Anemia is a very common comorbidity in patients with heart failure (HF), affecting ∼30% of stable ambulatory patients and 50% patients with acute decompensated HF. Absolute or functional iron ...deficiency (ID) is seen in ∼50% patients with HF. Both of these comorbidities often coexist and are independently associated with increased mortality and hospitalizations. These findings led several investigators to test the hypotheses that treatment of anemia and ID in HF would improve symptoms and long-term outcomes. Small studies showed that erythropoiesis-stimulating agents (ESAs) improve subjective measures of HF. However, a large pivotal outcome trial found that the ESA darbepoetin alfa did not improve long-term outcomes in patients with HF with reduced ejection fraction and instead was associated with adverse effects. Studies using IV iron have had somewhat greater success, showing improvements in subjective and some objective measures of HF. However, more research is needed to establish the best treatment options for these high-risk patients. We present 5 common scenarios of patients with HF and anemia and describe our personal approach on how we might treat them based on objective evidence where available. An algorithm that offers guidance in regard to personalized therapy for such patients is also presented.
Biannual ultrasound has poor sensitivity for hepatocellular carcinoma (HCC) screening. MRI is accurate for the detection of HCC, but a complete MRI is not feasible as a screening tool. Abbreviated ...MRI (AMRI) is an acceptable alternative. The diagnostic performance of different AMRI protocols is not known. We performed a systematic review to determine the diagnostic accuracy of AMRI for HCC screening.
We searched the MEDLINE and EMBASE databases for studies reporting the diagnostic accuracy of AMRI for HCC screening. The pooled sensitivity and specificity of different AMRI protocols were calculated based on a random intercept logistic regression model. The diagnostic performance of AMRI was compared with ultrasound. Study quality was assessed using the QUADAS-2 tool.
Of the 11,327 studies screened by titles, 15 studies (3 prospective and 12 retrospective: 2,807 patients, 917 with HCC) were included in the final analysis. The pooled per-patient sensitivity and specificity were 86% (95% CI 84–88%, I2 0%) and 94% (95% CI 91–96%, I2 83%), respectively. Pooled per-lesion sensitivity was 77% (95% CI 74–81%, I2 8%). There was no influence of study type, screening setting, reference standard, and presence and etiology of cirrhosis on the performance of AMRI. The sensitivity of AMRI for detection of HCC <2 cm was lower than that for HCC ≥2 cm (69% vs. 86%). The sensitivity and specificity of non-contrast AMRI were comparable to contrast-enhanced AMRI (86% and 94% vs. 87% and 94%, respectively). The diagnostic performance of different non-contrast AMRI and contrast-enhanced AMRI protocols was comparable. The sensitivity of ultrasound was lower than AMRI (53% vs. 82%).
AMRI has high sensitivity and specificity for HCC screening. Different AMRI protocols have comparable diagnostic performance.
Abbreviated MRI (AMRI) has been suggested as an alternative to ultrasound and complete MRI for hepatocellular carcinoma (HCC) screening. Our study results showed that AMRI has a high per-patient and per-lesion sensitivity for HCC. Although the sensitivity of AMRI for detection of HCC <2 cm is considerably lower than for HCC ≥2 cm, it is substantially higher than ultrasound, making it a potential alternative for HCC screening in high-risk populations.
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•Abbreviated MRI is an attractive alternative to ultrasonography and complete MRI for HCC screening.•Abbreviated MRI has high sensitivity and specificity for HCC screening.•Different abbreviated MRI protocols have comparable sensitivity and specificity for HCC screening.•Non-contrast abbreviated MRI is ideal for HCC screening due to its non-invasiveness and lower cost.
Bacopa monnieri L. (Scrophulariaceae) is commonly known as Brahmi and traditionally used as a neuroprotective herbal medicine. Recently, Bacopa monnieri exhibited significant therapeutic activity ...against animal model of neuropathic pain. However, the therapeutic potential of methanolic extract of Bacopa monnieri in experimental animal model is yet to establish.
The present study was designed to evaluate the anti-nociceptive potential of standardized methanolic extract of Bacopa monnieri in experimental adult zebrafish (Danio rerio) model of pain.
The methanolic extract of Bacopa monnieri (BME) was standardized to bacoside-A using chromatographic method. Subsequently, BME (0.75, 1.25 and 5.0 mg/ml) was evaluated for anti-nociceptive activity using adult zebrafish model.
Standardized BME showed antioxidant effect through radical quenching activity in in vitro study. BME at 1.25 mg/ml significantly decreased the nociceptive effect induced by different noxious agents like acetic acid where as BME at 2.5 mg/ml exhibited significant antinociceptive activity against glutamate, formalin, capsaicin, cinnamaldehyde when compared to control and sham group animals.
BME exerted antinociceptive activity in adult zebrafish. It could be presumed that BME may involve glutamatergic receptor, ASIC and TRP channel activity in its anti-nociceptive effect. BME could be considered as a potential therapeutic option in the management of pain.
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•The methanolic extract of Bacopa monnieri (BME) was standardized to Bacoside-A.•BME exhibited antinociceptive activity in acetic acid treated adult zebrafish.•BME exhibited antinociceptive activity in glutamate and formalin treated zebrafish.•BME showed antinociceptive effect in capsaicin and cinnamaldehyde treated animals.•BME could be a potential therapeutic option in the management of pain.
Unraveling the intriguing aspects of the intramolecular charge transfer (ICT) phenomenon of multi‐modular donor‐acceptor‐based push–pull systems are of paramount importance considering their ...promising applications, particularly in solar energy harvesting and light‐emitting devices. Herein, a series of symmetrical and unsymmetrical donor‐acceptor chromophores 1–6, are designed and synthesized by the Corey‐Fuchs reaction via Evano's condition followed by 2+2 cycloaddition retroelectrocyclic ring‐opening reaction with strong electron acceptors TCNE and TCNQ in good yields (~60–85 %). The photophysical, electrochemical, and computational studies are investigated to explore the effect of incorporation of strong electron acceptors 1,1,4,4‐tetracyanobuta‐1,3‐diene (TCBD) and dicyanoquinodimethane (DCNQ) with phenothiazine (PTZ) donor. An additional low‐lying broad absorption band extended towards the near‐infrared (NIR) region suggests charge polarization after the introduction of the electron acceptors in both symmetrical and asymmetrical systems, leading to such strong ICT bands. The electrochemical properties reveal that reduction potentials of 3 and 6 are lower than those of 2 and 5, suggesting DCNQ imparts more on the electronic properties and hence largely contributes to the stabilization of LUMO energy levels than TCBD, in line with theoretical observations. Relative positions of the frontier orbitals on geometry‐optimized structures further support accessing donor‐acceptor sites responsible for the ICT transitions. Eventually, ultrafast carrier dynamics of the photoinduced species are investigated by femtosecond transient absorption studies to identify their spectral characteristics and target analysis further provides information about different excited states photophysical events including ICT and their associated time profiles. The key findings obtained here related to excited state dynamical processes of these newly synthesized systems are believed to be significant in advancing their prospect of utilization in solar energy conversion and related photonic applications.
A new family of symmetrical and asymmetrical ynamide‐based donor‐acceptor chromophores exhibiting strong intramolecular charge transfer have been designed, synthesized, and insight into their ultrafast carrier dynamics is investigated. Broadly tunable absorption extending even in the near‐infrared region coupled with novel excited state dynamical processes brightens their prospect of utilization in advanced photonic applications.
This paper addresses the problem of portfolio selection with fuzzy parameters from a perspective of chance-constrained multiobjective programming. The key financial criteria used here are ...conventional, namely, return, risk, and liquidity; however, we use short- and long-term variants of return rather than a single measure of an investor's expectations in respect thereof. The proposed model aims to achieve the maximal return (short term as well as long term) and liquidity of the portfolio. It does so at a credibility, which is no less than the confidence levels defined by the investor. Further, to capture uncertain behavior of the financial markets more realistically, fuzzy parameters used here are such as those characterized by general functional forms. To solve the problem, we rely on a specially developed algorithm that hybridizes fuzzy simulation and real-coded genetic algorithm. Numerical experiments are included to showcase the applicability and efficiency of the model in a real investment environment.
Cloud storage allows individuals to store and access data from remote locations, providing the convenience of on-demand access to high-quality cloud applications. This eliminates the need for ...individuals to manage local hardware and software. The cloud storage system facilitates the efficient storage of data on cloud servers, allowing users to work with their data seamlessly without encountering resource constraints such as memory or storage limitations. Cloud computing is a technology that shows great promise owing to its ability to provide unlimited resources for computing and data storage services. These services are crucial for effectively managing the data according to specific requirements. In the current system, data is saved in the cloud using dynamic data operations and computations. This study explored the underlying principles of scalable data-partitioning techniques in the context of distributed data processing in cloud environments. The significance of this study lies in the increasing dependence of enterprises on cloud platforms for data-intensive tasks such as machine learning, data analytics, and real-time data processing. This study examines several data-partitioning strategies and methodologies developed to address the unique issues posed by cloud systems. The evaluation included an examination of their influence on the scalability, load distribution, and overall efficiency of the system. The main aim of this study is to enhance the domain of cloud-based data-processing techniques, thereby enabling enterprises to effectively leverage the full potential of the cloud for data-centric projects.
Peptide nucleic acids containing thymidine and 2‐aminopyridine (M) nucleobases form stable and sequence‐selective triple helices with double‐stranded RNA at physiologically relevant conditions. The ...M‐modified PNA showed unique RNA selectivity by having two orders of magnitude higher affinity for the double‐stranded RNAs than for the same DNA sequences.
Background Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. Objectives We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to ...severe psoriasis. Methods Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. Results At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. Limitations There was no dose comparison beyond week 52. Conclusions Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.
Non-adherence to therapy is an important cause of suboptimal blood pressure control but few practical tools exist to accurately and routinely detect it. We used a simple urine-based assay to evaluate ...the prevalence of antihypertensive treatment non-adherence and its impact on blood pressure in a specialist hypertension centre.
208 hypertensive patients (125 new referrals, 66 follow-up patients with inadequate blood pressure control and 17 renal denervation referrals) underwent assessment of antihypertensive drug intake using high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis at the time of clinical appointment. A total of 40 most commonly prescribed antihypertensive medications (or their metabolites) were screened for in spot urine samples.
Overall, 25% of patients were totally or partially non-adherent to antihypertensive treatment (total non-adherence 10.1%, partial non-adherence 14.9%). The highest prevalence of partial and total non-adherence was among follow-up patients with inadequate blood pressure control (28.8%) and those referred for consideration of renal denervation (23.5%), respectively. There was a linear relationship between blood pressure and the numerical difference in detected/prescribed antihypertensive medications-every unit increase in this difference was associated with 3.0 (1.1) mm Hg, 3.1 (0.7) mm Hg and 1.9 (0.7) mm Hg increase in adjusted clinic systolic blood pressure, clinic diastolic blood pressure (DBP) and 24 h mean daytime DBP (p=0.0051, p=8.62 × 10(-6), p=0.0057), respectively.
Non-adherence to blood pressure lowering therapy is common, particularly in patients with suboptimal blood pressure control and those referred for renal denervation. HP LC-MS/MS urine analysis could be used to exclude non-adherence and better stratify further investigations and intervention.
Summary Background New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic ...plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population. Methods In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3–4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of “clear” or “almost clear” (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov , number NCT01241591. Findings Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events. Intepretation In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis. Funding Pfizer Inc.
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