Frailty is recognized as a major prognostic indicator in heart failure. There has been interest in understanding whether pre-operative frailty is associated with worse outcomes after implantation of ...a left ventricular assist device (LVAD) as destination therapy.
Patients undergoing LVAD implantation as destination therapy at the Mayo Clinic, Rochester, Minnesota, from February 2007 to June 2012, were included in this study. Frailty was assessed using the deficit index (31 impairments, disabilities and comorbidities) and defined as the proportion of deficits present. We divided patients based on tertiles of the deficit index (>0.32 = frail, 0.23 to 0.32 = intermediate frail, <0.23 = not frail). Cox proportional hazard regression models were used to examine the association between frailty and death. Patients were censored at death or last follow-up through October 2013.
Among 99 patients (mean age 65 years, 18% female, 55% with ischemic heart failure), the deficit index ranged from 0.10 to 0.65 (mean 0.29). After a mean follow-up of 1.9 ± 1.6 years, 79% of the patients had been rehospitalized (range 0 to 17 hospitalizations, median 1 per person) and 45% had died. Compared with those who were not frail, patients who were intermediate frail (adjusted HR 1.70, 95% CI 0.71 to 4.31) and frail (HR 3.08, 95% CI 1.40 to 7.48) were at increased risk for death (p for trend = 0.004). The mean (SD) number of days alive out of hospital the first year after LVAD was 293 (107) for not frail, 266 (134) for intermediate frail and 250 (132) for frail patients.
Frailty before destination LVAD implantation is associated with increased risk of death and may represent a significant patient selection consideration.
Summary
Emollients can perform an important role in the treatment of a number of dermatological conditions. Currently, the use of emollient therapy in the UK is supported only by limited guidelines ...and a best‐practice statement, although guidelines do exist for specific conditions such as childhood eczema. To address this need, a group of clinical professionals covering acute community‐care settings and medicines management met to review current data and practice. Their aim was to support other professionals in their approach to the use of emollient therapies in dry‐skin conditions.
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The epidermal growth factor receptor (EGFR) is a clinically validated target in head and neck squamous cell carcinoma (HNSCC), where EGFR-blocking antibodies are approved for first-line treatment. ...However, as with other targeted therapies, intrinsic/acquired resistance mechanisms limit efficacy. In the FaDu HNSCC xenograft model, we show that combined blockade of EGFR and ERBB3 promotes rapid tumor regression, followed by the eventual outgrowth of resistant cells. RNA sequencing revealed that resistant cells express FGFR3-TACC3 fusion proteins, which were validated as drivers of the resistant phenotype by several approaches, including CRISPR-mediated inactivation of FGFR3-TACC3 fusion genes. Interestingly, analysis of signaling in resistant cell lines demonstrated that FGFR3-TACC3 fusion proteins promote resistance by preferentially substituting for EGFR/RAS/ERK signaling rather than ERBB3/PI3K/AKT signaling. Furthermore, although FGFR3-TACC3 fusion proteins promote resistance of additional EGFR-dependent HNSCC and lung cancer cell lines to EGFR blockade, they are unable to compensate for inhibition of PI3K signaling in PIK3CA-mutant HNSCC cell lines. Validation of FGFR3-TACC3 fusion proteins as endogenous drivers of resistance in our screen provides strong evidence that these fusions are capable of substituting for EGFR signaling. Thus, FGFR3-TACC3 fusion proteins may represent a novel mechanism of acquired resistance in EGFR-dependent cancers of multiple cell lineages.
This paper presents an all-digital, non-coherent, pulsed-UWB transmitter. By exploiting relaxed center frequency tolerances in non-coherent wideband communication, the transmitter synthesizes UWB ...pulses from an energy-efficient, single-ended digital ring oscillator. Dual capacitively coupled digital power amplifiers (PAs) are used in tandem to attenuate low frequency content typically associated with single-ended digital circuits driving single-ended antennas. Furthermore, four level digital pulse shaping is employed to attenuate RF sidelobes, resulting in FCC compliant operation in the 3.5, 4.0, and 4.5 GHz IEEE 802.15.4a bands without the use of any off-chip filters or large passive components. The transmitter is fabricated in a 90 nm CMOS process and occupies a core area of 0.07 mm 2 . The entirely digital architecture consumes zero static bias current, resulting in an energy efficiency of 17.5 pJ/pulse at data rates up to 15.6 Mb/s.
Molecular probes with the ability to differentiate between subcellular variations in acidity levels remain important for the investigation of dynamic cellular processes and functions. In this ...context, a series of cyclic peptide and PEG bio-conjugated dual near-infrared emissive BF2-azadipyrromethene fluorophores with maxima emissions at 720 nm (at pH > 6) and 790 nm (at pH < 5) have been developed and their aqueous solution photophysical properties determined. Their inter-converting emissions and fluorescence lifetime characteristics were exploited to track their spatial and temporal progression from first contact with the plasma membrane to subcellular locales to their release within extracellular vesicles. A pH-dependent reversible phenolate/phenol interconversion on the fluorophore controlled the dynamic changes in dual emission responses and corresponding lifetime changes. Live-cell confocal microscopy experiments in the metastatic breast cancer cell line MDA-MB-231 confirmed the usability of the dual emissive properties for imaging over prolonged periods. All three derivatives performed as probes capable of real-time continuous imaging of fundamental cellular processes such as plasma membrane interaction, tracking endocytosis, lysosomal/large acidic vesicle accumulation, and efflux within extracellular vesicles without perturbing cellular function. Furthermore, fluorescence lifetime imaging microscopy provided valuable insights regarding fluorophore progression through intracellular microenvironments over time. Overall, the unique photophysical properties of these fluorophores show excellent potential for their use as information-rich probes.
Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence ...and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide.
We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations.
We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10−7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype–phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14–23% of MH families.
Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
This study investigated the stories of heterosexual women who experienced a husband coming out as gay and a consequential marital separation. Interpretative phenomenological analysis (IPA) was used. ...Loss, anger, spousal empathy and concerns regarding societal prejudice were reported. Additional stress was experienced when others minimised the experience due to the gay sexual orientation of their husband. Experiencing positive communication with their husband during and after the disclosure aided the resolution of the emotional injury experienced by them. They all eventually 'let go' of their husband. This involved a process of reconceptualising the self as separated. Findings indicate the importance of supporting women to re-focus on their needs during and following marital dissolution. The importance of non-judgemental support for marital loss, rather than a focus on the gay sexual orientation of the spouse, was highlighted.
We assess the importance of interpersonal income comparisons using data on suicide deaths. We examine whether suicide risk is related to others' income, holding own income and other individual and ...environmental factors fixed. We estimate models of the suicide hazard using two independent data sets: the National Longitudinal Mortality Study and the National Center for Health Statistics' Multiple Cause of Death Files combined with the 5% Public Use Micro Sample of the 1990 decennial census. Results from both data sources show that, controlling for own income and individual characteristics, individual suicide risk rises with others' income.
There is accumulating clinical data supporting the role of probiotics in human health particularly in benefiting the immune system, strengthening the mucosal barrier and suppressing intestinal ...infection. Fermented and unfermented dairy products enriched with probiotic bacteria have developed into one of the most successful categories of functional foods. From a functional ingredient perspective, the generation of these live cultures in dried formats is particularly attractive, however, it does present challenges in terms of retaining probiotic functionality during powder manufacture and storage. Both freeze-dying and spray-drying can be used for manufacture of probiotic powders on a large-scale, however, both approaches expose the cultures to extreme environmental conditions. Methods of production of dried probiotic powders should be such that viability is maintained in the dried powders following manufacture, and storage to ensure that an adequate number of bacteria can be delivered in the final product. This review will focus on how this can be achieved through approaches such as optimizing drying technology, and the drying matrix, and by manipulating probiotic bacteria by classical (microbiological) or genetic approaches.
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