Control-based drug tailoring schemes towards personalized influenza treatment

Influenza infections continue to be a global threat. This chapter provides a current overall view of the influenza infection pathogenesis, historical landmarks with pandemic events, features of the viral particle – the virion – and treatment regimes with neuraminidase inhibitors. In addition, treatment optimization schemes are introduced integrating host infection modeling, drug dynamics under the PK/PD approach, and control-based methods. Combining inverse optimal and impulsive control, the chapter hypothesizes schemes of dose tailoring towards personalized treatment, where the dose dynamically adapts according to the viral load evolution. The proposed control-based treatment is compared with the current fixed-dose framework in terms of treatment efficacy and reduction of the total amount of drug. The chapter closes by highlighting the implications of the control-based schemes not only to tackle influenza infections but also to combat similar acute infectious diseases such as COVID-19. © 2022 Elsevier Inc. All rights reserved.

Disentangling early and late onset of psychosis in women: identifying new targets for treatment.

Women present a second peak of incidence of psychosis during the menopausal transition, partially explained by the loss of estrogen protection conferred during the reproductive years. In view of the lack of studies comparing sociodemographic, biological, and clinical variables and neurocognitive performance between women with early onset of psychosis (EOP) and those with late onset of psychosis (LOP), our aim was to characterize both groups in a large sample of 294 first-episode psychosis (FEP) patients and 85 healthy controls (HC). In this cross-sectional study, the participants were interviewed to gather information on sociodemographic variables. We assessed laboratory features of interest and conducted a clinical assessment of psychopathological symptoms and neurocognitive abilities. From the latter, we derived a global cognitive functioning score. Analysis of covariance (ANCOVA) was used to compare EOP and LOP groups, and each group with age-comparable HC. EOP women were more frequently single and unemployed than HC age peers. While cholesterol levels in LOP women were higher than those in EOP women, no statistically significant differences were found in leptin levels. Women with LOP presented with less severe negative symptoms and higher cognitive processing speed scores than women with EOP. Cannabis and alcohol use was greater in EOP than in LOP women. Within the total FEP group, there was a history of significantly more recent traumatic events than in the HC group. Women with EOP and LOP show several sociodemographic and clinical differences, which may be valuable for planning personalized treatment.

Complex analysis of the personalized pharmacotherapy in the management of COVID-19 patients and suggestions for applications of predictive, preventive, and personalized medicine attitude.

AIMS: Coronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19. METHODS: Clinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. "Gene Score" and "Drug Score" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs. RESULTS: Our results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient. CONCLUSION: We recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00247-0.

Evaluating the Role of the Interleukin-23/17 Axis in Critically Ill COVID-19 Patients.

Studies have hypothesized a potential role of the interleukin (IL)-23/17 axis in coronavirus disease 2019 (COVID-19). However, to date, levels of IL-23 and 17 have not been compared between critically ill COVID-19 patients and critically ill non-COVID-19 patients. IL-23 and 17 were measured on admission to the intensive care unit (ICU) in critically ill COVID-19 (N = 38) and critically ill non-COVID-19 (N = 34) patients with an equal critical illness severity. Critically ill non-COVID-19 patients did not have sepsis or septic shock on ICU admission. None of the enrolled patients had previously received corticosteroids. In our study, circulating IL-17 levels were higher in the COVID-19 patients. More specifically, critically ill COVID-19 patients had levels of 0.78 (0.05-1.8) pg/mL compared to 0.11 (0.05-0.9) pg/mL in the critically ill non-COVID-19 patients (p = 0.04). In contrast, IL-23 levels were comparable between groups. A group of patients hospitalized in the specialized COVID-19 clinic (N = 16) was also used to evaluate IL-17 and IL-23 levels with respect to COVID-19 severity. Non-critically ill COVID-19 patients had undetectable levels of both cytokines. Our results support the notion of inhibiting IL-17 in critical COVID-19 infection.

Challenging management of severe chronic disorders in acute pandemic situation: Chronic liver disease under COVID-19 pandemic as the proof-of-principle model to orchestrate the measures in 3PM context.

Chronic liver disease management is a comprehensive approach requiring multi-professional expertise and well-orchestrated healthcare measures thoroughly organized by responsible medical units. Contextually, the corresponding multi-faceted chain of healthcare events is likely to be severely disturbed or even temporarily broken under the force majeure conditions such as global pandemics. Consequently, the chronic liver disease is highly representative for the management of any severe chronic disorder under lasting pandemics with unprecedented numbers of acutely diseased persons who, together with the chronically sick patient cohorts, have to be treated using the given capacity of healthcare systems with their limited resources. Current study aimed at exploring potentially negative impacts of the SARS CoV-2 outbreak on the quality of the advanced chronic liver disease (ACLD) management considering two well-classified parameters, namely, (1) the continuity of the patient registrations and (2) the level of mortality rates, comparing pre-COVID-19 statistics with these under the current pandemic in Slovak Republic. Altogether 1091 registrations to cirrhosis registry (with 60.8% versus 39.2% males to females ratio) were included with a median age of 57 years for patients under consideration. Already within the very first 3 months of the pandemic outbreak in Slovakia (lockdown declared from March 16, 2020, until May 20, 2020), the continuity of the patient registrations has been broken followed by significantly increased ACLD-related death rates. During this period of time, the total number of new registrations decreased by about 60% (15 registrations in 2020 versus 38 in 2018 and 38 in 2019). Corresponding mortality increased by about 52% (23 deaths in 2020 versus 10 in 2018 and 12 in 2019). Based on these results and in line with the framework of 3PM guidelines, the pandemic priority pathways (PPP) are strongly recommended for maintaining tertiary care uninterrupted. For the evidence-based implementation of PPP, creation of predictive algorithms and individualized care strategy tailored to the patient is essential. Resulting classification of measures is summarized as follows:The Green PPP Line is reserved for prioritized (urgent and comprehensive) treatment of patients at highest risk to die from ACLD (tertiary care) as compared to the risk from possible COVID-19 infection.The Orange PPP Line considers patients at middle risk of adverse outcomes from ACLD with re-addressing them to the secondary care. As further deterioration of ACLD is still probable, pro-active management is ascertained with tertiary center serving as the 24/7 telemedicine consultation hub for a secondary facility (on a physician-physician level).The Red PPP Line is related to the patients at low risk to die from ACLD, re-addressing them to the primary care. Since patients with stable chronic liver diseases without advanced fibrosis are at trivial inherent risk, they should be kept out of the healthcare setting as far as possible by the telemedical (patient-nurse or patient- physician) measurements. The assigned priority has to be monitored and re-evaluated individually-in intervals based on the baseline prognostic score such as MELD. The approach is conform with principles of predictive, preventive and personalized medicine (PPPM / 3PM) and demonstrates a potential of great clinical utility for an optimal management of any severe chronic disorder (cardiovascular, neurological and cancer) under lasting pandemics.

Emerging technologies for diagnostics and drug delivery in the fight against COVID-19 and other pandemics.

INTRODUCTION: A pandemic is the worst-case scenario in the field of infectious diseases. Innovative technologies have the potential to address the challenges associated with the manufacture of personalized drug delivery systems, biosensors, and medical devices during a pandemic. 3D-Printing, microfluidics, and Microelectromechanical systems (MEMS) can provide an important part on this fight, as are cheap, easy to be operated, capable to provide rapid detection and monitoring of a disease, and deliver medicines. AREAS COVERED: This manuscript answers the question of how these emerging technologies can save lives during a pandemic by avoiding supply chain delays and also by providing rapid diagnostics, disease monitoring, or by offering personalized treatments. The manuscript covers recent approaches in the topic with a focus in manuscripts published in the last year and by emphasising recent regulatory considerations by regulatory agencies in the manufacturing of 3DP systems or other medical devices during COVID. EXPERT OPINION: New manufacturing techniques are emerging with the ability to address the challenges associated with the development of medical devices or diagnostics, during a pandemic. Are many challenges in order to achieve this and especially in short times that are required under a pandemic attack, which will also be covered in this manuscript.