A comprehensive Study of the Out of Field Non Target Dose Associated with 6 and 10 MV Flattened and Flattening Filter Free X Ray Beam in a True Beam Linear Accelerator.

AIM: To evaluate the out-of-field dose associated with flattened (FF) and flattening filter-free (FFF) 6 and 10 MV X-ray beams in a TrueBeam linear accelerator (Linac). MATERIALS AND METHODS: Measurements were taken in a slab phantom using the metal oxide semiconductor field effect transistor (MOSFET) detector at varying depths (dmax, 5 cm, and 10 cm) for clinically relevant field sizes and up to 30 cm from the field edges for 6 and 10 MV FF and FFF beams in TrueBeam Linac. Dose calculation accuracy of the analytic anisotropic algorithm (AAA) and Acuros algorithm was investigated in the out-of-field region. Similarly, the out-of-field dose associated with volumetric modulated arc therapy (VMAT) head-and-neck plan delivered to a body phantom was evaluated. RESULTS: The out-of-field dose for both FF and FFF photon beams (6 and 10 MV) decreased with increasing distance from the field boundary and size. Furthermore, regardless of FF in the field, higher-energy photon beams were associated with lower out-of-field dose. Both algorithms underestimated the dose in the out-of-field region, with AAA failing to calculate the out-of-field dose at 15 cm from the field edge and Acuros failing to calculate out-of-field radiation at 20 cm. At 5 cm from the field edge, an average of 50% underestimation was observed, and at 10 cm, an average of 60% underestimation was observed for both FF and FFF (6 and 10 MV) beams. The VMAT head-and-neck plan performed with the FFF beam resulted in a lower out-of-field dose than the FF beam for a comparable dose distribution. CONCLUSION: Compared with flattened beams, the FFF modes on TrueBeam Linac exhibited a clinically relevant reduction in the out-of-field dose. Further dosimetric studies are warranted to determine the significant benefit of FFF beams across different cancer sites.

Combination MCP-Mod for two-drug combination dose-ranging studies.

Combination therapies with multiple mechanisms of action can offer improved efficacy and/or safety profiles when compared to a single therapy with one mechanism of action. Consequently, the number of combination therapy studies have increased multi-fold, both in oncology and non-oncology indications. However, identifying the optimal doses of each drug in a combination therapy can require a large sample size and prolong study timelines, especially when full factorial designs are used. In this paper, we extend the MCP-Mod design of Bretz, Pinheiro, and Branson to a three-dimensional space to model the dose-response surface of a two-drug combination under the framework of Combination (Comb) MCP-Mod. The resulting model yields a set of dosages for each drug in the combination that elicits the target response so that an optimal dose for the combination can be selected for pivotal studies. We construct three-dimensional dose-response models for the combination and formulate the contrast test statistic to select the best model, which can then be used to select the optimal dose. Guidance to calculate power and sample size calculations are provided to assist study design. Simulation studies show that Comb MCP-Mod performs as well as the conventional multiple comparisons approach in controlling the family-wise error rate at the desired alpha level. However, Comb MCP-Mod is more powerful than the classical multiple comparisons approach in detecting dose-response relationships when treatment is non-null. The probability of correctly identifying the underlying dose-response relationship is generally higher when using Comb MCP-Mod than when using the multiple comparisons approach.

Impact of Multidisciplinary Heart Failure Clinic on Guideline-Directed Medical Therapy and Clinical Outcomes.

Background: Heart failure (HF) is associated with recurrent hospital admissions and high mortality. Guideline-directed medical therapy has been shown to improve prognosis for patients who have HF with reduced ejection fraction (HFrEF). Despite the proven benefits of guideline-directed medical therapy, its utilization is less than optimal among patients with HF in Malaysia. Objective: To determine the impact of a multidisciplinary team HF (MDT-HF) clinic on the use of guideline-directed medical therapy and patients' clinical outcomes at 1 year. Methods: This retrospective study was conducted in a single cardiac centre in Malaysia. Patients with HFrEF who were enrolled in the MDT-HF clinic between November 2017 and June 2020 were compared with a matched control group who received the standard of care. Data were retrieved from the hospital electronic system and were analyzed using statistical software. Results: A total of 54 patients were included in each group. Patients enrolled in the MDT-HF clinic had higher usage of renin-angiotensin system blockers (54 [100%] vs 47 [87%], p < 0.001) and higher attainment of the target dose for these agents (35 [65%] vs 5 [9%], p < 0.001). At 1 year, the mean left ventricular ejection fraction (LVEF) was significantly greater in the MDT-HF group (35.7% [standard deviation 12.3%] vs 26.2% [standard deviation 8.7%], p < 0.001), and care in the MDT-HF clinic was significantly associated with better functional class, with a lower proportion of patients categorized as having New York Heart Association class III HF at 1 year (1 [2%] vs 14 [26%], p = 0.001). Patients in the MDT-HF group also had a significantly lower rate of readmission for HF (4 [7%] vs 32 [59%], p < 0.001). Conclusions: Patients who received care in the MDT-HF clinic had better use of guideline-directed medical therapy, greater improvement in LVEF, and a lower rate of readmission for HF at 1 year relative to patients who received the standard of care.

Contexte: L'insuffisance cardiaque (IC) est associée à des hospitalisations récurrentes et à une mortalité élevée. Il a été démontré qu'un traitement médical orienté par des lignes directrices améliore le pronostic des patients atteints d'insuffisance cardiaque avec fraction d'éjection réduite (ICFER). Malgré les avantages éprouvés du traitement médical orienté par des lignes directrices, son utilisation est loin d'être optimale chez les patients atteints d'IC en Malaisie. Objectif: Déterminer l'incidence d'une clinique d'IC en équipe multidisciplinaire (IC-ÉM) sur l'utilisation d'un traitement médical orienté par des lignes directrices et les résultats cliniques des patients à 1 an. Méthodes: Cette étude rétrospective a été menée dans un seul centre cardiaque en Malaisie. Les patients atteints d'ICFER inscrits à la clinique d'IC-ÉM entre novembre 2017 et juin 2020 ont été comparés à un groupe témoin apparié ayant reçu des soins standard. Les données ont été extraites du système électronique de l'hôpital et analysées à l'aide d'un logiciel statistique. Résultats: Au total, 54 patients ont été inclus dans chaque groupe. L'utilisation d'inhibiteurs du système rénine-angiotensine était plus élevée chez les patients inscrits à la clinique d'IC-ÉM (54 [100 %] contre 47 [87 %], p < 0,001) et la dose cible pour ces agents était mieux atteinte (35 [65 %] contre 5 [9 %], p < 0,001). Á 1 an, la fraction d'éjection ventriculaire gauche (FÉVG) moyenne était significativement plus élevée chez les patients ayant reçu des soins dans la clinique d'IC-ÉM (35,7 % [écart type 12,3 %] contre 26,2 % [écart type 8,7 %], p < 0,001), et les soins prodigués dans la clinique d'IC-ÉM étaient significativement associés à une meilleure classe fonctionnelle, avec une proportion plus faible de personnes classées comme ayant une IC de classe III selon la New York Heart Association à 1 an (1 [2 %] contre 14 [26 %], p = 0,001). Le taux de réadmission pour IC des patients du groupe IC-ÉM était aussi significativement plus faible (4 [7 %] contre 32 [59 %], p < 0,001). Conclusions: L'utilisation du traitement médical orienté par des lignes directrices chez les patients ayant reçu des soins dans la clinique d'IC-ÉM était meilleure, leur FÉVG s'est améliorée dans une plus grande mesure, et leur taux de réadmission pour IC à 1 an était plus faible par rapport aux patients ayant reçu les soins standard.

Difference in target dose distributions between Acuros XB and collapsed cone convolution/superposition and the impact of the tumor locations in clinical cases of stereotactic ablative body radiotherapy for lung cancer.

Objectives: The objective of the study is to analyze the difference in target dose distributions between Acuros XB (AXB) and collapsed cone convolution (CCC)/superposition and the impact of the tumor locations in clinical cases of stereotactic ablative body radiotherapy (SABR) for lung cancer. Materials and Methods: Ninety-six patients underwent SABR for lung cancers Kyushu University Hospital from 2014 to 2017. We recalculated clinical plans originally calculated by AXB using CCC with the identical monitor units (MUs) and beam arrangements. We calculated the following dosimetric parameters: maximum dose (Dmax), minimum dose (Dmin), homogeneity index (HI), conformity index (CI), and D95 of the planning target volume (PTV). We investigated the difference between the results of two calculations and examined the impact of tumor location. Moreover, we determined the target central dose using a thorax phantom and assessed the calculation accuracy of the two algorithms for each fraction. Results: CCC significantly overestimated the dose to PTV, compared to AXB (P < 0.05). The mean differences of Dmax, Dmin, and D95 were 1.17, 1.95, and 1.85 Gy, respectively. The mean differences of HI and CI were 0.02 and - 0.06. Dmin, HI, and D95 had significant correlations with the tumor location, and the difference was greater when the PTV was included the chest wall (P < 0.05). The discrepancy between the calculated and irradiated dose was 2.48% for CCC, whereas it was 0.14% for AXB. Conclusions: We demonstrated that CCC significantly overestimated the dose to PTV relative to AXB in clinical cases of lung SABR.

Optimization of guideline-directed medical treatment for heart failure patients with reduced ejection fraction.

With the increasing number of medications demonstrating mortality benefits in heart failure with reduced ejection fraction (HFrEF), the pharmacological treatment of HFrEF is entering a new phase. To enhance outcomes in heart failure patients through medical treatment, the choice of appropriate medications and simultaneous and rapid uptitration are critical. However, there are several challenges encountered during this medication uptitration, including issues like hypotension, fatigue, worsening renal function, and hyperkalemia. This paper addresses strategies for effectively managing these challenges to successfully reach the maximum tolerated dose in patients. Additionally, it will discuss the management of comorbidities often associated with heart failure, the importance of exercise and rehabilitation, and the significance of proper nutrition intake, in addition to guideline-directed medical therapy.

Use of and association between heart failure pharmacological treatments and outcomes in obese versus non-obese patients with heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry.

AIMS: To investigate the use of guideline-directed medical therapies (GDMT) and associated outcomes in obese (body mass index ≥30 kg/m2 ) versus non-obese patients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with HFrEF from the Swedish HF Registry were included. Of 16 116 patients, 24% were obese. In obese versus non-obese patients, use of treatments was 91% versus 86% for renin-angiotensin system inhibitors (RASi)/angiotensin receptor-neprilysin inhibitors (ARNi), 94% versus 91% for beta-blockers, 53% versus 43% for mineralocorticoid receptor antagonists. Obesity was shown to be independently associated with more likely use of each treatment, triple combination therapy, and the achievement of target dose by multivariable logistic regressions. Multivariable Cox regressions showed use of RASi/ARNi and beta-blockers being independently associated with lower risk of all-cause/cardiovascular death regardless of obesity, although, when considering competing risks, a lower risk of cardiovascular death with RASi/ARNi in obese versus non-obese patients was observed. RASi/ARNi were associated with lower risk of HF hospitalization in obese but not in non-obese patients, whereas beta-blockers were not associated with the risk of HF hospitalization regardless of obesity. At the competing risk analysis, RASi/ARNi use was associated with higher risk of HF hospitalization regardless of obesity. CONCLUSION: Obese patients were more likely to receive optimal treatments after adjustment for factors affecting tolerability, suggesting that perceived beyond actual tolerance issues limit GDMT implementation. RASi/ARNi and beta-blockers were associated with lower mortality regardless of obesity, with a greater association between RASi/ARNi and lower cardiovascular death in obese versus non-obese patients when considering competing risk.

Study of radiotherapy dose effect of neoadjuvant chemotherapy versus concurrent chemoradiotherapy in cervical cancer / 中华放射肿瘤学杂志

Objective:To compare the effect of neoadjuvant chemotherapy vs. concurrent chemoradiotherapy on the target volume and organs at risk for locally advanced bulky (>4 cm) cervical cancer. Methods:From March 1, 2019 to June 30, 2021, 146 patients pathologically diagnosed with cervical cancer were selected and randomly divided into two groups using random number table method: the neoadjuvant chemotherapy (NACT) + concurrent chemoradiotherapy (CCRT) group ( n=73) and CCRT group ( n=73). Patients in the NACT+CCRT group received 2 cycles of paclitaxel combined with cisplatin NACT, followed by CCRT, the chemotherapy regimen was the same as NACT. In the CCRT group, CCRT was given. Statistical description of categorical data was expressed by rate. The measurement data between two groups were compared by Wilcoxon rank-sum test for comparison of two independent samples, and the rate or composition ratio of two groups was compared by χ2 test. Results:Before radiotherapy, GTV in the NACT+CCRT group was (31.95±25.96) cm 3, significantly lower than (71.54±33.59) cm 3 in the CCRT group ( P<0.01). Besides, CTV and PTV in the NACT+CCRT group were also significantly lower compared with those in the CCRT group (both P<0.05). In terms of target volume dosimetry, D 100GTV, D 95CTV, V 100GTV, V 100CTV and V 95PTV in the NACT+CCRT group were significantly higher than those in the CCRT group (all P<0.05). The complete remision (CR) rates in the NACT+CCRT and CCRT groups were 86.3% and 67.6%, with statistical significance between two groups ( P<0.01) . Regarding organs at risk, NACT+CCRT group significantly reduced the dose to the bladder, rectum, small intestine and urethra compared with CCRT group (all P<0.05). Conclusions:NACT can reduce the volume of tumors in patients with large cervical masses, increase the radiation dose to tumors, reduce the dose to organs at risk, and make the three-dimensional brachytherapy easier. Therefore, NACT combined with CCRT may be a new choice for patients with locally advanced cervical cancer with large masses.

Vancomycin therapeutic drug monitoring in patients on continuous renal replacement therapy: a retrospective study.

OBJECTIVES: This study aimed to investigate vancomycin therapeutic drug monitoring (TDM) in patients on continuous renal replacement therapy (CRRT) and explore the risk factors for exceeding the target concentration. METHODS: This retrospective study enrolled patients aged ≥18 years who were admitted to the intensive care unit and treated with ≥3 intravenous vancomycin doses during CRRT, and who underwent vancomycin TDM. Demographic and other information were collected. Multivariate logistic regression was used assess the risk factors for exceeding the target concentration. RESULTS: Sixty-nine patients were included, and 40.6% patients underwent TDM. Additionally, 14.5% of patients reached the optimal concentration, and 87.5% of patients who exceeded the target received a daily dose adjustment. The cumulative dose of vancomycin and serum albumin were risk factors for exceeding the target concentration in patients on CRRT. CONCLUSIONS: Patients on CRRT did not meet the optimal vancomycin management; <50% of the patients routinely received vancomycin TDM, and <15% achieved the optimal concentration. Fewer patients in the subtherapeutic group received a daily dose adjustment than those who exceeded the target concentration. Cumulative vancomycin and serum albumin doses before TDM were the risk factors for exceeding the target concentration in CRRT patients.

Combined effect of heterogeneous target dose and heterogeneous radiosensitivity on tumor control probability for different fractionation regimens.

PURPOSE: To evaluate the combined effect of heterogeneous target dose and heterogeneous radiosensitivity on tumor control probability (TCP) for different number of fractions (Nf). METHODS: The linear-quadratic (LQ) model is employed to study dependence of TCP on Nf under the condition of fixed nominal biologically effective dose (BEDnom). RESULTS: Formula for the optimum target dose which maximizes TCP under the condition BEDnom=const is analytically derived. It is shown that the dependence of TCP on Nfis non-monotonic. In addition, the dependence of TCP on Nf for different variances of the target dose and radiosensitivity of malignant cells is demonstrated by using numerical computations. CONCLUSIONS: It is shown that the optimum mean dose in the target is defined by the standard deviations of the target dose (σD) and standard deviations of parameters alpha (σα) and beta (σß). The findings of this study indicate that hypofractionated regimens for stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) with Nf⩽3 can be radiobiologically inferior to the regimens with five or more fractions.

Prognostic value of beta-blocker doses in patients with ventricular tachyarrhythmias.

The study investigates the prognostic significance of beta-blocker (BB) dose in patients with ventricular tachyarrhythmias. Limited data regarding the prognostic impact of BB dose in ventricular tachyarrhythmias is available. A large retrospective registry was used including consecutive patients on BB treatment with episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2015. Discharge BB doses were grouped as > 0-12.5%, > 12.5-25%, > 25-50%, and > 50% according to doses used in randomized trials. The primary endpoint was all-cause mortality at three years. Secondary endpoints comprised of a composite arrhythmic endpoint (i.e., recurrences of ventricular tachyarrhythmias and appropriate ICD therapies) and cardiac rehospitalization. Kaplan-Meier survival curves and multivariable Cox regression analyses were applied for statistics. A total of 1313 patients with BB were included; most patients were discharged with > 25-50% of BB target dose (59%). At three years, > 12.5-25% of BB target dose was associated with improved long-term mortality as compared to the > 0-12.5% group (HR = 0.489; 95% CI 0.297-0.806; p = 0.005), whereas higher BB doses did not improve survival (> 25-50%: HR = 0.849; p = 0.434; > 50%: HR = 0.735; p = 0.285). In contrast, the composite endpoint and risk of rehospitalization were not affected by BB target dose. In conclusion, > 12.5-25% of BB target dose is associated with best long-term survival among patients with ventricular tachyarrhythmias. In contrast, risk of the composite arrhythmic endpoint and risk of cardiac rehospitalization were not affected by BB dose.

Evaluation of the Usage and Dosing of Guideline-Directed Medical Therapy for Heart Failure With Reduced Ejection Fraction Patients in Clinical Practice.

BACKGROUND: Although strategies for optimization of pharmacologic therapy in patients with heart failure with reduced ejection fraction (HFrEF) are scripted by guidelines, data from HF registries suggests that guideline-directed medical therapies (GDMT) are underutilized among eligible patients. Whether this discrepancy reflects medication intolerance, contraindications, or a quality of care issue remains unclear. OBJECTIVE: The objective of this initiative was to identify reasons for underutilization and under-dosing of HFrEF therapy in patients at a large, academic medical center. METHODS: Among 500 patients with HFrEF enrolled in a quality improvement project at a tertiary center, we evaluated usage and dosing of 4 categories of GDMT: ACE inhibitors/Angiotensin Receptor Blockers (ACE-i/ARB), Angiotensin Receptor-Neprilysin Inhibitors (ARNi), beta blockers, and Mineralocorticoid Receptor Antagonists (MRA). Reasons for nonprescription and usage of suboptimal doses were abstracted from notes in the chart and from telephone review of previous medication trials with the patient. RESULTS: Of 500 patients identified, 472 subjects had complete data for analysis. Among eligible patients, ACE-i/ARB were prescribed in 81.4% (293 of 360) and beta blockers in 94.4% (442 of 468). Of these patients, 10.6% were prescribed target doses of ACE-i/ARB and 12.4% were prescribed target doses of beta blockers. Utilization of other categories of GDMT was lower, with 54% of eligible patients prescribed MRAs and 27% prescribed an ARNi. In most cases, the reasons for nonprescription or under-dosing of GDMT were not apparent on review of the health record or discussion with the patient. CONCLUSION: Clear rationale for nonprescription and under-dosing of GDMT often cannot be ascertained from detailed review and is only rarely related to documented medication intolerance or contraindications, suggesting an opportunity for quality improvement.

Settling dynamics of nanoparticles in simple and biological media.

The biological response of organisms exposed to nanoparticles is often studied in vitro using adherent monolayers of cultured cells. In order to derive accurate concentration-response relationships, it is important to determine the local concentration of nanoparticles to which the cells are actually exposed rather than the nominal concentration of nanoparticles in the cell culture medium. In this study, the sedimentation-diffusion process of different sized and charged gold nanoparticles has been investigated in vitro by evaluating their settling dynamics and by developing a theoretical model to predict the concentration depth profile of nanoparticles in solution over time. Experiments were carried out in water and in cell culture media at a range of controlled temperatures. The optical phenomenon of caustics was exploited to track nanoparticles in real time in a conventional optical microscope without any requirement for fluorescent labelling that potentially affects the dynamics of the nanoparticles. The results obtained demonstrate that size, temperature and the stability of the nanoparticles play a pivotal role in regulating the settling dynamics of nanoparticles. For gold nanoparticles larger than 60 nm in diameter, the initial nominal concentration did not accurately represent the concentration of nanoparticles local to the cells. Finally, the theoretical model proposed accurately described the settling dynamics of the nanoparticles and thus represents a promising tool to support the design of in vitro experiments and the study of concentration-response relationships.

In the era of disease-modifying antirheumatic drugs, how close are we to treating rheumatoid arthritis without the use of glucocorticoids?

We wanted to see how close we could get to our goal of treating rheumatoid arthritis (RA) without the use of glucocorticoids (GCs) in the disease-modifying antirheumatic drugs (DMARDs) era using real-life data. Established in 2017, the TReasure database is a web-based, prospective, observational cohort for Turkey. As of May 2019, there were 2,690 RA patients recorded as receiving biologic and targeted synthetic DMARDs (bDMARDs and tsDMARDs) therapy. At the start of the bDMARDs or tsDMARDs, patients with follow-up visits of at least 3 months were registered. At the time of registration and the last visit, doses of GCs were recorded and it was determined if the target dose of ≤ 7.5 mg was achieved. During registration and follow-up, 23.4% of the patients did not receive GCs and 76.5% of the patients received GCs at any time. GCs could be stopped after 59 (25-116) months in 28.4% of these patients, but 71.6% of patients were still using GC. The target GC dose could not be achieved in 18.2% of these patients (n = 352). The rate of continuing to use GC was significantly higher in women, in the elderly, those with rheumatoid factor (RF) positive, with higher Visual Analog Scale (VAS) pain and Disease Activity Score (DAS)-28. The initial GC dose of ≥ 7.5 mg/day was found to be crucial in not reaching the GC target dose (p < 0.001, OR 39.0 (24.1-63.2)). The initial GC dose of ≥ 7.5 mg/day, female gender, age, RF positivity, high DAS28, and VAS pain level were all highly related for GC continuation. Despite the use of DMARDs, our data revealed that we are still far from achieving our goal of treating RA without using steroids.

Effect of heterogeneous target dose and radiosensitivity on BED and TCP for different treatment regimens.

Purpose.To evaluate how heterogeneity of the target dose and heterogeneity of intra-tumor radiosensitivity affect biologically effective dose (BED) and tumor control probability (TCP) depending on the number of fractions (Nf).Methods.The dependences of TCP and BED in the planning target volume onNfare studied using the linear-quadratic model. In the considered case, the nominal biologically effective dose(BEDnom)is fixed and the variances of the target dose (σD) and radiosensitivity (σα) are assumed to be small.Results.By using series expansion of the survival probability of malignant cells, it is analytically shown that for smallσDandσαboth BED and TCP increase with increasingNfunder the conditionBEDnom=const.In addition, the dependences of BED and TCP onNffor different values ofσDandσαare studied by using an analytical expression for BED in the case of Gaussian distributions of both target dose and radiosensitivity.Conclusions.Small variations in the absorbed dose and intratumor radiosensitivity can significantly reduce BED and TCP. The decreases in these quantities can be reduced by increasing the number of fractions. The findings of this study indicate that hypofractionated regimens withNf=20and dose per fractiond≤5Gy can lead to higher BED and TCP compared to treatment regimens withNf≤5andd≥10Gy commonly used for stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS).

Optimal management of neuromyelitis optica spectrum disorder with aquaporin-4 antibody by oral prednisolone maintenance therapy.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing neuroinflammatory disease associated with aquaporin-4 antibody. Since disabilities in patients with NMOSD accumulate with attacks, relapse prevention is crucially important for improving long-term outcomes. Corticosteroids are inexpensive and promising drugs for relapse prevention in NMOSD, but few studies have analysed the efficacy of corticosteroids in NMOSD, especially regarding the appropriate dosing and tapering regimens. METHODS: A single-center, retrospective analysis of corticosteroid therapy in aquaporin-4 antibody-positive NMOSD patients fulfilling the 2015 international consensus diagnostic criteria was conducted. RESULTS: Medical records of a total of 89 Japanese patients with aquaporin-4 antibody-positive NMOSD seen at Department of Neurology, Tohoku University Hospital (2000~2016) were reviewed. At the last follow-up, 66% of the patients were treated with prednisolone (PSL) monotherapy, and the percentage of those receiving PSL monotherapy or a combination of PSL and other immunosuppressants increased from 17.5% in 2000 to 94.1% in 2016. On the other hand, annualised relapse rate (ARR) decreased from 0.78 (13 attacks in 200 person-months) in 2000 to 0.07 (5 attacks in 819 person-months) in 2016. Under PSL treatment, the mean ARR significantly decreased, and disabilities stabilized (PSL treatment vs no-medication; ARR: 0.21 vs 0.98, P < 0.01, Expanded Disability Status Scale score change: +0.02 vs +0.89, P < 0.01, observation periods: 60.1 vs 68.2 months, P=0.26). Using Kaplan-Meier curves, the 10-year relapse-free rate was 46.5% with PSL monotherapy and 7.1% with no medication (hazard ratio: 0.069, 95% confidence interval [CI] 0.024-0.199, P < 0.01). Rapid tapering of PSL (10 mg or less in one year and/or 5 mg or less in two years after clinical attacks) was associated with frequent relapses compared to gradual tapering (more than 10 mg in one year and more than 5 mg in two years after clinical attacks) (rapid vs gradual, 36.7% vs 17.7%, odds ratio 2.69, 95% CI 1.12-6.44, P = 0.02). However, even with PSL of 5 mg/day or less, the relapse rate was low after two years of acute treatment (before vs after, 53.8% vs 13.6%, odds ratio 0.12, 95% CI 0.03-0.50, P < 0.01). Nine patients needed additional immunosuppressants due to insufficient relapse prevention by PSL monotherapy. PSL monotherapy was generally well tolerated, but seven patients had severe adverse events, mainly bone fractures (5 with bone fracture, 1 with femoral capital necrosis and 1 with cerebral infarction). CONCLUSION: Our study suggests that PSL monotherapy is effective to prevent relapses in about half of patients with aquaporin-4 antibody-positive NMOSD if the doses are gradually reduced. Although it is important to have a treatment strategy tailored to each patient, this study provides evidence that PSL monotherapy can be an option for relapse prevention in some patients with NMOSD.

Clinical inertia in the treatment of heart failure: a major issue to tackle.

Despite an enormous improvement in heart failure management during the last decades, the hospitalization and mortality rate of heart failure patients still remain very high. Clinical inertia, defined as the lack of treatment intensification in a patient not at evidence-based goals for care, is an important underlying cause. Clinical inertia is extensively described in hypertension and type 2 diabetes mellitus, but increasingly recognized in heart failure as well. Given the well-established guidelines for the management of heart failure, these are still not being reflected in clinical practice. While the absolute majority of patients were treated by guideline-directed heart failure drugs, only a small percentage of these patients reached the correct guideline-recommended target dose of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. This considerable under-treatment leads to a large number of avoidable hospitalizations and deaths. This review discusses clinical inertia in heart failure and explains its major contributing factors (i.e., physician, patient, and system) and touches upon some recommendations to prevent clinical inertia and ameliorate heart failure treatment.

Body surface area and medication dosing in patients with heart failure with reduced ejection fraction.

Multiple medications are proven to reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), but data regarding personalized approaches to optimize medication dosing remain limited. Current treatment guidelines recommend up-titration to target or maximally tolerated doses of these medications, yet use and dosing remain suboptimal in clinical practice. Body surface area (BSA) is a readily available clinical metric, used for dosing many medications, closely associated with blood pressure, renal function, and vascular congestion, and may influence efficacy, safety, and tolerability of HFrEF medications. In this review, we examine the rationale, strengths/weaknesses, and potential utility of BSA as a means of optimizing HFrEF medication use and dosing.

Guideline-directed medical therapy in heart failure patients: impact of focused care provided by a heart failure clinic in comparison to general cardiology out-patient department.

BACKGROUND: The usage of guideline-directed medical therapy (GDMT) in the treatment of heart failure (HF) has shown to reduce morbidity and mortality. However, majority of the HF patients do not receive GDMT or do not achieve the target dose. Literature has shown that the patients who are managed in HF clinics receive GDMT and target doses of disease-modifying drugs (DMD) when compared to those treated in other general cardiology outpatient departments (OPD's). It was a retrospective hospital-based study in which patients treated in HF clinic and other cardiology OPD in the year of 2017 were included (200 patients in each arm). The aim of this study was to assess the impact of heart failure clinics in medication therapy management including usage of guideline-directed medical therapy, if target dose specified by the guideline is achieved and time to reach target dose in comparison to other general cardiology OPD's. IRB and IEC approval were obtained before the commencement of the study. Data relevant to the study were obtained from the electronic medical record (EMR) and were compared between the study groups to see for the adherence to guideline and achievement of target doses. Data storage and analysis were performed using SPSS Version 24. A significance level of 5% was used. RESULTS: The usage of GDMT was higher in HF clinic when compared to other cardiology OPD (81% vs 55%, P = 0.001). A significantly higher number of patients in HF clinic achieved target dose when compared to other cardiology OPD (58% vs 29% -betablockers, 45% vs 9% -ACEI/ARB/ARNI, P = 0.000). Moreover, the number of eligible patients receiving DMD was found to be higher in HF clinic (98% vs 85% -betablockers, 69% vs 44% -ACEI/ARB/ARNI, 76% vs 44% -MRA). Also, the patients in HF clinic attained the target doses faster when compared to other cardiology OPD. In addition, there was better improvement in ejection fraction, as well as decreased rate of rehospitalisation and mortality in patients managed in HF clinic. CONCLUSION: HF clinics were compared with other cardiology OPD for various parameters and it was observed that HF clinics were better than other cardiology OPD in maintaining the medication therapy management.

Antidepressant Target Dose Optimization and Control of Severe Asthma Exacerbations in Uninsured and Underinsured Patients with Anxiety and/or Depression.

BACKGROUND: Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are prevalent in patients with asthma. These disorders may increase asthma severity and decrease asthma control. No studies have evaluated the impact of achieving antidepressant target dose optimization compared with not achieving antidepressant target doses on asthma control in uninsured and underinsured patients. OBJECTIVE: To evaluate the impact of achieving antidepressant target dose optimization in uninsured and underinsured adult asthma patients with GAD and/or MDD on the risk of severe asthma exacerbations and number of asthma-related outcomes. METHODS: We conducted a retrospective cohort study of uninsured and underinsured adult asthma patients with GAD and/or MDD who have been initiated on a single antidepressant and maintained on a stable dose for 8 weeks (index date). Eligible patients were followed for 12-24 months after the index date and separated into those who achieved a target dose (target group) and those who did not (control group). Poisson regression was used to compare the risk of severe exacerbations, and analysis of covariance was used to compare the number of severe exacerbations and other asthma-related outcomes between the target and control groups during the 1- and 2-year post-index periods. RESULTS: A total of 61 patients (24 in the target group and 37 in the control group) met inclusion criteria. The target group had a reduced risk of severe asthma exacerbations compared with the control group during the 1-year post-index (adjusted risk reduction [RR] 0.46, 95% confidence interval [CI] 0.26-0.82) and 2-year post-index (adjusted RR 0.5, 95% CI 0.3-0.82) periods. The target group also experienced a lower number of severe asthma exacerbations and other asthma-related outcomes during the 1- and 2-year post-index periods compared with the control group after adjusting for confounders. CONCLUSIONS: Among uninsured and underinsured asthma patients with GAD and/or MDD who were initiated on a single antidepressant, those who were titrated to achieve target doses had a reduced risk of severe asthma exacerbations and a lower number of asthma-related outcomes than those who were not optimized to achieve target doses.

Sacubitril-Valsartan in a routine community population: attention to volume status critical to achieving target dose.

AIMS: In the PARADIGM-heart failure trial, sacubitril-valsartan demonstrated a reduction in heart failure admissions and reduced all-cause mortality in patients with heart failure with reduced ejection fraction. Although real world data have shown similar benefits regarding efficacy and safety, there has been difficulty in achieving the target dose (TD). The factors preventing the achievement of TD remains unclear. This study assesses the tolerability, ability to achieve, and factors linked to attaining TD in a routine clinical population. METHODS AND RESULTS: This is a retrospective single-centre review of patients switched from angiotensin-converting enzyme inhibitors/angiotensin receptor blockers to sacubitril-valsartan between May 2016 and August 2018. Baseline and follow-up clinical characteristics and biomarker profiles were collected. Univariate and multivariate analyses were used to analyse predictors of achieving TD. Clinical response to sacubitril-valsartan was defined as a reduction in N terminal pro BNP of ≥30%, or an increase in left ventricular ejection fraction of ≥5% compared with baseline values. To date, a total of 322 patients (75% male patients) have been switched to sacubitril-valsartan. Those still in the titration phase were excluded (n = 25). Sacubitril-valsartan was not tolerated in 40 patients (12.4%). Those intolerant were older (73.4 years [68.3, 80.6] vs. 69.1 years [61.2, 76]; P = 0.003) and had worse renal function with estimated glomerular filtration rate (53.5 mL/min/1.72 m2 [36.8, 60.2] vs 60 mL/min/1.72 m2 [47, 77]; P ≤ 0.001). Of the remaining 257 patients, TD (97/103 mg BD) was achieved in 194 patients (75.5%), while 37 patients (11.4%) were maintained on 49/51 mg BD and 26 patients (8.1%) remained on 24/26 mg BD. Symptomatic hypotension (74.6%) was the main impediment to attaining TD, followed by renal deterioration (12.7%), and to a lesser extent hyperkalaemia and gastrointestinal symptoms (4.8% each). Diuretic dose decrease was achieved in 37.2% of patients, and this was the strongest independent predictor of achieving TD (odds ratio = 2.1; 95% confidence interval [1.16, 3.8]; P = 0.014). Responder status by N terminal pro BNP criterion was observed in 99 of 214 patients (46.3%) while 70 of 142 (49.3%) attained the left ventricular ejection fraction response status. Achieving this response was independently linked to achieving TD. CONCLUSIONS: Sacubitril-valsartan was well tolerated. Achievement of TD was possible in the majority of the cohort and was linked to response metrics. Reduction in diuretic was required in a large percentage of the population and was the strongest predictor of attaining TD. Therefore, careful clinical attention to volume status assessment is essential to maximising the benefits of sacubitril-valsartan.