ResearchPad - 5 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin–creatinine ratio]]> https://www.researchpad.co/article/elastic_article_12606 Raised albumin–creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular-related disease. We performed a genome-wide association study of ACR using 437 027 individuals from the UK Biobank in the discovery phase, 54 527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P < 5 × 10–8), of which 20 were not previously reported. Pathway analyses and the identification of 20 of the 62 variants (at r2 > 0.8) coinciding with signals for at least 16 related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes—a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene–diabetes interactions (P ≤ 4 × 10–5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR.

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<![CDATA[Arousal State-Dependent Alterations in VTA-GABAergic Neuronal Activity]]> https://www.researchpad.co/article/elastic_article_8070 Decades of research have implicated the ventral tegmental area (VTA) in motivation, learning and reward processing. We and others recently demonstrated that it also serves as an important node in sleep/wake regulation. Specifically, VTA-dopaminergic neuron activation is sufficient to drive wakefulness and necessary for the maintenance of wakefulness. However, the role of VTA-GABAergic neurons in arousal regulation is not fully understood. It is still unclear whether VTA-GABAergic neurons predictably alter their activity across arousal states, what is the nature of interactions between VTA-GABAergic activity and cortical oscillations, and how activity in VTA-GABAergic neurons relates to VTA-dopaminergic neurons in the context of sleep/wake regulation. To address these, we simultaneously recorded population activity from VTA subpopulations and electroencephalography/electromyography (EEG/EMG) signals during spontaneous sleep/wake states and in the presence of salient stimuli in freely-behaving mice. We found that VTA-GABAergic neurons exhibit robust arousal-state-dependent alterations in population activity, with high activity and transients during wakefulness and REM sleep. During wakefulness, population activity of VTA-GABAergic neurons, but not VTA-dopaminergic neurons, was positively correlated with EEG γ power and negatively correlated with θ power. During NREM sleep, population activity in both VTA-GABAergic and VTA-dopaminergic neurons negatively correlated with δ, θ, and σ power bands. Salient stimuli, with both positive and negative valence, activated VTA-GABAergic neurons. Together, our data indicate that VTA-GABAergic neurons, like their dopaminergic counterparts, drastically alter their activity across sleep-wake states. Changes in their activity predicts cortical oscillatory patterns reflected in the EEG, which are distinct from EEG spectra associated with dopaminergic neural activity.

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<![CDATA[Graphene quantum dot electrochemiluminescence increase by bio-generated H2O2 and its application in direct biosensing]]> https://www.researchpad.co/article/N27bd9237-1356-4815-b8bc-ac1feee46e96

In this study, a novel signal-increase electrochemiluminescence (ECL) biosensor has been developed for the detection of glucose based on graphene quantum dot/glucose oxidase (GQD/GOx) on Ti foil. The proposed GQD with excellent ECL ability is synthesized through a green one-step strategy by the electrochemical reduction of graphene oxide quantum dot. Upon the addition of glucose, GOx can catalytically oxidize glucose and the direct electron transfer between the redox centre of GOx and the modified electrode also has been realized, which results in the bio-generated H2O2 for ECL signal increase in GQD and realizes the direct ECL detection of glucose. The signal-increase ECL biosensor enables glucose detection with high sensitivity reaching 5 × 10−6 mol l−1 in a wide linear range from 5 × 10−6 to 1.5 × 10−3 mol l−1. Additionally, the fabrication process of such GQD-based ECL biosensor is also suitable to other biologically produced H2O2 system, suggesting the possible applications in the sensitive detection of other biologically important targets (e.g. small molecules, protein, DNA and so on).

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<![CDATA[Spectroscopic and molecular docking studies reveal binding characteristics of nazartinib (EGF816) to human serum albumin]]> https://www.researchpad.co/article/N4761127c-a88e-4441-ba6f-200345abcef3

The interactions of novel anti-cancer therapeutic agents with the different plasma and tissue components, specifically serum albumins, have lately gained considerable attention due to the significant influence of such interactions on the pharmacokinetics and/or -dynamics of this important class of therapeutics. Nazartinib (EGF 816; NAZ) is a new anti-cancer candidate proposed as a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that is being developed and clinically tested for the management of non-small cell lung cancer. The current study aimed to characterize the interaction between NAZ and human serum albumin (HSA) using experimental and theoretical approaches. Experimental results of fluorescence quenching of HSA induced by NAZ revealed the development of a statically formed complex between NAZ and HSA. Interpretation of the observed fluorescence data using Stern–Volmer, Lineweaver–Burk and double-log formulae resulted in binding constants for HSA-NAZ complex in the range of (2.34–2.81) × 104 M–1 over the studied temperatures. These computed values were further used to elucidate thermodynamic attributes of the interaction, which showed that NAZ spontaneously binds to HSA with a postulated electrostatic force-driven interaction. This was further verified by theoretical examination of the NAZ docking on the HSA surface that revealed an HSA-NAZ complex where NAZ is bound to HSA Sudlow site I driven by hydrogen bonding in addition to electrostatic forces in the form of pi-H bond. The HSA binding pocket for NAZ was shown to encompass ARG 257, ARG 222, LYS 199 and GLU 292 with a total binding energy of −25.59 kJ mol–1.

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<![CDATA[Synthesis and characterization of cyclodextrin-based acrylamide polymer flocculant for adsorbing water-soluble dyes in dye wastewater]]> https://www.researchpad.co/article/N8b7ee2e3-f1e2-40aa-9387-be5494ced778

A novel hydrophobic and cationic cyclodextrin-based acrylamide flocculant (AM-β-CD-DMDAAC) was prepared by chemical oxidative polymerization to adsorb water-soluble dyes in dye wastewater. Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscope and thermogravimetric (TG) measurements results demonstrated that the AM-β-CD-DMDAAC was successfully synthesized. The effects of pH, contact time, initial dye concentration, temperature and adsorbent dose on dye removal efficiency for AM-β-CD-DMDAAC flocculants were investigated. The kinetic data were found to follow the pseudo-second-order kinetic model. The equilibrium adsorption data were fitted to the Langmuir isotherm model, with the maximum adsorption capacity of 147.1 mg g−1. The adsorbent retained about 60% of the adsorption efficiency after three adsorption/desorption cycles, which implied a promising application as the dye adsorbent.

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<![CDATA[Synchronization of Sensory Gamma Oscillations Promotes Multisensory Communication]]> https://www.researchpad.co/article/Ne93998eb-2f8e-424f-99d1-1825b8829504

Abstract

Rhythmic neuronal activity in the gamma range is a signature of cortical processing and its synchronization across distant sites has been proposed as a fundamental mechanism of network interactions. While this has been shown within sensory streams, we tested whether cross talk between the senses relies on similar mechanisms. Direct sensory interactions in humans (male and female) were studied with a visual–tactile amplitude matching paradigm. In this task, congruent stimuli are associated with behavioral benefits, which are proposed to be mediated by increased binding between sensory cortices through coherent gamma oscillations. We tested this hypothesis by applying 4-in-1 multi-electrode transcranial alternating current stimulation (tACS) with 40 Hz over visual and somatosensory cortices. In phase stimulation (0°) was expected to strengthen binding and thereby enhance the congruence effect, while anti-phase (180°) stimulation was expected to have opposite effects. Gamma tACS was controlled by alpha (10 Hz) and sham stimulation, as well as by applying tACS unilaterally while visual–tactile stimuli were presented lateralized. Contrary to our expectations, gamma tACS over the relevant hemisphere delayed responses to congruent trials. Additionally, reanalysis of EEG data revealed decoupling of sensory gamma oscillations during congruent trials. We propose that gamma tACS prevented sensory decoupling and thereby limited the congruence effect. Together, our results favor the perspective that processing multisensory congruence involves corticocortical communication rather than feature binding. Furthermore, we found control stimulation over the irrelevant hemisphere to speed responses under alpha stimulation and to delay responses under gamma stimulation, consistent with the idea that contralateral alpha/gamma dynamics regulate cortical excitability.

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<![CDATA[Genetic Characterization of Japanese Encephalitis Virus Genotype 5 Isolated from Patient, South Korea, 2015]]> https://www.researchpad.co/article/N1821a57c-d409-4eee-88b6-cbff24bd145d

We isolated Japanese encephalitis virus genotype 5 from human specimens in South Korea. Whole-genome analysis showed 90.4% identity with other genotype 5 viruses from humans. This virus had a unique insertion in the NS4A gene. However, the envelope protein contained Lys 84, which was specific to strains of genotype 5 viruses from South Korea.

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<![CDATA[A systematic analysis of online public engagement with 10 videos on major global health topics involving 229 459 global online viewers]]> https://www.researchpad.co/article/N3b3d99f1-0091-4076-884f-455c1341be28

Background

Online interest in issues specific to global health outside of times of pandemics or other crises is rather limited. To achieve long term global health goals, public support and engagement needs to be fostered on a continual basis. Strategies for capturing the attention of the general public online for the persisting problems outside of emergency situations are poorly defined. There are only a few isolated examples of success. In this study we explored the engagement of the viewers with different global health topics that were provided on public and privately advertised YouTube channels.

Methods

We developed the Massive Open Online Course “Survival: The Story of Global Health”, consisting of 10 educational videos on major global health topics. We conducted two experiments in two separate samples of viewers. The first was based on posting videos on a YouTube channel between August 30 and September 30, 2017 and collecting analytics on the viewership. By June 30, 2019 this approach attracted 41 305 viewers. The second experiment was more controlled and conducted on a private YouTube channel and the videos were advertised to reach a high number of viewers. This attracted 188 154 viewers and we collected data on viewers' behaviour using YouTube Analytics. We investigated the nature of engagement, which was defined by 22 different parameters.

Results

In the first experiment, there were clear differences in all measured parameters of engagement based on the topic of the video. Episodes on pandemics (14 594 views) and human evolution (10 761 views) were clear outliers, while the remaining 8 episodes received between 1110 and 3197 views. In the second experiment, there were several clear differences between the 10 videos in the parameters analysed through YouTube Analytics. Episode 2 on maternal and child health had the highest view rate (18.90%), followed by Episode 7 on international organisations in global health (16.83%). At the bottom of the rank were Episode 6 on ageing and dying (view rate of 13.83%) and Episode 5 on non-communicable diseases (view rate 14.59%).

Conclusions

We determined that 5 main interdependent factors contributed to the success or failure of our global health videos: Responsive content, timing, contribution to public debate, emotional valency and endorsement from an authentic scientific voice with a strong public profile. Several of these factors are also recognised as important in marketing research which may indicate the value of such techniques for use in a global health context. In order to communicate long term sustainable solutions to complex issues in a capricious media landscape focused on transient issues the global health community needs to embrace novel marketing approaches.

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<![CDATA[Analysis of public engagement with ten major global health topics on a social network profile and a newspaper website]]> https://www.researchpad.co/article/Nfefaa75f-8e4c-4445-8ad6-5caf91d38138

Background

Efforts in global health and development have broad political support and substantial financial commitment from most governments. However, this support could be greater if global health issues featured more prominently in the public debate. It has proven quite difficult to make global health issues attractive for viewing and engaging with, as compared to other forms of entertainment or public debates in the media.

Methods

Within the Massive Open Online Course “Survival: The Story of Global Health”, we created 10 educational videos on major global health topics. Between August 1 and September 30, 2017, we posted each episode with a brief background text on the Facebook profile of the narrator, who had an average of 450 friends and further 800 followers throughout the period of study. We studied the interaction of Facebook friends and followers with each posted video, tracing the number of their “likes”, “shares” and “comments”. Moreover, a popular Croatian online newspaper portal with about 250 000 daily viewers shared three of these stories after they were posted on Facebook and views, shares and comments were monitored. We recorded the effect on the number of YouTube views of the featured videos.

Results

The 10 posts received between 65 and 274 “likes” on the Facebook profile and between 2 and 124 shares, receiving between 0 and 17 comments. The three episodes that were shared by the online newspaper portal were further shared between 164 and 2820 times, receiving between 8 and 111 comments from the general public. The effect of these two promotion channels on YouTube viewership resulted in between 107 and 9784 views of the 10 featured videos, with the number of “likes” received on YouTube ranging between 0 and 43. The video that raised the most attention and shares was the one on the history of pandemics, which also had the highest number of shares on YouTube (n=69), followed by the video on human evolution (n = 14). Topics of non-communicable diseases, ageing and dying, and the future of humanity were also popular, while the topics more specific to global health raised less interest - ie, maternal and child mortality, major infectious diseases, international organizations, inequality and equity, and the UN Millennium Development Goals.

Conclusion

Our study showed that the interest in “core” global health topics was, as a rule, lower than in the topics which have a more general appeal - such as pandemic threat, human origins, ageing and dying. If we aim to increase public interest in global health topics, a feasible strategy would be to adjust the language and presentation used to be of more appeal to popular culture. Linking promotional materials to other popular topics that are dominating the public debate or capturing their interest could prove to be a successful strategy to achieve this.

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<![CDATA[Effective approaches to public engagement with global health topics]]> https://www.researchpad.co/article/Nca773a2c-bd49-40a7-8ae0-42aca2c36a60

Background

“Public engagement” in science is a term that covers a broad spectrum of activities undertaken by the scientific community. The precise definitions are constantly evolving to incorporate new means of engagement, facilitated by emerging technologies. Global health research is amenable to community engagement and popularization, but it is difficult to know which strategies work best to attract considerable attention from the public.

Methods

This is a review of the articles and documents that address the question of public engagement with topics in medical sciences, particularly in global health. Semantic searches were conducted using Google Scholar rather than indexed databases due to poor indexing of the topic. More than 1000 titles were screened and 48 articles were retained as most useful. It then moves to a more specific topic of the online public engagement in global health.

Results

The review presents the attempts to define public engagement in science and its general importance, particularly in the field of global health. Examples of the latter include tobacco use, vaccination, and maternal and child health. In reviewing effective approaches to public engagement in global health through online video campaigns, it studies the examples of crowdfunding, USAID’s First Public Engagement Campaign, World Health Organization's Social Media Campaigns and the impact of Global Health Media Project.

Conclusions

This review reveals three key gaps in the understanding of determinants of effective online public engagement in global health. The mixed results of traditional mass media campaigns in global health emphasise the calls for more research on message content. A framework for effective message content would help in both raising awareness of key issues and creating behaviour change in the general public. Moreover, it is surprising to find no formal research on what constitutes effective video content in global health. Finally, few studies considered important metrics to track in social media campaigns. There is a clear need to investigate which video features are effective in global health online public engagement. Success will be defined through key video marketing metrics and tracked in order to isolate effective content features.

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<![CDATA[High Incidence of Active Tuberculosis in Asylum Seekers from Eritrea and Somalia in the First 5 Years after Arrival in the Netherlands]]> https://www.researchpad.co/article/Nc8af2d48-d8ba-4dff-a071-b7ce5fd281b7

Three quarters of tuberculosis (TB) patients in the Netherlands are foreign-born; 26% are from Eritrea or Somalia. We analyzed TB incidence rates in asylum seekers from Eritrea and Somalia in the first 5 years after arrival in the Netherlands (2013–2017) and performed survival analysis with Cox proportional hazards regression to analyze the effect of age and sex on the risk for TB. TB incidence remained high 5 years after arrival in asylum seekers from Eritrea (309 cases/100,000 person-years) and Somalia (81 cases/100,000 person-years). Age >18 years was associated with a higher risk for TB in asylum seekers from Eritrea (3.4 times higher) and Somalia (3.7 times higher), and male sex was associated with a 1.6 times higher risk for TB in asylum seekers from Eritrea. Screening and treating asylum seekers from high-incidence areas for latent TB infection upon arrival would further reduce TB incidence in the Netherlands.

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<![CDATA[Metabolite identification, tissue distribution, excretion and preclinical pharmacokinetic studies of ET-26-HCl, a new analogue of etomidate]]> https://www.researchpad.co/article/N3e9af32e-8f30-4f74-9015-60afcc66f723

ET-26-HCl, a novel anaesthetic agent with promising pharmacological properties, lacks extensive studies on pharmacokinetics and disposition in vitro and in vivo. In this study, we investigated the metabolic stability, metabolite production and plasma protein binding (PPB) of ET-26-HCl along with its tissue distribution, excretion and pharmacokinetics in animals after intravenous administration. Ultra-high performance liquid chromatography–tandem quadrupole time-of-flight mass spectrometry identified a total of eight new metabolites after ET-26-HCl biotransformation in liver microsomes from different species. A hypothetical cytochrome P450-metabolic pathway including dehydrogenation, hydroxylation and demethylation was proposed. The PPB rate was highest in mouse and lowest in human. After intravenous administration, ET-26-HCl distributed rapidly to all tissues in rats and beagle dogs, with the highest concentrations in fat and liver. High concentrations of ET-26-acid, a major hydroxylation metabolite of ET-26-HCl, were found in liver, plasma and kidney. Almost complete clearance of ET-26-HCl from plasma occurred within 4 h after administration. Only a small fraction of the parent compound and its acid form were excreted via the urine and faeces. Taken together, the results added to a better understanding of the metabolic and pharmacokinetic properties of ET-26-HCl, which may contribute to the further development of this drug.

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<![CDATA[Continuous professional development: elevating sleep andbreathing disorder education in Europe]]> https://www.researchpad.co/article/Nb3e702d1-e87a-423d-9bee-14e1a082cccb

Sleep and breathing disorders are highly prevalent, representing a growing subspecialty of respiratory medicine. The term sleep disordered breathing (SDB) encompasses a range of conditions characterised by abnormal breathing during sleep, from chronic or habitual snoring, to frank obstructive sleep apnoea (OSA) or, in some cases, central sleep apnoea (CSA) and hypoventilation syndromes. OSA is the commonest form of SDB, leading to many potential consequences and adverse clinical outcomes, including excessive daytime sleepiness, impaired daytime function, metabolic dysfunction, and an increased risk of cardiovascular disease and mortality [1]. The estimated reported prevalence of moderate-to-severe SDB (≥15 events·h−1) was 23.4% in women and 49.7% in men, and the prevalence of symptomatic OSA was 9% and 13%, respectively [2]. However, in some populations, the prevalence of OSA is substantially higher, such as in patients been evaluated for bariatric surgery (estimated range 70–80%), in patients who have had a transient ischaemic attack or stroke (estimated range 60–70%) and in patients with cardiometabolic disease [3–6]. Limited data have been reported on CSA and non-obstructive sleep-related hypoventilation, which have received considerable interest in the sleep field within the past 10 years. Even if their prevalence was noted to be quite low relative to the prevalence of OSA [7], they are quite common in specific subpopulations [8–10].

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<![CDATA[Screening for obstructive sleep apnoea in professional drivers]]> https://www.researchpad.co/article/N2337233f-1c86-4077-9bcc-ecf815160c25

Professional drivers show a higher prevalence of obstructive sleep apnoea (OSA) compared with the general population. Furthermore, there is concern about the association between OSA and car crash risk given that drivers with OSA show an increased risk for car accidents. Despite this risk, OSA is often underdiagnosed and undertreated in this population, mainly due to lack of appropriate screening and sleep study referrals. Polysomnography (PSG), the gold standard test, is inappropriate for systematic screening because of its high expense, complexity and relative inaccessibility in this population. Therefore, there is a strong demand for good screening tools, including both subjective and objective data that may assist in early identification of possible OSA among professional drivers and, thus, aid in PSG examination referral and OSA management in an accredited sleep centre. However, there is considerable disagreement over screening methods and criteria for triggering a sleep study referral in different countries. There is also a strong need for further research in the area of OSA screening of commercial drivers in order to improve the diagnostic accuracy of screening tools and ensure that patients with OSA are accurately identified.

Key points

  • Obstructive sleep apnoea (OSA) is often undiagnosed and undertreated in professional drivers.

  • Professional drivers often under-report and are reluctant to report OSA symptoms.

  • Barriers to OSA diagnosis include appropriate screening and sleep study referrals.

  • Screening tools including both subjective and objective data may assist in early identification of possible OSA among professional drivers.

Educational aims

  • To evaluate screening instruments currently used to identify OSA risk in professional drivers.

  • To provide guidance for developing an assessment strategy for OSA by professional driver medical examiners.

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<![CDATA[Charge-Balanced Electrical Stimulation Can Modulate Neural Precursor Cell Migration in the Presence of Endogenous Electric Fields in Mouse Brains]]> https://www.researchpad.co/article/Nbddecc0c-ed5f-4413-8ae5-4050a029bb8d

Abstract

Electric fields (EFs) can direct cell migration and are crucial during development and tissue repair. We previously reported neural precursor cells (NPCs) are electrosensitive cells that can undergo rapid and directed migration towards the cathode using charge-balanced electrical stimulation in vitro. Here, we investigate the ability of electrical stimulation to direct neural precursor migration in mouse brains in vivo. To visualize migration, fluorescent adult murine neural precursors were transplanted onto the corpus callosum of adult male mice and intracortical platinum wire electrodes were implanted medial (cathode) and lateral (anode) to the injection site. We applied a charge-balanced biphasic monopolar stimulation waveform for three sessions per day, for 3 or 6 d. Irrespective of stimulation, the transplanted neural precursors had a propensity to migrate laterally along the corpus callosum, and applied stimulation affected that migration. Further investigation revealed an endogenous EF along the corpus callosum that correlated with the lateral migration, suggesting that the applied EF would need to overcome endogenous cues. There was no difference in transplanted cell differentiation and proliferation, or inflammatory cell numbers near the electrode leads and injection site comparing stimulated and implanted non-stimulated brains. Our results support that endogenous and applied EFs are important considerations for designing cell therapies for tissue repair in vivo.

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<![CDATA[Patient-defined outcomes for pain, fatigue, emotional distress, and interference with activities did not differ by age for individuals with musculoskeletal pain]]> https://www.researchpad.co/article/N25b7bcf4-f33d-4ccb-8603-5f13c2928e5b

Abstract

Introduction:

Age impacts the prevalence and experience of musculoskeletal pain; however, it is unknown whether this factor impacts patient's anticipated outcomes after treatment.

Objective:

Using the Patient-Centered Outcomes Questionnaire (PCOQ), the primary purpose was to determine whether there are age-related differences in desired, successful, expected levels, and importance of improvement in pain, fatigue, emotional distress, and interference with daily activities. As a secondary purpose, anatomical location and sex were then included in the model to examine for interaction effects.

Methods:

A secondary analysis of the Optimal Screening for Prediction of Referral and Outcome cross-sectional and longitudinal cohorts was conducted. Included in this analysis were 572 individuals seeking physical therapy for nonsurgical neck, low back, shoulder, and knee pain who completed the PCOQ at the initial evaluation. A three-way analysis of variance examined PCOQ domains by age categories, sex, and anatomical location.

Results:

Interaction effects were not observed for any of the domains of interest (P > 0.01). Significant main effects were also not observed for age, sex, and anatomical location (P > 0.01).

Conclusion:

Musculoskeletal pain prevalence may differ across age categories but, in this cohort, neither age, nor sex, nor anatomical location impacted patient-defined outcomes for intensity, fatigue, emotional distress, and interference with daily activities.

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<![CDATA[Oxygen for the treatment of obstructive sleep apnoea hypopnoea syndrome]]> https://www.researchpad.co/article/Nd9555766-12e9-4f50-a8e4-dc85e364b44d

Oxygen, in the form of diatomic oxygen (O2), comprises 20.8% of the Earth's atmosphere and is essential to most life forms on the planet. In 1777, Lavoisier was the first to name oxygen and recognise that it was a chemical element involved in combustion.

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<![CDATA[Atti del 52° Congresso Nazionale]]> https://www.researchpad.co/article/N40742df4-0c85-42be-960e-c80df7e02214

Nel promuovere e gestire i cambiamenti necessari per coniugare pratiche sicure ed efficaci con l’efficienza, l’equità e la sostenibilità dei servizi sanitari, essenziale è la conoscenza, la diffusione e l’adesione alle raccomandazioni per la pratica professionale derivanti da linee guida (LG). In Italia la Legge 24/2017 (“Disposizioni in materia di sicurezza delle cure e della persona assistita, nonché in materia di responsabilità professionale degli esercenti le professioni sanitarie”), stabilendo che “gli esercenti le professioni sanitarie, nell’esecuzione delle prestazioni sanitarie con finalità preventive, diagnostiche, terapeutiche, palliative, riabilitative e di medicina legale, si attengono, salve le specificità del caso concreto, alle raccomandazioni previste dalle linee guida pubblicate ed elaborate da enti e istituzioni pubblici e privati nonché dalle società scientifiche e dalle associazioni tecnico-scientifiche delle professioni sanitarie iscritte in apposito elenco”, ha rinnovato l’impulso legislativo, culturale, professionale e scientifico alla diffusione delle LG nel Servizio Sanitario Nazionale. L’attuale quadro regolamentare italiano prevede che la loro produzione venga garantita sulla base degli standard di predisposizione e valutazione della qualità metodologica definiti dal Centro Nazionale per l’Eccellenza Clinica (CNEC) dell’Istituto Superiore di Sanità, punto di riferimento per l’attuazione del nuovo Sistema Nazionale Linee Guida (istituito con il DM 27 febbraio 2018) (https://snlg.iss.it).

Secondo la vigente definizione adottata dal CNEC, le LG sono uno “strumento di supporto decisionale finalizzato a consentire che, fra opzioni alternative, sia adottata quella che offre un migliore bilancio fra benefici ed effetti indesiderati, tenendo conto della esplicita e sistematica valutazione delle prove disponibili, commisurandola alle circostanze peculiari del caso concreto e condividendola-laddove possibile-con il paziente o i caregiver”. Le linee guida servono dunque a supportare i processi decisionali che connotano la pratica professionale preventiva, diagnostica, terapeutica e assistenziale, ma anche le scelte manageriali e le politiche sanitarie. Ai diversi livelli del sistema sanitario, infatti, la disponibilità di LG è fondamentale per contrastare alcune delle criticità sistemiche della sanità connesse, tra l’altro, all’erogazione di cure di qualità sub-ottimale, alla variazione ingiustificata di pratiche ed esiti e alle diseguaglianze, in un quadro di risorse limitate.

Se dunque oggi il valore delle linee guida per la pratica clinica è indiscutibile in tutti gli ambiti disciplinari della medicina, peculiare è il significato, professionale e organizzativo, che le stesse possono assumere nello sviluppo e nella specifica applicazione alla sanità pubblica. In particolare, la sanità pubblica si caratterizza per: la forte eterogeneità nelle evidenze scientifiche disponibili (non di rado costituite solamente da studi osservazionali), l’adozione di un approccio di population health e la frequente individuazione di target costituiti da persone sane, la molteplicità (anche in relazione all’importanza attribuita dagli stakeholder coinvolti) degli ambiti di produzione di linee guida (www.who.int/publications/guidelines), degli interventi sanitari e degli outcome individuati nei contesti reali (e non di ricerca), condizionati da una molteplicità di variabili culturali, organizzative, socio-economiche e ambientali.

Spesso le raccomandazioni prodotte in sanità pubblica sono destinate ad avere un impatto quali-quantitativamente molto rilevante sul sistema sanitario e necessitano di modelli in grado di prevederne l’implementazione, non sempre agevolmente correlabili alle evidenze scientifiche disponibili a priori. Altresì, il percorso di costruzione del consenso e implementazione degli interventi è articolato e complesso. In misura maggiore rispetto ad altre discipline mediche, i comportamenti degli operatori non si basano solo sulle conoscenze tecnico-scientifiche disponibili (talora limitate e non sempre esplicitamente generalizzabili), ma risentono e sono condizionati da dettati normativi, meccanismi di consenso locale, eterogeneità di strutture erogatrici e risorse (professionali, organizzative e tecnologiche), nonché da relazioni con una molteplicità di portatori di interesse dentro e fuori il sistema sanitario (che a loro volta esprimono valori e preferenze anche contrastanti).

Il metodo scelto dal CNEC (e adottato anche dall’Agenzia Italiana del Farmaco per le valutazioni di propria competenza) per la produzione di linee guida è il metodo GRADEGrading of Recommendations Assessment, Development and Evaluation – che costituisce oggi la principale cornice riferimento per la valutazione di affidabilità delle prove scientifiche e per la formulazione di raccomandazioni cliniche basate sulle evidenze in sanità: viene utilizzato da più di 100 organizzazioni in tutto il mondo comprendenti anche l’Organizzazione Mondiale della Sanità e il National Institute for Health and Care Excellence (www.gradeworkinggroup.org). Il GRADE assicura standardizzazione e trasparenza della procedura con cui viene valutata la qualità delle prove disponibili e la forza delle raccomandazioni per la produzione di linee guida, favorendo una valutazione integrata della qualità metodologica delle prove disponibili con altri aspetti che devono essere considerati per sviluppare e stabilire la forza di una raccomandazione, mediante i cosiddetti Evidence to Decision Framework, quali: priorità della problematica trattata (es. impatto sanitario, variabilità, costi), benefici e rischi attesi, valori e preferenze dei pazienti, costo-efficacia, accettabilità, fattibilità ed equità. Il GRADE offre un approccio flessibile e pragmatico che può essere applicato sia alla produzione di una linea guida ex novo che all’adattamento di linee guida già esistenti, per le quali si applicano gli schemi di GRADE-ADOLOPMENT, calibrati su un determinato contesto culturale e organizzativo. Il panel di esperti (gruppi di lavoro multidisciplinari e multistakeholder che sistematicamente devono coinvolgere anche utenti/cittadini) definisce chiaramente la domanda di ricerca, il protocollo condiviso secondo l’acronimo PICO (Patient-Intervention-Comparator-Outcome) per l’analisi della qualità delle prove di evidenza ed esprimere giudizi sui diversi criteri di valutazione necessari alla formulazione e valutazione della forza delle raccomandazioni. Mediante una gestione trasparente (e una particolare attenzione alla disclosure e alla gestione dei conflitti di interesse dei membri dei panel), fortemente ancorata al mondo reale, con il processo di “evidence to decision” il GRADE si pone l’obiettivo di ordinare per gradi la forza delle raccomandazioni espresse dai panel di esperti in modo da offrire strumenti interpretativi e decisionali per pazienti/utenti, clinici e decisori sanitari. La rappresentatività e il coinvolgimento con modalità strutturate di tutte le figure competenti e rilevanti per i quesiti e sulle raccomandazioni in oggetto costituisce un aspetto fondamentale di qualità e credibilità della linea guida.

Accanto alla chiara affinità tra metodo GRADE e logiche epidemiologiche e di centralità di un approccio multidimensionale, multidisciplinare e inter-professionale che caratterizza il processo decisionale in sanità pubblica, è interessante evidenziare l’opportunità della promozione dell’applicazione del GRADE per gli igienisti sia nella veste di proponenti, esperti per gli ambiti tecnico-scientifici di propria competenza e destinatari “professionali” delle raccomandazioni, che in qualità di manager e decisori che possono essere coinvolti nei panel (anche su pratiche di non esclusiva pertinenza della sanità pubblica), nonché, naturalmente di metodologi, parte dei team di revisione della letteratura e a supporto dell’utilizzo del metodo stesso che richiede una specifica formazione e competenza.

Gli indirizzi sulle LG comprendono anche la fase di implementazione attinente come a partire dalle raccomandazioni prodotte e diffuse si riesce ad incidere sui comportamenti professionali, ovvero colmare il gap tra ricerca e pratica professionale. Questo richiede leadership e facilitazione del giusto mix di interventi (preferibilmente multifattoriali) di supporto al cambiamento (audit & feedback, interventi formativi mirati, processi di consenso locali, uso di strumenti di comunicazione, ecc), calibrati su ostacoli e fattori favorenti l’adozione delle linee guida. L’implementazione di LG promuove la gestione e la condivisione di informazioni, conoscenze e pratiche che favoriscono un approccio trasversale rispetto alle funzioni e ai team di lavoro che promuove l’integrazione (sia all’interno che con l’esterno delle organizzazioni sanitarie) e può assicurare processi decisionali più affidabili ed efficienti.

La coerenza tra raccomandazioni per l’ottimizzazione dell’efficacia e altre dimensioni della qualità dell’intervento sanitario (quali sicurezza, accessibilità ed equità) con le esigenze di efficienza e razionalità organizzativa dei servizi configura un importante ancoraggio delle LG al paradigma emergente del valore in sanità. Costruire una sanità basata sul valore implica una chiara analisi del profilo di efficacia degli interventi sanitari e la disponibilità di robusti strumenti valutativi e infrastrutture digitali di supporto alla misurazione accurata e tempestiva dei dati epidemiologici della popolazione, da trasformare in informazioni cliniche rilevanti per integrare e analizzare tutti i passaggi (e i risultati ottenuti) del ciclo di assistenza in oggetto e da correlare costantemente con i costi sostenuti dal sistema sanitario. Massimizzare il valore, ovvero gli esiti prodotti in relazione alle risorse a disposizione, per gli individui e le popolazioni presuppone l’adozione di criteri di finanziamento e di gestione delle risorse (umane e organizzative) e soluzioni tecnologiche che facilitino la costruzione di reti e percorsi, da coniugare con la capacità di tradurre i risultati della ricerca sanitaria e le best practice in raccomandazioni. D’altro canto, la diffusione di pratiche sicure, efficaci e appropriate consente di concorrere in maniera determinante all’uniformità di tassonomia, modelli e comportamenti professionali in contesti decisionali affini, ovvero di contribuire a standardizzare l’operatività dei servizi, aspetto quest’ultimo rilevante nel contesto della sanità pubblica italiana e delle sue articolazioni operative territoriali.

L’adozione di linee guida ovviamente presenta anche aspetti di criticità, legati all’effettiva traduzione dei risultati della ricerca e dell’innovazione in comportamenti professionali diffusi e virtuosi; ma anche all’adeguatezza delle LG e dei correlati processi decisionali di fronte a quesiti o target di popolazione per loro natura complessi, come quelli che si incontrano per esempio nel produrre indirizzi che siano effettivamente rispondenti alle esigenze di prevenzione e personalizzazione dell’assistenza del “paziente complesso”. A ciò vanno aggiunte alcune difficoltà organizzative e professionali che connotano l’odierna fase di avvio della concreta applicazione del metodo GRADE allo sviluppo delle raccomandazioni per la pratica clinica proposto nel “nuovo Sistema Nazionale Linee Guida”. Per esempio, rispetto alla sanità pubblica, pur esistendo oggi molte LG autorevoli e di diffusa applicazione, queste spesso risultano essere datate e realizzate con meccanismi di consenso e formulazione delle raccomandazioni di tipo tradizionale, rendendo dunque necessari aggiornamenti e adattamenti secondo le menzionate modalità di lavoro proposte a livello nazionale e internazionale per produrre linee guida di alta qualità.

Per operare nel quadro della nuova cornice metodologica sulle LG, ai medici e agli altri professionisti sanitari, ai manager e ai policy maker della sanità, al mondo accademico e alle società scientifiche è richiesto un investimento prioritario nella gestione di conoscenze fondate su un approccio scientifico, strutturato e trasparente alla definizione dell’efficacia e dell’appropriatezza degli interventi medici. In questo contesto nazionale, per gli igienisti in collaborazione con tutti gli attori della Sanità Pubblica, è strategico un impegno permanente sulla tematica delle linee guida, da sostenere anche mediante azioni di formazione, condivisione di conoscenza e di comunicazione. Valorizzare l’applicazione critica di strumenti per governare i processi decisionali secondo logiche di partecipazione e fiducia reciproca tra gli stakeholder è fondamentale per il perseguimento degli obiettivi di ottimizzazione della qualità e della sostenibilità nel Servizio Sanitario Nazionale, a beneficio dei cittadini-pazienti e della società nella sua globalità.

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<![CDATA[TELEPRO: Patient‐Reported Carcinoid Syndrome Symptom Improvement Following Initiation of Telotristat Ethyl in the Real World]]> https://www.researchpad.co/article/N7e871d18-350a-4ad0-ac43-fe12ddb361de

Patients with carcinoid syndrome diarrhea that is not controlled with long‐acting somatostatin analogs can benefit from the addition of the tryptophan hydroxylase inhibitor, telotristat ethyl. This article evaluates the real‐world effectiveness of telotristat ethyl using patient‐reported data.

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<![CDATA[Characterization of mammalian Lipocalin UTRs in silico: Predictions for their role in post-transcriptional regulation]]> https://www.researchpad.co/article/5c897780d5eed0c4847d2e76

The Lipocalin family is a group of homologous proteins characterized by its big array of functional capabilities. As extracellular proteins, they can bind small hydrophobic ligands through a well-conserved β-barrel folding. Lipocalins evolutionary history sprawls across many different taxa and shows great divergence even within chordates. This variability is also found in their heterogeneous tissue expression pattern. Although a handful of promoter regions have been previously described, studies on UTR regulatory roles in Lipocalin gene expression are scarce. Here we report a comprehensive bioinformatic analysis showing that complex post-transcriptional regulation exists in Lipocalin genes, as suggested by the presence of alternative UTRs with substantial sequence conservation in mammals, alongside a high diversity of transcription start sites and alternative promoters. Strong selective pressure could have operated upon Lipocalins UTRs, leading to an enrichment in particular sequence motifs that limit the choice of secondary structures. Mapping these regulatory features to the expression pattern of early and late diverging Lipocalins suggests that UTRs represent an additional phylogenetic signal, which may help to uncover how functional pleiotropy originated within the Lipocalin family.

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