Simultaneous measurement of glomerular filtration rate, effective renal plasma flow and tubular secretion in different poultry species by single intravenous bolus of iohexol and para-aminohippuric acid

Simple Summary The aim of this study was to investigate the simultaneous measurement of two different renal markers (iohexol and p-aminohippuric acid) in the plasma of different poultry species as the gold standard method. The two markers reflect three different renal processes: glomerular filtration, effective renal plasma flow, and tubular secretion. The rate at which the kidneys filter blood is called the glomerular filtration rate. The effective renal plasma flow is the volume of plasma that reaches the kidney per time unit. Tubular secretion can be defined as active transport from the peritubular capillaries to the renal tubules. A moderate correlation was observed between tubular secretion and the glomerular filtration rate. A good correlation was demonstrated between the effective renal plasma flow and the glomerular filtration rate. This might be useful to model both renal processes. This approach could support the further development and validation of clinical renal biomarkers. These markers can be useful in the case of a chronic renal disease or renal failure, for which repeated evaluations of the renal function are required. The aim of the current study was to investigate the simultaneous measurement of plasma p-aminohippuric acid (PAH) clearance as a potential marker to assess effective renal plasma flow (eRPF) and tubular secretion (TS), and the plasma clearance of iohexol (IOH) as a marker of the glomerular filtration rate in poultry species. The PAH was administered intravenously (IV) to broiler chickens, layers, turkeys, Muscovy ducks, and pigeons. Each animal received successively a single bolus dose of 10 mg PAH/kg bodyweight (BW) and 100 mg PAH/kg BW to assess the eRPF and TS, respectively. Simultaneously with both PAH administrations, a single IV bolus of 64.7 mg/kg BW of IOH was administered. A high linear correlation (R-2= 0.79) between eRPF, based on the clearance of the low dose of PAH, and BW was observed for the poultry species. The correlation between TS, based on the clearance of the high dose of PAH, and BW was moderate (R-2= 0.50). Finally, a moderate correlation (R-2= 0.68) was demonstrated between GFR and eRPF and between GFR and TS (R-2= 0.56). This presented pharmacokinetic approach of the simultaneous administration of IOH and PAH enabled a simultaneous evaluation of eRPF/TS and GFR, respectively, in different poultry species

Treatment patterns and clinical outcomes

BACKGROUND: Treatment resistant depression (TRD) characterizes a subgroup of 10-30% of patients with major depressive disorder, and is associated with considerable morbidity and mortality. A consensus treatment for TRD does not exist, which often leads to wide variations in treatment strategies. Real-world studies on treatment patterns and outcomes in TRD patients in Europe are lacking and could help elucidate current treatment strategies and their efficacy. METHODS: This non-interventional cohort study of patients with TRD (defined as treatment failure on ≥2 oral antidepressants given at adequate dose and duration) with moderate to severe depression collected real-world data on treatment patterns and outcomes in several European countries. Patients were started on a new treatment for depression according to routine clinical practice. RESULTS: Among 411 patients enrolled, after 6 months, only 16.7% achieved remission and 73.5% showed no response. At Month 12, while 19.2% achieved remission and 69.2% showed no response, 33.3% of those in remission at Month 6 were no longer in remission. Pharmacological treatments employed were heterogenous; 54 different drugs were recorded at baseline, and the top 5 treatment types according to drug classes accounted for 40.0% of patients. Even though remission rates were very low, at Month 12, 60.0% of patients had not changed treatment since enrolment. CONCLUSIONS: The heterogeneity of treatments highlights a lack of consensus. Moreover, despite low response rates, patients often remained on treatments for substantial periods of time. These data further support existence of an unmet treatment need for TRD patients in Europe.publishersversionpublishe

Healthcare resource utilization

Background: Treatment resistant depression (TRD) is diagnosed when patients experiencing a major depressive episode fail to respond to ≥2 treatments. Along with substantial indirect costs, patients with TRD have higher healthcare resource utilization (HCRU) than other patients with depression. However, research on the economic impact of this HCRU, and differences according to response to treatment, is lacking. Methods: This multicenter, observational study documented HCRU among patients with TRD in European clinical practice initiating new antidepressant treatments. Data regarding access to outpatient consultations and other healthcare resources for the first 6 months, collected using a questionnaire, were analyzed qualitatively according to response and remission status. The economic impact of HCRU, estimated using European costing data, was analyzed quantitatively. Results: Among 411 patients, average HCRU was higher in non-responders, attending five times more general practitioner (GP) consultations and spending longer in hospital (1.7 versus 1.1 days) than responders. Greater differences were observed according to remission status, with non-remitters attending seven times more GP consultations and spending approximately three times longer in hospital (1.7 versus 0.6 days) than remitters. Consequently, the estimated economic impacts of non-responders and non-remitters were significantly greater than those of responders and remitters, respectively. Limitations: Key limitations are small cohort size, absence of control groups and generalizability to different healthcare systems. Conclusion: Patients with TRD, particularly those not achieving remission, have considerable HCRU, with associated economic impact. The costs of unmet TRD treatment needs are thus substantial, and treatment success is fundamental to reduce individual needs and societal costs.publishersversionpublishe

Indirect adjusted comparison of 6-month clinical outcomes between esketamine nasal spray and other real-world polypharmacy treatment strategies for treatment resistant depression: results from the ICEBERG study

BackgroundThe efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known.MethodICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling.ResultsEsketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6–53.9]) and remission (33.6% [95% CI 29.7–37.6]) versus RW polypharmacy (26.8% [95% CI 21.0–32.5] and 19.4%, [95% CI 14.2–24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474–2.345; p < 0.0001) times as likely to result in response and 1.735 (1.297–2.322; p = 0.0002) times as likely to result in remission versus RW polypharmacy at 6 months. Threshold and extensive sensitivity analyses supported that analyses of esketamine NS superiority were robust.ConclusionICEBERG supports esketamine NS being superior to current RW individualized polypharmacy strategies, including augmentation, with benefits extending beyond acute use, to improved chance of 6-month response and remission. While unobserved confounding factors may certainly impact results of an indirect comparison, threshold analysis supported a low likelihood of this affecting the conclusions.To view an animated summary of this publication, please click on the Supplementary video

ICEBERG study: an indirect adjusted comparison estimating the long-term benefit of esketamine nasal spray when compared with routine treatment of treatment resistant depression in general psychiatry

BackgroundTreatment resistant depression (TRD) affects 10–30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking.MethodsICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were.ResultsPatients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6–53.9]) and remission (33.6% [95% CI 29.7–37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5–31.4] and 18.2% [95% CI 13.9–22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034–3.733], p < 0.0001; RR 1.882 [95% CI 1.534–2.310], p < 0.0001) and remission (OR 2.276 [95% CI 1.621–3.196], p < 0.0001; RR 1.847 [95% CI 1.418–2.406], p < 0.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses.ConclusionICEBERG supports that, at 6 months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.To view an animated summary of this publication, please click on the Supplementary video

Harmonization of human biomonitoring studies in Europe: characteristics of the HBM4EU-aligned studies participants

Human biomonitoring has become a pivotal tool for supporting chemicals' policies. It provides information on real-life human exposures and is increasingly used to prioritize chemicals of health concern and to evaluate the success of chemical policies. Europe has launched the ambitious REACH program in 2007 to improve the protection of human health and the environment. In October 2020 the EU commission published its new chemicals strategy for sustainability towards a toxic-free environment. The European Parliament called upon the commission to collect human biomonitoring data to support chemical's risk assessment and risk management. This manuscript describes the organization of the first HBM4EU-aligned studies that obtain comparable human biomonitoring (HBM) data of European citizens to monitor their internal exposure to environmental chemicals. The HBM4EU-aligned studies build on existing HBM capacity in Europe by aligning national or regional HBM studies. The HBM4EU-aligned studies focus on three age groups: children, teenagers, and adults. The participants are recruited between 2014 and 2021 in 11 to 12 primary sampling units that are geographically distributed across Europe. Urine samples are collected in all age groups, and blood samples are collected in children and teenagers. Auxiliary information on socio-demographics, lifestyle, health status, environment, and diet is collected using questionnaires. In total, biological samples from 3137 children aged 6-12 years are collected for the analysis of biomarkers for phthalates, HEXAMOLL((R)) DINCH, and flame retardants. Samples from 2950 teenagers aged 12-18 years are collected for the analysis of biomarkers for phthalates, Hexamoll((R)) DINCH, and per- and polyfluoroalkyl substances (PFASs), and samples from 3522 adults aged 20-39 years are collected for the analysis of cadmium, bisphenols, and metabolites of polyaromatic hydrocarbons (PAHs). The children's group consists of 50.4% boys and 49.5% girls, of which 44.1% live in cities, 29.0% live in towns/suburbs, and 26.8% live in rural areas. The teenagers' group includes 50.6% girls and 49.4% boys, with 37.7% of residents in cities, 31.2% in towns/suburbs, and 30.2% in rural areas. The adult group consists of 52.6% women and 47.4% men, 71.9% live in cities, 14.2% in towns/suburbs, and only 13.4% live in rural areas. The study population approaches the characteristics of the general European population based on age-matched EUROSTAT EU-28, 2017 data; however, individuals who obtained no to lower educational level (ISCED 0-2) are underrepresented. The data on internal human exposure to priority chemicals from this unique cohort will provide a baseline for Europe's strategy towards a non-toxic environment and challenges and recommendations to improve the sampling frame for future EU-wide HBM surveys are discussed

Relationships among neurocognition, symptoms and functioning in patients with schizophrenia: a path-analytic approach for associations at baseline and following 24 weeks of antipsychotic drug therapy

<p>Abstract</p> <p>Background</p> <p>Neurocognitive impairment and psychiatric symptoms have been associated with deficits in psychosocial and occupational functioning in patients with schizophrenia. This post-hoc analysis evaluates the relationships among cognition, psychopathology, and psychosocial functioning in patients with schizophrenia at baseline and following sustained treatment with antipsychotic drugs.</p> <p>Methods</p> <p>Data were obtained from a clinical trial assessing the cognitive effects of selected antipsychotic drugs in patients with schizophrenia. Patients were randomly assigned to 24 weeks of treatment with olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Psychosocial functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale [QLS], cognition with a standard battery of neurocognitive tests; and psychiatric symptoms with the Positive and Negative Syndrome Scale [PANSS]. A path-analytic approach was used to evaluate the effects of changes in cognitive functioning on subdomains of quality of life, and to determine whether such effects were direct or mediated via changes in psychiatric symptoms.</p> <p>Results</p> <p>At baseline, processing speed affected functioning mainly indirectly via negative symptoms. Positive symptoms also affected functioning at baseline although independent of cognition. At 24 weeks, changes in processing speed affected changes in functioning both directly and indirectly via PANSS negative subscale scores. Positive symptoms no longer contributed to the path-analytic models. Although a consistent relationship was observed between processing speed and the 3 functional domains, variation existed as to whether the paths were direct and/or indirect. Working memory and verbal memory did not significantly contribute to any of the path-analytic models studied.</p> <p>Conclusion</p> <p>Processing speed demonstrated direct and indirect effects via negative symptoms on three domains of functioning as measured by the QLS at baseline and following 24 weeks of antipsychotic treatment.</p