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Most ionizing radiation produces δ-rays of ≈1 keV that can impart MGy doses to 100 nm3 volumes of DNA. These events can produce severe dual double-strand breaks (DDSBs) on nucleosomes, particularly in dense heterochromatic DNA. This is the most common multiply damaged site, and their probabilities determine the biological effectiveness of different types of radiation. We discuss their frequency, effect on cell survival, DNA repair, and imaging by gold nanoparticle tracers and electron microscopy. This new and valuable nanometer resolution information can be used for determining the optimal tumor cure by maximizing therapeutic effects on tumors and minimizing therapeutic effects on normal tissues. The production of DDSBs makes it important to deliver a rather high dose and LET to the tumor (>2.5 Gy/Fr) and at the same time reach approximately 1.8–2.3 Gy of the lowest possible LET per fraction in TP53 intact normal tissues at risk. Therefore, their intrinsic low-dose hyper-sensitivity (LDHS)-related optimal daily fractionation window is utilized. Before full p53 activation of NHEJ and HR repair at ≈½ Gy, the low-dose apoptosis (LDA) and LDHS minimize normal tissue mutation probabilities. Ion therapy should thus ideally produce the lowest possible LET in normal tissues to avoid elevated DDSBs. Helium to boron ions can achieve this with higher-LET Bragg peaks, producing increased tumor DDSB densities. Interestingly, the highest probability of complication-free cure with boron or heavier ions requires a low LET round-up for the last 10–15 GyE, thereby steepening the dose response and further minimizing normal tissue damage. In conclusion, the new high-resolution DSB and DDSB diagnostic methods, and the new more accurate DNA-repair-based radiation biology, have been combined to increase our understanding of what is clinically important in curative radiation therapy. In fact, we must understand that we already passed the region of optimal LET and need to go back one step rather than forward, with oxygen being contemplated. As seen by the high overkill and severely high LET in the distal tumor and the increased LET to normal tissues (reminding of neutrons or neon ions), it is therefore preferable to use lithium–boron ions or combine carbon with an optimal 10–15 GyE photon, electron, or perhaps even a proton round-up, thus allowing optimized, fractionated, curative, almost complication-free treatments with photons, electrons, and light ions, introducing a real paradigm shift in curative radiation therapy with a potential 5 GyE tumor boost, 25% increase in complication-free cure and apoptotic–senescent Bragg Peak molecular light ion radiation therapy.

Most ionizing radiation produces δ-rays of ≈1 keV that can impart MGy doses to 100 nm3 volumes of DNA. These events can produce severe dual double-strand breaks (DDSBs) on nucleosomes, particularly in dense heterochromatic DNA. This is the most common multiply damaged site, and their probabilities determine the biological effectiveness of different types of radiation. We discuss their frequency, effect on cell survival, DNA repair, and imaging by gold nanoparticle tracers and electron microscopy. This new and valuable nanometer resolution information can be used for determining the optimal tumor cure by maximizing therapeutic effects on tumors and minimizing therapeutic effects on normal tissues. The production of DDSBs makes it important to deliver a rather high dose and LET to the tumor (>2.5 Gy/Fr) and at the same time reach approximately 1.8–2.3 Gy of the lowest possible LET per fraction in TP53 intact normal tissues at risk. Therefore, their intrinsic low-dose hyper-sensitivity (LDHS)-related optimal daily fractionation window is utilized. Before full p53 activation of NHEJ and HR repair at ≈½ Gy, the low-dose apoptosis (LDA) and LDHS minimize normal tissue mutation probabilities. Ion therapy should thus ideally produce the lowest possible LET in normal tissues to avoid elevated DDSBs. Helium to boron ions can achieve this with higher-LET Bragg peaks, producing increased tumor DDSB densities. Interestingly, the highest probability of complication-free cure with boron or heavier ions requires a low LET round-up for the last 10–15 GyE, thereby steepening the dose response and further minimizing normal tissue damage. In conclusion, the new high-resolution DSB and DDSB diagnostic methods, and the new more accurate DNA-repair-based radiation biology, have been combined to increase our understanding of what is clinically important in curative radiation therapy. In fact, we must understand that we already passed the region of optimal LET and need to go back one step rather than forward, with oxygen being contemplated. As seen by the high overkill and severely high LET in the distal tumor and the increased LET to normal tissues (reminding of neutrons or neon ions), it is therefore preferable to use lithium–boron ions or combine carbon with an optimal 10–15 GyE photon, electron, or perhaps even a proton round-up, thus allowing optimized, fractionated, curative, almost complication-free treatments with photons, electrons, and light ions, introducing a real paradigm shift in curative radiation therapy with a potential 5 GyE tumor boost, 25% increase in complication-free cure and apoptotic–senescent Bragg Peak molecular light ion radiation therapy. [ABSTRACT FROM AUTHOR]

Background Cardiorenal programs have emerged to improve the management of cardiorenal disease (CRD). Evidence about the benefits of these programs is still scarce. This work aims to evaluate the performance of a novel cardiorenal program and describe the clinical profile and outcomes of patients with CRD. Methods We conducted a retrospective observational study of patients with CRD attended in a cardiorenal unit (CRU) from February 2021 to February 2022. Demographics and laboratory tests were collected and events (all-cause death and cardiovascular hospitalizations) were evaluated. Optimization of comorbidities and protective therapies was also assessed. Results Eighty-two patients were included, with a mean age of 76.8 years [standard deviation (SD) 8.5] and 72% were men. A total of 58.5% (n  = 47) had left ventricular ejection fraction <50%. The mean follow-up was 11 months (SD 4.0). Almost 54% of the patients (n  = 44) required hospitalization, 30.5% for heart failure (HF) decompensation. Total hospitalizations significantly decreased after CRU inclusion: 0.70 versus 0.45 admissions/year (P  < .02). Global mortality was 17.1% (n  = 14). The percentage of patients with HF with reduced ejection fraction on quadruple therapy increased by 20%, and up to 60% of the patients were on three drugs. A total of 39% of the patients with HF and preserved ejection fraction started treatment with sodium–glucose co-transporter inhibitors. Hyperkalaemia required the use of potassium binders in 12.2% of the patients and treatment of secondary hyperparathyroidism was started in 42.7% and renal anaemia in 23.2%. Renal replacement therapy was initiated in 10% of the patients (n  = 8). Conclusion CRD confers a considerable risk of adverse outcomes. Cardiorenal programs may improve cardiorenal syndrome management by optimizing therapies, treating comorbidities and reducing hospitalizations. [ABSTRACT FROM AUTHOR]

Background: Ultrarapid-acting insulin analogs that could improve or even prevent postprandial hyperglycemia are now available for both research and clinical care. However, clear glycemic benefits remain elusive, especially when combined with automated insulin delivery (AID) systems. In this work, we study two insulin formulations in silico and highlight adjustments of both open-loop and closed-loop insulin delivery therapies as a critical step to achieve clinically meaningful improvements. Methods: Subcutaneous insulin transport models for two faster analogs, Fiasp (Novo Nordisk, Bagsværd, Denmark) and AT247 (Arecor, Saffron Walden, United Kingdom), were identified using data collected from prior clamp experiments, and integrated into the UVA/Padova type 1 diabetes simulator (adult cohort, N = 100). Pump therapy parameters and the aggressiveness of our full closed-loop algorithm were adapted to the new insulin pharmacokinetic and pharmacodynamic profiles through a sequence of in silico studies. Finally, we assessed these analogs' glycemic impact with and without modified therapy parameters in simulated conditions designed to match clinical trial data. Results: Simply switching to faster insulin analogs shows limited improvements in glycemic outcomes. However, when insulin acceleration is accompanied by therapy adaptation, clinical significance is found comparing time-in-range (70–180 mg/dL) with Aspart versus AT247 in open-loop (+5.1%); and Aspart versus Fiasp (+5.4%) or AT247 (+10.6%) in full closed-loop with no clinically significant differences in the exposure to hypoglycemia. Conclusion: In silico results suggest that properly adjusting intensive insulin therapy profiles, or AID tuning, to faster insulin analogs is necessary to obtain clinically significant improvements in glucose control. [ABSTRACT FROM AUTHOR]

Objectives: Spinal cord stimulation (SCS) has been challenged by the lack of neurophysiologic data to guide therapy optimization. Current SCS programming by trial-and-error results in suboptimal and variable therapeutic effects. A novel system with a physiologic closed-loop feedback mechanism using evoked-compound action potentials enables the optimization of physiologic neural dose by consistently and accurately activating spinal cord fibers. We aimed to identify neurophysiologic dose metrics and their ranges that resulted in clinically meaningful treatment responses., Materials and Methods: Subjects from 3 clinical studies (n = 180) with baseline back and leg pain ≥60 mm visual analog scale and physical function in the severe to crippled category were included. Maximal analgesic effect (MAE) was operationally defined as the greatest percent reduction in pain intensity or as the greatest cumulative responder score (minimal clinically important differences [MCIDs]) obtained within the first 3 months of SCS implant. The physiologic metrics that produced the MAE were analyzed., Results: We showed that a neural dose regimen with a high neural dose accuracy of 2.8μV and dose ratio of 1.4 resulted in a profound clinical benefit to chronic pain patients (MAE of 79 ± 1% for pain reduction and 12.5 ± 0.4 MCIDs). No differences were observed for MAE or neurophysiological dose metrics between the trial phase and post-implant MAE visit., Conclusion: For the first time, an evidence-based neural dose regimen is available for a neurostimulation intervention as a starting point to enable optimization of clinical benefit, monitoring of adherence, and management of the therapy., Competing Interests: Conflict of Interest Robert M. Levy is an uncompensated consultant for Biotronik, Abbott, Nalu, Saluda, and Mainstay Medical and has stock options from Nalu and Saluda Medical. Nagy A. Mekhail reports receiving grants from Neuros, Mesoblast, and Vivex Biologics, as well as consulting as a medical monitor for Saluda Medical, Nevro, Vivex Biologics, Mainstay, Presidio Medical, and Vertos outside the submitted work. Leonardo Kapural reports receiving grants from Nevro, Neuros, Avanos, Medtronic, Neuralace, and Xalud Therapeutics and financial support from Nevro, Avanos, and Saluda Medical outside the submitted work. Christopher A. Gilmore reports personal fees and other assistance from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific, and Saluda Medical outside the submitted work. Erika A. Petersen has received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda Medical outside the submitted work, as well as personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda Medical, and Vertos outside the submitted work. She holds stock options from SynerFuse and neuro42. Jonathan H. Goree is a consultant for Saluda Medical, Abbott, and Stratus Medical outside the submitted work. He has received research support paid to the institution by SPR Therapeutics and Mainstay Medical. Jason E. Pope reports research and consulting fees from Saluda Medical during the conduct of the study; stock options from Saluda Medical; consultancy for Abbott, Medtronic, Saluda Medical, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil outside the submitted work; has received grant and research support from Abbott, Flowonix, Aurora, Painteq, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil outside the submitted work; and is a minority shareholder of Vertos, Stimgenics, SPR Therapeutics, Painteq, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil, Abbott and Anesthetic Gas Reclamation. Shrif J. Costandi reports receiving grants from Saluda Medical, Vertos, Mainstay, and Vivex outside the submitted work. Jan Willem Kallewaard is an advisory board member for Boston Scientific, Medtronic, Abbott, and Saluda Medical. Simon Thomson has received consultancy fees from Boston Scientific, Mainstay Medical, and Saluda Medica outside the submitted work. He has received department research funding from the National Institute for Health Research, Boston Scientific, Saluda Medical, and Mainstay Medical. Christopher Gilligan reports consulting fees and stock options received from Mainstay, personal fees from Mainstay, Saluda Medical, Persica, and Iliad outside the submitted work, research funded by Sollis, expert witness testimony fees, and serves as Editor-in-Chief of Pain Practice. Corey W. Hunter has received consultancy fees from Saluda Medical and Genecentrix outside the submitted work. Kasra Amirdelfan reports consultancy for Medtronic, Nevro, Boston Scientific, Nalu, Presidio, Biotronik, Mesoblast, and Vivex Laboratories outside the submitted work. Steven M. Falowski reports consulting fees from Abbott, Medtronic, Saluda, VertiFlex, Vertos, Surgentec, CornerLoc, Mainstay, and Relievant outside the submitted work, has received a grant for research funding from Mainstay, Relievant, Medtronic, Abbott, VertiFlex, Saluda, Nalu, CornerLoc, Aurora, Biotronik, and Stimgenics outside the submitted work, and has an equity position in SynerFuse, Aurora Spine, Thermaquil. SPR Therapeutics, Saluda, CornerLoc, PainTEQ, Stimgenics, Anesthetic Gas Reclamation, Neural Integrative Solutions, SpineThera, and Celeri Health. Sean Li reports receiving grants and personal fees from Saluda Medical during the conduct of the study; he reports grants from Avanos, Nalu Medical, SPR Therapeutics, Averitas Pharma, Biotronik, Neuralace, Presidio, SGX Therapeutics, and PainTeq, as well as consultancy for Abbott, Avanos, Presidio, SPR Therapeutics, Averitas Pharma, Biotronik, Nalu Medical, PainTeq, and Vertos Medical outside the submitted work, as well as holding stock options for Nalu Medical and NeuroOne. Shivanand P. Lad reports personal fees from Mainstay Medical and Nevro outside the submitted work; he is a consultant for Abbott Laboratories, Boston Scientific, Higgs Boson Health, Medtronic, Minnetronix, Nevro, and Presidio Medical. Dawood Sayed reports personal fees from Abbott, Boston Scientific, Flowonix, Medtronic, Nevro, Saluda, and Vertiflex outside the submitted work, personal fees and stock options from Mainstay, SPR Therapeutics, PainTEQ, and Vertos, and stock options from Neuralace and Surgentec. Ajay Antony reports consultancy fees from Boston Scientific outside the submitted work. Timothy R. Deer reports consultancy for Axonics, Abbott, Nalu, Vertos, SpineThera, Mainstay, Cornerloc, Ethos, SPR Therapeutics, Medtronic, Boston Scientific, PainTeq, Saluda Medical, Tissue Tech, Spinal Simplicity, and Avanos outside the submitted work. Maged N. Guirguis has received consulting fees from Avanos Medical, Avertis Pharmacy, Boston Scientific, and Saluda Medical outside the submitted work, as well as research support from Boston Scientific, Neuros Medical, Nevro Corp, and Saluda Medical outside the submitted work. Aaron K. Calodney reports personal fees from Medtronic, Nevro, Stryker, PainTeq, Saluda Medical, and Boston Scientific outside the submitted work. Brian Bruel reports consultancy for Saluda Medical, Boston Scientific, Spinal Simplicity, Biotronik, TerSera, Stratus, and Neurovasis outside the submitted work. Patrick Buchanan reports consulting fees from Saluda Medical, Abbott, and PainTEQ outside the submitted work. Nicole Soliday, Rui V. Duarte, and Angela Leitner report being employees of Saluda Medical. Peter S. Staats has received consultancy fees from Medtronic, Saluda Medical, Nalu, and Biotronic outside the submitted work, and has stock options from Saluda Medical and Nalu. The remaining authors report no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.

Abstract Background Bone metastasis is the most frequent complication in prostate cancer patients and associated outcome remains fatal. Radium223 (Rad223), a bone targeting radioisotope improves overall survival in patients (3.6 months vs. placebo). However, clinical response is often followed by relapse and disease progression, and associated mechanisms of efficacy and resistance are poorly understood. Research efforts to overcome this gap require a substantial investment of time and resources. Computational models, integrated with experimental data, can overcome this limitation and drive research in a more effective fashion. Methods Accordingly, we developed a predictive agent-based model of prostate cancer bone metastasis progression and response to Rad223 as an agile platform to maximize its efficacy. The driving coefficients were calibrated on ad hoc experimental observations retrieved from intravital microscopy and the outcome further validated, in vivo. Results In this work we offered a detailed description of our data-integrated computational infrastructure, tested its accuracy and robustness, quantified the uncertainty of its driving coefficients, and showed the role of tumor size and distance from bone on Rad223 efficacy. In silico tumor growth, which is strongly driven by its mitotic character as identified by sensitivity analysis, matched in vivo trend with 98.3% confidence. Tumor size determined efficacy of Rad223, with larger lesions insensitive to therapy, while medium- and micro-sized tumors displayed up to 5.02 and 152.28-fold size decrease compared to control-treated tumors, respectively. Eradication events occurred in 65 ± 2% of cases in micro-tumors only. In addition, Rad223 lost any therapeutic effect, also on micro-tumors, for distances bigger than 400 μm from the bone interface. Conclusions This model has the potential to be further developed to test additional bone targeting agents such as other radiopharmaceuticals or bisphosphonates.

Current research is aimed at studying the fundamental therapeutic targets and discovering new drugs acting on previously set targets. Until recently, the only therapeutic strategy to influence the molecular pathway of nitric oxide (NO) – soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) was the use of phosphodiesterase type 5 inhibitors (PDE-5 inhibitors), such as sildenafil. In September 2014, the first member of sGC stimulators riociguat was licensed in Russia. In the paper, the results of 5 multicenter studies (CHEST-1 and PATENT-1, CHEST-2 and PATENT-2, RESPITE), which reflect the effectiveness and safety of mono – and combination therapy with riociguat in patients suffer from some forms of pulmonary arterial hypertension, and patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTPH), as well as the possibility of optimizing therapy in patients with PAH using iPDE-5 -> riociguat switching was reviewed. It also provides information on the recently launched international registries EXPERT CTEPH; new REPLACE study was announced.

Nowadays the therapeutic strategies to manage Parkinson's Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient's needs. The results of the proposed ROP film as a new dosage form show that it is flexible; uniform; and characterized by suitable surface pH; good mucoadhesiveness; low swelling degree; and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm2 and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm2·h-1 vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient's need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials. [ABSTRACT FROM AUTHOR]

Literacy is a tool to analyze a problem in different scenarios. A skill that can give a person/business/stakeholders insight to differentiate and explain and how to follow a particular protocol. In the healthcare ecosystem, eHealth literacy is very critical for the promotion of a product/service when it comes to the patient for following or selection of a care plan or doctor level for communication at patient level as well as at a technological level. Young people are more familiar with digital tools. When it comes to an older population, we observe resistance because of weak cognitive skills or suspicious behaviour towards technologies that exist and culture variance. Different stakeholders should consider the level of literacy, deep dig into technological advancement while making policies for the Health care ecosystem and cultural aspects for technological promotion to ensure eHealth solutions to be followed. A business model should be improvised concerning eHealth literacy and culture literacy in different countries in the health care sector for the promotion of a particular assistive technology product/device/service. This paper highlights the various essential aspects concerning eHealth literacy, cultural influences its importance while following a specific plan of care and its adherence at the patient as well as the policy-making level for the healthcare ecosystem. [ABSTRACT FROM AUTHOR]

Background: Bone metastasis is the most frequent complication in prostate cancer patients and associated outcome remains fatal. Radium223 (Rad223), a bone targeting radioisotope improves overall survival in patients (3.6 months vs. placebo). However, clinical response is often followed by relapse and disease progression, and associated mechanisms of efficacy and resistance are poorly understood. Research efforts to overcome this gap require a substantial investment of time and resources. Computational models, integrated with experimental data, can overcome this limitation and drive research in a more effective fashion.Methods: Accordingly, we developed a predictive agent-based model of prostate cancer bone metastasis progression and response to Rad223 as an agile platform to maximize its efficacy. The driving coefficients were calibrated on ad hoc experimental observations retrieved from intravital microscopy and the outcome further validated, in vivo.Results: In this work we offered a detailed description of our data-integrated computational infrastructure, tested its accuracy and robustness, quantified the uncertainty of its driving coefficients, and showed the role of tumor size and distance from bone on Rad223 efficacy. In silico tumor growth, which is strongly driven by its mitotic character as identified by sensitivity analysis, matched in vivo trend with 98.3% confidence. Tumor size determined efficacy of Rad223, with larger lesions insensitive to therapy, while medium- and micro-sized tumors displayed up to 5.02 and 152.28-fold size decrease compared to control-treated tumors, respectively. Eradication events occurred in 65 ± 2% of cases in micro-tumors only. In addition, Rad223 lost any therapeutic effect, also on micro-tumors, for distances bigger than 400 μm from the bone interface.Conclusions: This model has the potential to be further developed to test additional bone targeting agents such as other radiopharmaceuticals or bisphosphonates. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) is becoming more and more clinically important. The extracorporeal circuit for membrane oxygenation consists of a pump, a membrane oxygenator and large volume tubing. The ECMO device forms an additional compartment, which can absorb drugs with high lipophilia and protein binding. Thus, ECMO affects the volume of distribution and the clearance. As a consequence, the pharmacokinetic-pharmacodynamic (pk-pd) target parameters cannot be achieved. The selection of an appropriate substance and the mode of application, combined with therapeutic drug monitoring (TDM), can significantly improve the therapeutic outcome of critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Limited real-world evidence exists for outcomes with contemporary guideline-directed medical therapy (GDMT) or GDMT with implantable cardioverter-defibrillator (ICD)/cardiac resynchronization therapy defibrillator (CRT-D) therapy for patients with heart failure with reduced ejection fraction (HFrEF) and left ventricular ejection fraction (LVEF) ≤35%., Objective: The present study aimed to assess survival associated with GDMT or GDMT with ICD/CRT-D therapy., Methods: This retrospective observational study included real-world de-identified data from January 1, 2016, to December 19, 2023, from 24 U.S. institutions per participating institutional agreements (egnite Database; egnite, Inc.). Patients with a diagnosis of HFrEF and an echocardiographic study documenting LVEF ≤35% were included for analysis., Results: Of 43,591 patients with eligible index event of LVEF ≤35%, prescription history through ≥1 year preindex, and no ICD/CRT-D therapy preindex, mean ± standard deviation age at index was 71.2 ± 13.2 years; 14,805 (34.0%) patients were female. At 24 months, an estimated 99.1% (95% confidence interval [CI] 99.0%-99.2%), 89.9% (95% CI 89.7%-90.1%), 54.8% (95% CI 54.4%-55.2%), and 17.2% (95% CI 16.9%-17.5%), had ≥1, 2, 3, or all 4 GDMT classes prescribed, respectively; an estimated 15.7% (95% CI 15.3%-16.1%) had device placement. Of those without a device, by 24 months, an estimated 45.1% (95% CI 44.4%-45.7%) had a documented LVEF >35%. Counts of GDMT classes prescribed as well as ICD/CRT-D device therapy were associated with lower mortality risk in this population, even after adjustment for patient age, sex, and comorbidities., Conclusion: Both GDMT classes prescribed and device therapy were independently associated with lower mortality risk, even in the presence of more GDMT options for this more contemporary population., (© 2024 Heart Rhythm Society. Published by Elsevier Inc.)

Since the first report on biventricular pacing in 1994, cardiac resynchronization therapy (CRT) has become standard for patients with advanced heart failure (HF) and ventricular conduction delay. CRT improves myocardial function by resynchronizing myocardial contraction, which results in reverse left ventricular remodeling and improves symptoms and clinical outcomes. Despite the accelerated development of CRT device technology and its increased application in treating HF patients, almost one-third of these patients do not respond to the therapy or gain any clinical benefit from device implantation. Over the last decade, multiple cardiac imaging modalities have provided a deeper understanding of myocardial pathophysiology, thereby improving HF treatment management. However, the optimal strategy for improving the CRT response remains debatable. This article provides an updated overview of the electropathophysiology of myocardial dysfunction in ventricular conduction delay and the diagnostic approaches involving the use of multiple modalities. [ABSTRACT FROM AUTHOR]

According to the 2021 European Society of Cardiology guidelines, the four pillars of medical therapy in heart failure with reduced ejection fraction (HFrEF) include sodium-glucose co-transporter-2 inhibitors, beta-blockers, mineralocorticoid receptor antagonists and angiotensin-converting enzyme inhibitors or angiotensin receptor-nephrilysin inhibitors. However, in clinical practice, concomitant use of all four drug groups in target doses is often limited by their intolerance or fear of potential complications. Herein, we present strategies to initiate or modify HFrEF therapy in frequent but challenging clinical scenarios (symptomatic hypotension, atrial fibrillation, kidney disease or worsening renal function, hyperkalemia) in a way that does not lead to unnecessary reduction or cessation of life-saving medications.

Objective. To optimize the therapeutic and preventive care for epilepsy patients based on the results of examination and therapy correction performed by an epileptologist. Patients and Methods. Results of clinico-epidemiological examination of 587 adult patients with epilepsy (320 males and 267 females) are presented. The effectiveness of the antiepileptic therapy before and after it had been optimized by an epileptologist was analyzed. Results. The results demonstrated that optimization of antiepileptic drug therapy according to the recommendations of the International League Against Epilepsy (ILAE) allowed 91.87% of patients to achieve positive result: the termination of seizures was observed in 66.61% of cases; a decrease in seizure frequency by over 50% was observed in 25.26% of cases. A total of 6.26% of patients showed clinical improve- ment (seizure frequency was reduced by less than 50%). The therapy turned out to be inefficient in 1.87% of patients.

Purpose: Unpredictable drug efficacy and safety of combined antiepileptic therapy is a major challenge during pharmacotherapy decisions in everyday clinical practice. The aim of this study was to describe the pharmacokinetics of valproic acid (VA), lamotrigine (LTG), and levetiracetam (LEV) in a pediatric population using nonlinear mixed-effect modeling, while machine learning (ML) algorithms were applied to identify any relationships among the plasma levels of the three medications and patients' characteristics, as well as to develop a predictive model for epileptic seizures., Methods: The study included 71 pediatric patients of both genders, aged 2-18 years, on combined antiepileptic therapy. Population pharmacokinetic (PopPK) models were developed separately for VA, LTG, and LEV. Based on the estimated pharmacokinetic parameters and the patients' characteristics, three ML approaches were applied (principal component analysis, factor analysis of mixed data, and random forest). PopPK models and ML models were developed, allowing for greater insight into the treatment of children on antiepileptic treatment., Results: Results from the PopPK model showed that the kinetics of LEV, LTG, and VA were best described by a one compartment model with first-order absorption and elimination kinetics. Reliance on random forest model is a compelling vision that shows high prediction ability for all cases. The main factor that can affect antiepileptic activity is antiepileptic drug levels, followed by body weight, while gender is irrelevant. According to our study, children's age is positively associated with LTG levels, negatively with LEV and without the influence of VA., Conclusion: The application of PopPK and ML models may be useful to improve epilepsy management in vulnerable pediatric population during the period of growth and development., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

In medicine, there are two main methods of improving the healthcare provided: perfecting (optimizing) the existing ones and seeking new treatment procedures. Despite of tremendous development in the central nervous system research, current treatment of severe mental illnesses, such as schizophrenia and depressive disorder, is suboptimal. Nowadays, optimization of treatment in psychiatry includes therapeutic drug monitoring (TDM) and pharmacogenomic testing, which examines genetic variation involved in medication metabolism and drug action. The TDM enables to determine drug concentrations in blood and adjust the dose accordingly if clinical effects correlate better with drug blood levels than drug doses. The first international guidelines for TDM in neuropsychopharmacology were published in 2004 and regularly updated. The recent update provides therapeutic reference ranges for a majority of commonly prescribed psychiatric medications and gives example of patients regularly treated in clinical practice profiting from TDM (using antipsychotics and changing their smoking habits). TDM in psychiatry is an underused tool, given its ability to optimize treatment, as well as to improve treatment effectiveness.

Abstract: The objective of this paper is to identify the parameters of a human immunodeficiency virus (HIV) evolution model from a clinical data set of patients treated with two different highly active antiretroviral therapy (HAART) protocols. After introducing a model with six state variables, a preliminary step considers the reduction of the number of parameters to be identified by means of sensitivity analysis, and then identifiability items are discussed. A nonlinear optimization-based procedure for identification is developed, which divides the unknown parameters into two families: the group dependent and the patient dependent parameters. Numerical results show that the identified model can be individually adapted to each patient and this result is promising for predicting the effects (e.g., failures or successes) of therapeutic actions. [Copyright &y& Elsevier]

In this paper, model predictive control (MPC) strategies are applied to the control of human immunodeficiency virus infection, with the final goal of implementing an optimal structured treatment interruptions protocol. The MPC algorithms proposed in this paper use a dynamic model recently developed [1] in order to mimic both transient responses and ultimate behavior, and to describe accordingly the different effect of commonly used drugs in highly active antiretroviral therapy (HAART). Simulation studies show that the proposed methods achieve the goal of reducing the drug consumption (thus minimizing the severe side effects of HAART drugs) while respecting the desired constraints on CD4+ cells and free virions concentration. Such promising results are obtained with realistic assumptions of infrequent (possibly noisy) measurements of a subset of model state variables. Furthermore, the control objectives are achieved even in the presence of mismatch between the dynamics of true patients and that of theMPC model. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs) are antisecretory agents that are widely used in the short- and long-term management of gastroesophageal reflux disease (GERD) to relieve symptoms, heal esophagitis, and prevent complications, such as strictures and Barrett’s esophagus. The total healthcare costs of GERD are high, especially for maintenance treatment. Therefore, the choice of cost-effective therapeutic options is an ineluctable challenge for public health authorities, third-party payers, and patients. In some European Union countries, a recent trend of public health authorities is to promote the choice of less expensive PPIs, regardless of their antisecretory potency – this in spite of the evidence that newer PPIs provide superior symptom relief and esophageal erosion healing compared to earlier drugs. Several large clinical trials have demonstrated the superiority of esomeprazole over other PPIs at standard doses for both initial and continuous maintenance therapy in patients with moderate/severe erosive esophagitis. The non-erosive GERD poses a major challenge as this condition appears more frequently to be less responsive to PPIs. The use of PPIs with the strongest antisecretory properties might reveal to be more adequate and cost-effective, particularly for this indication. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

• Hepatitis C Virus optimized therapy taking into account pharmacological cost. • Non-Linear Model Predictive Control to optimize drug consumption. • Analysis of different disease scenarios: PVR and Triphasic Decline. • Therapy discretization of continuous drug dosage. • Robustness of therapy to different patient scenarios. Background and Objective : The recent introduction of antivirals for the treatment of the hepatitis C virus opens new frontiers but also poses a significant burden on public health systems. This paper presents a simulation study in which model predictive control (MPC) is proposed for optimizing the therapy aiming to obtain a reduction of the costs of therapy, while maintaining the best pharmacological control of the infection. Methods : A dynamic model describing the evolution of hepatitis C is deployed as internal model for MPC implementation, using nominal values of parameters. Different closed-loop simulations are presented both in nominal and in mismatch conditions. In addition, a more easily implementable treatment is proposed, which is based on a discrete dosage approach, where days on/off therapy are considered instead of continuous therapy modulation. Results : Results show that therapy modulation allows one to achieve the same infection evolution as with full therapy, with a reduction of drug consumption between 10% and 40%. The alternative discrete dosage approach shows similar results achieved with therapy modulation, both in terms of therapy effectiveness and drug consumption reduction. Conclusions : The proposed model predictive control therapy optimization strategies appear to be effective, implementable and robust to model errors. It therefore represents a potentially useful approach to alleviate the burden of HCV therapy cost on national health systems. [ABSTRACT FROM AUTHOR]

Background: Radiation therapy has undergone significant technical development in the past decade. However, the complex therapy of intermediate-risk patients with organ-confined prostate carcinoma still poses many questions. Our retrospective study investigated the impact of selected components of the treatment process including radiotherapy, hormone deprivation, risk classification, and patients' response to therapy. Methods: The impact of delivered dose, planning accuracy, duration of hormone deprivation, risk classification, and the time to reach prostate-specific antigen (PSA) nadir state were analyzed among ninety-nine individuals afflicted with organ-confined disease. Progression was defined as a radiological or biochemical relapse within five years from radiotherapy treatment. Results: We found that 58.3% of the progressive population consisted of intermediate-risk patients. The progression rate in the intermediate group was higher (21.9%) than in the high-risk population (12.1%). Dividing the intermediate group, according to the International Society of Urological Pathology (ISUP) recommendations, resulted in the non-favorable subgroup having the highest rate of progression (33.3%) and depicting the lowest percentage of progression-free survival (66.7%). Conclusion: Extended pelvic irradiation on the regional lymph nodes may be necessary for the ISUP Grade 3 subgroup, similarly to the high-risk treatment. Therapy optimization regarding the intermediate-risk population based on the ISUP subgrouping suggestions is highly recommended in the treatment of organ-confined prostate cancer. [ABSTRACT FROM AUTHOR]

Oestrogen receptor (ER)-positive breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of any targeted therapy often results in resistance to the therapy. Our ultimate goal is to use mathematical modelling to optimize alternating therapies that not only decrease proliferation but also stave off resistance. Toward this end, we measured levels of key proteins and proliferation over a 7-day time course in ER+ MCF-7 breast cancer cells. Treatments included endocrine therapy, either oestrogen deprivation, which mimics the effects of an aromatase inhibitor, or fulvestrant, an ER degrader. These data were used to calibrate a mathematical model based on key interactions between ER signalling and the cell cycle. We show that the calibrated model is capable of predicting the combination treatment of fulvestrant and oestrogen deprivation. Further, we show that we can add a new drug, palbociclib, to the model by measuring only two key proteins, cMyc and hyperphosphorylated RB1, and adjusting only parameters associated with the drug. The model is then able to predict the combination treatment of oestrogen deprivation and palbociclib. We illustrate the model's potential to explore protocols that limit proliferation and hold off resistance by not depending on any one therapy.

Background: In the 1990s, the beta interferons and glatiramer acetate were introduced for treating relapsing-remitting multiple sclerosis. These medications have a demonstrated record of efficacy and safety, although they require frequent administration via injection and are only partially effective. The optimization of treatment in patients who do not respond adequately to this first-line therapy is essential for attaining the best long-term outcomes. Switching to the recently approved emergent therapies is a strategy to consider for treatment of patients with a suboptimal response., Objective: This review summarizes the mechanisms of action, clinical benefits, and safety profiles of current multiple sclerosis disease-modifying therapies, including highly efficacious monoclonal antibodies or convenient oral therapies, and with a special focus on the pegylated interferon beta 1a formulation., Methods: We reviewed the recent literature and human clinical trials on multiple sclerosis therapies by bibliographic search in PubMed and clinicaltrials.gov., Results and Conclusion: Although the first-line interferon beta exhibits a favorable benefit-torisk profile, treatment compliance is compromised potentially due to its known adverse events and frequent injectable administration. Less frequent dosing and improved pharmacological properties have been achieved by reaction of interferon beta with chemically activated polyethylene glycol. Provided that none of the available therapies show better effectiveness for all outcomes and their safety in clinical practice is of a fundamental concern, the pegylated form of interferon beta seems to keep its place as a competitive therapeutic option., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)