Hypertrophic cardiomyopathy (HCM) is a worldwide genetic heart disease and a common cause of sudden death in the young. Penetration of the implantable cardioverter-defibrillator (ICD) into this ...patient population over the past 20 years has made accurate selection of patients for primary prevention ICDs a priority. Consequently, a new paradigm has emerged in the management of this complex disease with ICD therapy responsible for a substantial decrease in overall HCM-related mortality (to 0.5%/y) and independent of patient age. Selection of candidates for ICDs has matured substantially with the formulation of an enhanced risk stratification algorithm. One or more contemporary risk markers judged major within a given patient's clinical profile, in association with physician judgment and shared decision-making, is sufficient to consider a primary prevention ICD implant. An enhanced American College of Cardiology/American Heart Association risk factor model (including new contrast-magnetic resonance-based markers, such as left ventricular apical aneurysm) used prospectively to make ICD decisions proved to be 95% sensitive for identifying patients who would experience ≥1 appropriate device therapies terminating ventricular tachycardia/fibrillation. The number of HCM patients required to treat with ICDs to save 1 patient with abolition of lethal ventricular tachyarrhythmias was 6:1, similar to randomized defibrillator trials in other cardiomyopathies. In contrast to patients with ischemic heart disease, after ICD shock HCM patients rarely experience transformation to heart failure deterioration or sudden arrhythmic death. The mathematically derived risk score model proposed by the European Society of Cardiology was inferior for identifying high-risk patients susceptible to arrhythmic sudden death with a sensitivity of only 33%, leaving many patients exposed to the possibility of sudden death without ICDs. In conclusion, introduction of the ICD associated with a matured risk stratification algorithm has altered management strategy and clinical course of many HCM patients, making the likelihood of sudden death prevention a reality and fulfilling the aspiration of preservation of life and reduced mortality for this vulnerable patient population.
Lynch-like syndrome is diagnosed when there is an expression deficit in DNA mismatch repair proteins but a normal genetic study. The behavior and management of that pathology are currently a subject ...of debate. We present herein the characteristics of patients with Lynch-like syndrome, together with a surveillance proposal.
Immunohistochemistry was carried out on families suspected of presenting with Lynch syndrome. Germline analysis was done if there was loss of mismatch repair protein expression and no BRAF mutation.
Of the 148 patients that underwent immunohistochemistry testing, 23 presented with loss of mismatch repair protein expression. Seven of those patients were identified as having Lynch-like syndrome: 3had colon cancer, 2had endometrial tumor, and 2were healthy, with an affected relative. Mean patient age was 56.9 years and only one patient presented with another tumor associated with Lynch syndrome.
Until there is a better understanding of the etiology of that heterogeneous entity, intermediate surveillance is an adequate strategy.
A new Prins cyclization process that builds up one carbon−carbon bond, one heteroatom-carbon bond, and one halogen-carbon bond, (in an oxa- and azacycle) relies on an iron catalyst system formed from ...Fe(acac)3 and trimethylsilyl halide. The method displays a broad substrate scope and is economical, environmentally friendly, and experimentally simple. This catalytic method permits the construction of chloro, bromo and iodo heterocycles, by the suitable combination of iron(III) source, the corresponding trimethylsilyl halide and the solvent, in high yields.
High-density lipoprotein (HDL) is highly heterogeneous and the link of its subclasses to prognosis remains controversial. We aimed to rigorously examine the associations of HDL subclasses with ...prognosis in secondary prevention.
We collaboratively analysed data from two, complementary prospective cohorts: the TRIUMPH study of 2465 acute myocardial infarction patients, and the IHCS study of 2414 patients who underwent coronary angiography. All patients had baseline HDL subclassification by vertical-spin density gradient ultracentrifugation. Given non-linearity, we stratified by tertiles of HDL-C and its two major subclasses (HDL2-C, HDL3-C), then compared multivariable-adjusted hazard ratios for mortality and mortality/myocardial infarction. Patients were middle-aged to elderly (TRIUMPH: 58.2 ± 12.2 years; IHCS: 62.6 ± 12.6 years), and the majority were men (TRIUMPH: 68.0%; IHCS: 65.5%). IHCS had lower mean HDL-C levels (34.6 ± 10.1 mg/dL) compared with TRIUMPH (40 ± 10.6 mg/dL). HDL3-C accounted for >3/4 of HDL-C (mean HDL3-C/HDL-C 0.78 ± 0.05 in both cohorts). During 2 years of follow-up in TRIUMPH, 226 (9.2%) deaths occurred, while death/myocardial infarction occurred in 401 (16.6%) IHCS patients over 5 years. No independent associations with outcomes were observed for HDL-C or HDL2-C. In contrast, the lowest tertile of HDL3-C was independently associated with >50% higher risk in each cohort (TRIUMPH: with middle tertile as reference, fully adjusted HR for mortality of HDL3-C, 1.57; 95% CI, 1.13-2.18; IHCS: fully adjusted HR for mortality/myocardial infarction, 1.55; 95% CI, 1.20-2.00).
In secondary prevention, increased risk for long-term hard clinical events is associated with low HDL3-C, but not HDL2-C or HDL-C, highlighting the potential value of subclassifying HDL-C.
Inverting the reactivity of the functional groups in ambiphilic molecules provides a new synthetic strategy to perform late‐stage enantiodivergence. Both enantiomers of the final compound can be ...obtained from a common chiral precursor. As a proof of concept, the synthesis of substituted five‐ and six‐membered oxacycles is described. The key step is the cyclization of an ambiphilic linear precursor bearing a propargylic alcohol and an epoxide linked through an alkyl chain. Through a slight modification of these linear precursors and employing different reaction conditions, these functional groups can inverse their chemical reactivity, producing one enantiomer or another of the final product. This enantiodivergent cyclization involves three stereogenic centers that can undergo fully controlled retention or inversion of their configuration depending on the cyclization pathway that is activated. The cyclization provides late‐stage enantiodivergence, enabling the synthesis of either enantiomers of the oxacycles from a common chiral substrate with total transfer of the enantiomeric purity.
Two for one: Inverting the reactivity of the functional groups in ambiphilic molecules provides a new way to perform late‐stage enantiodivergence. Thus, starting from a common chiral substrate both enantiomers of the final product can be obtained. This concept is exemplified by the synthesis of substituted five‐ and six‐membered oxacycles.
Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited primary cardiac disease, has now transformed into a contemporary highly treatable condition with ...effective options that alter natural history along specific personalized adverse pathways at all ages. HCM patients with disease-related complications benefit from: matured risk stratification in which major markers reliably select patients for prophylactic defibrillators and prevention of arrhythmic sudden death; low risk to high benefit surgical myectomy (with percutaneous alcohol ablation a selective alternative) that reverses progressive heart failure caused by outflow obstruction; anticoagulation prophylaxis that prevents atrial fibrillation-related embolic stroke and ablation techniques that decrease the frequency of paroxysmal episodes; and occasionally, heart transplant for end-stage nonobstructive patients. Those innovations have substantially improved outcomes by significantly reducing morbidity and HCM-related mortality to 0.5%/y. Palliative pharmacological strategies with currently available negative inotropic drugs can control symptoms over the short-term in some patients, but generally do not alter long-term clinical course. Notably, a substantial proportion of HCM patients (largely those identified without outflow obstruction) experience a stable/benign course without major interventions. The expert panel has critically appraised all available data and presented management insights and recommendations with concise principles for clinical decision-making.
Introduction
Ipilimumab has been approved in patients with advanced melanoma by different regulatory bodies worldwide, but its use in clinical practice is not fully consistent among oncologists. We ...have surveyed a representative sample of Spanish medical oncologists on issues related to the use of ipilimumab.
Materials and methods
The survey was based on the Delphi method, where experts respond anonymously to two rounds of a questionnaire. Questionnaire consisted of 42 statements divided among the following eight categories: Pathology and Diagnosis; Patterns of Response; Parameters affecting Treatment Selection; Patient Profile; Sequencing of Treatment; Definition of Long-Term Survivors; Quality of Life; Concept of Immuno-oncology. The experts were asked to rate each statement on a scale of 1–9, where 1 meant “completely disagree” and 9 meant “completely agree”.
Results
Thirty-three oncologists responded to both rounds of the survey (62.3 % of total surveyed). On issues related to pathology and diagnosis, patterns of response, and immuno-oncology, the specialists reached a high level of consensus. There was also a high level of agreement, albeit without consensus on assessment of BRAF mutations before deciding on treatment with ipilimumab. However, there was a lower level of agreement on sequencing treatment with BRAF inhibitors and ipilimumab, on predictive factors, on the use of corticosteroids, and on patient quality of life.
Conclusions
The disparity in many of these topics suggests that oncologists need more information on certain aspects of ipilimumab treatment. We need to define generally accepted algorithms of treatment, especially with regard to issues that were shown to be controversial or unclear.
It is increasingly recognized that symbiotic microbiota (especially those present in the gut) have important influences on the functioning of their host. Here, we review the interplay between this ...microbial community and the growth, metabolic rate and nutritional energy harvest of the host.
We show how recent developments in experimental and analytical methods have allowed much easier characterization of the nature, and increasingly the functioning, of the gut microbiota. Manipulation studies that remove or augment gut microorganisms or transfer them between hosts have allowed unprecedented insights into their impact. Whilst much of the information to date has come from studies of laboratory model organisms, recent studies have used a more diverse range of host species, including those living in natural conditions, revealing their ecological relevance.
The gut microbiota can provide the host with dietary nutrients that would be otherwise unobtainable, as well as allow the host flexibility in its capacity to cope with changing environments. The composition of the gut microbial community of a species can vary seasonally or when the host moves between environments (e.g. fresh and sea water in the case of migratory fish). It can also change with host diet choice, metabolic rate (or demands) and life stage. These changes in gut microbial community composition enable the host to live within different environments, adapt to seasonal changes in diet and maintain performance throughout its entire life history, highlighting the ecological relevance of the gut microbiota.
Whilst it is evident that gut microbes can underpin host metabolic plasticity, the causal nature of associations between particular microorganisms and host performance is not always clear unless a manipulative approach has been used. Many studies have focussed on a correlative approach by characterizing microbial community composition, but there is now a need for more experimental studies in both wild and laboratory‐based environments, to reveal the true role of gut microbiota in influencing the functioning of their hosts, including its capacity to tolerate environmental change. We highlight areas where these would be particularly fruitful in the context of ecological energetics.
This article draws together literature from multiple fields, including ecology and molecular biology, to highlight the links between the gut microbiota and host energetics. The authors discuss the gut microbiota within an ecological context, showing how the work discussed can have implications within the field of ecology. They provide examples from a range of taxa to highlight the wide relevance of these insights.
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