Anorectal function and symptoms 6 months after robot-assisted laparoscopic radical prostatectomy: a single-center study.

INTRODUCTION: Robot-assisted laparoscopic radical prostatectomy (RALP) is a common procedure for the treatment of localised prostate cancer. Anorectal symptoms such as fecal incontinence (FI), rectal urgency or disturbed defecation have been reported after the operation. Anorectal function is dependent on the integrity of anal and pelvic nerves and muscles, rectal sensory function as well as rectal reservoir function. The aim of this study was to investigate the potential influence of RALP on anorectal physiological function and bowel symptoms. MATERIALS AND METHODS: In this pilot study, 29 patients with localised prostate cancer scheduled for RALP were included. Anorectal physiology was used to measure rectal sensitivity and reservoir function as well as anal sphincter pressures. Bowel symptoms were measured by a bowel function questionnaire and a 2-week bowel function diary. Measurements were done before the operation and repeated at 6 months after the operation. RESULTS: The study observed a significant postoperative increase in rectal sensory threshold for rectal balloon distention, from 20 to 40 mmHg, P < 0.001. This change is indicative of a decrease in rectal sensation after RALP. There were no other statistical significant differences in any of the physiological tests performed. Importantly, there was no change in any of the bowel symptoms after surgery. CONCLUSION: This study showed that RALP may lead to impaired rectal sensory function. This finding did not, however, seem to have any influence on the patients´ postoperative clinical bowel function.

Establishment and representativeness of the Stockholm Sodium Cohort: A laboratorial and pharmacoepidemiologic database covering 1.6 million individuals in the Stockholm County.

OBJECTIVE: Hyponatremia is associated with considerable morbidity and mortality, but causal links have been difficult to establish. Here, we describe the establishment and representativeness of the Stockholm Sodium Cohort (SSC), designed to study etiologies and outcomes of hyponatremia. STUDY DESIGN AND SETTING: All residents of Stockholm County undertaking at least one serum sodium test between 2005-2018 were included in the SSC. Individual-level test results from over 100 laboratory parameters relevant to hyponatremia were collected and linked to data on demographics, socioeconomic status, healthcare contacts, diagnoses and dispensed prescription medications using national registers. RESULTS: A total of 1,632,249 individuals, corresponding to 64% of the population of Stockholm County, were included in the SSC. Coverage increased with advancing age, ranging from 32% in children and adolescents (≤18 years) to 97% among the oldest (≥80 years). The coverage of SSC included the vast majority of patients in Stockholm County diagnosed with diabetes mellitus (93%), myocardial infarction (98%), ischemic stroke (97%), cancer (85%), pneumonias requiring inpatient care (95%) and deaths (88%). CONCLUSION: SSC is the first cohort specifically designed to investigate sodium levels in a large, population-based setting. It includes a wide range of administrative health data and laboratory analyses. The coverage is high, particularly among elderly and individuals with comorbidities. Consequently, the cohort has a large potential for exploration of various aspects of hyponatremia.

Effect of Drying Methods on Chemical and Sensory Properties of Cannabis sativa Leaves.

Hemp is used as a source of fiber, oil and bioactive substances including volatile and cannabinoid-containing substances. This paper presents, for the first time, results on the evaluation of drying methods (convective, vacuum-microwave and combined convective pre-drying and vacuum-microwave finishing drying) of hemp leaves on the qualitative and quantitative changes in secondary metabolites, including essential oils, cannabinoids and sterols. A ranking and descriptive test of hemp leaves was also performed. Drying kinetics was presented using three models, including logarithmic, Midilli and modified Page. The SPME-Arrow technique was used to determine 41 volatile compounds, of which caryophyllene, ß-myrcene and α-humulene were dominant in dried and fresh leaves. Regarding the essential oils obtained, 64 were identified, with caryophyllene, humulene epoxide II and limonene being the dominant ones. For preserving the highest amount of oils, the best method was the convective pre-drying followed by vacuum-microwave finishing drying (CD60-VMD) combined method, where the retention of volatile compounds was 36.08%, whereas the CD70 and 240-VMD methods resulted in the highest loss of 83%. The predominant cannabinoids in fresh hemp leaves were CBDA 6.05 and CBD 2.19 mg g-1. Drying caused no change in the cannabinoid profile of the plant material. ß-Sitosterol, campesterol and lupeol were dominant in the phytosterol and triterpene fractions. No changes in either quality or quantity were observed in any of the variants found.

Chemistry behind Quality-Emission of Volatile Enantiomers from Mentha spp. Plant Tissue in Relationship to Odor Sensory Quality.

The quality of food, considering increasing consumer demands and competition among producers, is a highly important issue. Quality concerns are also applicable to the odor quality of herbs and spices (HSs). Meanwhile, HSs commonly are graded based on their essential oils (EOs) content and analysis; but does the instrumental analysis really provide general information about the HSs sensory quality? Three chemotypes of Mentha spp. were used in the present study. From samples diversified by convective drying at different temperatures, EOs were hydrodistillated and analyzed by enantioselective GC-MS; moreover, the source plant material's volatile profile was analyzed by the HS-SPME technique. The instrumental analysis was confronted with the results of the sensory panel. Changes in enantiomeric composition were observed during the drying process, although no clear correlations or trends could be found for individual chiral components. Furthermore, even with significant differences in particular volatiles' contribution to plants' EOs and their volatile profiles, judges were not able to match the sample EOs and plant samples with sufficient effectiveness (~40%). Based on those results, we suggest that volatile enantiomeric distribution does not have an actual influence on odor quality and that the sensory analysis should not be replaced with instrumental analysis, which cannot predict general sensory quality.

Acrylamide and 5-Hydroxymethylfurfural in Synthetic Sugar Cane Syrup: Mitigation by Additives.

The ability of additives to reduce the formation of acrylamide in simulated sugar cane syrups was investigated. Organic acids, B vitamins, and inorganic salts were added individually and in combination to simulated thickened cane juice, and the mixtures were heated at 120 °C for 30 min. Calcium chloride (1%), citric acid (0.1%), and vitamin B3 (0.1%) were the most effective individual additives from each chemical family. The effects of CaCl2 (0-1%), citric acid (0-0.125%), and vitamin B3 (0-0.1125%), when added in combination, on the concentrations of acrylamide and hydroxymethylfurfural (HMF) were studied using a Box-Behnken design. Combinations of all three additives lowered the acrylamide production, but only the combination of citric acid and vitamin B3 had a significant synergistic effect. However, all these additives stimulated the production of HMF, and no significant interactive effect between pairs of additives on HMF production was observed. Calcium chloride stimulated the formation of HMF most strongly. These results indicate that certain combinations of these additives effectively reduce acrylamide formation, but they also lead to an increase in the formation of HMF in sugar syrup.

Time-dependent association between omeprazole and esomeprazole and hospitalization due to hyponatremia.

PURPOSE: The aim of this study was to explore the time-course of hospitalization due to hyponatremia associated with omeprazole and esomeprazole. METHODS: In this register-based case-control study, we compared patients hospitalized with a main diagnosis of hyponatremia (n = 11,213) to matched controls (n = 44,801). We used multiple regression to investigate time-related associations between omeprazole and esomeprazole and hospitalization because of hyponatremia. RESULTS: The overall adjusted OR (aOR) between proton pump inhibitor (PPI) exposure, regardless of treatment duration and hospitalization with a main diagnosis of hyponatremia, was 1.23 (95% confidence interval CI 1.15-1.32). Exposure to PPIs was associated with a prompt increase in risk of hospitalization for hyponatremia from the first week (aOR 6.87; 95% CI 4.83-9.86). The risk then gradually declined, reaching an aOR of 1.64 (0.96-2.75) the fifth week. The aOR of ongoing PPI treatment was 1.10 (1.03-1.18). CONCLUSION: The present study shows a marked association between omeprazole and esomeprazole and hyponatremia related to recently initiated treatment. Consequently, newly initiated PPIs should be considered a potential culprit in any patient suffering from hyponatremia. However, if the patient has had this treatment for a longer time, the PPI should be considered a less likely cause.

[Lipomatous ependymomas of the posterior fossa. An infrequent and little-known subtype. A case report and review of the literature]. / Ependimomas lipomatosos de la fosa posterior. Un subtipo muy infrecuente y poco conocido. Presentación de caso y revisión de la literatura.

Ependymomas are well defined glial tumours composed of uniform small cells with round nuclei in a fibrillar matrix. They have characteristic perivascular acellular areas (pseudorosettes) and, in some cases, ependymal rosettes. The three most well-known histological phenotypes are papillary, clear-cell and tanycytic. The WHO classification includes rare cases of ependymoma with lipomatous metaplasia. Lipomatous ependymomas of the posterior fossa are extremely rare; we only found 7reports of cases in adults. They usually arise in the fourth ventricle and may extend into the cerebellum, when they often show extensive vacuolization, pushing the nucleus to the periphery and giving rise to a signet-ring cell appearance. Radiologically, there are few findings characteristic of these tumours. Immunohistochemistry is essential to differentiate this subtype from other more common lesions, such as metastatic adenocarcinoma, especially from breast, intestine and kidney.

Ependimomas lipomatosos de la fosa posterior. Un subtipo muy infrecuente y poco conocido. Presentación de caso y revisión de la literatura / Lipomatous ependymomas of the posterior fossa. An infrequent and little-known subtype. A case report and review of the literature

Los ependimomas son tumores gliales bien circunscritos compuestos de células pequeñas uniformes con un núcleo redondo en una matriz fibrilar. Se caracterizan por zonas anucleadas perivasculares (pseudorrosetas) y, en algunos casos, rosetas ependimarias. Tres fenotipos histológicos son los más reconocidos: papilar, de células claras y tanicítico. La OMS reconoce casos raros de ependimomas con metaplasia lipomatosa. Los ependimomas lipomatosos de fosa posterior son extremadamente infrecuentes, y en nuestra búsqueda hemos encontrado 7casos reportados en la literatura (excluyendo niños). Se originan habitualmente del 4.° ventrículo y podrían presentar extensión cerebelosa. Estos suelen presentar extensa vacuolización empujando el núcleo a la periferia y simulando la apariencia de «signet-ring cells» (células en anillo de sello). Radiológicamente hay pocos hallazgos que sean característicos de este tipo de tumores. La inmunohistoquímica es decisiva para no confundir esta variante con lesiones más comunes, como el adenocarcinoma metastásico, especialmente los de mama, intestino y renal.(AU)

Ependymomas are well defined glial tumours composed of uniform small cells with round nuclei in a fibrillar matrix. They have characteristic perivascular acellular areas (pseudorosettes) and, in some cases, ependymal rosettes. The three most well-known histological phenotypes are papillary, clear-cell and tanycytic. The WHO classification includes rare cases of ependymoma with lipomatous metaplasia. Lipomatous ependymomas of the posterior fossa are extremely rare; we only found 7reports of cases in adults. They usually arise in the fourth ventricle and may extend into the cerebellum, when they often show extensive vacuolization, pushing the nucleus to the periphery and giving rise to a signet-ring cell appearance. Radiologically, there are few findings characteristic of these tumours. Immunohistochemistry is essential to differentiate this subtype from other more common lesions, such as metastatic adenocarcinoma, especially from breast, intestine and kidney.(AU)

Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome-associated glioma.

Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.

Hsp90 inhibition sensitizes DLBCL cells to cisplatin.

PURPOSE: Platinum-containing therapy is standard treatment for relapsed Diffuse Large B-Cell Lymphoma (DLBCL). However, the efficacy of treatment is limited by drug resistance leading to relapse. Cisplatin resistance has been linked to impairments of the DNA damage response, and several DNA repair proteins have been identified as clients of the molecular chaperone Hsp90. Here, we investigated the combinatory treatment of cisplatin and the Hsp90 inhibitor, 17AAG, in DLBCL cells to evaluate if inhibition of Hsp90 could sensitize DLBCL cells to cisplatin treatment. METHODS: Cell viability was assessed for cisplatin and 17AAG as monotherapies and for 25 different combinations in 7 DLBCL cell lines, where the Bliss Independence Model and the Combination Index were applied to assess their interaction. Induction of apoptosis and DNA damage response were evaluated by measuring Annexin V and γH2AX levels after 48 h of exposure. RESULTS: 17AAG synergized with cisplatin in DLBCL cells as detected in both interaction assessment models, resulting in a lower viability after 48 h for the combination-treated cells compared to both vehicle and single drug-treated cells. The combination also induced a stronger apoptotic response and an increase in DNA damage in 17AAG, cisplatin- and combination-treated cells compared to vehicle-treated cells, with the effect of the combination generally being higher than compared to both single drugs. CONCLUSION: This study demonstrates that 17AAG sensitizes DLBCL cells to cisplatin treatment. This effect is correlated with increased apoptotic and DNA damage response, potentially mediated by downregulation of Hsp90 clients in DNA repair pathways. Thus, cisplatin resistance could plausibly be overcome by combining the treatment with an Hsp90 inhibiting drug.

Consumer Profile and Drivers Influencing Consumer Behavior towards Fondillón, a European Protected Naturally Sweet Red Wine.

Fondillón is a naturally sweet red wine, protected within the Alicante Denomination of Origin (Alicante, Spain) and recognized by the European Union in its E-Bacchus database. The aims of this study were (i) to evaluate the degree of consumer acceptance and satisfaction towards Fondillón, (ii) to establish key drivers controlling consumer satisfaction, and (iii) to establish a general profile of the typical Fondillón consumer. The experiment consisted of three complementary studies: (i) a descriptive sensory analysis of five Fondillón samples representing all samples being marketed, (ii) an affective test using wine consumers (n = 100), and (iii) an online questionnaire to identify the main characteristic of a Fondillón consumer (n = 294). The main consumption drivers were good balance, intense floral and fruity notes, and long aftertaste. The current typical Fondillón consumer is a 42-52 year-old man, with a higher education level, with a 25,000-50,000 euros/year income, and who drinks it mainly at home. The online study showed that 50% of respondents do not consume Fondillón because they do not know it, because it is very expensive, or because it is not so easy to find. Therefore, producers should improve their communication campaigns and distribution networks as key parts of their marketing strategies regarding Fondillón.

High-flow nasal oxygen (HFNO) for patients with Covid-19 outside intensive care units.

INTRODUCTION: High-flow nasal oxygen (HFNO) has traditionally only been used in intensive care units (ICU) especially in acute respiratory distress syndrome (ARDS). METHODS: We studied the use of HFNO at Södersjukhuset, Stockholm, in patients with moderate to severe ARDS related to Covid-19 as well as its benefits both for patients and to offload the ICU. The patients were observed with frequent controls to assess the need of ICU in case of deterioration. RESULTS: We studied 41 patients with HFNO treatment either as primarily treatment (Step-Up) or after stabilizing in the ICU (Step-Down). The average duration for treatment with HFNO was 5.6 days. Of these patients 55% were discharged home or to geriatric rehabilitation and 10% avoided ICU completely. The usage of HFNO saved in total 229 days in the ICU. Mortality was higher among elderly patients, and patients with comorbidities (mainly hypertension and obesity). DISCUSSION AND CONCLUSION: HFNO treatment is feasible and efficient for patients with Covid-19, saving resources in the ICU and offering additional advantages as waken proning and fewer complications compared to traditional ICU care. It requires however frequent controls as deterioration is recurrent.

A bendamustine resistance gene signature in diffuse large B-cell lymphoma and multiple myeloma.

Aim: Bendamustine is primarily used for treatment of indolent lymphomas but has shown efficacy in some patients with diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Molecular-based patient stratification for identification of resistant patients, who will benefit from alternative treatments, is important. The aim of this study was to develop a resistance gene signature (REGS) from bendamustine dose-response assays in cultures of DLBCL and MM cell lines, enabling prediction of bendamustine response in DLBCL and MM patients. Methods: Bendamustine response was determined in 14 DLBCL and 11 MM cell lines. Using baseline gene expression profiles and degree of growth inhibition after bendamustine exposure, a bendamustine REGS was developed and examined for the risk stratification potential in DLBCL (n = 971) and MM (n = 1,126) patients divided into prognostic subtypes. Results: Bendamustine resistance significantly correlated with resistance to cyclophosphamide in DLBCL and melphalan in MM cell lines. The bendamustine REGS showed significantly lower bendamustine resistance probabilities in DLBCL patients with GCB subtype tumors and in tumors of the differentiation dependent centrocyte and plasmablast subtypes. In MM patients, pre-BII classified tumors displayed high bendamustine resistance probabilities and the plasma cell subtype had lower bendamustine resistance probability than memory cells. Furthermore, tumors belonging to the 4p14, MAF, and D2 TC subclasses consistently displayed high bendamustine resistance probabilities. Conclusion: Significant differences in predicted response to bendamustine were found in molecular subtypes of DLBCL and MM, encouraging validation in prospective bendamustine-treated cohorts with available gene expression profiles and follow-up data.

The relation of structural valve deterioration to adverse remodelling and outcome in patients with biological heart valve prostheses.

AIMS: Native valve aortic stenosis is associated with adverse remodelling of the left ventricle and remodelling is stopped or even reversed with aortic valve replacement (AVR). However, the degeneration of bioprostheses and development of structural valve deterioration (SVD) may affect this. METHODS AND RESULTS: To assess the association with SVD, remodelling and outcome 451 patients from a single surgical centre who had undergone AVR with a Mitroflow pericardial bioprosthesis were studied. All patients were assessed in 2014 and a subgroup of patients (N = 327) were re-exanimated again after at least 18 months [median time of 27 (interquartile range, IQR 26-33) months] including echocardiography, measurements of N-terminal pro-brain natriuretic peptide, and assessment of functional status. SVD was based on echocardiography. Moderate SVD was present in 63 patients (14%) and severe SVD in 19 (4%), in the subgroup with follow-up echocardiography 48 patients (15%) patients had moderate to severe SVD at first examination. Patients with SVD had significantly greater increase in left ventricular (LV) mass index [21.6 g/m2 (IQR 5.7-48.3 g/m2) vs. 9.1 g/m2 (-8.6 to 27.3 g/m2), P = 0.01]. Further, patients with SVD had lower LV ejection fraction [55% (IQR 51-62%) vs. 60% (IQR 54-63%), P = 0.01] at follow-up. During follow-up, 94 patients (21%) met the composite endpoint of death or reoperation due to SVD and 41 patient readmitted for heart failure. In multivariable Cox regression analysis, severe SVD [hazard ratio (HR) 2.64 (1.37-5.07), P = 0.004] was associated with composite endpoint, and readmission for heart failure [HR 3.82 (1.53-9.51), P = 0.004]. CONCLUSION: SVD in aortic bioprostheses is associated with adverse LV remodelling and adverse outcome.

Volatile Composition and Sensory Attributes of Smoothies Based on Pomegranate Juice and Mediterranean Fruit Purées (Fig, Jujube and Quince).

To increase the intake of fruits and vegetables-especially among young people-the food industry is trying to develop new, easy-to-eat and long-shelf-life products, such as smoothies. Nowadays, consumers are choosing their foods based not only on nutritional/functional properties (content of polyphenols, vitamins, minerals, among others), but also on sensory attributes. The aim of this study was to investigate the volatile composition by HS-SPME and the sensory profile by descriptive sensory analysis of novel smoothies prepared by blending fig, jujube or quince purée with pomegranate juices (cv. Mollar de Elche or Wonderful) at two ratios purée:juice (40:60 or 60:40). Twenty-three volatile compounds were identified by GC-MS and classified as alcohols, aldehydes, esters, furans, ketones, terpenes and terpenoids. Among volatile compounds, the five predominant ones in the studied smoothies were: (i) 5-HMF (30.6%); (ii) 3-hexen-1-ol (9.87%); (iii) hexanal (9.43%); (iv) 1-hexanol (8.54%); and (v) 3-octanone (7.67%). Fig smoothies were sweet and had flavor and volatiles related to fig, pomegranate, and grape. While jujube products were bitter and had jujube and pear notes. Finally, quince smoothies were consistent, sour and had quince, apple and floral notes. Thus, the type of fruit purée used clearly determined the flavor of the final product. The smoothies prepared with Mollar de Elche pomegranate juice were characterized by having high intensity of pear odor/aroma and consistency, and the Wonderful smoothies were characterized by lower consistency and more intense pomegranate aroma and sourness.

Astrocytic expression of ZIP14 (SLC39A14) is part of the inflammatory reaction in chronic neurodegeneration with iron overload.

Neurodegeneration is associated with inflammation and mismanaged iron homeostasis, leading to increased concentration of non-transferrin-bound iron (NTBI) in the brain. NTBI can be taken up by cells expressing Zrt-, Irt-like protein-14 (ZIP14), which is regulated by iron overload and pro-inflammatory cytokines, for example, interleukin-1ß (IL-1ß) and IL-6. Here, we focus on the astrocytic involvement and regulation of ZIP14 in an experimental model of chronic neurodegeneration with inflammation and iron overload. Rats were unilaterally injected with ibotenic acid in striatum resulting in excitotoxicity-induced neuronal loss in substantia nigra pars reticulata (SNpr). ZIP14 expression was measured in SNpr using immunohistochemistry, western blotting, and RT-qPCR. Cultures of primary astrocytes were examined for Zip14 mRNA expression after stimulation with ferric ammonium citrate (FAC), IL-6, or IL-1ß. To study the involvement of ZIP14 in astrocytic iron uptake, uptake of 59 Fe was investigated after treatment with IL-1ß and siRNA-mediated ZIP14 knockdown. In the lesioned SNpr, reactive astrocytes, but not microglia, revealed increased ZIP14 expression with a main confinement to cell bodies and cellular processes. In astrocyte cultures, FAC and IL-1ß stimulation increased Zip14 expression and IL-1ß stimulation increased uptake of 59 Fe. Increased 59 Fe uptake was also observed after siRNA-mediated ZIP14 knockdown suggesting that lowering of ZIP14 impaired the balance between astrocytic uptake and export of iron. We conclude that astrocytes increase ZIP14 expression in response to inflammation and iron exposure and that ZIP14 seems pertinent for iron uptake in astrocytes and plays a role for a balanced astrocytic iron homeostasis.

Aroma-active compounds, sensory profile, and phenolic composition of Fondillón.

The Fondillón is a wine made from overripe grapes of the Monastrell variety, which is characterized by a high alcohol content and a minimum barrel ageing of 10 years. The objective of this study was to analyze the Fondillón volatile composition, key aroma-active compounds, sensory profile and phenolic composition. Fifty-four volatile compounds were identified, quantified and classified as alcohols, esters, acids, aldehydes, lactones, phenols, hydrocarbons and ketone. From these compounds, 22 aroma-active compounds were identified, with phenylethyl alcohol, diethyl succinate and ethyl lactate having the highest flavor dilution factor. The Fondillón wines were characterized by having high intensity of alcohol, fruity and toasted odor and flavor notes, and long aftertaste. Besides, 25 phenolic compounds were also identified and quantified; the phenolic acids (gallic, protocatechuic and syringic acids) were the predominant phenolic compounds.

C3 and C6 Modification-Specific OYE Biotransformations of Synthetic Carvones and Sequential BVMO Chemoenzymatic Synthesis of Chiral Caprolactones.

The scope for biocatalytic modification of non-native carvone derivatives for speciality intermediates has hitherto been limited. Additionally, caprolactones are important feedstocks with diverse applications in the polymer industry and new non-native terpenone-derived biocatalytic caprolactone syntheses are thus of potential value for industrial biocatalytic materials applications. Biocatalytic reduction of synthetic analogues of R-(-)-carvone with additional substituents at C3 or C6, or both C3 and C6, using three types of OYEs (OYE2, PETNR and OYE3) shows significant impact of both regio-substitution and the substrate diastereomer. Bioreduction of (-)-carvone derivatives substituted with a Me and/or OH group at C6 is highly dependent on the diastereomer of the substrate. Derivatives bearing C6 substituents larger than methyl moieties are not substrates. Computer docking studies of PETNR with both (6S)-Me and (6R)-Me substituted (-)-carvone provides a model consistent with the outcomes of bioconversion. The products of bioreduction were efficiently biotransformed by the Baeyer-Villiger monooxygenase (BVase) CHMO_Phi1 to afford novel trisubstituted lactones with complete regioselectivity to provide a new biocatalytic entry to these chiral caprolactones. This provides both new non-native polymerization feedstock chemicals, but also with enhanced efficiency and selectivity over native (+)-dihydrocarvone Baeyer-Villigerase expansion. Optimum enzymatic reactions were scaled up to 60-100 mg, demonstrating the utility for preparative biocatalytic synthesis of both new synthetic scaffold-modified dihydrocarvones and efficient biocatalytic entry to new chiral caprolactones, which are potential single-isomer chiral polymer feedstocks.

International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM).

BACKGROUND: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. METHODS: This was an observational, retrospective, longitudinal cohort study. RESULTS: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9-3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93-1.12), C-index of 0.70 (95% CI, 0.68-0.72), and D-statistic of 1.17 (95% CI, 1.05-1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8-2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96-13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. CONCLUSIONS: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.