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Hydraulic failure due to xylem embolism has been identified as one of the main mechanisms involved in drought-induced forest decline. Trees vulnerability to hydraulic failure depends on their hydraulic safety margin (HSM). While it has been shown that HSM globally converges between tree species and biomes, there is still limited knowledge regarding how HSM can adjust locally to varying drought conditions within species. In this study, we relied on three long-term partial rainfall exclusion experiments to investigate the plasticity of hydraulic traits and HSM for three Mediterranean tree species (Quercus ilex L., Quercus pubescens Willd., and Pinus halepensis Mill.). For all species, a homeostasis of HSM in response to rainfall reduction was found, achieved through different mechanisms. For Q. ilex, the convergence in HSM is attributed to the adjustment of both the turgor loss point (Ψtlp) and the water potential at which 50% of xylem conductivity is lost due to embolism (P50). In contrast, the maintenance of HSM for P. halepensis and Q. pubescens is related to its isohydric behavior for the first and leaf area adjustment for the latter. It remains to be seen whether this HSM homeostasis can be generalized and if it will be sufficient to withstand extreme droughts expected in the Mediterranean region.
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In the Mediterranean region, a reduction of annual precipitation and a longer and drier summer season are expected with climate change by the end of the century, eventually endangering forest survival. To cope with such rapid changes, trees may modulate their morpho-anatomical and physiological traits. In the present study, we focused on the variation in leaf gas exchange and different leaf morpho-anatomical functional traits of Quercus pubescens Willd. in summer using a long-term drought experiment in natura consisting of a dynamic rainfall exclusion system where trees have been submitted to amplified drought (AD) (~-30% of annual precipitation) since April 2012 and compared them with trees under natural drought (ND) in a Mediterranean forest. During the study, we analyzed net CO2 assimilation (An), stomatal conductance (gs), transpiration (E), water-use efficiency (WUE), stomatal size and density, density of glandular trichomes and non-glandular trichomes, thickness of the different leaf tissues, specific leaf area and leaf surface. Under AD, tree functioning was slightly impacted, since only An exhibited a 49% drop, while gs, E and WUE remained stable. The decrease in An under AD was regulated by concomitant lower stomatal density and reduced leaf thickness. Trees under AD also featured leaves with a higher non-glandular trichome density and a lower glandular trichome density compared with ND, which simultaneously limits transpiration and production costs. This study points out that Q. pubescens exhibits adjustments of leaf morpho-anatomical traits which can help trees to acclimate to AD scenarios as those expected in the future in the Mediterranean region.
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Sequías , Bosques , Hojas de la Planta , Quercus , Quercus/fisiología , Quercus/anatomía & histología , Hojas de la Planta/fisiología , Hojas de la Planta/anatomía & histología , Lluvia , Transpiración de Plantas/fisiología , Árboles/fisiología , Árboles/anatomía & histología , Cambio Climático , Estomas de Plantas/fisiología , Estomas de Plantas/anatomía & histologíaRESUMEN
OBJECTIVE: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints. METHODS: Longitudinal analysis of peripheral blood and SG biopsies was performed pre- and post-treatment from the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing. RESULTS: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class-switched memory B cells within the SG. Furthermore, rituximab significantly down-regulated genes involved in immune-cell recruitment, lymphoid organization alongside antigen presentation, and T cell co-stimulatory pathways. In the peripheral compartment, rituximab down-regulated immunoglobulins and auto-antibodies together with pro-inflammatory cytokines and chemokines. Interestingly, patients classified as responders according to STAR displayed significantly higher baseline levels of C-X-C motif chemokine ligand-13 (CXCL13), interleukin (IL)-22, IL-17A, IL-17F, and tumor necrosis factor-α (TNF-α), whereas a longitudinal analysis of serum T cell-related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS-responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ-receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration. CONCLUSION: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification.
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BACKGROUND: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting. METHODS: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants. FINDINGS: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication. INTERPRETATION: To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).
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Síndrome del Colon Irritable , Humanos , Masculino , Femenino , Persona de Mediana Edad , Síndrome del Colon Irritable/tratamiento farmacológico , Amitriptilina/efectos adversos , Inglaterra , Método Doble Ciego , Atención Primaria de Salud , Resultado del TratamientoRESUMEN
With climate change, an aggravation in summer drought is expected in the Mediterranean region. To assess the impact of such a future scenario, we compared the response of Quercus pubescens, a drought-resistant deciduous oak species, to long-term amplified drought (AD) (partial rain exclusion in natura for 10 years) and natural drought (ND). We studied leaf physiological and physico-chemical trait responses to ND and AD over the seasonal cycle, with a focus on chemical traits including major groups of central (photosynthetic pigments and plastoquinones) and specialized (tocochromanols, phenolic compounds, and cuticular waxes) metabolites. Seasonality was the main driver of all leaf traits, including cuticular triterpenoids, which were highly concentrated in summer, suggesting their importance to cope with drought and thermal stress periods. Under AD, trees not only reduced CO2 assimilation (-42%) in summer and leaf concentrations of some phenolic compounds and photosynthetic pigments (carotenoids from the xanthophyll cycle) but also enhanced the levels of other photosynthetic pigments (chlorophylls, lutein, and neoxanthin) and plastochromanol-8, an antioxidant located in chloroplasts. Overall, the metabolomic adjustments across seasons and drought conditions reinforce the idea that Q. pubescens is highly resistant to drought although significant losses of antioxidant defenses and photoprotection were identified under AD.
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Quercus , Quercus/metabolismo , Antioxidantes/metabolismo , Estaciones del Año , Bosques , Lluvia , Hojas de la Planta/metabolismo , Árboles/metabolismo , Sequías , Agua/metabolismoRESUMEN
The metabolome is the biochemical basis of plant form and function, but we know little about its macroecological variation across the plant kingdom. Here, we used the plant functional trait concept to interpret leaf metabolome variation among 457 tropical and 339 temperate plant species. Distilling metabolite chemistry into five metabolic functional traits reveals that plants vary on two major axes of leaf metabolic specialization-a leaf chemical defense spectrum and an expression of leaf longevity. Axes are similar for tropical and temperate species, with many trait combinations being viable. However, metabolic traits vary orthogonally to life-history strategies described by widely used functional traits. The metabolome thus expands the functional trait concept by providing additional axes of metabolic specialization for examining plant form and function.
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Longevidad , Metaboloma , Fenotipo , Hojas de la PlantaRESUMEN
OBJECTIVE: To determine the effectiveness of risk stratification using the Global Registry of Acute Coronary Events (GRACE) risk score (GRS) for patients presenting to hospital with suspected non-ST elevation acute coronary syndrome. DESIGN: Parallel group cluster randomised controlled trial. SETTING: Patients presenting with suspected non-ST elevation acute coronary syndrome to 42 hospitals in England between 9 March 2017 and 30 December 2019. PARTICIPANTS: Patients aged ≥18 years with a minimum follow-up of 12 months. INTERVENTION: Hospitals were randomised (1:1) to patient management by standard care or according to the GRS and associated guidelines. MAIN OUTCOME MEASURES: Primary outcome measures were use of guideline recommended management and time to the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospital admission, and readmission for cardiovascular event. Secondary measures included the duration of hospital stay, EQ-5D-5L (five domain, five level version of the EuroQoL index), and the composite endpoint components. RESULTS: 3050 participants (1440 GRS, 1610 standard care) were recruited in 38 UK clusters (20 GRS, 18 standard care). The mean age was 65.7 years (standard deviation 12), 69% were male, and the mean baseline GRACE scores were 119.5 (standard deviation 31.4) and 125.7 (34.4) for GRS and standard care, respectively. The uptake of guideline recommended processes was 77.3% for GRS and 75.3% for standard care (odds ratio 1.16, 95% confidence interval 0.70 to 1.92, P=0.56). The time to the first composite cardiac event was not significantly improved by the GRS (hazard ratio 0.89, 95% confidence interval 0.68 to 1.16, P=0.37). Baseline adjusted EQ-5D-5L utility at 12 months (difference -0.01, 95% confidence interval -0.06 to 0.04) and the duration of hospital admission within 12 months (mean 11.2 days, standard deviation 18 days v 11.8 days, 19 days) were similar for GRS and standard care. CONCLUSIONS: In adults presenting to hospital with suspected non-ST elevation acute coronary syndrome, the GRS did not improve adherence to guideline recommended management or reduce cardiovascular events at 12 months. TRIAL REGISTRATION: ISRCTN 29731761.
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Síndrome Coronario Agudo , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/terapia , Hospitalización , Hospitales , Sistema de Registros , Factores de Riesgo , Persona de Mediana EdadRESUMEN
INTRODUCCIÓN: COVID-19 cobró millones de vidas especialmente en la era pre-vacunas. Estudios preliminares mostraban eficacia promisoria del plasma de personas convalecientes anti SARS-CoV-2 (PPC). Objetivo: evaluar la eficacia del PPC en hospitalizados por COVID-19 de moderada gravedad. MATERIAL Y MÉTODOS: Estudio retrospectivo, bicéntrico, en adultos hospitalizados por COVID-19 moderado (no crítico) que requirieron oxigenoterapia. Al plasma donado por sobrevivientes de cuadros leves (600 cc) se les realizó búsqueda de IgG anti SARS-CoV-2. Se evaluó su impacto en mortalidad, estadía hospitalaria (días) y necesidad de ventilación mecánica (VMI). RESULTADOS: De los 119 pacientes incluidos, 58% eran hombres (edad mediana 60 años), 88% poseía comorbilidad y 43% tenía "CALL score" de alto riesgo. 43 pacientes (36%) recibieron PPC, sólo 15 (12,6%) precozmente (< 7 días). 22 pacientes debieron trasladarse a unidad intensiva, 18 recibieron VMI y 15 fallecieron (12,6%). El uso de PPC no se asoció a cambios en la mortalidad (p = 0,16), necesidad de VMI (p = 0,79) ni en la estadía hospitalaria (p = 0,24). Su administración en forma precoz (< 7 días de síntomas) tampoco demostró asociación significativa. La presencia de cardiopatía y el requerir posteriormente VMI fueron factores independientes asociados a mortalidad. CONCLUSIONES: El uso de PPC en pacientes hospitalizados por COVID-19 de moderada gravedad no se asoció a menor mortalidad, estadía hospitalaria ni necesidad de VMI.
INTRODUCTION: COVID-19 claimed millions of lives, mainly in the pre-vaccine era. Preliminary studies showed promising efficacy of convalescent plasma against SARS-CoV-2 (CP). Objective: To evaluate the efficacy of CP in patients hospitalized for COVID-19 with moderate severity. METHODS: Retrospective, bicentric study including adults hospitalized for moderate (non-critical) COVID-19 who required oxygen therapy. CP donated by survivors of mild cases (600 cc) were searched for IgG anti-SARS-CoV-2. Its impact on mortality, hospital stay (days), and need for mechanical ventilation (IMV) was evaluated. RESULTS: Of the 119 patients included, 58% were men (median age 60 years), 88% had comorbidity, and 43% had a high-risk CALL score. Forty-three patients (36%) received CP, only 15 (12.6%) early (< 7 days). Twenty-two patients had to be transferred to the intensive care unit; 18 received IMV, and 15 died (12.6%). The use of CP was not associated with changes in mortality (p = 0.16), need for IMV (p = 0.79), or hospital stay (p = 0.24). Its early administration (< 7 days of symptoms) did not show a significant association either. The presence of heart disease and subsequently requiring IMV were independent factors of mortality. CONCLUSIONS: The use of CP in patients hospitalized for moderately severe COVID-19 was not associated with lower mortality, hospital stay, or the need for IMV.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Índice de Severidad de la Enfermedad , Inmunización Pasiva , SARS-CoV-2 , COVID-19/mortalidad , COVID-19/terapia , Sueroterapia para COVID-19 , Hospitalización/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Respiración Artificial/estadística & datos numéricos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
AIMS: Guidelines for suspected cardiac chest pain have used historical risk stratification tools, advocating invasive coronary angiography (ICA) first-line in those at highest risk. We aimed to determine whether different strategies to manage suspected stable angina affected medium-term cardiovascular event rates and patient-reported quality of life (QoL) measures. METHODS: CE-MARC 2, a three-arm parallel group trial, randomised patients with suspected stable cardiac chest pain and a Duke Clinical pretest likelihood of coronary artery disease between 10% and 90%. Patients were randomised to either first-line cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT) or the UK National Institute for Health and Care Excellence (NICE) CG95 (2010) guidelines-directed care. For the three arms, 1-year and 3-year first major adverse cardiovascular event (MACE) rates and QoL assessed by the Seattle Angina Questionnaire, Short Form 12 (V.12) Questionnaire and EuroQol-5 Dimension Questionnaire were recorded. RESULTS: 1202 patients were randomised to CMR (n=481), SPECT (n=481) and NICE (n=240). Forty-two patients (18 CMR, 18 SPECT, 6 NICE) experienced one or more MACEs. The percentage rates (95% CIs) of MACE in the CMR, SPECT and NICE groups at 3 years were 3.7% (2.4%, 5.8%), 3.7% (2.4%, 5.8%) and 2.1% (0.9%, 4.8%), respectively. QoL scores did not significantly differ across domains. CONCLUSION: Despite a fourfold increase in referrals for ICA, the NICE CG95 (2010) guidelines risk-stratified care strategy did not significantly reduce 3-year MACE or improve QoL, as compared with functional imaging with CMR or SPECT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT01664858).
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Angina Estable , Enfermedad de la Arteria Coronaria , Humanos , Calidad de Vida , Angiografía Coronaria/métodos , Dolor en el Pecho , Angina Estable/diagnóstico por imagen , Angina Estable/terapiaRESUMEN
OBJECTIVE: To analyze the impact of modern glucose-monitoring strategies on glycemic and patient-related outcomes in individuals with type 2 diabetes (T2D) and recent myocardial infarction (MI) and assess cost effectiveness. RESEARCH DESIGN AND METHODS: LIBERATES was a multicenter two-arm randomized trial comparing self-monitoring of blood glucose (SMBG) with intermittently scanned continuous glucose monitoring (isCGM), also known as flash CGM, in individuals with T2D and recent MI, treated with insulin and/or a sulphonylurea before hospital admission. The primary outcome measure was time in range (TIR) (glucose 3.9-10 mmol/L/day) on days 76-90 post-randomization. Secondary and exploratory outcomes included time in hypoglycemia, hemoglobin A1c (HbA1c), clinical outcome, quality of life (QOL), and cost effectiveness. RESULTS: Of 141 participants randomly assigned (median age 63 years; interquartile range 53, 70), 73% of whom were men, isCGM was associated with increased TIR by 17 min/day (95% credible interval -105 to +153 min/day), with 59% probability of benefit. Users of isCGM showed lower hypoglycemic exposure (<3.9 mmol/L) at days 76-90 (-80 min/day; 95% CI -118, -43), also evident at days 16-30 (-28 min/day; 95% CI -92, 2). Compared with baseline, HbA1c showed similar reductions of 7 mmol/mol at 3 months in both study arms. Combined glycemic emergencies and mortality occurred in four isCGM and seven SMBG study participants. QOL measures marginally favored isCGM, and the intervention proved to be cost effective. CONCLUSIONS: Compared with SMBG, isCGM in T2D individuals with MI marginally increases TIR and significantly reduces hypoglycemic exposure while equally improving HbA1c, explaining its cost effectiveness. Studies are required to understand whether these glycemic differences translate into longer-term clinical benefit.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Masculino , Humanos , Persona de Mediana Edad , Femenino , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada , Calidad de Vida , Automonitorización de la Glucosa Sanguínea/métodos , Hipoglucemiantes/uso terapéuticoRESUMEN
INTRODUCTION: COVID-19 claimed millions of lives, mainly in the pre-vaccine era. Preliminary studies showed promising efficacy of convalescent plasma against SARS-CoV-2 (CP). OBJECTIVE: To evaluate the efficacy of CP in patients hospitalized for COVID-19 with moderate severity. METHODS: Retrospective, bicentric study including adults hospitalized for moderate (non-critical) COVID-19 who required oxygen therapy. CP donated by survivors of mild cases (600 cc) were searched for IgG anti-SARS-CoV-2. Its impact on mortality, hospital stay (days), and need for mechanical ventilation (IMV) was evaluated. RESULTS: Of the 119 patients included, 58% were men (median age 60 years), 88% had comorbidity, and 43% had a high-risk CALL score. Forty-three patients (36%) received CP, only 15 (12.6%) early (< 7 days). Twenty-two patients had to be transferred to the intensive care unit; 18 received IMV, and 15 died (12.6%). The use of CP was not associated with changes in mortality (p = 0.16), need for IMV (p = 0.79), or hospital stay (p = 0.24). Its early administration (< 7 days of symptoms) did not show a significant association either. The presence of heart disease and subsequently requiring IMV were independent factors of mortality. CONCLUSIONS: The use of CP in patients hospitalized for moderately severe COVID-19 was not associated with lower mortality, hospital stay, or the need for IMV.
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Sueroterapia para COVID-19 , COVID-19 , Hospitalización , Inmunización Pasiva , Tiempo de Internación , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Humanos , COVID-19/terapia , COVID-19/mortalidad , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Femenino , Anciano , Hospitalización/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Resultado del Tratamiento , Adulto , Respiración Artificial/estadística & datos numéricosRESUMEN
Mangroves are the only forests located at the sea-land interface in tropical and subtropical regions. They are key elements of tropical coastal ecosystems, providing numerous ecosystem services. Among them is the production of specialized metabolites by mangroves and their potential use in agriculture to limit weed growth in cultures. We explored the in vitro allelopathic potential of eight mangrove species' aqueous leaf extracts (Avicennia marina, Kandelia obovata, Bruguiera gymnorhiza, Sonneratia apetala, Sonneratia caseolaris, Aegiceras corniculatum, Lumnitzera racemosa and Rhizophora stylosa) on the germination and growth of Echinochloa crus-galli, a weed species associated with rice, Oryza sativa. Leaf methanolic extracts of mangrove species were also studied via UHPLC-ESI/qToF to compare their metabolite fingerprints. Our results highlight that A. corniculatum and S. apetala negatively affected E. crus-galli development with a stimulating effect or no effect on O. sativa. Phytochemical investigations of A. corniculatum allowed us to putatively annotate three flavonoids and two saponins. For S. apetala, three flavonoids, a tannin and two unusual sulfated ellagic acid derivatives were found. Some of these compounds are described for the first time in these species. Overall, A. corniculatum and S. apetala leaves are proposed as promising natural alternatives against E. crus-galli and should be further assessed under field conditions.
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In Mediterranean ecosystems, the projected rainfall reduction of up to 30% may alter plant-soil interactions, particularly litter decomposition and Home Field Advantage (HFA). We set up a litter transplant experiment in the three main forests encountered in the northern part of the Medi-terranean Basin (dominated by either Quercus ilex, Quercus pubescens, or Pinus halepensis) equipped with a rain exclusion device, allowing an increase in drought either throughout the year or concentrated in spring and summer. Senescent leaves and needles were collected under two precipitation treatments (natural and amplified drought plots) at their "home" forest and were left to decompose in the forest of origin and in other forests under both drought conditions. MS-based metabolomic analysis of litter extracts combined with multivariate data analysis enabled us to detect modifications in the composition of litter specialized metabolites, following amplified drought treatment. Amplified drought altered litter quality and metabolomes, directly slowed down litter decomposition, and induced a loss of home field (dis)advantage. No indirect effect mediated by a change in litter quality on decomposition was observed. These results may suggest major alterations of plant-soil interactions in Mediterranean forests under amplified drought conditions.
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BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear. METHODS: ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care. DISCUSSION: Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. TRIAL REGISTRATION: ISRCTN ISRCTN48075063 . Registered on 7th June 2019.
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Amitriptilina , Síndrome del Colon Irritable , Adulto , Amitriptilina/administración & dosificación , Amitriptilina/efectos adversos , Método Doble Ciego , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Estudios Multicéntricos como Asunto , Atención Primaria de Salud , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
INTRODUCTION: Knee replacement (KR) is a clinically proven procedure typically offered to patients with severe knee osteoarthritis (OA) to relieve pain and improve quality of life. However, artificial joints fail over time, requiring revision associated with higher mortality and inferior outcomes. With more young people presenting with knee OA and increasing life expectancy, there is an unmet need to postpone time to first KR. Knee joint distraction (KJD), the practice of using external fixators to open up knee joint space, is proposed as potentially effective to preserve the joint following initial studies in the Netherlands, however, has not been researched within an NHS setting. The KARDS trial will investigate whether KJD is non-inferior to KR in terms of patient-reported postoperative pain 12 months post-surgery. METHODS AND ANALYSIS: KARDS is a phase III, multicentre, pragmatic, open-label, individually randomised controlled non-inferiority trial comparing KJD with KR in patients with severe knee OA, employing a hybrid-expertise design, with internal pilot phase and process evaluation. 344 participants will be randomised (1:1) to KJD or KR. The primary outcome measure is the Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain domain score at 12 months post-operation. Secondary outcome measures include patient-reported overall KOOS, Pain Visual Analogue Scale and Oxford Knee Scores, knee function assessments, joint space width, complications and further interventions over 24 months post-operation. Per patient cost difference between KR and KJD and cost per quality-adjusted life year (QALY) gained over 24 months will be estimated within trial, and incremental cost per QALY gained over 20 years by KJD relative to KR predicted using decision analytic modelling. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Research Ethics Committee (REC) and Health Research Authority (HRA). Trial results will be disseminated at clinical conferences, through relevant patient groups and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN14879004; recruitment opened April 2021.
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Artroplastia de Reemplazo de Rodilla , Osteoartritis de la Rodilla , Adolescente , Artroplastia de Reemplazo de Rodilla/métodos , Ensayos Clínicos Fase III como Asunto , Análisis Costo-Beneficio , Humanos , Articulación de la Rodilla/cirugía , Estudios Multicéntricos como Asunto , Osteoartritis de la Rodilla/cirugía , Dolor Postoperatorio , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
The intensification of summer drought expected with climate change can induce metabolism modifications in plants to face such constraints. In this experiment, we used both a targeted approach focused on flavonoids, as well as an untargeted approach, to study a broader fraction of the leaf metabolome of Quercus pubescens exposed to amplified drought. A forest site equipped with a rainfall exclusion device allowed reduction of natural rainfall by ~30% over the tree canopy. Leaves of natural drought (ND) and amplified drought (AD) plots were collected over three seasonal cycles (spring, summer, and autumn) in 2013 (the second year of rain exclusion), 2014, and 2015. As expected, Q. pubescens metabolome followed a seasonal course. In the summer of 2015, the leaf metabolome presented a shifted and early autumnal pattern because of harsher conditions during this year. Despite low metabolic modification at the global scale, our results demonstrated that 75% of Quercus metabolites were upregulated in springs when trees were exposed to AD, whereas 60 to 73% of metabolites (93% in summer 2015), such as kaempferols and quercetins, were downregulated in summers/autumns. Juglanin, a kaempferol pentoside, as well as rhododendrin derivatives, were upregulated throughout the year, suggesting an antioxidant ability of these metabolites. Those changes in terms of phenology and leaf chemistry could, in the end, affect the ecosystem functioning.
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INTRODUCTION: Hand eczema (HE) is one of the most common skin disorders and an important cause for morbidity and occupational disability. The 1-year prevalence of HE is estimated to be up to 10% and it is estimated that 5%-7% of those develop severe chronic HE. However, current clinical evidence is not compelling enough to guide clinical practice. In a survey among 194 UK dermatologists the most frequent first choice approaches were psoralen combined with ultraviolet A (UVA) treatment (PUVA), oral steroids and alitretinoin (AL). When asked which strategy was most efficient for long-term outcome 20% of clinicians indicated they did not know; 43% of clinicians reported AL and 30% reported PUVA. METHODS AND ANALYSIS: ALPHA is a multicentre, open, prospective, two-arm parallel group, randomised controlled trial comparing PUVA and AL with a planned sample size re-estimation. Between 500 and 780 participants will be randomised on a 1:1 basis. The physician's global assessment (PGA) will direct treatment after randomisation, non-responders will be treated according to usual clinical practice; providing valuable pilot data on second line therapeutic approaches to inform future trials.Assessments will be conducted up to 52 weeks post randomisation. The primary outcome measure is the Hand Eczema Severity Index at 12 weeks. Secondary outcome measures include modified Total Lesion Symptom Score, PGA, time to relapse, patient reported outcome measures and DNA extraction and assessment of genetic variants. A substudy on molecular inflammatory mediators will provide information on subgroup specific treatment responses. Photographs will be taken and HE severity assessed by a central review panel. ETHICS AND DISSEMINATION: Ethics approval was obtained from Leeds West Research Ethics Committee (14/YH/1259).Trial results will be disseminated at relevant clinical conferences and societies, published in peer-reviewed journals and through relevant patient groups. TRIAL REGISTRATION NUMBER: ISRCTN80206075.
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Eccema , Humanos , Alitretinoína/uso terapéutico , Eccema/tratamiento farmacológico , Estudios Multicéntricos como Asunto , Medición de Resultados Informados por el Paciente , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Flavonoids are specialized metabolites largely widespread in plants where they play numerous roles including defense and signaling under stress conditions. These compounds encompass several chemical subgroups such as flavonols which are one the most represented classes. The most studied flavonols are kaempferol, quercetin and myricetin to which research attributes antioxidative properties and a potential role in UV-defense through UV-screening mechanisms making them critical for plant adaptation to climate change. Despite the great interest in flavonol functions in the last decades, some functional aspects remain under debate. This review summarizes the importance of flavonoids in plant defense against climate stressors and as signal molecules with a focus on flavonols in Mediterranean plant species. The review emphasizes the relationship between flavonol location (at the organ, tissue and cellular scales) and their function as defense metabolites against climate-related stresses. It also provides evidence that biosynthesis of flavonols, or flavonoids as a whole, could be a crucial process allowing plants to adapt to climate change, especially in the Mediterranean area which is considered as one of the most sensitive regions to climate change over the globe.
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Biogenic Volatile Organic Compounds (BVOC) are largely accepted to contribute to both atmospheric chemistry and ecosystem functioning. While the forest canopy is recognized as a major source of BVOC, emissions from plant litter have scarcely been explored with just a couple of studies being focused on emission patterns over litter decomposition process. The aim of this study was to quantitatively and qualitatively characterize BVOC emissions (C1-C15) from Pinus halepensis litter, one of the major Mediterranean conifer species, over a 15-month litter decomposition experiment. Senescent needles of P. halepensis were collected and placed in 42 litterbags where they underwent in situ decomposition. Litterbags were collected every 3 months and litter BVOC emissions were studied in vitro using both online (PTR-ToF-MS) and offline analyses (GC-MS). Results showed a large diversity of BVOC (58 compounds detected), with a strong variation over time. Maximum total BVOC emissions were observed after 3 months of decomposition with 9.18 µg gDM -1 hr-1 mainly composed by terpene emissions (e.g., α-pinene, terpinolene, ß-caryophyllene). At this stage, methanol, acetone, and acetic acid were the most important nonterpenic volatiles representing, respectively, up to 26%, 10%, and 26% of total emissions. This study gives an overview of the evolution of BVOC emissions from litter along with decomposition process and will thus contribute to better understand the dynamics and sources of BVOC emission in Mediterranean pine forests.
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Hyperglycaemia in individuals with type 2 diabetes (T2D) and myocardial infarction (MI) is associated with guarded clinical prognosis. Studies improving glucose levels in T2D following MI relied on HbA1c as the main glycaemic marker, failing to address potential adverse effects of hypoglycaemia and glucose variability. We describe the design of the LIBERATES trial that investigates the role of flash glucose monitoring in optimising glycaemic markers in high vascular risk individuals with T2D. This multicentre trial is designed to recruit up to 150 insulin and/or sulphonylurea-treated T2D patients, within 5 days of a proven MI. Individuals will be randomised 1:1 into intervention and control groups using flash glucose monitoring sensors and traditional self-monitoring of blood glucose, respectively. The control group will also wear a blinded continuous glucose monitoring sensor. The primary outcome is the difference in time spent in euglycaemia (defined as glucose levels between 3.9-10.0 mmol/l), comparing study groups 3 months following recruitment, assessed daily for 14 days and as an average. Secondary and exploratory end points include time spent in hypoglycaemia and hyperglycaemia, HbA1c, quality of life measures, major adverse cardiac events and cost-effectiveness of the intervention. This study will establish the role of flash glucose monitoring in glycaemic management of individuals with T2D sustaining a cardiac event.(Trial Registration: ISRCTN14974233, registered 12th June 2017).