009 and 2020 (Netherlands Cancer Registry) who underwent palliative treatment were included. Patients who underwent emergency surgery or curative intent treatment were excluded. Patients were categorized into upfront palliative primary tumor resection (with or without additional systemic treatment) or palliative systemic treatment only. Overall survival (OS) was compared between both groups and multivariable cox regression analysis was performed. Of 1031 included patients, 364 (35%) patients underwent primary tumor resection and 667 (65%) patients received systemic treatment only. Sixty-day mortality was 9% in the primary tumor resection group and 5% in the systemic treatment group (P = 0.007). OS was 13.8 months in the primary tumor resection group and 10.3 months in the systemic treatment group (P < 0.001). Multivariable analysis showed that primary tumor resection was associated with improved OS (HR 0.68; 95%CI 0.57-0.81; P < 0.001). Palliative primary tumor resection appeared to be associated with improved survival compared to palliative systemic treatment alone in patients with isolated synchronous CRC-PM despite a higher 60-day mortality. This finding must be interpreted with care as residual bias probably played a significant role. Nevertheless, this option may be considered in the decision-making process by clinicians and their patients.

Venous Blood Oxygenation Measurements Using TRUST and T2-TRIR MRI During Hypoxic and Hypercapnic Gas Challenges.

BACKGROUND: Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) may serve as biomarkers in several diseases. OEF and CMRO2 can be estimated from venous blood oxygenation (Yv ) levels, which in turn can be calculated from venous blood T2 values (T2b ). T2b can be measured using different MRI sequences, including T2-relaxation-under-spin-tagging (TRUST) and T2-prepared-blood-relaxation-imaging-with-inversion-recovery (T2-TRIR). The latter measures both T2b and T1 (T1b ) but was found previously to overestimate T2b compared to TRUST. It remained unclear, however, if this bias is constant across higher and lower oxygen saturations. PURPOSE: To compare TRUST and T2-TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. STUDY TYPE: Prospective. POPULATION: Twelve healthy volunteers (four female, age 36 ± 10 years). FIELD STRENGTH/SEQUENCE: A 3T; turbo-field echo-planar-imaging (TFEPI), echo-planar-imaging (EPI), and fast-field-echo (FFE). ASSESSMENT: TRUST- and T2-TRIR-derived T2b , Yv , OEF, and CMRO2 were compared across different respiratory challenges. T1b from T2-TRIR was used to estimate Hct (HctTRIR ) and compared with venipuncture (HctVP ). STATISTICAL TESTS: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, Friedman test, Bland-Altman, and correlation analysis. Bonferroni multiple-comparison correction was performed. Significance level was 0.05. RESULTS: A significant bias was observed between TRUST- and T2-TRIR-derived T2b , Yv , and OEF values (-13 ± 11 msec, -5.3% ± 3.5% and 5.9 ± 4.1%, respectively). For Yv and OEF, this bias was constant across the range of measured values. T1b was significantly lower during severe hypoxia and hypercapnia compared to baseline (1712 ± 86 msec and 1634 ± 79 msec compared to 1757 ± 90 msec). While no significant bias was found between HctVP and HctTRIR (0.02% ± 0.06%, P = 0.20), the correlation between these Hct values was significant but weak (r = 0.19). DATA CONCLUSION: Given the constant bias, TRUST- and T2-TRIR-derived venous T2b values can be used interchangeably to estimate Yv , OEF, and CMRO2 across a broad range of oxygen saturations. Hct from T2-TRIR-derived T1-values only weakly correlated with Hct from venipuncture. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

The Direct and Long-Term Effects of Raloxifene as Adjunctive Treatment for Schizophrenia-Spectrum Disorders: A Double-Blind, Randomized Clinical Trial.

BACKGROUND AND HYPOTHESIS: Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD. STUDY DESIGN: This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models. STUDY RESULTS: We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups. CONCLUSIONS: Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment.

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.

Sinusoidal CO2 respiratory challenge for concurrent perfusion and cerebrovascular reactivity MRI.

Introduction: Deoxygenation-based dynamic susceptibility contrast (dDSC) has previously leveraged respiratory challenges to modulate blood oxygen content as an endogenous source of contrast alternative to gadolinium injection in perfusion-weighted MRI. This work proposed the use of sinusoidal modulation of end-tidal CO2 pressures (SineCO 2 ), which has previously been used to measure cerebrovascular reactivity, to induce susceptibility-weighted gradient-echo signal loss to measure brain perfusion. Methods: SineCO 2 was performed in 10 healthy volunteers (age 37 ± 11, 60% female), and tracer kinetics model was applied in the frequency domain to calculate cerebral blood flow, cerebral blood volume, mean transit time, and temporal delay. These perfusion estimates were compared against reference techniques, including gadolinium-based DSC, arterial spin labeling, and phase contrast. Results: Our results showed regional agreement between SineCO 2 and the clinical comparators. SineCO 2 was able to generate robust CVR maps in conjunction to baseline perfusion estimates. Discussion: Overall, this work demonstrated feasibility of using sinusoidal CO2 respiratory paradigm to simultaneously acquire both cerebral perfusion and cerebrovascular reactivity maps in one imaging sequence.