Abstract
Cardiac troponins (cTns) I and T have long been the most successful cardiac-specific circulating biomarkers in cardiovascular (CV) medicine, having changed dramatically the diagnosis of ...acute myocardial infarction, while being independent predictors of outcome in several cardiac conditions and non-cardiac conditions. The latest-generation high-sensitivity (hs) cTn assays demonstrate both enhanced diagnostic performance and improved analytical performance, with the ability to measure detectable concentrations in a substantial proportion of the asymptomatic and presumably healthy populations. Given this unique analytical feature, recent evidence suggests that hs-cTn can be used for the stratification of CV risk in the general population. High-sensitivity cTn predicts future CV events, are responsive to preventive pharmacological or lifestyle interventions, change in parallel to risk modifications, and offer incremental risk prediction when added to well-established prognosticators. The implementation of CV risk stratification and prevention strategies incorporating hs-cTn requires further investigation to define the optimal target populations, timing of measurement, and preventive interventions.
Natriuretic peptide NP; B‐type NP (BNP), N‐terminal proBNP (NT‐proBNP), and midregional proANP (MR‐proANP) concentrations are quantitative plasma biomarkers for the presence and severity of ...haemodynamic cardiac stress and heart failure (HF). End‐diastolic wall stress, intracardiac filling pressures, and intracardiac volumes seem to be the dominant triggers. This paper details the most important indications for NPs and highlights 11 key principles underlying their clinical use shown below.
NPs should always be used in conjunction with all other clinical information.
NPs are reasonable surrogates for intracardiac volumes and filling pressures.
NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the early diagnosis and risk stratification of HF.
NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that dyspnoea is caused by HF.
Optimal NP cut‐off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting to the emergency department with acute dyspnoea are higher compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild increase in filling pressures at rest).
Obese patients have lower NP concentrations, mandating the use of lower cut‐off concentrations (about 50% lower).
In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization.
Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular risk factors may help to identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF.
BNP, NT‐proBNP and MR‐proANP have comparable diagnostic and prognostic accuracy.
In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic.
NPs cannot identify the underlying cause of HF and, therefore, if elevated, must always be used in conjunction with cardiac imaging.
Standard treatment options for patients with stage IIA or stage IIB seminoma include either para-aortic and pelvic radiotherapy or three to four cycles of cisplatin-based combination chemotherapy. ...These options result in 3-year progression free survival rates of at least 90%, but bear risks for acute and late toxic effects, including secondary malignancies. We tested a novel approach combining de-escalated chemotherapy with de-escalated involved node radiotherapy, with the aim of reducing toxicity while preserving efficacy.
In the single-arm, multicentre, phase 2 SAKK 01/10 trial, patients with stage IIA or IIB classic seminoma (either at primary diagnosis or at relapse during active surveillance for stage I) were enrolled at ten centres of the Swiss Group for Clinical Cancer Research and ten centres of the German Testicular Cancer Study Group. WHO performance status 0–2, age 18 years or older, and adequate bone marrow and kidney function were required for eligibility. Treatment comprised one cycle of carboplatin (area under the curve 7) followed by involved-node radiotherapy (30 Gy in 15 fractions for stage IIA disease and 36 Gy in 18 fractions for stage IIB disease). The primary endpoint was 3-year progression-free survival. Efficacy analyses were done on the full analysis set, which comprised all patients who signed the informed consent, were registered in the trial, initiated trial treatment, and met all medically relevant inclusion or exclusion criteria. Safety was assessed in all patients who were treated at least once with one of the trial treatments. The study is ongoing but no longer recruiting, and is registered with Clinicaltrials.gov, NCT01593241.
Between Oct 18, 2012, and June 22, 2018, 120 patients were registered in the study. 116 patients were eligible and started treatment according to the study protocol (46 patients with stage IIA disease and 70 with stage IIB disease). After a median follow-up of 4·5 years (IQR 3·9–6·0), 3-year progression-free survival was 93·7% (90% CI 88·5–96·6). With a target progression-free survival of 95% at 3 years, the primary endpoint was not met. Acute treatment-related adverse events of any grade were noted in 58 (48%) of 116 patients, and grade 3 or 4 treatment-related adverse events occurred in the form of neutropenia in five (4%) patients, thrombocytopenia in three (3%) patients, and vomiting in one (1%) patient. No treatment-related deaths and no late treatment-related adverse events were reported. Serious adverse events were reported in five (4%) of 116 patients (one transient creatinine increase and four second primary tumours).
Despite the fact that the primary endpoint was not met, we observed favourable 3-year progression-free survival with single-dose carboplatin area under the curve 7 and involved-node radiotherapy, with minimal toxic effects. Our findings might warrant discussion with patients about the SAKK 01/10 regimen as an alternative to standard-of-care treatment, but more research on this strategy is needed.
Swiss State Secretariat for Education, Research and Innovation and Rising Tide Foundation for Clinical Cancer Research.
Most people who are regular consumers of psychoactive drugs are not drug addicts, nor will they ever become addicts. In neurobiological theories, non-addictive drug consumption is acknowledged only ...as a "necessary" prerequisite for addiction, but not as a stable and widespread behavior in its own right. This target article proposes a new neurobiological framework theory for non-addictive psychoactive drug consumption, introducing the concept of "drug instrumentalization." Psychoactive drugs are consumed for their effects on mental states. Humans are able to learn that mental states can be changed on purpose by drugs, in order to facilitate other, non-drug-related behaviors. We discuss specific "instrumentalization goals" and outline neurobiological mechanisms of how major classes of psychoactive drugs change mental states and serve non-drug-related behaviors. We argue that drug instrumentalization behavior may provide a functional adaptation to modern environments based on a historical selection for learning mechanisms that allow the dynamic modification of consummatory behavior. It is assumed that in order to effectively instrumentalize psychoactive drugs, the establishment of and retrieval from a drug memory is required. Here, we propose a new classification of different drug memory subtypes and discuss how they interact during drug instrumentalization learning and retrieval. Understanding the everyday utility and the learning mechanisms of non-addictive psychotropic drug use may help to prevent abuse and the transition to drug addiction in the future.
Current epidemiologic predictions of COVID-19 suggest that SARS-CoV-2 mitigation strategies must be implemented long-term. In-office aerosol-generating procedures pose a risk to staff and patients ...while necessitating examination room shutdown to allow aerosol decontamination by indwelling ventilation. This review summarizes the current state of knowledge on portable high-efficiency particulate air (HEPA) purifiers' effectiveness in eliminating airborne SARS-CoV-2 from indoor environments.
Medline, Embase, Cochrane Databases, and the World Health Organization's COVID-19 Global Literature on Coronavirus Disease.
Data sources were systematically searched for original English-language published studies indexed up to January 14, 2021 per the following search strategy: ("HEPA" OR "High-efficiency" OR "High-efficiency particulate air" OR "Efficiency particulate" OR "Purifier" OR "Filter" OR "Cleaner" OR "Filtration") AND ("COVID" OR "COVID-19" OR "SARS-CoV-2" OR "Coronavirus"). Additional relevant studies were identified by searching the reference lists of included articles.
Eleven published studies have evaluated the effectiveness of portable HEPA purifiers in eliminating airborne SARS-CoV-2 with relevantly sized surrogate particles. Ten studies evaluated aerosols and submicron particles similar in size to SARS-CoV-2 virions. In all studies, portable HEPA purifiers were able to significantly reduce airborne SARS-CoV-2-surrogate particles. The addition of portable HEPA purifiers augmented other decontamination strategies such as ventilation.
Experimental studies provide evidence for portable HEPA purifiers' potential to eliminate airborne SARS-CoV-2 and augment primary decontamination strategies such as ventilation. Based on filtration rates, additional air exchanges provided by portable HEPA purifiers may be calculated and room shutdown times potentially reduced after aerosol-generating procedures.
The question of designing high electron mobility polymers by increasing the planarization using diffusive nonbonding heteroatom interactions in diketopyrrolopyrrole polymers is addressed in this. For ...this, three different diketopyrrolo3,4‐cpyrrole (DPP) derivatives with thienyl‐, 2‐pyridinyl‐, and phenyl‐flanked cores are copolymerized with an electron‐rich thiophene unit as well as an electron‐deficient 3,4‐difluorothiophene unit as comonomer to obtain diverse polymeric DPPs which vary systematically in their structures. The crystallinity differs significantly with clear trends on varying both flanking unit and comonomer. The optical gap and energy levels depend more on the nature of the flanking aryl units rather than on fluorination. Additionally, the charge transport properties are compared using different methods to differentiate between interface or orientation effects and bulk charge carrier transport. In organic field effect transistor devices with very high electron as well as hole mobilities (up to 0.6 cm2 V−1 s−1) are obtained and fluorination leads to a more pronounced n‐type nature in all polymers, resulting in ambipolar behavior in otherwise p‐type materials. In contrast, space‐charge limited current measurements show a strong influence of the flanking units only on electron mobilities. Especially, the elegant synthetic strategy of combining pyridyl flanking units with difluorothiophene as the comonomer culminates in a record bulk electron mobility of 4.3 × 10−3 cm2 V−1 s−1 in polymers.
An excellent bulk electron mobility of 4.3 × 10−3 cm2 V−1 s−1 is obtained for diketopyrrolo3,4‐cpyrrole copolymers by systematically tuning the diffusive nonbonding heteroatom interactions and dihedral angles between the aryl flanking units, DPP core and comonomer. Differences in crystalline packing, absorption, energy levels, and charge carrier properties are comparatively studied in a series of copolymers.
Appropriate interpretation of changes in markers of kidney function is essential during the treatment of acute and chronic heart failure. Historically, kidney function was primarily assessed by serum ...creatinine and the calculation of estimated glomerular filtration rate. An increase in serum creatinine, also termed worsening renal function, commonly occurs in patients with heart failure, especially during acute heart failure episodes. Even though worsening renal function is associated with worse outcome on a population level, the interpretation of such changes within the appropriate clinical context helps to correctly assess risk and determine further treatment strategies. Additionally, it is becoming increasingly recognized that assessment of kidney function is more than just glomerular filtration rate alone. As such, a better evaluation of sodium and water handling by the renal tubules allows to determine the efficiency of loop diuretics (loop diuretic response and efficiency). Also, though neurohumoral blockers may induce modest deteriorations in glomerular filtration rate, their use is associated with improved long‐term outcome. Therefore, a better understanding of the role of cardio–renal interactions in heart failure in symptom development, disease progression and prognosis is essential. Indeed, perhaps even misinterpretation of kidney function is a leading cause of not attaining decongestion in acute heart failure and insufficient dosing of guideline‐directed medical therapy in general. This position paper of the Heart Failure Association Working Group on Cardio‐Renal Dysfunction aims at improving insights into the interpretation of renal function assessment in the different heart failure states, with the goal of improving heart failure care.
RNA interference has become a ubiquitous biological tool, and is being harnessed for therapeutic purposes as well. Therapeutic posttranscriptional gene silencing takes advantage of the endogenous ...RNAi pathway through delivery of either chemically synthesized siRNAs, or transgenes expressing hairpin-based inhibitory RNAs (e.g., shRNAs and artificial miRNAs). RNAi has expanded the field of viral gene therapy from gene replacement to gene knockdown. Here, we review various noncoding RNAs such as shRNAs, miRNAs, and miRNA decoys which can be utilized for therapeutic applications when expressed from recombinant adeno-associated vectors (AAV), and present examples of their basic design. In addition the basis of exploiting cellular miRNA profiles for detargeting AAV expression from specific cells is described. Finally, an overview of AAV-mediated RNAi preclinical studies is presented, and current RNAi-based clinical trials are reviewed.
In thin films of semiconductor polymers, the polymer chains often exhibit distinct orientation with respect to the substrate. The planar π-face of the backbone typically orients either in an edge-on ...or face-on manner. Generally, an edge-on alignment is thought to be favorable for transport in thin film transistors, whereas face-on alignment is considered to improve vertical transport as desired in solar cells. However, molecular orientation is among the very few parameters that usually cannot be controlled when tailoring new semiconducting polymers. Here we show for an important class of semiconducting polymer that both the mode of orientation as well as the degree of alignment can be well-controlled by exploiting diffusive noncovalent interactions along the backbone. Studying polydiketopyrrolopyrroles (PDPPs) as a case study, by strategically varying chemical structure, we demonstrate systematic variation in molecular orientation with degree of chain planarization resulting from different degrees of diffusive noncovalent interactions. This observation opens the possibility of controlling and optimizing the orientation of semiconducting polymer chains in thin films by rational design. We anticipate our findings to open the door to new high-performance organic semiconductors with the additional benefit of tailored orientation that fits the desired application.
Peripartum cardiomyopathy (PPCM) is a potentially life‐threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the ...months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre‐existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline‐directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress‐mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease‐specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter‐defibrillators, cardiac resynchronization therapy and implanted long‐term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.
PDF
