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Aims: To explore levers and barriers to providing culturally responsive care for general practice nurses (GPNs) using normalization process theory., Design: A self-administered online cross-sectional survey., Methods: A participatory co-designed adapted version of the normalization of complex interventions measure (NoMAD) validated tool was distributed to a convenience sample of GPNs between December 2022 and February 2023. The sample comprised of GPNs working in general practice services in Ireland (n = 122). Data were analysed using descriptive and analytical statistics (Pearson correlations) and principles of content analysis. This study was conducted and reported in line with the Consensus-Based Checklist for Reporting of Survey Studies (CROSS)., Results: GPNs in this study indicated their familiarity with, acknowledged the importance of and were committed to, providing culturally responsive care. However, implementing culturally responsive care in daily practice was problematic due to insufficient education and training, scarcity of resources and supports and a lack of organizational leadership. Subsequently, GPNs experience difficulties adapting everyday practices to respond appropriately to the care needs of culturally and linguistically diverse (CaLD) patients., Conclusion: This analysis highlights the necessity of exploring the intricacies of factors that influence capabilities and capacity for providing culturally responsive care. Despite demonstrating awareness of the importance of providing nursing care that responds to the needs of CaLD patients, GPNs do not have full confidence or capacity to integrate culturally responsive care into their daily work practices., Impact: Using normalization process theory, this study elucidates for the first time how GPNs in Ireland make sense of, legitimize, enact and sustain culturally responsive care as a routine way of working. It illuminates the multitude of micro-level (individual), meso-level (organizational) and macro-level (structural) factors that require attention for normalizing culturally responsive care in general practice services., Patient or Public Contribution: The study question was identified in a participatory research prioritization for Irish research about migrant health that involved migrants in the process., (© 2024 The Author(s). Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

The development of dressings based on electrospun membranes with polymers and plant extracts is an interesting approach to skin regeneration, providing elements to prevent contamination and a matrix that accelerates the healing process. We developed a membrane composed of polyvinylpyrrolidone (PVP), gel and Aloe vera peel extract via the electrospinning technique. Additionally, an optimal ratio of PVP/ Av gel/ Av skin extract was determined to facilitate membrane formation. Electrospun membranes were obtained with fiber diameters of 1403 ± 57.4 nm for the PVP and 189.2 ± 11.4 nm for PVP/ Av gel/ Av peel extract, confirming that the use of extracts generally reduced the fiber diameter. The incorporation of gel and peel extract of Aloe vera into the electrospun membrane was analyzed via FTIR and UV-Vis spectroscopies. FTIR revealed the presence of functional groups associated with phenolic compounds such as aloin, aloe-emodin, emodin and aloesin, which was confirmed by UV-Vis, revealing absorption bands corresponding to aloin, phenols and carbonyl groups. This finding provides evidence of the effective integration and prevalence of bioactive compounds of a phenolic and polysaccharide nature from the gel and the Av skin extract in the electrospun fibers, resulting in an advanced membrane that could improve and accelerate the healing process and protect the wound from bacterial infections.

Objective: This study aimed to evaluate whether the suspension of intrapartum maternal oxygen supplementation for nonreassuring fetal heart rate is associated with adverse perinatal outcomes., Study Design: A retrospective cohort study, including all individuals that underwent labor in a single tertiary medical center. On April 16, 2020, the routine use of intrapartum oxygen for category II and III fetal heart rate tracings was suspended. The study group included individuals with singleton pregnancies that underwent labor during the 7 months between April 16, 2020, and November 14, 2020. The control group included individuals that underwent labor during the 7 months before April 16, 2020. Exclusion criteria included elective cesarean section, multifetal pregnancy, fetal death, and maternal oxygen saturation <95% during delivery. The primary outcome was defined as the rate of composite neonatal outcome, consisting of arterial cord pH <7.1, mechanical ventilation, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage grade 3/4, and neonatal death. The secondary outcome was the rate of cesarean and operative delivery., Results: The study group included 4,932 individuals, compared with 4,906 individuals in the control group. The suspension of intrapartum oxygen treatment was associated with a significant increase in the rate of composite neonatal outcome (187 [3.8%] vs. 120 [2.4%], p  < 0.001), including the rate of abnormal cord arterial pH <7.1 (119 [2.4%] vs. 56 [1.1%], p  < 0.01). A higher rate of cesarean section due to nonreassuring fetal heart rate was noted in the study group (320 [6.5%] vs. 268 [5.5%], p  = 0.03).A logistic regression analysis revealed that the suspension of intrapartum oxygen treatment was independently associated with the composite neonatal outcome (adjusted odds ratio = 1.55 [95% confidence interval, 1.23-1.96]) while adjusting for suspected chorioamnionitis, intrauterine growth restriction, and recent coronavirus disease 2019 exposure., Conclusion: Suspension of intrapartum oxygen treatment for nonreassuring fetal heart rate was associated with higher rates of adverse neonatal outcomes and urgent cesarean section due to fetal heart rate., Key Points: · The available data on intrapartum maternal oxygen supplementation are equivocal.. · Suspension of maternal oxygen for nonreassuring fetal heart rate during labor was associated with adverse neonatal outcomes.. · Oxygen treatment might still be important and relevant during labor.., Competing Interests: None declared., (Thieme. All rights reserved.)

The TMEM16/Anoctamin protein family (TMEM16x) is composed of members with different functions; some members form Ca 2+ -activated chloride channels, while others are lipid scramblases or combine the two functions. TMEM16x proteins are typically activated in response to agonist-induced rises of intracellular Ca 2+ ; thus, they couple Ca 2+ -signalling with cell electrical activity or plasmalemmal lipid homeostasis. The structural domains underlying these functions are not fully defined. We used a Naïve Bayes classifier to gain insights into these domains. The method enabled identification of regions involved in either ion or lipid transport, and suggested domains for possible pharmacological exploitation. The method allowed the prediction of the transport property of any given TMEM16x. We envisage this strategy could be exploited to illuminate the structure-function relationship of any protein family composed of members playing different molecular roles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In the present work, electrospun membranes of polyvinylpyrrolidone (PVP) nanofibers were manufactured using extracts and phenolic fractions of Dysphania ambrosioides (epazote), Opuntia ficus-indica (nopal), and Tradescantia pallida (chicken grass). The characterization of the membranes was carried out by scanning electron microscopy and Fourier transform infrared spectroscopy. The membranes synthesized through the use of the extracts generally showed a slight decrease in the diameter of the fibers but an increase in the size of the pores due to the presence of nanoparticles (rosaries) on the surface of the fibers, while the membranes synthesized using the phenolic fraction demonstrated an inversely proportional relationship between the compounds of this family with the diameter of the fibers and the size of the pore, allowing to elucidate part of the polymerization mechanisms of PVP nanofibers, in addition to proposing a reaction mechanism in the interaction between PVP and phenolic compounds for surface functionalization. Likewise, we demonstrate that the generation of reaction seeds through functionalization allows the addition of other compounds to the fibers in the membranes synthesized using the complete extract.

Cystic fibrosis (CF), the most common autosomal recessive fatal genetic disease in the Caucasian population, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that regulates salt and water transport across a variety of secretory epithelia. Deletion of phenylalanine at position 508, F508del, the most common CF-causing mutation, destabilises the CFTR protein, causing folding and trafficking defects that lead to a dramatic reduction in its functional expression. Small molecules called correctors have been developed to rescue processing-defective F508del CFTR. We have combined in silico and in vitro approaches to investigate the mechanism of action and potential as CFTR correctors of three hybrid derivatives ( 2a , 7a , and 7m ) obtained by merging the amino-arylthiazole core with the benzodioxole carboxamide moiety characterising the corrector lumacaftor. Molecular modelling analyses suggested that the three hybrids interact with a putative region located at the MSD1/NBD1 interface. Biochemical analyses confirmed these results, showing that the three molecules affect the expression and stability of the F508del NBD1. Finally, the YFP assay was used to evaluate the influence of the three hybrid derivatives on F508del CFTR function, assessing that their effect is additive to that of the correctors VX661 and VX445 . Our study shows that the development and testing of optimised compounds targeting different structural and functional defects of mutant CFTR is the best strategy to provide more effective correctors that could be used alone or in combination as a valuable therapeutic option to treat an even larger cohort of people affected by CF.

None., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest to disclose., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

According to the amyloid hypothesis, in the early phases of Alzheimer's disease (AD), small soluble prefibrillar aggregates of the amyloid β-peptide (Aβ) interact with neuronal membranes, causing neural impairment. Such highly reactive and toxic species form spontaneously and transiently in the amyloid building pathway. A therapeutic strategy consists of the recruitment of these intermediates, thus preventing aberrant interaction with membrane components (lipids and receptors), which in turn may trigger a cascade of cellular disequilibria. Milk α s1 -Casein is an intrinsically disordered protein that is able to inhibit Aβ amyloid aggregation in vitro , by sequestering transient species. In order to test α s1 -Casein as an inhibitor for the treatment of AD, it needs to be delivered in the place of action. Here, we demonstrate the use of large unilamellar vesicles (LUVs) as suitable nanocarriers for α s1 -Casein. Proteo-LUVs were prepared and characterized by different biophysical techniques, such as multiangle light scattering, atomic force imaging, and small-angle X-ray scattering; α s1 -Casein loading was quantified by a fluorescence assay. We demonstrated on a C. elegans AD model the effectiveness of the proposed delivery strategy in vivo . Proteo-LUVs allow efficient administration of the protein, exerting a positive functional readout at very low doses while avoiding the intrinsic toxicity of α s1 -Casein. Proteo-LUVs of α s1 -Casein represent an effective proof of concept for the exploitation of partially disordered proteins as a therapeutic strategy in mild AD conditions.

Cystic fibrosis (CF) is one of the most frequent lethal autosomal recessive diseases affecting the Caucasian population. It is caused by loss of function variants of the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein located on the apical side of epithelial cells. The most prevalent CF-causing mutation, the deletion of phenylalanine at position 508 (F508del), is characterized by folding and trafficking defects, resulting in the decreased functional expression of the protein on the plasma membrane. Two classes of small-molecule modulators, termed potentiators and correctors, respectively, have been developed to rescue either the gating or the cellular processing of defective F508del CFTR. Kaftrio, a next-generation triple-combination drug, consisting of the potentiator ivacaftor (VX770) and the two correctors tezacaftor (VX661) and elexacaftor (VX445), has been demonstrated to be a life-changing therapeutic modality for the majority of people with CF worldwide. While the mechanism of action of VX770 and VX661 is almost known, the precise mechanism of action and binding site of VX445 have not been conclusively determined. We investigated the activity of VX445 on mutant F508del to identify the protein domains whose expression is mostly affected by this corrector and to disclose its mechanisms of action. Our biochemical analyses revealed that VX445 specifically improves the expression and the maturation of MSD2, heterologously expressed in HEK 293 cells, and confirmed that its effect on the functional expression of defective F508del CFTR is additive either with type I or type II CFTR correctors. We are confident that our study will help to make a step forward in the comprehension of the etiopathology of the CF disease, as well as to give new information for the development and testing of combinations of even more effective correctors able to target mutation-specific defects of the CFTR protein.

In this work, the structural, electronic, and optical stability properties of the chitosan monomer (M-Ch) and atomic silver complex are reported, as well as a unitary cell of a silver cluster in the gas phase and acetic acid. The generalized gradient approximation HSEh1PBE/def2-TZVPP50 results established the structures' anionic charge (Q = -1|e|) and the doublet state (M = 2). The high cohesive energy indicates structural stability, and the quantum-mechanical descriptors show a high polarity and low chemical reactivity. Also, the quantum-mechanical descriptors present a low work function that shows the structures are suitable for applications in light-emitting diodes. Finally, the electronic behavior observed by the |HOMO-LUMO| gap energy changes depending on the atomic silver incorporated into the complex.

Heavy metals are among the toxic substances longest recognized by man. Today, due to the myriad sources of exposure, such as contaminated water, food, or air, they have become a major public health problem. This work presents the effects manifested in the infrared spectrum behavior caused by the presence of Cd 2+ , Cr 6+ , and Pb 2+ at different concentrations in three different matrices: water, casein, and milk; observing that the spectral modifications in the regions of different vibrational modes of nucleophilic groups such as -OH, COO- and NH 2 depending on the nature of the metal and its concentration. These findings were correlated in-silico using optimized models in Gabedit software and structural optimization was performed with MOPAC 2016 showing stable structures between the metals and Gln, Hys, Glu, and Phe of casein. By applying chemometrics (Principal Component Analysis), it was possible to observe a good correlation between the experimental data and to discriminate between the type of metal, the matrix that contains it, and the concentration could be represented through linear models that showed adjustments with a value of r 2 ≥ 0.95.

Background: Exercise-based cardiac rehabilitation (CR) is recommended for coronary heart disease (CHD). However, poor uptake of and poor adherence to CR exercise programs have been reported globally. Delivering CR exercise classes remotely may remove some of the barriers associated with traditional hospital- or center-based CR., Objective: We have developed a bespoke platform, Eastern Corridor Medical Engineering Centre-Cardiac Rehabilitation (ECME-CR), to support remotely delivered CR exercise. This pilot trial sought to test the ECME-CR platform and examine the efficacy and feasibility of a remote CR exercise program compared to a traditional center-based program., Methods: In all, 21 participants with CHD were recruited and assigned to either the intervention or control group. Both groups performed the same 8-week exercise program. Participants in the intervention group took part in web-based exercise classes and used the ECME-CR platform during the intervention period, whereas participants in the control group attended in-person classes. Outcomes were assessed at baseline and following the 8-week intervention period. The primary outcome measure was exercise capacity, assessed using a 6-minute walk test (6MWT). Secondary outcomes included measurement of grip strength, self-reported quality of life, heart rate, blood pressure, and body composition. A series of mixed between-within subjects ANOVA were conducted to examine the mean differences in study outcomes between and within groups. Participant adherence to the exercise program was also analyzed., Results: In all, 8 participants (male: n=5; age: mean 69.7, SD 7.2 years; height: mean 163.9, SD 5.4 cm; weight: mean 81.6, SD 14.1 kg) in the intervention group and 9 participants (male: n=9; age: mean 69.8, SD 8.2 years; height: mean 173.8, SD 5.2 cm; weight: mean 94.4, SD 18.0 kg) in the control group completed the exercise program. Although improvements in 6MWT distance were observed from baseline to follow-up in both the intervention (mean 490.1, SD 80.2 m to mean 504.5, SD 93.7 m) and control (mean 510.2, SD 48.3 m to mean 520.6, SD 49.4 m) group, no significant interaction effect (F 1,14 =.026; P=.87) nor effect for time (F 1,14 =2.51; P=.14) were observed. No significant effects emerged for any of the other secondary end points (all P>.0275). Adherence to the exercise program was high in both the intervention (14.25/16, 89.1%) and control (14.33/16, 89.6%) group. No adverse events or safety issues were reported in either group during the study., Conclusions: This pilot trial did not show evidence of significant positive effect for either the remotely delivered or center-based program. The 6MWT may not have been sufficiently sensitive to identify a change in this cohort of participants with stable CHD. This trial does provide evidence that remote CR exercise, supported with digital self-monitoring, is feasible and may be considered for individuals less likely to participate in traditional center-based programs., International Registered Report Identifier (irrid): RR2-10.2196/31855., (©Oonagh M Giggins, Julie Doyle, Suzanne Smith, Grainne Vavasour, Orla Moran, Shane Gavin, Nisanth Sojan, Gordon Boyle. Originally published in JMIR Cardio (https://cardio.jmir.org), 10.02.2023.)

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein determines abnormalities of chloride and bicarbonate secretion and, in general, of the transepithelial homeostasis that lead to alterations of airway surface liquid (ASL) composition and properties. The reduction of ASL volume impairs ciliary beating with the consequent accumulation of a sticky mucus. This situation prevents normal mucociliary clearance, favoring the survival and proliferation of bacteria and contributing to the genesis of the CF pulmonary disease. We explored the potential of some CFTR modulators, namely ivacaftor, tezacaftor, elexacaftor and their combination Kaftrio TM , capable of partially recovering the basic defects of the CFTR protein, to ameliorate the transepithelial fluid transport and the viscoelastic properties of the mucus when used singly or in combination. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of correctors tezacaftor, elexacaftor and their combination with potentiator ivacaftor on the key properties of ASL, such as fluid reabsorption, viscosity, protein content and pH. The treatment of airway epithelia bearing the deletion of a phenylalanine at position 508 (F508del) in the CFTR gene with tezacaftor and elexacaftor significantly improved the pericilial fluid composition, reducing the fluid reabsorption, correcting the ASL pH and reducing the viscosity of the mucus. Kaftrio TM was more effective than single modulators in improving all the evaluated parameters, demonstrating once more that this combination recently approved for patients 6 years and older with cystic fibrosis who have at least one F508del mutation in the CFTR gene represents a valuable tool to defeat CF.

Throughout its lifetime the heart is buffeted continuously by dynamic mechanical forces resulting from contraction of the heart muscle itself and fluctuations in haemodynamic load and pressure. These forces are in flux on a beat-by-beat basis, resulting from changes in posture, physical activity or emotional state, and over longer timescales due to altered physiology (e.g. pregnancy) or as a consequence of ageing or disease (e.g. hypertension). It has been known for over a century of the heart's ability to sense differences in haemodynamic load and adjust contractile force accordingly (Frank, Z. biology, 1895, 32, 370-447; Anrep, J. Physiol., 1912, 45 (5), 307-317; Patterson and Starling, J. Physiol., 1914, 48 (5), 357-79; Starling, The law of the heart (Linacre Lecture, given at Cambridge, 1915), 1918). These adaptive behaviours are important for cardiovascular homeostasis, but the mechanism(s) underpinning them are incompletely understood. Here we present evidence that the mechanically-activated ion channel, Piezo, is an important component of the Drosophila heart's ability to adapt to mechanical force. We find Piezo is a sarcoplasmic reticulum (SR)-resident channel and is part of a mechanism that regulates Ca 2+ handling in cardiomyocytes in response to mechanical stress. Our data support a simple model in which Drosophila Piezo transduces mechanical force such as stretch into a Ca 2+ signal, originating from the SR, that modulates cardiomyocyte contraction. We show that Piezo mutant hearts fail to buffer mechanical stress, have altered Ca 2+ handling, become prone to arrhythmias and undergo pathological remodelling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zechini, Camilleri-Brennan, Walsh, Beaven, Moran, Hartley, Diaz and Denholm.)

Background and Purpose: The volume regulated anion channel (VRAC) is known to be involved in different aspects of cancer cell behaviour and response to therapies. For this reason, we investigated the effect of DCPIB, a presumably specific blocker of VRAC, in two types of cancer: pancreatic duct adenocarcinoma (PDAC) and melanoma., Experimental Approach: We used patch-clamp electrophysiology, supported by Ca 2+ imaging, gene expression analysis, docking simulation and mutagenesis. We employed two PDAC lines (Panc-1 and MiaPaCa-2), as well as a primary (IGR39) and a metastatic (IGR37) melanoma line., Key Results: DCPIB markedly increased whole-cell currents in Panc-1, MiaPaca2 and IGR39, but not in IGR37 cells. The currents were mostly mediated by K Ca 1.1 channels, commonly known as BK channels. We confirmed DCPIB activation of BK channels also in HEK293 cells transfected with α subunits of this channel. Further experiments showed that in IGR39, and to a smaller degree also in Panc-1 cells, DCPIB induced a rapid Ca 2+ influx. This, in turn, indirectly potentiated BK channels and, in IGR39 cells, additionally activated other Ca 2+ -dependent channels. However, Ca 2+ influx was not required for activation of BK channels by DCPIB, as such activation involved the extracellular part of the protein and we have identified a residue crucial for binding., Conclusion and Implications: DCPIB directly targeted BK channels and, also, acutely increased intracellular Ca 2+ . Our findings extend the list of DCPIB effects that should be taken into consideration for future development of DCPIB-based modulators of ion channels and other membrane proteins., (© 2022 The British Pharmacological Society.)

Multimorbidity, defined as the concurrent experience of more than one chronic health condition in an individual, affects ∼65% of people over 65 and 85% of those over 85 years old with 30% of those also experiencing mental health concerns. This can lead to reduced quality of life and functioning as well as poorer outcomes in terms of condition management, adherence to treatment, and ultimately disease prognosis and progression. Digital health interventions offer a viable means of condition self-management, as well as psychological support, particularly for those who may have difficulty accessing in-person services. To best meet the needs of older adults with multimorbidity, deeper insights are needed into their specific concerns and issues around condition management, particularly with regard to distress in relation to managing one's condition. The present study aimed to explore this using one-to-one qualitative interviews and focus groups with people with chronic health conditions and healthcare professionals. Participants were 11 older adults with multimorbidity (4 males; mean age: M  = 72.7 years) and 14 healthcare professionals including five clinical nurse specialists, four pharmacists, two general practitioners, one occupational therapist, one speech and language therapist and one dietician. Thematic analysis was used to identify key themes, which included: patient feelings of anxiety or worry leading to an unwillingness to access essential information; the various mental health challenges faced by those with multimorbidity; the importance of personal values in providing motivation; and the importance of social support. Findings are discussed in relation to the potential development of transdiagnostically applicable digital interventions for the management of distress in those with multimorbidity., Competing Interests: Declaration of conflicting interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Irish general practice nursing roles have developed and grown exponentially in response to changing policy, clinical and workforce demands, this is reflective of international primary healthcare nursing trends. However, as nursing care in general practice advances, comprehensive evaluation of the general practice nurse (GPN) role has not been undertaken. Therefore, processes which enable robust data collection to assess the role and facilitate development of services are required. Nursing quality care metrics are an established mechanism which evaluate quality of care. Nursing quality care process metrics (QCP-Ms) specifically refer to measurement of care delivered directly to patients by nurses, benchmarking these interventions adherence to best practice guidance. The use of nursing metrics has been adopted within seven distinct healthcare settings in Ireland but not general practice. This scoping review is the first stage of a project which aims to inform development and implementation of QCP-Ms by Irish GPNs. Aim: To explore and map the literature regarding the development and implementation of QCP-Ms within general practice settings. Methods: The following five-stage methodological framework for scoping reviews proposed by Arksey and O'Malley will be used: (1) identifying the research question, (2) identifying relevant studies, (3) study selection, (4) charting/mapping the data and (5) collating, summarizing, and reporting results. The review will be conducted and reported in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR). Conclusions: The focus of this scoping review relates to QCP-Ms which specifically measure the work of general practice nurses. It is envisioned that synthesis of international literature will give a broad perspective about nursing QCP-Ms, their use in general practice or primary healthcare settings, enriching understanding regarding their development. It is anticipated that findings will provide key information to policy makers and health professionals interested in planning, strengthening, and delivering primary healthcare., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Loftus Moran O et al.)

Background: Research indicates that the management of distress levels in those with cardiac disease is not only important for improving quality of life and functioning but also critical for condition management; adherence to treatment; and, ultimately, disease prognosis and progression. Acceptance and commitment therapy (ACT) has consistently demonstrated positive long-term outcomes across a wide array of conditions, including chronic illness. However, most empirical investigations conducted to date have also involved in-person therapy, which can be difficult to access, particularly for those dealing with the demands of chronic disease., Objective: The objective of our research is to evaluate a digital ACT intervention for improving self-management behaviors and distress levels in those with cardiac conditions., Methods: The digital ACT intervention will be delivered via a digital health self-management platform over 6 sessions. This will involve a randomized, multiple baseline, single case experimental design with approximately 3 to 15 adults with cardiac disease. The independent variable for each participant will be the pre-post intervention phase. The dependent variables will be a daily self-report measure of psychological flexibility as well as objective measures of condition self-management (eg, blood pressure readings) and engagement with the app (eg, completing guided mindfulness). One-to-one qualitative interviews will also be conducted to further examine participants' experiences with using the intervention and what factors contribute to or impede successful outcomes., Results: Participant recruitment and data collection began in October 2021, and it is projected that the study findings will be available for dissemination by spring 2022., Conclusions: The findings will be discussed in terms of how a digital ACT intervention can best meet the needs of cardiac patients., International Registered Report Identifier (irrid): PRR1-10.2196/33783., (©Orla Moran, Julie Doyle, Oonagh Giggins, Louise McHugh, Evelyn Gould, Suzanne Smith, Shane Gavin, Nisanth Sojan, Gordon Boyle. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 01.04.2022.)

Background: Irish general practice nursing roles have developed and grown exponentially in response to changing policy, clinical and workforce demands over the past three decades. However, as nursing care in general practice advances at pace, comprehensive evaluation of the general practice nurse (GPN) role has not been undertaken. Therefore, processes which enable robust data collection to carefully assess the role and facilitate development of services are required. Nursing quality care metrics (QCM) are an established mechanism which measure nursing care process, evaluate quality, and impact of care, and inform service development. The use of nursing QCM has been adopted within seven distinct healthcare settings in Ireland but not general practice. This scoping review is the first stage of a project which aims to inform development of QCM within Irish GPN settings. Aim: To explore and map the literature regarding the use, application, and impact of nursing quality care metrics within a general practice, primary care setting. Methods: The following five-stage methodological framework for scoping reviews proposed by Arksey and O'Malley will be used: (1) identifying the research question, (2) identifying relevant studies, (3) study selection, (4) charting/mapping the data and (5) collating, summarizing, and reporting results. The review will be conducted and reported in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR). Conclusions: The focus of this scoping review relates to QCM which specifically measure the work of general practice nurses. It is envisioned that synthesis of international literature will give a broad perspective about QCM, their use in general practice or primary care settings, and enrich understanding of their development. It is anticipated that findings will provide key information to policy makers and health professionals interested in planning, strengthening, and delivering  primary care in Ireland., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Loftus Moran O et al.)

The early impairments appearing in Alzheimer's disease are related to neuronal membrane damage. Both aberrant Aβ species and specific membrane components play a role in promoting aggregation, deposition, and signaling dysfunction. Ganglioside GM1, present with cholesterol and sphingomyelin in lipid rafts, preferentially interacts with the Aβ peptide. GM1 at physiological conditions clusters in the membrane, the assembly also involves phospholipids, sphingomyelin, and cholesterol. The structure of large unilamellar vesicles (LUV), made of a basic POPC:POPS matrix in a proportion of 9:1, and containing different amounts of GM1 (1%, 3%, and 4% mol/mol) in the presence of 5% mol/mol sphingomyelin and 15% mol/mol cholesterol, was studied using small angle X-ray scattering (SAXS). The effect of the membrane composition on the LUVs-Aβ-peptide interaction, both for Aβ 1-40 and Aβ 1-42 variants, was, thus, monitored. The presence of GM1 leads to a significant shift of the main peak, towards lower scattering angles, up to 6% of the initial value with SM and 8% without, accompanied by an opposite shift of the first minimum, up to 21% and 24% of the initial value, respectively. The analysis of the SAXS spectra, using a multi-Gaussian model for the electronic density profile, indicated differences in the bilayer of the various compositions. An increase in the membrane thickness, by 16% and 12% when 2% and 3% mol/mol GM1 was present, without and with SM, respectively, was obtained. Furthermore, in these cases, in the presence of Aβ 40 , a very small decrease of the bilayer thickness, less than 4% and 1%, respectively, was derived, suggesting the inhibiting effect that the presence of sphingomyelin has on the GM1-Aβ interaction.

Mobility is an important factor in maintaining health and independence in an aging population. Facilitating community-dwelling older adults to independently identify signs of functional decline could help reduce disability and frailty development. Step-count from a body-worn sensor system was compared with a criterion measure in healthy young (n = 10) and healthy older adults (n = 10) during a Timed Up and Go test under different conditions. Spearman's rank correlation coefficient indicated strong agreement between the sensor-obtained step-count and that of the criterion measure in both age groups, in all mobility tests. A body-worn sensor system can provide objective, quantitative measures of step-count over short distances in older adults. Future research will examine if step-count alone can be used to identify functional decline and risk of frailty.Clinical Relevance-This demonstrates the correlation between step-count derived from a wearable sensor and a criterion measure over a short distance in older adults.

This study compared heart rate (HR) measurements taken from two wrist-worn devices; the Empatica E4 and the Apple Watch Series 5, to that taken from a Polar H10 chest strap. Ten healthy adult volunteers took part in a laboratory validation study and performed a treadmill exercise protocol. A single-subject validity study was also conducted to evaluate the accuracy of continuous HR measurements obtained during free-living activities. The participant wore both wrist devices, as well as the Polar H10 for 12-hours, as she continued her habitual daily activities. The key findings of the laboratory study were that the Apple Watch was accurate at assessing HR compared to the Polar H10 with Mean Absolute Percentage Error (MAPE) values < 5% during treadmill exercise. The accuracy of the E4 however was generally poor with MAPE values > 15%. Findings from the single-subject validity study indicate that the Apple Watch produces accurate measurements of HR, whereas the E4 device overestimated HR, except for during the more strenuous activities undertaken where HR was underestimated.Clinical Relevance- The Apple Watch has acceptable accuracy in measuring HR during treadmill exercise and during free-living activities in healthy adult volunteers.

Background: Exercise-based cardiac rehabilitation is recognized as a core component of cardiovascular disease management and has been shown to reduce all-cause and cardiovascular mortality and reduce the risk of hospital readmission following a cardiac event. However, despite this, the uptake of and long-term adherence to cardiac rehabilitation exercise is poor. Delivering cardiac rehabilitation exercise virtually (ie, allowing patients to participate from their own homes) may be an alternative approach that could enhance uptake and increase adherence., Objective: The aim of this study is to assess the feasibility of delivering a virtual cardiac rehabilitation exercise program supported by the Eastern Corridor Medical Engineering - Cardiac Rehabilitation (ECME-CR) platform., Methods: A convenience sample (n=20) of participants eligible to participate in community-based cardiac rehabilitation exercise will be recruited. Participants will be randomized to one of two study groups. Both study groups will perform the same exercise program, consisting of twice-weekly sessions of 60 minutes each, over an 8-week intervention period. Participants in the intervention group will partake in virtually delivered cardiac rehabilitation exercise classes in their own home. The virtual exercise classes will be delivered to participants using a videoconferencing platform. Participants in the control group will attend the research center for their cardiac rehabilitation exercise classes. Intervention group participants will receive the ECME-CR digital health platform for monitoring during the class and during the intervention period. Outcomes will be assessed at baseline and following the 8-week intervention period. The primary outcome will be exercise capacity as assessed using the 6-minute walk test. Other outcome measures will include heart rate, blood pressure, weight, percentage body fat, muscle strength, and self-reported quality of life. Semistructured interviews will also be conducted with a subset of participants to explore their experiences of using the digital platform., Results: Participant recruitment and data collection will begin in July 2021, and it is anticipated that the study results will be available for dissemination in spring 2022., Conclusions: This pilot trial will inform the design of a randomized controlled trial that will assess the clinical effectiveness of the ECME-CR digital health platform., International Registered Report Identifier (irrid): PRR1-10.2196/31855., (©Oonagh M Giggins, Julie Doyle, Suzanne Smith, Orla Moran, Shane Gavin, Nisanth Sojan, Gordon Boyle. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 07.10.2021.)

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel that regulates epithelial surface fluid secretion. The deletion of phenylalanine at position 508 (F508del) is the most common CFTR mutation. F508del CFTR is characterized by folding and trafficking defects, resulting in decreased functional expression of the protein on the plasma membrane. Several classes of small molecules, named correctors, have been developed to rescue defective F508del CFTR. Although individual correctors failed to improve the clinical status of CF patients carrying the F508del mutation, better results were obtained using correctors combinations. These results were obtained according to the premise that the administration of correctors having different sites of action should enhance F508del CFTR rescue. We investigated the putative site of action of an aminoarylthiazole 4-(3-chlorophenyl)-N-(3-(methylthio)phenyl)thiazol-2-amine, named FCG, with proven CFTR corrector activity, and its synergistic effect with the corrector VX809. We found that neither the total expression nor the maturation of WT CFTR transiently expressed in human embryonic kidney 293 cells was influenced by FCG, administrated alone or in combination with VX809. On the contrary, FCG was able to enhance F508del CFTR total expression, and its combination with VX809 provided a further effect, being able to increase not only the total expression but also the maturation of the mutant protein. Analyses on different CFTR domains and groups of domains, heterologously expressed in HEK293 cells, show that NBD2 is necessary for FCG corrector activity. Molecular modelling analyses suggest that FCG interacts with a putative region located into the NBD2, ascribing this molecule to class II correctors. Our study indicates that the continuous development and testing of combinations of correctors targeting different structural and functional defects of mutant CFTR is the best strategy to ensure a valuable therapeutic perspective to a larger cohort of CF patients.

Cystic fibrosis (CF) is a genetic disease associated with the defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that causes obstructive disease and chronic bacterial infections in airway epithelia. Deletion of phenylalanine at position 508, p.F508del, the most frequent mutation among CF patients, causes a folding and traffic defect, resulting in a dramatic reduction in the CFTR expression. To investigate whether the direct application of bicarbonate could modify the properties of the airway surface liquid (ASL), we measured the micro-viscosity, fluid transport and pH of human bronchial epithelial cells monolayers. We have demonstrated that the treatment of a CF-epithelia with an iso-osmotic solution containing bicarbonate is capable of reducing both, the ASL viscosity and the apical fluid re-absorption. We suggest the possibility of design a supportive treatment based on topical application of bicarbonate, or any other alkaline buffer.

Prodiginines and tambjamines are anion-selective ionophores capable of facilitating the transport of anions across the plasma membrane in mammalian cells. One of the potential applications of these anionophores is the possibility of employing them as a substitutive therapy for pathologies involving anion channels, as in cystic fibrosis. We have studied the interaction of a large anion as gluconate with three prodiginine- and two tambjamine-like compounds. Apparent dissociation constants for the chloride, iodide and gluconate complexes were estimated from iodide influx experiments in mammalian cells exposed to different extracellular anion combinations. Our experiments indicate that gluconate is not transported by the prodiginines, leaving the anionophores free to transport chloride and iodide. Conversely, gluconate would be transported to some extent by the tambjamines, competing with halides for the anionophores, and consequently reducing their flux. This might be related to the different structural features of both families of compounds. These data have important implications for the selection of impermeable anions in the analysis of the anionophore mechanism., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The risk of cesarean delivery after a successful external cephalic version for breech presentation is higher as compared with fetuses in cephalic presentation. However, the role of the time interval between version attempt to delivery on the risk for cesarean delivery is unclear. We aimed to study the effect of the time interval from a successful external cephalic version to delivery on the risk for cesarean delivery and assess factors associated with cesarean delivery after a successful version., Methods: We conducted a multicenter, retrospective cohort study, including all successful external cephalic version at two medical centers between 2011 and 2019. We compared patient baseline characteristics, obstetric characteristics, maternal and neonatal outcomes in women that delivered by vaginal delivery with those who delivered by cesarean delivery., Results: Overall, 769 deliveries were included. Of these, 98 women (12.7%) had cesarean delivery and 671 (87.3%) had vaginal delivery. Women who had cesarean delivery had a higher rate of obesity (44.9% vs 21.9%, p < 0.001; OR 2.88, CI 1.65-5.03) and nulliparity (45.9% vs 24.5%, p < 0.001; OR = 2.58, CI 1.67-3.98). The risk for intrapartum cesarean delivery did not differ according to time interval from external cephalic version to delivery., Conclusions: The time interval between successful external cephalic version and delivery was not associated with mode of delivery. This finding is in contrast to previous reports. The risk for cesarean delivery after successful version is higher in nulliparous, obese women, and women whose weight gain in pregnancy was higher.

Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping airways free of infection and mucus obstruction. Airway surface liquid volume, ciliary beating, and mucus are central for proper MCC and critically regulated by sodium absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive diseases. The calcium-activated potassium channel KCa.3.1, encoded by Kcnn4, participates in ion secretion, and studies showed that its activation increases Na+ absorption in airway epithelia, suggesting that KCa3.1-induced hyperpolarization was sufficient to drive Na+ absorption. However, its role in airway epithelium is not fully understood. We aimed to elucidate the role of KCa3.1 in MCC using a genetically engineered mouse. KCa3.1 inhibition reduced Na+ absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency and MCC ex vivo and in vivo. Kcnn4 silencing in the Scnn1b-transgenic mouse (Scnn1btg/+), a model of muco-obstructive lung disease triggered by increased epithelial Na+ absorption, improved MCC, reduced Na+ absorption, and did not change the amount of mucus but did reduce mucus adhesion, neutrophil infiltration, and emphysema. Our data support that KCa3.1 inhibition attenuated muco-obstructive disease in the Scnn1btg/+ mice. K+ channel modulation may be a therapeutic strategy to treat muco-obstructive lung diseases.

One of the most common mutations in Cystic Fibrosis (CF) patients is the deletion of the amino acid phenylalanine at position 508. This mutation causes both the protein trafficking defect and an early degradation. Over time, small molecules, called correctors, capable of increasing the amount of mutated channel in the plasma membrane and causing an increase in its transport activity have been developed. This study shows that incubating in vitro cells permanently transfected with the mutated channel with the correctors VX809, VX661 and Corr4a, and the combination of VX809 and Corr4a, a recovery of anion transport activity is observed. Interestingly, the permeability of bicarbonate increases in the cells containing corrected p.F508del CFTR channels is greater than the increase of the halide permeability. These different increases of the permeability of bicarbonate and halides are consistent with the concept that the structural conformation of the pore of the corrector-rescued p.F508del channels would be different than the normal wild type CFTR protein.

The activity of human paraoxonase 2 (PON2) is rapidly reduced in cells incubated with the bacterial quorormone 3-Oxo-dodecanoyl Homoserine Lactone (3OC12HSL), an observation that led to hypothesize a fast PON2 post-translational modification (PTM). Recently, we detected a 3OC12HSL-induced PTM in a cell-free system in which a crude extract from 3OC12HSL-treated HeLa cells was able to inactivate and ubiquitinate at position 144 a recombinant PON2. Here we show the occurrence of this and new PTMs on PON2 in HeLa cells. PTMs were found to gather nearby the two SNPs, A148G, and S311C, that are related to type-2 diabetes and its complications. Furthermore, we detected a PTM nearby a 12 amino acids region that is deleted in PON2 Isoform 2. An in vitro mutation analysis showed that the SNPs and the deletion are involved in PON2 activity and suggested a role of PTMs on its modulation, while a SAXS analysis pointed to Isoform 2 as being largely unstructured, compared to the wild type. Besides, we discovered a control of PON2 expression via a putative mRNA operon involving the Wilms tumor 1 associated protein (WTAP) and the E3 ubiquitin ligase (E3UbL) baculoviral IAP repeat-containing 3 (BIRC3).

Cystic fibrosis (CF) is a genetic disease characterized by the lack of cystic fibrosis transmembrane conductance regulator (CFTR) protein expressed in epithelial cells. The resulting defective chloride and bicarbonate secretion and imbalance of the transepithelial homeostasis lead to abnormal airway surface liquid (ASL) composition and properties. The reduced ASL volume impairs ciliary beating with the consequent accumulation of sticky mucus. This situation prevents the normal mucociliary clearance, favouring the survival and proliferation of bacteria and contributing to the genesis of CF lung disease. Here, we have explored the potential of small molecules capable of facilitating the transmembrane transport of chloride and bicarbonate in order to replace the defective transport activity elicited by CFTR in CF airway epithelia. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of our compounds on some key properties of ASL. The treatment of these functional models with non-toxic doses of the synthetic anionophores improved the periciliary fluid composition, reducing the fluid re-absorption, correcting the ASL pH and reducing the viscosity of the mucus, thus representing promising drug candidates for CF therapy., Competing Interests: E.C., O.M. and R.Q. are inventors of a patent application (PCT/EP2019/057696) which protects the composition and use of the compounds described in the present study. The other authors declare no conflict of interest.

Objectives: To assess if measurement of the head progression distance (PD) during the first stage of labor in nulliparous women can predict the delivery method. Methods: A prospective study was conducted on consecutive nulliparous women beyond 37 week's gestation during the first stage of labor. Transperineal ultrasound was performed to assess the PD. Analysis was performed on the relationships between PD during rest and during voluntary pushing and the fetal and maternal characteristics, delivery mode, and immediate postnatal outcomes. Results: Eighty seven suitable nulliparous women were suitable for analysis. PD was found to be significantly longer in women who delivered vaginally (VD) compared to those who underwent a cesarean section (CS) for obstructed labor: PD at rest was 2.51 ± 1.71 cm in women who delivered vaginally compared to 1.48 ± 1.9 cm in women who delivered by CS ( p  = .01). The PD during pushing was 3.43 ± 1.8 cm for a VD compared to 1.5 ± 2.1 cm for CS ( p  = .015). Logistic regression and receiver-operating characteristics curve analysis demonstrated a moderate predictive value of PD with respect to the mode of delivery (area under the curve was 0.67 during both resting and pushing period). Conclusion: PD measurements during the first stage of labor among nulliparous women differ significantly both in rest and during pushing between patients who delivered vaginally compared to CS and can therefore assist in predicting the mode of delivery.

Cystic fibrosis (CF) is a genetic disease associated with the defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that causes obstructive disease and chronic bacterial infections in airway epithelia. The most prevalent CF-causing mutation, the deletion of phenylalanine at position 508 (F508del), leads to CFTR misfolding, trafficking defects and premature degradation. A number of correctors that are able to partially rescue F508del-CFTR processing defects have been identified. Clinical trials have demonstrated that, unfortunately, mono-therapy with the best correctors identified to date does not ameliorate lung function or sweat chloride concentration in homozygous F508del patients. Understanding the mechanisms exerted by currently available correctors to increase mutant F508del-CFTR expression is essential for the development of new CF-therapeutics. We investigated the activity of correctors on the mutant F508del and wild type (WT) CFTR to identify the protein domains whose expression is mostly affected by the action of correctors, and we investigated their mechanisms of action. We found that the four correctors under study, lumacaftor (VX809), the quinazoline derivative VX325, the bithiazole compound corr4a, and the new molecule tezacaftor (VX661), do not influence either the total expression or the maturation of the WT-CFTR transiently expressed in human embryonic kidney 293 (HEK293) cells. Contrarily, they significantly enhance the expression and the maturation of the full length F508del molecule. Three out of four correctors, VX809, VX661 and VX325, seem to specifically improve the expression and the maturation of the mutant CFTR N-half (M1N1, residues 1-633). By contrast, the CFTR C-half (M2N2, residues 837-1480) appears to be the region mainly affected by corr4a. VX809 was shown to stabilize both the WT- and F508del-CFTR N-half isoforms, while VX661 and VX325 demonstrated the ability to enhance the stability only of the mutant F508del polypeptide., Competing Interests: The authors declare no conflict of interest.

Deletion of phenylalanine at position 508, F508del, the most frequent mutation among Cystic fibrosis (CF) patients, destabilizes the protein, thus causing both a folding and a trafficking defect, resulting in a dramatic reduction in expression of CFTR. In vitro treatment with lumacaftor produces an enhancement of anion transport in cells. We studied the permeability properties of the CFTR mutant F508del treated with the corrector lumacaftor, showing that the rescued protein has selectivity properties different than the wild type CFTR, showing an augmented bicarbonate permeability. This difference would indicate a diverse conformation of the rescued F508del-CFTR, that is plausibly reflected on an improper regulation of the airway surface liquid, lessening the efficacy of the corrector. Our findings rather support the idea that a combination of correctors would be required to address the CFTR-dependent bicarbonate permeability., (Copyright © 2019. Published by Elsevier B.V.)

Background: Mammographic density is one of the strongest risk factors for breast cancer. In the general population, mammographic density can be modified by various exposures; whether this is true for women a strong family history is not known. Thus, we evaluated the association between reproductive, hormonal, and lifestyle risk factors and mammographic density among women with a strong family history of breast cancer but no BRCA1 or BRCA2 mutation., Methods: We included 97 premenopausal and 59 postmenopausal women (age range: 27-68 years). Risk factor data was extracted from the research questionnaire closest in time to the mammogram performed nearest to enrollment. The Cumulus software was used to measure percent density, dense area, and non-dense area for each mammogram. Multivariate generalized linear models were used to evaluate the relationships between breast cancer risk factors and measures of mammographic density, adjusting for relevant covariates., Results: Among premenopausal women, those who had two live births had a mean percent density of 28.8% vs. 41.6% among women who had one live birth (P=0.04). Women with a high body weight had a lower mean percent density compared to women with a low body weight among premenopausal (17.6% vs. 33.2%; P=0.0006) and postmenopausal women (8.7% vs. 14.7%; P=0.04). Among premenopausal women, those who smoked for 14 years or longer had a lower mean dense area compared to women who smoked for a shorter duration (25.3cm 2 vs. 53.1cm 2 ; P=0.002). Among postmenopausal women, former smokers had a higher mean percent density (19.5% vs. 10.8%; P=0.003) and dense area (26.9% vs. 16.4%; P=0.01) compared to never smokers. After applying the Bonferroni correction, the association between body weight and percent density among premenopausal women remained statistically significant., Conclusions: In this cohort of women with a strong family history of breast cancer, body weight was associated with mammographic density. These findings suggest that mammographic density may explain the underlying relationship between some of these risk factors and breast cancer risk, and lend support for the inclusion of mammographic density into risk prediction models.

Background and Purpose: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CF transmembrane conductance regulator (CFTR) protein, a cAMP-dependent anion channel involved in fluid transport across epithelium. Because small synthetic transmembrane anion transporters (anionophores) can replace the biological anion transport mechanisms, independent of genetic mutations in the CFTR, such anionophores are candidates as new potential treatments for CF., Experimental Approach: In order to assess their effects on cell physiology, we have analysed the transport properties of five anionophore compounds, three prodigiosines and two tambjamines. Chloride efflux was measured in large uni-lamellar vesicles and in HEK293 cells with chloride-sensitive electrodes. Iodide influx was evaluated in FRT cells transfected with iodide-sensitive YFP. Transport of bicarbonate was assessed by changes of pH after a NH 4 + pre-pulse using the BCECF fluorescent probe. Assays were also carried out in FRT cells permanently transfected with wild type and mutant human CFTR., Key Results: All studied compounds are capable of transporting halides and bicarbonate across the cell membrane, with a higher transport capacity at acidic pH. Interestingly, the presence of these anionophores did not interfere with the activation of CFTR and did not modify the action of lumacaftor (a CFTR corrector) or ivacaftor (a CFTR potentiator)., Conclusion and Implications: These anionophores, at low concentrations, transported chloride and bicarbonate across cell membranes, without affecting CFTR function. They therefore provide promising starting points for the development of novel treatments for CF., (© 2019 The British Pharmacological Society.)

The optical transport of images through a multimode fibre remains an outstanding challenge with applications ranging from optical communications to neuro-imaging. State of the art approaches either involve measurement and control of the full complex field transmitted through the fibre or, more recently, training of artificial neural networks that however, are typically limited to image classes belong to the same class as the training data set. Here we implement a method that statistically reconstructs the inverse transformation matrix for the fibre. We demonstrate imaging at high frame rates, high resolutions and in full colour of natural scenes, thus demonstrating general-purpose imaging capability. Real-time imaging over long fibre lengths opens alternative routes to exploitation for example for secure communication systems, novel remote imaging devices, quantum state control processing and endoscopy.

The understanding of amyloid β-peptide (Aβ) interactions with cellular membranes is a crucial molecular challenge against Alzheimer's disease. Indeed, Aβ prefibrillar oligomeric intermediates are believed to be the most toxic species, able to induce cellular damages directly by membrane damage. We present a neutron-scattering study on the interaction of large unilamellar vesicles (LUV), as cell membrane models, with both freshly dissolved Aβ and early toxic prefibrillar oligomers, intermediate states in the amyloid pathway. In addition, we explore the effect of coincubating the Aβ-peptide with the chaperonin Hsp60, which is known to strongly interact with it in its aggregation pattern. In fact, the interaction of the LUV with coincubated Aβ/Hsp60, right after mixing and after following the aggregation protocol leading to the toxic intermediates in the absence of Hsp60, is studied. Neutron spin echo experiments show that the interaction with both freshly dissolved and aggregate Aβ species brings about an increase in membrane stiffness, whereas the presence of even very low amounts of Hsp60 (ratio Aβ/Hsp60 = 25:1) maintains unaltered the elastic properties of the membrane bilayer. A coherent interpretation of these results, related to previous literature, can be based on the ability of the chaperonin to interfere with Aβ aggregation, by the specific recognition of the Aβ-reactive transient species. In this framework, our results strongly suggest that early in a freshly dissolved Aβ solution are present some species able to modify the bilayer dynamics, and the chaperonin plays the role of an assistant in such stochastic "misfolding events", avoiding the insult on the membrane as well as the onset of the aggregation cascade.

Purpose: To investigate the correlation between the angle of progression and the clinical fetal head station (FHS) during the second stage of labor, and to build reference range., Materials and Methods: A prospective, observational study was conducted. Women carrying singleton term pregnancies were enrolled during the second stage of labor. FHS was assessed manually by a senior obstetrician, while the angle of progression (AOP) was assessed by transperineal ultrasound (TPU). Both examiners were blinded to each others results. The correlation between the sonographic AOP and the clinical FHS was analyzed., Results: Seventy patients comprised the study group. Clinical FHS demonstrated an excellent correlation with the sonographic measurement of AOP (Pearson's Correlation 0.642, p < 0.001). This correlation was best described by a cubic regression according to the formula: 123.800 + 10.290 × FHS -2.889 * FHS +0.910, (r 2  = 0.423, p < .001). After aggregation of the mean AOP per FHS, the relative predicted centiles values and standard deviation were calculated. The mean Z score between measured and predicted values of the AOP for a given FHS was 0.007 (range -0.13 to +0.006)., Conclusions: Our results demonstrate a significant correlation between the clinical FHS and the TPU measured AOP. These standardized sonographic values may serve the obstetrician as a reliable, objective auxiliary tool for the evaluation of the FHS during the second stage of labor.

Liposomes are shell nanoparticles able to embed hydrophobic molecules into their lipid layers to be released to cells. In pharmaceutical sciences, liposomes remain the delivery system with the highest biocompatibility, stability, loading characteristics, tunable physicochemical properties. Squalene is a natural, water insoluble, lipid, abundant in olive oil and shark liver. Studies in vitro and in animal models suggest protective and inhibitory effects of squalene against cancer. To study its effect on cells, and to overcome its insolubility in water, we have designed and produced large unilamellar liposomes containing different quantities of this terpene (0%, 2.8%, 5% w/w). Liposomes have been characterized by different biophysical techniques. Size-exclusion and affinity chromatography showed a unimodal size distribution and confirmed the squalene loaded dose. Laurdan fluorescence evidenced the changes in the hydration of the external layer of liposomes as a function of squalene concentration. Dynamic light scattering and small angle X-ray scattering revealed squalene induced structural differences in the hydrodynamic radius distribution and in the bilayer thickness respectively. Finally, preliminary experiments on the effects of liposome-delivered squalene on tumor and non-tumor cell lines showed time- and dose-dependent cytotoxic effects on LAN5 tumor cells and no effect on NIH-3T3 normal cells., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These integral membrane proteins are composed of a pore-forming α-subunit, and one or more auxiliary β subunits. Mutation p.Asp25Asn (D25N; c.73G > A) of the β1 subunit, coded by the gene SCN1B, has been reported in a patient with generalized epilepsy with febrile seizure plus type 1 (GEFS+). In human embryonic kidney 293 (HEK) cells, the heterologous coexpression of D25N-β1 subunit with Nav1.2, Nav1.4, and Nav1.5 α subunits, representative of brain, skeletal muscle, and heart voltage gated sodium channels, determines a reduced sodium channel functional expression and a negative shift of the activation and inactivation steady state curves. The D25N mutation of the β1 subunit causes a maturation (glycosylation) defect of the protein, leading to a reduced targeting to the plasma membrane. Also the β1-dependent gating properties of the sodium channels are abolished by the mutation, suggesting that D25N is no more able to interact with the α subunit. Our work underscores the role played by the β1 subunit, highlighting how a defective interaction between the sodium channel constituents could lead to a disabling pathological condition, and opens the possibility to design a mutation-specific GEFS+ treatment based on protein maturation., (© 2018 Wiley Periodicals, Inc.)

Cystic fibrosis (CF) is a genetic lethal disease, originated from the defective function of the CFTR protein, a chloride and bicarbonate permeable transmembrane channel. CF mutations affect CFTR protein through a variety of molecular mechanisms which result in different functional defects. Current therapeutic approaches are targeted to specific groups of patients that share a common functional defect. We seek to develop an innovative therapeutic approach for the treatment of CF using anionophores, small molecules that facilitate the transmembrane transport of anions. We have characterized the anion transport mechanism of a synthetic molecule based on the structure of prodigiosine, a red pigment produced by bacteria. Anionophore-driven chloride efflux from large unilamellar vesicles is consistent with activity of an uniporter carrier that facilitates the transport of anions through lipid membranes down the electrochemical gradient. There are no evidences of transport coupling with protons. The selectivity sequence of the prodigiosin inspired EH160 ionophore is formate > acetate > nitrate > chloride > bicarbonate. Sulfate, phosphate, aspartate, isothionate, and gluconate are not significantly transported by these anionophores. Protonation at acidic pH is important for the transport capacity of the anionophore. This prodigiosin derived ionophore induces anion transport in living cells. Its low toxicity and capacity to transport chloride and bicarbonate, when applied at low concentration, constitute a promising starting point for the development of drug candidates for CF therapy.

Purpose: Mammographic density is a risk factor for breast cancer but the mechanism behind this association is unclear. The receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) pathway has been implicated in the development of breast cancer. Given the role of RANK signaling in mammary epithelial cell proliferation, we hypothesized this pathway may also be associated with mammographic density. Osteoprotegerin (OPG), a decoy receptor for RANKL, is known to inhibit RANK signaling. Thus, it is of interest to evaluate whether OPG levels modify breast cancer risk through mammographic density., Methods: We quantified serum OPG levels in 57 premenopausal and 43 postmenopausal women using an enzyme-linked immunosorbent assay (ELISA). Cumulus was used to measure percent density, dense area, and non-dense area for each mammographic image. Subjects were classified into high versus low OPG levels based on the median serum OPG level in the entire cohort (115.1 pg/mL). Multivariate models were used to assess the relationship between serum OPG levels and the measures of mammographic density., Results: Serum OPG levels were not associated with mammographic density among premenopausal women (P ≥ 0.42). Among postmenopausal women, those with low serum OPG levels had higher mean percent mammographic density (20.9% vs. 13.7%; P = 0.04) and mean dense area (23.4 cm 2 vs. 15.2 cm 2 ; P = 0.02) compared to those with high serum OPG levels after covariate adjustment., Conclusions: These findings suggest that low OPG levels may be associated with high mammographic density, particularly in postmenopausal women. Targeting RANK signaling may represent a plausible, non-surgical prevention option for high-risk women with high mammographic density, especially those with low circulating OPG levels.

Anion selective ionophores, anionophores, are small molecules capable of facilitating the transmembrane transport of anions. Inspired in the structure of natural product prodigiosin, four novel anionophores 1a-d, including a 1,2,3-triazole group, were prepared. These compounds proved highly efficient anion exchangers in model phospholipid liposomes. The changes in the hydrogen bond cleft modified the anion transport selectivity exhibited by these compounds compared to prodigiosin and suppressed the characteristic high toxicity of the natural product. Their activity as anionophores in living cells was studied and chloride efflux and iodine influx from living cells mediated by these derivatives was demonstrated. These compounds were shown to permeabilize cellular membranes to halides with efficiencies close to the natural anion channel CFTR at doses that do not compromise cellular viability. Remarkably, optimal transport efficiency was measured in the presence of pH gradients mimicking those found in the airway epithelia of Cystic Fibrosis patients. These results support the viability of developing small molecule anionophores as anion channel protein surrogates with potential applications in the treatment of conditions such as Cystic Fibrosis derived from the malfunction of natural anion transport mechanisms.

Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These membrane integral proteins are composed by a pore-forming α-subunit, and one or more auxiliary β subunits. Mutation E87Q of the β1 subunit is correlated with Brugada syndrome, a genetic disease characterised by ventricular fibrillation, right precordial ST segment elevation on ECG and sudden cardiac death. Heterologous expression of E87Q-β1 subunit in CHO cells determines a reduced sodium channel functional expression. The effect the E87Q mutation of the β1 subunit on sodium currents and α protein expression is correlated with a reduced availability of the mature form of the α subunit in the plasma membrane. This finding offers a new target for the treatment of the Brugada syndrome, based on protein maturation management. This work highlights the role played by the β1 subunit in the maturation and expression of the entire sodium channel complex and underlines how the defective interaction between the sodium channel constituents could lead to a disabling pathological condition.

Objective: To determine the preferred mode of delivery (vacuum, forceps or cesarean delivery) for second-stage dystocia., Methods: Retrospective cohort study of women delivered by forceps, vacuum or cesarean delivery due to abnormalities of the second stage of labor. Primary outcome included neonatal and maternal composite adverse effects., Results: A total of 547 women were included: 150 (27.4%) had forceps delivery, 200 (36.5%) had vacuum extraction, and 197 (36.1%) had cesarean section. The rate of neonatal composite outcome was significantly increased in vacuum extraction (27%) compared to forceps delivery (14.7%) or cesarean section (9.7%) (p < 0.001). There was no difference in the rate of maternal composite outcome among the groups. Both operative vaginal delivery modes were associated with significantly lower rate of postpartum infection compared to cesarean delivery (0% versus 3%, p = 0.004)., Conclusion: Operative vaginal delivery was associated with reduced postpartum infection compared to cesarean section. Forceps delivery was associated with reduced risk for adverse neonatal outcome compared to vacuum extraction, with no increase in the risk of composite maternal complications.

The transfer of genomic information into the primary RNA sequence can be altered by RNA editing. We have previously shown that genomic variants can be RNA-edited to wild-type. The presence of distinct "edited" iduronate 2-sulfatase (IDS) mRNA transcripts ex vivo evidenced the correction of a nonsense and frameshift variant, respectively, in three unrelated Hunter syndrome patients. This phenomenon was confirmed in various patient samples by a variety of techniques, and was quantified by single-nucleotide primer extension. Western blotting also confirmed the presence of IDS protein similar in size to the wild-type. Since preliminary experimental evidence suggested that the "corrected" IDS proteins produced by the patients were similar in molecular weight and net charge to their wild-type counterparts, an in vitro system employing different cell types was established to recapitulate the site-specific editing of IDS RNA (uridine to cytidine conversion and uridine deletion), and to confirm the findings previously observed ex vivo in the three patients. In addition, confocal microscopy and flow cytometry analyses demonstrated the expression and lysosomal localization in HEK293 cells of GFP-labeled proteins translated from edited IDS mRNAs. Confocal high-content analysis of the two patients' cells expressing wild-type or mutated IDS confirmed lysosomal localization and showed no accumulation in the Golgi or early endosomes., (© 2017 Wiley Periodicals, Inc.)

Purpose: BRCA mutations contribute to about 20% of all hereditary breast cancers. With full-genome sequencing as the emerging standard for genetic testing, other breast cancer susceptibility genes have been identified and may collectively contribute to up to 30% of all hereditary breast cancers. We re-assessed women who had previously tested negative for a BRCA mutation when outdated techniques were used, and discuss the implications of identifying a mutation several years after initial genetic testing., Methods: We evaluated the prevalence of mutations in 12 breast cancer susceptibility genes (including BRCA1 and BRCA2) in 190 breast cancer patients with a strong family history of breast cancer. These women had previously tested negative for mutations in the large coding exons of BRCA1 and BRCA2 using the protein truncation test (PTT) between the years of 1996 and 2013., Results: We identified pathogenic mutations in 17 of 190 (9%) women. Six mutations were detected in BRCA1 (n = 2) and BRCA2 (n = 4). Eleven mutations were found in other breast cancer susceptibility genes including CHEK2 (n = 5), PALB2 (n = 2), BLM (n = 2), ATM (n = 1) and TP53 (n = 1)., Conclusion: Among 190 breast cancer patients with a family history of the disease, and who previously received a negative result for BRCA mutations using the PTT, 17 (9%) women were found to carry a high-risk pathogenic mutation in a breast cancer susceptibility gene. Six of these women were BRCA mutation carriers who were missed previously. These findings support the rationale for updated genetic testing in patients who tested BRCA mutation negative using outdated techniques.

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed in the apical membrane of epithelia. Mutations in the CFTR gene are the cause of cystsic fibrosis. CFTR is the only ABC-protein that constitutes an ion channel pore forming subunit. CFTR gating is regulated in complex manner as phosphorylation is mandatory for channel activity and gating is directly regulated by binding of ATP to specific intracellular sites on the CFTR protein. This review covers our current understanding on the gating mechanism in CFTR and illustrates the relevance of alteration of these mechanisms in the onset of cystic fibrosis.