Expert proposal to analyze the combination of aortic and mitral regurgitation in multiple valvular heart disease by comprehensive echocardiography.

The assessment of valvular pathologies in multiple valvular heart disease by echocardiography remains challenging. Data on echocardiographic assessment-especially in patients with combined aortic and mitral regurgitation-are rare in the literature. The proposed integrative approach using semi-quantitative parameters to grade the severity of regurgitation often yields inconsistent findings and results in misinterpretation. Therefore, this proposal aims to focus on a practical systematic echocardiographic analysis to understand the pathophysiology and hemodynamics in patients with combined aortic and mitral regurgitation. The quantitative approach of grading the regurgitant severity of each compound might be helpful in elucidating the scenario in combined aortic and mitral regurgitation. To this end, both the individual regurgitant fraction of each valve and the total regurgitant fraction of both valves must be determined. This work also outlines the methodological issues and limitations of the quantitative approach by echocardiography. Finally, we present a proposal that enables verifiable assessment of regurgitant fractions. The overall interpretation of echocardiographic results includes the symptomatology of patients with combined aortic and mitral regurgitation and the individual treatment options with respect to their individual risk. In summary, a reproducible, verifiable, and transparent in-depth echocardiographic investigation might ensure consistent hemodynamic plausibility of the quantitative results in patients with combined aortic and mitral regurgitation.

Eritema multiforme, una rara presentación de exantema en población pediátrica: a propósito de un caso / Erythema multiforme, a rare occurrence of exanthema in the pediatric population: on the subject of a case

El Eritema multiforme (EM) o eritema polimorfo es una enfermedad aguda de la piel de naturaleza inmunológica con o sin compromiso de mucosas, que puede comportarse como crónica recurrente. Se presenta con lesiones cutáneas en diana distintivas, a menudo acompañado de úlceras o bullas en mucosas (oral, genital u ocular). Entre sus formas clínicas se distingue: una forma menor caracterizado por un síndrome cutáneo leve y su forma mayor que se manifiesta como una afectación cutánea con daño mucoso marcado. Entre sus principales diagnósticos diferenciales se encuentran el Síndrome de Stevens-Johnson (SSJ) y Síndrome de Lyell (Necrólisis epidérmica tóxica (NET)). Tiene una incidencia estimada < 1%, siendo su forma mayor levemente más frecuente que su forma menor (0.8-6 por millón/año). Puede darse a cualquier edad, presentando un peak de incidencia entre los 20 y 30 años, predominando ligeramente el sexo masculino con una proporción 3:2, sin predilección racial. Su presentación en edad pediátrica es rara, más aún en la primera infancia. En esta población es más frecuente el EM menor recurrente. En el presente texto se reporta un caso de EM en población pediátrica como una rara forma de presentación exantemática, abordado en el Servicio de Pediatría del Complejo Asistencial Dr Victor Rios Ruiz (CAVRR)en la ciudad de Los Ángeles, Chile en el presente año.

Erythema multiforme (EM) also known as polymorph erythema is an acute skin disease of immunological nature with or without mucous membrane involvement, which may behave as chronic recurrent. It presents with distinctive targets like skin lesions, often together with ulcers or bullae in mucous membranes (oral, genital or ocular). Among its clinical forms are: a minor form characterized by a mild skin syndrome and its major form that manifests as a skin disease with marked mucosal damage. Among its main differential diagnoses are Stevens-Johnson Syndrome (SJS) and Lyell Syndrome (Toxic Epidermal Necrolysis (TEC)). It has an estimated incidence < 1%, with its major form being slightly more frequent than its minor form (0. 8-6 per million/year). It can occur at any age, presenting a peak incidence at the age between 20 and 30 years, with a slight predominance of males with a 3:2 ratio, without racial predilection. Its presentation in pediatric age is rare, even more so in early childhood. Minor recurrent EM is more common in this population. This paper reports a case of EM in the pediatric population as a rare form of exanthematic presentation, addressed at the Department of Pediatrics of the Complejo Asistencial Victor Rios Ruiz (CAVRR) in the city of Los Angeles, Chile this year.

Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib.

Alectinib is a preferred first-line therapy for patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in several national clinical practice guidelines. The randomized, global, phase III ALEX study has demonstrated significant improvement in progression-free survival for alectinib over crizotinib in treatment-naive ALK-positive NSCLC. It was also the first study to show clinically meaningful improvement in overall survival for a next-generation ALK tyrosine kinase inhibitor relative to crizotinib. The J-ALEX and ALESIA phase III studies confirmed the clinical benefit of alectinib relative to crizotinib in the first-line ALK-positive NSCLC treatment setting in Japanese and Asian patients, respectively. Across these pivotal phase III trials, alectinib had a manageable, well-characterized safety profile. Here, we review the safety and tolerability of long-term alectinib treatment in patients with advanced ALK-positive NSCLC and provide guidance for physicians, based on clinical experience, on the management of the most frequently reported adverse events (AEs). Most AEs associated with alectinib can be managed by dose reduction. Some alectinib-related AEs are not yet fully characterized, including myalgia and peripheral oedema and deciphering their underlying mechanism of action could enhance their management. With longer-term follow-up, the safety profile of alectinib continues to remain consistent in the ALEX study, with no new safety signals observed. Safety and tolerability data from the first-line phase III alectinib trials are also consistent with those observed in clinical trials of alectinib in later-line settings. These results add to the weight of evidence recommending alectinib as a preferred therapy for treatment-naive advanced ALK-positive NSCLC.

Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer.

BACKGROUND: At the primary data cut-off, the ALUR study demonstrated significantly improved progression-free survival (PFS) and central nervous system (CNS) objective response rate (ORR) with alectinib versus chemotherapy in pretreated, advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer. We report final efficacy and safety data, and exploratory molecular profiling. PATIENTS AND METHODS: Patients who received prior platinum-doublet chemotherapy and crizotinib were randomized 2 : 1 to receive alectinib 600 mg twice daily (n = 79) or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, every 3 weeks; n = 40) until progressive disease, death or withdrawal. The primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, CNS ORR and safety. Plasma samples were collected at baseline, then every 6 weeks until progressive disease; molecular factors detected by next-generation sequencing were correlated with outcomes. RESULTS: Investigator-assessed PFS was significantly longer with alectinib than chemotherapy (median 10.9 versus 1.4 months; hazard ratio 0.20, 95% confidence interval 0.12-0.33; P < 0.001). ORR was 50.6% with alectinib versus 2.5% with chemotherapy (P < 0.001). In patients with measurable CNS metastases at baseline, CNS ORR was 66.7% with alectinib versus 0% with chemotherapy (P < 0.001). No new safety signals were seen. ALK rearrangement was identified in 69.5% (n = 41/59) of baseline plasma samples. Confirmed partial responses were observed with alectinib in 6/11 patients with a secondary ALK mutation and 4/6 patients with a non-EML4-ALK (where EML4 is echinoderm microtubule-associated protein-like 4) fusion. Detection of mutant TP53 in baseline plasma resulted in numerically shorter PFS with alectinib (hazard ratio 1.88, 95% confidence interval 0.9-3.93). CONCLUSIONS: Final efficacy data from ALUR confirmed the superior PFS, ORR and CNS ORR of alectinib versus chemotherapy in pretreated, advanced ALK-positive non-small-cell lung cancer. Alectinib prolonged PFS versus chemotherapy in patients with wild-type or mutant TP53; however, alectinib activity was considerably decreased in patients with mutant TP53.

Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.

BACKGROUND: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). PATIENTS AND METHODS: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. RESULTS: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. CONCLUSIONS: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. CLINICAL TRIALS NUMBER: NCT02075840.

[Evaluation of mitral regurgitation : How much quantification do we need?] / Diagnostik der Mitralinsuffizienz : Wie viel und welche Quantifizierung brauchen wir?

Severe mitral regurgitation (MR) is associated with increased morbidity and mortality. Thus, the correct evaluation of the underlying etiology, pathomechanism and severity is crucial for optimal treatment. Echocardiography is the predominant diagnostic modality in the clinical routine as it enables grading of mitral regurgitation, which can frequently be achieved by readily available qualitative parameters. Additionally, echocardiography provides several methods to quantify the hemodynamic significance of MR. The effective regurgitation orifice area (EROA) is the quantitative parameter best correlated with clinical events. American and European imaging guidelines both recommend the use of quantitative parameters even though they disagree on the cut-off values for secondary MR. The evaluation of MR should always include an assessment of the adjacent heart chambers in order to be able to assess the impact of volume overload on size and function of the left ventricle and left atrium. The final interpretation of the quantitative parameters requires knowledge of left ventricular volume and ejection fraction. Newer 3D-echocardiographic approaches to quantify MR are less dependent on mathematical assumptions and have shown convincing results in several studies but still lack sufficient clinical validation. As an alternative to echocardiography, for specific indications cardiac magnetic resonance imaging (MRI) has proven to be a systematic and observer-independent method for quantification of MR.

Effects of polystyrene nanoparticles on the microbiota and functional diversity of enzymes in soil.

BACKGROUND: The increasing production of nanoplastics and the fragmentation of microplastics into smaller particles suggest a plausible yet unclear hazard in the natural environment, such as soil. We investigated the short-term effects (28 days) of polystyrene nanoparticles (PS-NPs) on the activity and biomass of soil microbiota, and the functional diversity of soil enzymes at environmental relevant low levels in an incubation experiment. RESULTS: Our results showed a significant decrease in microbial biomass in treatments of 100 and 1000 ng PS-NP g-1 DM throughout the incubation period. Dehydrogenase activity and activities of enzymes involved in N-(leucine-aminopeptidase), P-(alkaline-phosphatase), and C-(ß-glucosidase and cellobiohydrolase) cycles in the soil were significantly reduced at day 28 suggesting a broad and detrimental impact of PS-NPs on soil microbiota and enzymes. Leucine-aminopeptidase and alkaline-phosphatase activities tended to decrease consistently, while ß-glucosidase and cellobiohydrolase activities increased at high concentrations (e.g., PS-NP-1000) in the beginning of the incubation period, e.g., at day 1. On the other hand, basal respiration and metabolic quotient increased with increasing PS-NP application rate throughout the incubation period possibly due to increased cell death that caused substrate-induced respiration (cryptic growth). CONCLUSIONS: We herewith demonstrated for the first time the potential antimicrobial activity of PS-NPs in soil, and this may serve as an important resource in environmental risk assessment of PS-NPs in the soil environment.

Effects of season and reproductive state on lipid intake and fatty acid composition of gastrointestinal tract contents in the European hare.

We investigated lipid content and fatty acid (FA) composition of gastrointestinal tract contents in free-living, herbivorous European hares (Lepus europaeus). Mean crude fat content in hare stomachs and total gastrointestinal (GI) tracts was higher than expected for typical herbivore forages and peaked in late fall when hares massively deposited body fat reserves. Changes of FA proportions in different parts of the GI-tract indicated a highly preferential absorption of polyunsaturated fatty acids (PUFA). A further reduction of PUFA content in the caecum, along with the appearance of odd-chained FAs in caecum, caecotrophes, and colon content, pointed to a biohydrogenation of PUFA in the hare's hindgut. GI-tract contents showed significant seasonal changes in their FA composition. Among PUFA, α-linolenic acid peaked in spring while linoleic acid was predominant in late summer and fall, which probably reflected changes in the plant composition of forage. However, independent of seasonal changes, GI-tracts of lactating females showed a significantly (+33%) higher content of linoleic acid, a FA that is known to increase reproductive performance in European hares. This finding suggests that lactating females actively selected dietary plants rich in linoleic acid, a PUFA that may represent a limited resource for European hares.

Peak energy turnover in lactating European hares: a test of the heat dissipation limitation hypothesis.

It has been suggested that maximum sustained metabolic rate (SusMR) in mammals as reached, for instance, during lactation, is due to a limited capacity for heat dissipation. Here, we experimentally tested whether heat dissipation limitation (HDL) also constrains energy turnover in lactating European hares. Experimentally, we made use of the fact that hares nurse their young only once per day, which allowed us to keep females and young either at the same or at different ambient temperatures. During the last lactation week (week 4) females kept at thermoneutrality (22 degrees C), irrespective of the cold load of their young, had significantly lower rates of metabolisable energy intake (MEI) than cold-exposed mothers (5 degrees C), as predicted by the HDL hypothesis. However, in week 2 of lactation females at thermoneutrality rearing cold-exposed young were able to increase MEI to levels indistinguishable from those of cold-exposed females. Thus, even at thermoneutral temperature females reached maximum rates of energy turnover, which was inconsistent with the HDL hypothesis. We conclude that SusMR in lactating European hares typically results not from physiological constraints but from an active restriction of their energy turnover in order to maximise lifetime reproductive success.

Peak energy turnover in lactating European hares: the role of fat reserves.

European hares (Lepus europaeus) in central Europe have high energetic costs of reproduction, mainly due to precocial, rapidly growing young that rely largely on energy-rich milk. Thus, hares in this climate build up large fat stores during winter that are then gradually depleted during the spring-to-autumn breeding season. We hypothesized that the diminishing fat stores of females over the breeding season might affect resource allocation, peak energy assimilation during lactation or the total investment in offspring. Therefore, we measured energy intake, milk quality and milk production throughout lactation in spring, summer and autumn in females raising (size-manipulated) litters with three young each, under a natural photoperiod but at buffered ambient temperatures inside our facility. Over the course of the breeding season, the amount of milk production remained constant, but the fat content of the milk decreased. Hence, total energy transfer to young decreased significantly in autumn. By using undecanoic acid as a tracer of body fat mobilization, we were able to show that milk fat partially originated from maternal fat stores, particularly in spring. The peak sustained energy assimilation rates of lactating females were significantly higher in autumn, due to increased rates of food intake. We conclude that fat stores allow female hares to downregulate energy intake and expenditure early in the breeding season, whereas late breeding forces them to reach peak energy intake levels. Accordingly, we suggest that in hares, peak energy turnover during lactation varies with the availability of fat reserves. Limits to the sustained metabolic rate serve as variable constraints on reproductive investment. Thus, there might be a trade-off in energetic costs to mothers rearing early versus late litters in the year.

High survival in poor years: life history tactics adapted to mast seeding in the edible dormouse.

Edible dormice (Glis glis) reproduce in years with beech mast seeding, but entire populations may skip reproduction in years when tree seeds, a major food resource of this small hibernator, are absent. We tested the hypothesis that the year-to-year variability in reproductive effort caused by this breeding strategy should lead to detectable differences in yearly survival rates. Therefore, we analyzed capture-recapture data from animals occupying nest boxes, collected over nine years at two study sites in Germany. Among fully grown adults (aged two years or older), survival probabilities were significantly lower (0.32 +/- 0.04) after reproductive years (n = 5) compared to years (n = 4) with absent or below-average reproduction (0.58 +/- 0.07) on both study sites. This trade-off between reproduction and subsequent survival was observed in both females and males and appears to be a relatively rare case in which costs of reproduction in terms of longevity are detectable at the population level. Effects of reproduction on survival were less pronounced when yearlings (with a generally lower reproductive effort) were included and were more distinct in a suboptimal habitat. Of those females breeding in nest boxes, 96.5% had only one or two litters within the study period. Considering these and previously published results, including a report of extremely high mean longevities (9-12 years) of dormice in a habitat with infrequent mast seeding, we conclude that edible dormice flexibly adjust life history tactics to local mast patterns. Long stretches of mast failures can in fact lead to relative semelparity, i.e., a strategy in which dormice "sit tight" for several years until environmental conditions are favorable for reproduction.

Food and nutrient intake, anthropometric measurements and smoking according to alcohol consumption in the EPIC Heidelberg study.

AIMS: The study was carried out to determine associations of reported alcohol intake with dietary habits, body mass index, waist-to-hip ratio (WHR) and smoking. SUBJECTS AND METHODS: 24,894 subjects who participated in the baseline examination of the German part of the European Prospective Investigation into Cancer and Nutrition (EPIC) in Heidelberg and were between 35 and 65 years of age at baseline were included in the present cross-sectional analysis (11,617 men, 13,277 women). Diet and alcohol consumption were assessed with a semiquantitative food frequency questionnaire. Analysis of covariance with age as a covariate was used to analyse the association between alcohol intake and dietary consumption patterns, BMI, WHR and smoking. RESULTS: Alcohol did not replace other food items, but was an addition to the diet. Among alcohol consumers, fat and protein intake as a percentage of energy was slightly higher and carbohydrate intake was slightly lower than among abstainers. Alcohol consumers had a lower intake of fruits, dairy products, cereal products, and added vegetable fat and a higher intake of animal products such as meat, fish, eggs and added animal fat than abstainers. The prevalence of current smoking showed a U-shaped relation to alcohol intake in men and women. In men, a U-shaped association was also seen between the prevalence of former smoking and alcohol intake, while the prevalence of former smoking increased linearly with alcohol intake in women. CONCLUSION: The results show that alcohol consumption is associated with dietary consumption patterns and smoking. Therefore, it will be important to consider dietary patterns and other lifestyle parameters when investigating the health effects of alcohol intake in the future.

High content of polyunsaturated fatty acids in muscle phospholipids of a fast runner, the European brown hare (Lepus europaeus).

To investigate both seasonal changes and possible intracorporal gradients of phospholipid fatty acid composition, skeletal muscles ( n=124), hearts ( n=27), and livers ( n=34) from free-living brown hares (Lepus europaeus) were analyzed. Phospholipids from both skeletal muscles and heart had a high degree of unsaturation with 66.8+/-0.63% and 65.7+/-0.5% polyunsaturated fatty acids, respectively. This is the highest proportion of polyunsaturated fatty acids reported in any mammalian tissue. Polyunsaturated fatty acid content in skeletal muscles was 2.3% greater in winter compared to summer (F(1,106)=17.7; P=0.0001), which may reflect thermoregulatory adjustments. Arachidonate (C20:4n-6) showed the greatest seasonal increase (+2.5%; F=7.95; P=0.0057). However, there were no pronounced differences in polyunsaturated fatty acid content between skeletal muscles from different locations in the body (m. iliopsoas, m. longissimus dorsi and m. vastus). Total muscle phospholipid polyunsaturated fatty acid content was correlated with polyunsaturated fatty acid content in triacyglycerols from perirenal white adipose tissue depots ( r(2)=0.61; P=0.004). Polyunsaturated fatty acids were enriched in muscle phospholipids (56.8-73.6%), compared to white adipose tissue lipids (20.9-61.2%), and liver phospholipids (25.1-54.2%). We suggest that the high degree of muscle membrane unsaturation is related to hare-specific traits, such as a high maximum running speed.

"Intrinsic" acceptor ground state splitting in silicon: an isotopic effect.

One of the oldest open questions in semiconductor physics is the origin of the small splittings of the neutral acceptor ground state in silicon which lead to a distribution of doublet splittings rather than the fourfold-degenerate state of Gamma(8) symmetry expected in the absence of perturbations. Here we show that these acceptor ground state splittings are absent in the photoluminescence spectra of acceptor bound excitons in isotopically purified 28Si, demonstrating conclusively the surprising result that the splittings previously observed in natural Si result from the randomness of the Si isotopic composition.

Postnatal development and thermoregulation in the precocial European hare (Lepus europaeus).

We investigated postnatal development of captive juvenile European hares (Lepus europaeus) with respect to growth, food intake and thermoregulation. Leverets increased their body weight on average 8.5-fold within 35 days, with a peak in relative growth rate on day 8. Although leverets started to take up solid food in the 2nd week of lactation, milk was the main energy source. Leverets of larger litters (two or three young) had less energy supply via milk than those of smaller litters (one young), and digested more energy in form of solid food. Weaning weight was positively correlated with body weight at birth and decreased with increasing litter size. Metabolic rates were largely determined by ambient temperature (Ta) and the increasing body weights. Leverets were able to maintain normothermic body temperatures from the Ist day of life during cold exposure down to Ta -8 degrees C. In their 1st week of life leverets showed reduced rates of heat loss in the cold, possibly by using peripheral vasoconstriction. Our results suggest that the precocial development of leverets is characterised by high maintenance costs due to rapid growth and thermoregulation, which may lead to negative energy balances when food supply is inadequate and T(a)s are low. We hypothesise that these physiological characteristics have played an important role in the recent decline of European hare populations.

Seasonal changes in morphology and function of the gastrointestinal tract of free-living alpine marmots ( Marmota marmota).

The gastrointestinal tracts of 76 free-living alpine marmots ( Marmota marmota) shot during a population control program in Switzerland were collected and analysed for patterns of change in morphology and function over the period from emergence from hibernation in April to just before re-entry into hibernation in September. Between first emergence and mid-summer (July) the fresh tissue mass of the stomach increased by 105%, the small intestine by 259% (among the largest recorded for a mammal), caecum by 185%, proximal colon by 138%, and distal colon by 144%. Mitotic activity was greatest in the small intestine; the mitotic index was high (40%) compared with indexes in the stomach and hindgut (approximately 4%) even at emergence, and increased to approximately 60% by mid-summer. Microbial activity in the caecum was also significant at emergence. The stomach (length) and caecum (length and fresh mass) increased in response to ingested food earlier than did the small intestine. Between mid-summer and September there were decreases in small intestinal tissue mass and mitotic activity. It is concluded that the gastrointestinal tract of alpine marmots probably continues to function throughout hibernation at a low level, with a mid-winter trough as part of an endogenous circannual rhythm. However, after emergence in spring, increases in size and activity of the tract appear to be a response to ingested food rather than to an endogenous signal. The early signs of down-regulation of the small intestine before re-entry into hibernation, together with its delayed up-regulation in response to food in spring, are consistent with the high costs of maintaining this section of the digestive system.