Activity-Based Prospective Memory in ADHD during Motor Sleep Inertia

Prospective memory (PM) is essential in everyday life because it concerns the ability to remember to perform an intended action in the future. Individuals diagnosed with attention deficit hyperactivity disorder (ADHD) often show poor performance in PM. Because age can be confounding, we decided to test PM in ADHD patients (children and adults) and healthy controls (children and adults). We examined 22 children (four females; mean age = 8.77 ± 1.77) and 35 adults (14 females; mean age = 37.29 ± 12.23) with ADHD, in addition to 92 children (57 females; mean age = 10.13 ± 0.42) and 95 adults (57 females; mean age = 27.93 ± 14.35) as healthy controls. Each participant originally wore an actigraph around the non-dominant wrist and was requested to push the event-marker at get-up time. To assess the efficiency of PM performance, we calculated the time elapsing between the end of sleep in the morning and the pushing of the event-marker button. The results showed lower PM performance in ADHD participants, regardless of age. However, the differences between ADHD and control groups were more evident in the children group. Our data seem to confirm that PM efficiency is compromised in individuals diagnosed with ADHD regardless of age, and agree with the idea of considering the PM deficit as a neuropsychological marker of ADHD

Antidepressant efficacy is correlated with plasma levels: mega-analysis and further evidence

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Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis

Rationale: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. Objectives: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. Methods: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. Results: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. Conclusions: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis

The sensitivity to chemotherapy of KRASG12C-mutated colorectal cancer has been investigated to verify whether the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care in the near future. To this aim, the present retrospective study was designed to assess the performance of irinotecan vs. oxaliplatin in the first-line treatment of KRASG12C-mutated mCRC patients and provide support for first-line decision making. In this setting of patients treated with FOLFIRI or FOLFOX +/ bevacizumab, irinotecan and oxaliplatin were compared using a propensity-score-matched analysis. the survival superiority of irinotecan was demonstrated over oxaliplatin in KRASG12C-mutated patients, while no differences were observed in a control cohort of KRASG12D-mutated patients. this should be considered when investigating chemotherapy plus targeted agent combinations.background: KRAS(G12C)-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRAS(G12C)inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. methods: a multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/ bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRAS(G12D)-mutated patients were analysed as control. results: one hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. however, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. no difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). Conclusions: First-line irinotecan-based regimens provided better survival results in KRAS(G12C)-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

IntroductionA titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11–21 ng/ml) that are expected under the approved dose range (10–20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy.MethodsFollowing our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram.ResultsOf 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C).ConclusionBased on our findings, we propose a target range of 20–40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram’s reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873]

Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

PURPOSE To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).METHODS TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect >= 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).RESULTS From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P= .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in RO resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).CONCLUSION The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC. (C) 2022 by American Society of Clinical Oncolog

What are the implications of the spontaneous spleno-renal shunts in liver cirrhosis?

<p>Abstract</p> <p>Background</p> <p>Although significant advances are expected to be made in the assessment of the portal hypertension-related complications, the prognostic role of spleno-renal shunts has not been fully explored so far. Clarifying this aspect could help tackle the life-treating events occurring in patients suffering from liver cirrhosis. The aim of the study was to analyze the relationships between the spleno-renal shunts presence at doppler ultrasound and the liver cirrhosis complications.</p> <p>Methods</p> <p>Design: eighty one patients out of 129 formed the study population (35 females). Chronic liver damage in these patients was caused by HCV (66), HBV (2), alcohol abuse (2) or unknown etiology, likely non-alcoholic steatohepatitis (11). Setting: two Liver Units of university/primary hospitals in Southern Italy. Main outcome measures: grading of esofageal varices; detection of ascites: assessment of hepatic encephalopathy; evaluation of liver cirrhosis severity; tracking hepatocellular carcinoma; doppler features of spleno-renal shunts and splenic flow velocity; spleen longitudinal diameter at sonography.</p> <p>Results</p> <p>The prevalence of spleno-renal shunts was 18.5%, without no difference concerning the etiology (HCV versus non-HCV, p = 0.870); the prevalence of hepatocellular carcinoma in patients with spleno-renal shunts was superior to that of patients without them (Pearson Chi-square, p = 0.006, power of sample size 74%), also after adjustment for liver decompensation (p = 0.024). The median score of hepatic encephalopathy in patients with and without spleno-renal shunts was similar, i.e., 0 (range, 0-2) versus 0 (0 - 3), p = 0.67. The median splenic vein flow velocity in patients with spleno-renal shunts was significantly inferior to that of patients without them, i.e., 13 cm/sec (95% confidence intervals, 6-18) versus 21 cm/sec (17-24), p < 0.0001. By far the largest percentage of large esophageal varices was in patients without spleno-renal shunts (p = 0.005). In contrast, the frequency of ascites and hepatic encephalopathy severity was overlapping in the two groups. BMI values but not Child-Pugh's classification predicted spleno-renal shunts (Ors = 1.84, 95% confidence intervals = 1.28-2.64, p = 0.001 and 1.145, 95% confidence intervals = 0.77-1.51, p = 0.66).</p> <p>Conclusion</p> <p>Taking into consideration the relatively small sample size, patients with spleno-renal shunts are burdened by an increased incidence of hepatocellular carcinoma. BMI predicted the spleno-renal shunts presence.</p

Scale-up of Innovative and Sustainable via-Nitrite Biological Processes for Resource Recovery in Existing Wastewater Treatment Plants

Over the last years, the transition from wastewater treatment plants to water resource recovery facilities has gained a lot of attention. The aim of these thesis was the deep investigation of novel via-nitrite bioprocesses for the integration of via-nitrite nitrogen and phosphorus removal from the sludge reject water with resource recovery such as nutrients, chemical precursors and high added-value bioproducts. The biological via-nitrite nitrogen and phosphorus removal from the sludge reject water through the S.C.E.N.A. process was investigated in a full-scale sequencing batch reactor (SBR) with a volume of 70 m3 located in Carbonera WWTP. Fermentation yields showed values in the range of 0.16-0.26 g CODVFA/gVSfed, while nitrogen mass balances showed that around 28-30 kg N per day were removed. At the same time, phosphorus was efficiently removed biologically, resulting in a phosphorus concentration in the sludge up to 39.7 mg P/kg TS and a daily phosphorus recovery of 1.21 kg P/day. The phosphorus-rich sludge was tested in real field and the results showed that the utilization of P-rich sludge led to similar effects on plant growth and quality parameters with respect to inorganic fertilizers. The combination of cellulosic primary sludge recovery by wastewater micro-sieving with production of bio-based volatile fatty acids in a pilot-scale platform was evaluated. The rotating belt filter allowed to separate around 50% of solids. The potential production of bio-based volatile fatty acids without pH control was 232 mgCOD/gVS and the yields further improved adjusting the initial pH to value of 9 (521 mgCOD/gVS). Semi-continuous reactor (2.6 m3) was employed and the acids production using a hydraulic retention time of 6 days was around 154 mgCOD/gVS. Conditioning primary cellulosic sludge to pH 9 enhanced volatile fatty acid production to 322 mgCOD/gVS. The utilization of the fermentation liquid fraction as carbon source for nutrients removal would reduce significantly the cost for external carbon source, while the biopolymer production would enhance the benefit from 72 to 186 \u20ac/ton TS of recovered sludge. The polyhydroxyalkanoates (PHAs) production integrated with the via-nitrite nitrogen removal from anaerobic reject water was investigated at pilot scale under long term period. Results showed that around 80% of the influent ammonia was efficiently removed by the system when both nitritation and selection SBR operated with volumetric nitrogen loading rate (vNLR) of 1.64-1.72 kgN/m3 d and 0.60-0.63 kgN/m3 d. Accumulation tests showed PHA yields ranging between 0.58 and 0.61 g CODPHA/g CODVFA, indicating an effective selection strategy. The integration of nitrogen removal and PHA production in the sidestream resulted in a methane recovery up to 4.0 m3CH4/PE y and a maximal PHA production of 1.2 kgPHA/PE y with a potential revenue for the WWTP up to 6.5 \u20ac/PE y. Data Analytics was deployed to predict the dissolved nitrous oxide (N2O) concentration in a full-scale sidestream sequence batch reactor (SBR) treating the sludge reject water. On average, the N2O emissions were equal to 7.6% of the NH4-N load and can contribute up to 97 % to the operational carbon footprint of the studied bioprocess. The results of the study revealed that the aerobic dissolved N2O concentration was correlated with the drop of average aerobic conductivity rate, the DO and the changes of conductivity between sequential cycles. Additionally, the analysis showed that N2O was always consumed after the depletion of NO2- during denitritation (after the \u201cnitrite knee\u201d). Based on these findings SVM classifiers were constructed to predict whether dissolved N2O will be consumed during the anoxic and anaerobic phases. The proposed approach accurately predicted the N2O emissions as a latent parameter from other low-cost sensors that are traditionally deployed in biological batch processes

Circadian pattern of motor activity in adults with attention-deficit/hyperactivity disorder

This study aims to describe the 24-hour activity rhythm in adults with attention-deficit/hyperactivity disorder (ADHD). A total of 18 ADHD patients and 37 healthy controls (HCs) wore an actigraph for 7 days. ADHD patients showed higher motor activity than HCs at 4:00, 6:00, 15:00 and 16:00 hour. Within the theoretical framework of the two-process model of sleep regulation, the observed data may be explained by lower homeostatic sleep pressure in ADHD. This could lead to an increase in motor activity in the second half of the night, when sleep need decreases more rapidly, and in the first half of the afternoon, when patients do not experience the typical post-lunch dip