Respiratory Syncytial Virus (RSV) Burden in Infants in the Kingdom of Saudi Arabia and the Impact of All-Infant RSV Protection: A Modeling Study.

INTRODUCTION: Respiratory syncytial virus (RSV) represents a considerable burden on the healthcare system and hospital resources. This study explored the impact of universal immunoprophylaxis with long-acting monoclonal antibody (nirsevimab) during infants' first RSV season on RSV-induced health events and related costs in the Kingdom of Saudi Arabia (KSA). METHODS: The burden of RSV-induced health events and related costs under the current standard of practice (SoP) and the impact of universal immunoprophylaxis with nirsevimab was estimated using a static decision-analytic model in a cohort of infants experiencing their first RSV season in the KSA. The model estimated hospital admissions (including pediatric intensive care unit [PICU] admissions and mechanical ventilation [MV]), emergency room (ER) visits, primary care (PC) visits, long-term sequelae, and RSV mortality. RESULTS: The model estimated that under the current SoP, RSV results in 17,179-19,607 hospitalizations (including 2932-3625 PICU and 172-525 MV admissions), 57,654-191,115 ER visits, 219,053-219,970 PC visits, 14 deaths, 12,884-14,705 cases of recurrent wheezing, and a total cost of SAR 480-619 million. Universal nirsevimab immunoprophylaxis was estimated to avert 58% of hospitalizations (58% PICU admissions, 58% MV episodes), 53% of ER visits, 53% of PC visits, 58% of episodes of recurrent wheezing, 8 deaths, and result in savings of SAR 274-343 million in total healthcare cost. CONCLUSION: Compared with current SoP, an nirsevimab immunoprophylaxis strategy in the KSA for all infants during their first RSV season was estimated to dramatically decrease healthcare resource use, and economic burden associated with RSV.

Efficacy of Bimekizumab and Other Biologics in Moderate to Severe Plaque Psoriasis: A Systematic Literature Review and a Network Meta-Analysis.

INTRODUCTION: Biologic treatments are increasingly being used in the management of moderate to severe plaque psoriasis (PSO). Bimekizumab is a selective inhibitor of both interleukin (IL)-17A and IL-17F approved for the treatment of moderate to severe PSO. Although bimekizumab trials provide comparisons to secukinumab, adalimumab and ustekinumab, there are no further head-to-head comparisons of bimekizumab to other biologics. This network meta-analysis (NMA) aimed to compare the short-term efficacy of bimekizumab versus other biologic systemic therapies for moderate to severe PSO. METHODS: A systematic literature review was conducted to identify randomised controlled trials (RCTs) in patients with moderate to severe PSO. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews and PsycINFO were searched on July 1, 2020. An enhanced multinomial Bayesian NMA model was used to evaluate the comparative efficacy in 50%, 75%, 90% and 100% improvement from baseline Psoriasis Area and Severity Index (PASI 50/75/90/100) at 10-16 weeks. The model was also adjusted for baseline risk, given the variable placebo responses across the trials. RESULTS: Eighty-six RCTs (including 34,476 patients) were included in the NMA. IL-17 and IL-23 inhibitors were the most effective treatments across all PASI levels. At 10-16 weeks, bimekizumab had the highest probability of achieving PASI 75 (92.3%), PASI 90 (84.0%) and PASI 100 (57.8%). Bimekizumab demonstrated statistical superiority over all biologics in achieving PASI 90 and PASI 100 thresholds. For PASI 75, the benefit of bimekizumab was statistically significant compared to all other treatments except risankizumab and ixekizumab. CONCLUSION: This analysis demonstrated that IL-17 and IL-23 inhibitors were highly effective in achieving short-term improvement among patients with moderate to severe PSO. Patients receiving bimekizumab were significantly more likely to achieve PASI 90 or PASI 100 within 10-16 weeks of the first injection than all other biologics.

Modeling Challenges in Cost-Effectiveness Analysis of First-Line Immuno-Oncology Therapies in Non-small Cell Lung Cancer: A Systematic Literature Review.

INTRODUCTION: The introduction of immuno-oncology (IO) therapies has changed the treatment landscape of non-small cell lung cancer (NSCLC). Numerous cost-effectiveness analyses (CEAs) and technology appraisals (TAs) evaluating IO therapies have been recently published. OBJECTIVE: We reviewed economic models of first-line (1L) IO therapies for previously untreated advanced or metastatic NSCLC to identify methodological challenges associated with modeling cost effectiveness from published literature and TAs and to make recommendations for future CEAs in this disease area. METHODS: A systematic literature review was conducted following Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched MEDLINE, Embase, EconLit (January 2009-January 2020), and select conferences (since 2016) for CEAs of 1L IO treatments in patients with recurrent or metastatic, epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC, published in English. TAs from England, Scotland, Canada, Australia, Germany, and France were also examined. Two reviewers screened the results and extracted the data. The quality of the CEAs was described using the Drummond checklist. RESULTS: In total, 46 records reporting on 38 unique models met protocol-defined criteria and were included. Five models adjusted for treatment switching or crossover in base-case analyses, and the remainder considered treatment switching or crossover to represent clinical practice and made no adjustment. Seven models used external real-world data for survival modeling or extrapolation validation. Six models that assumed long-term treatment benefit stopped at 3 or 5 years after initiation. Seven models used the observed time-on-treatment distribution from the trial, and eight used progression-free survival for treatment duration. All models compared one or more IO monotherapies or combination therapies with chemotherapy. Only one study directly compared different IO agents but did not consider the concordance issue across programmed death-ligand 1 (PD-L1) testing methods. Utilities were modeled by health state in 12 models, four applied a time-to-death approach, and ten explored both. None applied cure models. CONCLUSION: Variations in methodological challenges were seen across studies. Previous models took approaches that were followed in subsequent models, such as a 2-year stopping rule of IO duration or treatment-effect waning. Challenges such as heterogeneity in PD-L1 testing and survival extrapolation and validation using real-world data should be further considered for future models in advanced or metastatic NSCLC.

Clinical evidence for the first-line treatment of advanced urothelial carcinoma: Current paradigms and emerging treatment options.

BACKGROUND: Patients with advanced urothelial carcinoma (UC) have poor outcomes, with 5-year survival rates of <5% for those with metastatic, stage IV disease. We have reviewed current treatment paradigms and emerging treatment options for these patients. METHODS: The websites of seven national or international organizations were searched for metastatic UC treatment guidelines. Systematic literature reviews were conducted to identify evidence from randomized controlled trials (RCTs) of chemotherapy for patients with previously untreated, unresectable, stage IV UC. Searches included congress databases and articles published between 1990 and 2018. In order to align with the latest treatment paradigms in first-line advanced UC, a focused literature search was conducted to identify evidence supporting immuno-oncology (IO) agents. RESULTS: For advanced UC, guidelines universally recommend cisplatin-based chemotherapy as first-line treatment for eligible patients and carboplatin-based regimens for those unfit to receive cisplatin. Despite the evaluation of a number of different cytotoxic regimens over the years, including triplet combinations, survival outcomes have not improved markedly with chemotherapy. Median overall survival with standard of care chemotherapy is ~13 months. Based on the results of single-arm, phase II studies, recent treatment guidelines have included atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) as first-line options for cisplatin-ineligible patients whose tumors express high levels of PD-L1. However, emerging evidence from RCTs of IO agents, including both cisplatin-eligible and cisplatin-ineligible patients, suggest that survival times exceeding 20 months are possible. CONCLUSIONS: After having reached a plateau with chemotherapy, the treatment landscape for advanced UC is evolving. Survival outcomes for patients with advanced UC are improving with treatment modalities involving IO agents.

Postnatal Development of the Posterior Hypothalamic Theta Rhythm and Local Cell Discharges in Rat Brain Slices.

Theta rhythms have been recorded from rat brain slices of the posterior hypothalamic area (PHa), including the supramammillary and posterior hypothalamic nuclei. Additionally, in numerous studies theta-related neurons were identified in the PHa according to the classification of Bland and Colom (Progress in Neurobiology, 41, 157-208, 1993). It is currently widely accepted that the PHa contributes to the process of HPC theta frequency programming at least in certain behavioral states. The postnatal development of the HPC and its ability to generate theta has also been a subject of studies. Specifically, it was found that theta oscillations are present in the HPC of 8-10 days old rat pups and turn into a well-synchronized and high-amplitude activity in the following few days. In our current study, we therefore focused on the postnatal development of cholinergically-induced theta rhythm and theta-related neuronal activity in PHa slices obtained from 8 to 24 days old rat pups. Theta activity was observed in the PHa preparations at the age of 8-10 days and then progressively increased its probability of occurrence, amplitude and synchrony up to the age of 22-24 days when it reached a plateau phase. A steady increase in the number of recorded neurons correlated with local theta oscillations was also observed.

Fullerenol C60(OH)36 protects human erythrocyte membrane against high-energy electrons.

Fullerenols (polyhydroxylated fullerene C60) are nanomaterial with potentially broad applicability in biomedical sciences with high antioxidant ability, thus, we investigated the radioprotecting potential of fullerenol C60(OH)36 on human erythrocytes irradiated by high-energy electrons of 6 MeV. The results demonstrate that C60(OH)36 at concentration of 150 µg/mL protects the erythrocytes against the radiation-induced hemolysis (comparing to non-protected cells, we observed 30% and 39% protection for 0.65 and 1.3 kGy irradiation doses, respectively). The protecting effect was confirmed by 32% decreased release of potassium cations comparing to the cells irradiated without C60(OH)36. Measurements of the amount of lactate dehydrogenase (LDH) released from the irradiated erythrocytes showed that the size of the pores formed by irradiation was not sufficient to release LDH across the erythrocyte membranes. We also report a significant decrease of the affinity of acetylcholinesterase (AChE) for the substrate in the presence of fullerenol, indicating the relatively strong adsorption of C60(OH)36 to components of plasma membrane. Changes in membrane fluidity detected by fluorescence spectroscopy and conformational changes in membrane proteins detected by spin labeling suggest the dose-dependent formation of disulfide groups as an effect of oxidation and this process was inhibited by C60(OH)36. We suppose that scavenging the ROS as well as adsorption of fullerenol to membrane proteins and steric protection of -SH groups against oxidation are responsible for the observed effects.

Cell discharge correlates of posterior hypothalamic theta rhythm recorded in anesthetized rats and brain slices.

Kowalczyk et al. (Hippocampus 2014; 24:7-20) were probably the first to conduct a systemic study of posterior hypothalamic area (PHa) theta rhythm in anesthetized rats. They demonstrated that local PHa theta field potentials were tail-pinch resistant and could be generated in urethane-anesthetized rats independently of ongoing hippocampal formation theta rhythm. These in vivo data were also confirmed in PHa slice preparations perfused with cholinergic agonist, carbachol. In the current experiments we extend our earlier observations concerning PHa theta rhythm. Specifically, PHa field potentials were analyzed in relation to the ongoing local cell firing repertoire. Single-unit discharge patterns of cells localized in the posterior hypothalamic and supramammillary nuclei were characterized according to the criteria that was developed previously to classify theta-related cells in the hippocampal formation. The present study demonstrated that in addition to the earlier described theta-related cells (theta-on, theta-off and gating cells) the PHa also contains cells discharging in a very regular manner, which were labelled "timing cells". This type of neuron has not been previously documented. We suggest that "timing cells" form a part of the ascending brainstem synchronizing pathway, provideing a regular rhythmic signal which facilitates the transduction of tonic discharges of cells localized in the brain stem into theta-frequency rhythmic discharges. © 2016 Wiley Periodicals, Inc.

Development of theta rhythm in hippocampal formation slices perfused with 5-HT1A antagonist, (S)WAY 100135.

Numerous studies have revealed that median raphe nuclei stimulation induces desynchronization of hippocampal field activity in vivo. Some findings provide evidence for tonic regulation of the theta oscillation of the septo-hippocampal system via the serotonergic system. To date the involvement of serotonergic transmission in theta rhythm generation in hippocampal slices has never been investigated. Thus the aim of the present study was to test whether HPC in vitro preparation is capable of producing theta in the presence of compounds modulating the activity of 5-HT1A receptors. To achieve this a series of experiments designed to determine the effect of different concentrations of the 5-HT1A receptor antagonist (S)WAY 100135 on HPC field activity was carried out. The dominant field potential pattern recorded within HPC slices was epileptiform activity, with a maximum frequency ranging from 0.19 ± 0.06 Hz to 0.69 ± 0.10 Hz. In addition, after the bath application of (S)WAY 100135 in concentrations 3 and 10 µM rhythmic epochs in the theta frequency range were also noted. The highest probability of theta rhythm production was observed after the bath perfusion with a solution of (S) WAY 100135 at a concentration of 10 µM. These theta rhythm epochs were characterized by a higher-than-average amplitude compared to carbachol-induced theta epochs and shorter time duration, with no apparent differences in the average frequency and duration of intervals between theta epochs. These results obtained herein of in vitro studies provide direct evidence for the involvement of serotonergic receptors in the depression of oscillatory activity in the HPC theta band.

Orexinergic theta rhythm in the rat hippocampal formation: In vitro and in vivo findings.

Previous in vivo data suggested that orexin neuropeptides (ORX(A) and ORX(B) ) synthetized in hypothalamic neurons were involved in the mechanism of generation of the hippocampal formation theta rhythm. Surprisingly, this suggestion has never been directly proved by experiments using intraseptal or intrahippocampal administration of orexins. In this study, involving the use of in vitro hippocampal formation slices and in vivo model of anesthetized rat, we provide the first convergent electropharmacological evidence that in the presence of both ORX(A) and ORX(B) the hippocampal formation neuronal network is capable of producing oscillations in the theta band. This effect of orexin peptides was antagonized by selective blockers of orexin receptors (OX1 R and OX2 R), SB 334867 and TCS OX2 29, respectively. These results provide evidence for a novel, orexinergic mechanism responsible for the production of theta rhythm in the hippocampal formation neuronal network.

Fullerenols as a new therapeutic approach in nanomedicine.

Recently, much attention has been paid to the bioactive properties of water-soluble fullerene derivatives: fullerenols, with emphasis on their pro- and antioxidative properties. Due to their hydrophilic properties and the ability to scavenge free radicals, fullerenols may, in the future, provide a serious alternative to the currently used pharmacological methods in chemotherapy, treatment of neurodegenerative diseases, and radiobiology. Some of the most widely used drugs in chemotherapy are anthracycline antibiotics. Anthracycline therapy, in spite of its effective antitumor activity, induces systemic oxidative stress, which interferes with the effectiveness of the treatment and results in serious side effects. Fullerenols may counteract the harmful effects of anthracyclines by scavenging free radicals and thereby improve the effects of chemotherapy. Additionally, due to the hollow spherical shape, fullerenols may be used as drug carriers. Moreover, because of the existence of the currently ineffective ways for neurodegenerative diseases treatment, alternative compounds, which could prevent the negative effects of oxidative stress in the brain, are still sought. In the search of alternative methods of treatment and diagnosis, today's science is increasingly reaching for tools in the field of nanomedicine, for example, fullerenes and their water-soluble derivatives, which is addressed in the present paper.

[Fullerenol - properties and applications in biomedical sciences]. / Fulerenol - wlasciwosci i zastosowanie w naukach biomedycznych.

Fullerenols, the water-soluble derivatives of fullerenes, are currently being recently intensively studied in the context of the possibility of their application in the biomedicine. Due to their hydrophilic properties and the ability to eliminate free radicals, fullerenols may in the future provide a solid alternative to currently used pharmacological methods in chemotherapy, treatment of neurodegenerative diseases and radiobiology. Depending on the research protocol applied, fullerenols may also act as pro oxidants. The dualistic nature of fullerenols may contribute to finding new biomedical applications of these agents in the future, by exerting a cytotoxic or protective effect respectively against cancer cells or healthy cells. Because of the encapsulated structure of fullerenols, there exists the possibility of their application in medical diagnostics in the transfer of contrast agents or in the drug transport. During the planning of an experiment designed to investigate the effects of radiation in combination with derivatives of water-soluble fullerenes, the possibility of appearance of the "dose-response effect" should be taken into consideration since it significantly contributes to one of the two possible effects: protection or sensitization. The same applies to the possibility of using these compounds as potential neuroprotectors. Fullerenol may protect neurons in the particular areas of the brain but in the definedcertain doses it may also induce cell death. A giant leap in the field of nanotechnology not only leads scientists to search for new applications of nanomaterials such as fullerenols, but also raises the question about their harmful effect on the environment. High utilization of hardly biodegradable fullerenols increases the likelihood of their accidental release into natural systems and their bioaccumulation. Despite convincing evidences about the potential applications of fullerenols in biomedicine, we still have insufficient knowledge about the mechanism of action of these molecules and their possible side effects.

Development of NMDA-induced theta rhythm in hippocampal formation slices.

During the past 20 years experimental evidence has accumulated demonstrating that the appearance of theta rhythm requires a certain level of excitation of local neuronal networks. In this study we extended our earlier in vitro observations concerning the involvement of cholinergic and GABAergic neurotransmission in hippocampal theta production. Specifically, we investigated whether the hippocampal neuronal network is capable of generating theta oscillations in the presence of N-methyl-d-aspartic acid (NMDA) in a brain slice preparation. To answer this question, the effect of different concentrations of NMDA (Experiment I) and the effect of interaction between NMDA and GABAA/B agonists and antagonists on field potentials recorded in the CA3c region of hippocampal formation (HPC) slice preparations (Experiment II) was examined. We demonstrated for the first time that apart from the epileptiform activity recorded in almost all series of Experiments I and II, only the perfusion of HPC slices with NMDA in doses of 30 and 50 µM, as well as the perfusion of HPC slices with NMDA and GABAB agonist baclofen (50 µM NMDA+50 µM BACL), resulted in the appearance of individual theta epochs. The best synchronized theta oscillations obtained after administration of 50 µM NMDA+50 µM BACL resembled theta activity induced by a bath perfusion of 50 µM carbachol. In light of the obtained results we conclude that besides the cholinergic and GABAergic input, NMDA glutamatergic drive is also important for the appearance of theta oscillations in HPC in vitro.

Spatiotemporal characterization of mTOR kinase activity following kainic acid induced status epilepticus and analysis of rat brain response to chronic rapamycin treatment.

Mammalian target of rapamycin (mTOR) is a protein kinase that senses nutrient availability, trophic factors support, cellular energy level, cellular stress, and neurotransmitters and adjusts cellular metabolism accordingly. Adequate mTOR activity is needed for development as well as proper physiology of mature neurons. Consequently, changes in mTOR activity are often observed in neuropathology. Recently, several groups reported that seizures increase mammalian target of rapamycin (mTOR) kinase activity, and such increased activity in genetic models can contribute to spontaneous seizures. However, the current knowledge about the spatiotemporal pattern of mTOR activation induced by proconvulsive agents is rather rudimentary. Also consequences of insufficient mTOR activity on a status epilepticus are poorly understood. Here, we systematically investigated these two issues. We showed that mTOR signaling was activated by kainic acid (KA)-induced status epilepticus through several brain areas, including the hippocampus and cortex as well as revealed two waves of mTOR activation: an early wave (2 h) that occurs in neurons and a late wave that predominantly occurs in astrocytes. Unexpectedly, we found that pretreatment with rapamycin, a potent mTOR inhibitor, gradually (i) sensitized animals to KA treatment and (ii) induced gross anatomical changes in the brain.

Does an anti-oxidant ascorbic acid improve the condition of hippocampal formation slice preparations? A micro-EEG approach.

The objective of this study was to assess whether ascorbic acid (AA), an intracellular anti-oxidant critical for neuronal protection, when added to artificial cerebrospinal fluid (ACSF), is able to protect hippocampal (HPC) formation slice preparations from ageing. In this research, the micro-electroencephalographic (EEG) technique was applied. Experiments were performed on 72 HPC formation slices obtained from 12 male Wistar rats. Two series of experiments were conducted: the control experiment, in which ACSF was used as an incubation medium, and the research one, in which ACSF was supplemented with 200 µM AA. The experimental model of carbachol-induced EEG theta rhythm was applied. The following parameters of theta rhythm after 15, 30 and 45 min of recording were analysed: frequency, power, time duration of theta epochs and time duration of intervals between theta epochs. The results show that AA causes a statistically significant decrease in the power of theta rhythm after 15, 30 and 45 min of recording. The time duration of intervals between theta epochs was almost twice as long in slices incubated in ACSF + AA than in ACSF after 45 min of recording. The data obtained indicate that AA does not improve the condition of HPC slices. On the contrary, it worsens the ability of slice preparations to generate theta oscillations. We hypothesize that our data may result from the Fenton reaction or changes in the conformation of connexins.

Gap junction modulation of hippocampal formation theta and local cell discharges in anesthetized rats.

During the past decade experimental evidence has accumulated demonstrating that the electrical communication between neurons through gap junctions (GJs) is a necessary neural mechanism underlying oscillations and synchrony. Here we extended our earlier observations concerning the involvement of GJs in hippocampal theta production. Using trimethylamine, a GJ opener, we demonstrated a reversible increase in theta amplitude and power and an increase in the duration of theta epochs. This effect was accompanied by a decrease in the percentage of recorded theta-off cells, an increase in the percentage of recorded theta-on phasic cells, and an increase in the number of rhythmic cell discharges per theta wave. We suggest that all these findings result from an enhanced level of interneuronal excitation, mediated by an increase in the efficacy of local GJ coupling.

Uric acid but not apple polyphenols is responsible for the rise of plasma antioxidant activity after apple juice consumption in healthy subjects.

OBJECTIVE: To determine whether (1) rapid consumption of 1 L of apple juice increases blood antioxidant capacity, measured as ferric-reducing ability of plasma (FRAP) and serum 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity, and (2) apple polyphenols or fructose-induced elevation of plasma uric acid contributes to post-juice increase of blood antioxidant activity. METHODS: The study involved 12 (mean age 32 ± 5 years, mean body weight 73 ± 7 kg) healthy nonsmoking subjects. Tested subjects consumed 1 L of clear apple juice and then FRAP; serum DPPH-scavenging activity, serum uric acid, and total plasma phenolics and quercetin levels were measured just before juice ingestion and 1, 2.5, and 4 hours after ingestion. This was repeated 3 times with 4-day intervals, but volunteers drank either 1 L of clear apple juice without polyphenols (placebo), or 1 L of cloudy apple juice (positive control), or 1 L of water (negative control) at the time. All juices had similar content of sugars (i.e., saccharose, glucose, and fructose) and precisely defined composition of phenolics and antioxidant activity. RESULTS: Consumption of all 3 juices transiently increased FRAP and serum DPPH-scavenging activity, with peak values at 1 hour post-juice ingestion. This was paralleled by the rise of serum uric acid, but no significant changes in plasma total phenolics and quercetin levels were observed after all dietary interventions. At the same time, no substantial differences were found between juices (especially between clear apple juice and clear apple juice without polyphenols) concerning the measured variables. A strong significant correlation was noted instead between serum uric acid and plasma antioxidant activity at all analyzed time points, before and after juice ingestion. Plasma total phenolics and quercetin levels were not associated with FRAP and serum DPPH radical-scavenging activity. CONCLUSIONS: We have demonstrated that rapid consumption of apple juice increased plasma antioxidant activity in healthy subjects; this was caused by the fructose-induced rise of serum uric acid levels, but was not due to the presence of antioxidant polyphenols in juice. Thus, short-term consumption of apple juice seems not to be the effective dietary intervention to augment plasma antioxidant activity due to the concomitant possibility for uric acid to be a risk factor for several diseases, as verified by other authors.