RESUMO
OBJECTIVES: Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aß42 and Aß40 peptides. METHODS: Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months. RESULTS: Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aß40 and Aß42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-ß were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. INTERPRETATION: Our findings point to the involvement of increased levels of Aß42 and/or Aß40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aß42 and/or Aß40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390-404.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Síndrome de Down , Camundongos Transgênicos , Fragmentos de Peptídeos , Animais , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Síndrome de Down/metabolismo , Peptídeos beta-Amiloides/metabolismo , Camundongos , Secretases da Proteína Precursora do Amiloide/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , MasculinoRESUMO
Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.
Assuntos
COVID-19 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Ligação Proteica , Peptidil Dipeptidase A/metabolismoRESUMO
Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males. Penitrem A (blocker) exerted dose-dependent effects on moderate alcohol intake, while paxilline (blocker) and BMS-204352 (opener) were ineffective. Because pharmacological manipulations are inherently limited by non-specific effects, we then sought to investigate the behavioral relevance of ethanol's direct interaction with BK α by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanol in vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference. Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary ß subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.
Assuntos
Consumo de Bebidas Alcoólicas , Etanol , Camundongos Endogâmicos C57BL , Animais , Etanol/farmacologia , Masculino , Camundongos , Consumo de Bebidas Alcoólicas/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , FemininoRESUMO
The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, and other behavioral phenotypes associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms underlying the excessive alcohol use associated with alcohol dependence and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) and Visium spatial gene expression profiling on the medial prefrontal cortex (mPFC) obtained from C57BL/6 J mice exposed to the two-bottle choice-chronic intermittent ethanol (CIE) vapor exposure (2BC-CIE, defined as dependent group) paradigm which models phenotypes of alcohol dependence including escalation of alcohol drinking. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Dysregulated modules and their hub genes suggest novel understudied targets for studying molecular mechanisms contributing to the alcohol dependence state. A subtype of inhibitory neurons was the most alcohol-sensitive cell type and contained a downregulated gene co-expression module; the hub gene for this module is Cpa6, a gene previously identified by GWAS to be associated with excessive alcohol consumption. We identified an astrocytic Gpc5 module significantly upregulated in the alcohol-dependent group. To our knowledge, there are no studies linking Cpa6 and Gpc5 to the alcohol-dependent phenotype. We also identified neuroinflammation related gene expression changes in multiple cell types, specifically enriched in microglia, further implicating neuroinflammation in the escalation of alcohol drinking. Here, we present a comprehensive atlas of cell-type specific alcohol dependence mediated gene expression changes in the mPFC and identify novel cell type-specific targets implicated in alcohol dependence.
Assuntos
Alcoolismo , Animais , Camundongos , Alcoolismo/genética , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Encéfalo/metabolismo , Córtex Pré-Frontal/metabolismo , Etanol/toxicidadeRESUMO
PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative (TN) and Her2-positive (HER2) breast cancers is supported by international guidelines as it can decrease extent of surgery, provide prognostic information, and allow response-driven adjuvant therapies. Our goal was to describe practice patterns for patients with TN and HER2-positive breast cancer and identify the factors associated with the receipt of NAC versus surgery as initial treatment. METHODS: A retrospective population-based cohort study of adult women diagnosed with stage I-III TN or HER2-positive breast cancer (2012-2020) in Ontario was completed using linked administrative datasets. The primary outcome was NAC as first treatment. The association between NAC and patient, tumor, and practice-related factors was examined using multivariable logistic regression models. RESULTS: Of 14,653 patients included, 23.9% (n = 3500) underwent NAC as first treatment. Patients who underwent NAC were more likely to be younger and have larger tumors, node-positive disease, and stage 3 disease. Of patients who underwent surgery first, 8.8% were seen by a medical oncologist prior to surgery. On multivariable analysis, increasing tumor size (T2 vs T1/T0: 2.75 (2.31-3.28)) and node-positive (N1 vs N0: OR 3.54 (2.92-4.30)) disease were both associated increased odds of receiving NAC. CONCLUSION: A considerable proportion of patients with TN and HER2-positive breast cancer do not receive NAC as first treatment. Of those, most were not assessed by both a surgeon and medical oncologist prior to initiating therapy. This points toward potential gaps in multidisciplinary assessment and disparities in receipt of guideline-concordant care.
Assuntos
Terapia Neoadjuvante , Receptor ErbB-2 , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Estudos Retrospectivos , Adulto , Idoso , Padrão de Cuidado , Quimioterapia Adjuvante/métodos , Ontário/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismoRESUMO
Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and ß. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNß (IFNßKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNß but in a sex-dependent fashion. Notably, in cerebral cortex of IFNßKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNßKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNß-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNß-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNßKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNß on multiple components with more pronounced changes in IFNßKO females. In contrast, the effects of IFNßKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNß impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNß plays a vital role in maintaining neuronal homeostasis and memory function.
Assuntos
Infecções por HIV , HIV-1 , Interferon beta , Animais , Feminino , Masculino , Camundongos , Encéfalo/metabolismo , Infecções por HIV/metabolismo , HIV-1/metabolismo , Interferon beta/metabolismo , Camundongos TransgênicosRESUMO
Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.
Assuntos
Cisteína , Infecções por HIV , HIV-1 , Camundongos , Humanos , Animais , HIV-1/metabolismo , Macrófagos/metabolismo , Leucotrienos/metabolismo , Neurônios/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos Transgênicos , Infecções por HIV/metabolismoRESUMO
BACKGROUND: Atopic dermatitis (eczema), can have a significant impact on well-being and quality of life for affected people and their families. Standard treatment is avoidance of triggers or irritants and regular application of emollients and topical steroids or calcineurin inhibitors. Thorough physical and psychological assessment is central to good-quality treatment. Overcoming barriers to provision of holistic treatment in dermatological practice is dependent on evaluation of the efficacy and economics of both psychological and educational interventions in this participant group. This review is based on a previous Cochrane review published in 2014, and now includes adults as well as children. OBJECTIVES: To assess the clinical outcomes of educational and psychological interventions in children and adults with atopic dermatitis (eczema) and to summarise the availability and principal findings of relevant economic evaluations. SEARCH METHODS: We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, APA PsycINFO and two trials registers up to March 2023. We checked the reference lists of included studies and related systematic reviews for further references to relevant randomised controlled trials (RCTs) and contacted experts in the field to identify additional studies. We searched NHS Economic Evaluation Database, MEDLINE and Embase for economic evaluations on 8 June 2022. SELECTION CRITERIA: Randomised, cluster-randomised and cross-over RCTs that assess educational and psychological interventions for treating eczema in children and adults. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods, with GRADE to assess the certainty of the evidence for each outcome. Primary outcomes were reduction in disease severity, as measured by clinical signs, patient-reported symptoms and improvement in health-related quality-of-life (HRQoL) measures. Secondary outcomes were improvement in long-term control of symptoms, improvement in psychological well-being, improvement in standard treatment concordance and adverse events. We assessed short- (up to 16 weeks after treatment) and long-term time points (more than 16 weeks). MAIN RESULTS: We included 37 trials (6170 participants). Most trials were conducted in high-income countries (34/37), in outpatient settings (25/37). We judged three trials to be low risk of bias across all domains. Fifteen trials had a high risk of bias in at least one domain, mostly due to bias in measurement of the outcome. Trials assessed interventions compared to standard care. Individual educational interventions may reduce short-term clinical signs (measured by SCORing Atopic Dermatitis (SCORAD); mean difference (MD) -5.70, 95% confidence interval (CI) -9.39 to -2.01; 1 trial, 30 participants; low-certainty evidence) but patient-reported symptoms, HRQoL, long-term eczema control and psychological well-being were not reported. Group education interventions probably reduce clinical signs (SCORAD) both in the short term (MD -9.66, 95% CI -19.04 to -0.29; 3 studies, 731 participants; moderate-certainty evidence) and the long term (MD -7.22, 95% CI -11.01 to -3.43; 3 studies, 1424 participants; moderate-certainty evidence) and probably reduce long-term patient-reported symptoms (SMD -0.47 95% CI -0.60 to -0.33; 2 studies, 908 participants; moderate-certainty evidence). They may slightly improve short-term HRQoL (SMD -0.19, 95% CI -0.36 to -0.01; 4 studies, 746 participants; low-certainty evidence), but may make little or no difference to short-term psychological well-being (Perceived Stress Scale (PSS); MD -2.47, 95% CI -5.16 to 0.22; 1 study, 80 participants; low-certainty evidence). Long-term eczema control was not reported. We don't know whether technology-mediated educational interventions could improve short-term clinical signs (SCORAD; 1 study; 29 participants; very low-certainty evidence). They may have little or no effect on short-term patient-reported symptoms (Patient Oriented Eczema Measure (POEM); MD -0.76, 95% CI -1.84 to 0.33; 2 studies; 195 participants; low-certainty evidence) and probably have little or no effect on short-term HRQoL (MD 0, 95% CI -0.03 to 0.03; 2 studies, 430 participants; moderate-certainty evidence). Technology-mediated education interventions probably slightly improve long-term eczema control (Recap of atopic eczema (RECAP); MD -1.5, 95% CI -3.13 to 0.13; 1 study, 232 participants; moderate-certainty evidence), and may improve short-term psychological well-being (MD -1.78, 95% CI -2.13 to -1.43; 1 study, 24 participants; low-certainty evidence). Habit reversal treatment may reduce short-term clinical signs (SCORAD; MD -6.57, 95% CI -13.04 to -0.1; 1 study, 33 participants; low-certainty evidence) but we are uncertain about any effects on short-term HRQoL (Children's Dermatology Life Quality Index (CDLQI); 1 study, 30 participants; very low-certainty evidence). Patient-reported symptoms, long-term eczema control and psychological well-being were not reported. We are uncertain whether arousal reduction therapy interventions could improve short-term clinical signs (Eczema Area and Severity Index (EASI); 1 study, 24 participants; very low-certainty evidence) or patient-reported symptoms (visual analogue scale (VAS); 1 study, 18 participants; very low-certainty evidence). Arousal reduction therapy may improve short-term HRQoL (Dermatitis Family Impact (DFI); MD -2.1, 95% CI -4.41 to 0.21; 1 study, 91 participants; low-certainty evidence) and psychological well-being (PSS; MD -1.2, 95% CI -3.38 to 0.98; 1 study, 91 participants; low-certainty evidence). Long-term eczema control was not reported. No studies reported standard care compared with self-help psychological interventions, psychological therapies or printed education; or adverse events. We identified two health economic studies. One found that a 12-week, technology-mediated, educational-support programme may be cost neutral. The other found that a nurse practitioner group-education intervention may have lower costs than standard care provided by a dermatologist, with comparable effectiveness. AUTHORS' CONCLUSIONS: In-person, individual education, as an adjunct to conventional topical therapy, may reduce short-term eczema signs compared to standard care, but there is no information on eczema symptoms, quality of life or long-term outcomes. Group education probably reduces eczema signs and symptoms in the long term and may also improve quality of life in the short term. Favourable effects were also reported for technology-mediated education, habit reversal treatment and arousal reduction therapy. All favourable effects are of uncertain clinical significance, since they may not exceed the minimal clinically important difference (MCID) for the outcome measures used (MCID 8.7 points for SCORAD, 3.4 points for POEM). We found no trials of self-help psychological interventions, psychological therapies or printed education. Future trials should include more diverse populations, address shared priorities, evaluate long-term outcomes and ensure patients are involved in trial design.
Assuntos
Dermatite Atópica , Educação de Pacientes como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Criança , Dermatite Atópica/terapia , Dermatite Atópica/psicologia , Educação de Pacientes como Assunto/métodos , Adulto , Viés , Eczema/terapia , Eczema/psicologia , AdolescenteRESUMO
BACKGROUND: Eczema (atopic dermatitis) is the most burdensome skin condition worldwide and cannot currently be prevented or cured. Topical anti-inflammatory treatments are used to control eczema symptoms, but there is uncertainty about the relative effectiveness and safety of different topical anti-inflammatory treatments. OBJECTIVES: To compare and rank the efficacy and safety of topical anti-inflammatory treatments for people with eczema using a network meta-analysis. SEARCH METHODS: We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries on 29 June 2023, and checked the reference lists of included studies. SELECTION CRITERIA: We included within-participant or between-participant randomised controlled trials (RCTs) in people of any age with eczema of any severity, but excluded trials in clinically infected eczema, seborrhoeic eczema, contact eczema, or hand eczema. We included topical anti-inflammatory treatments used for at least one week, compared with another anti-inflammatory treatment, no treatment, or vehicle/placebo. Vehicle is a 'carrier system' for an active pharmaceutical substance, which may also be used on its own as an emollient for dry skin. We excluded trials of topical antibiotics used alone, complementary therapies, emollients used alone, phototherapy, wet wraps, and systemic treatments. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were patient-reported eczema symptoms, clinician-reported eczema signs and investigator global assessment. Secondary outcomes were health-related quality of life, long-term control of eczema, withdrawal from treatment/study, and local adverse effects (application-site reactions, pigmentation changes and skin thinning/atrophy were identified as important concerns through patient and public involvement). We used CINeMA to quantify our confidence in the evidence for each outcome. MAIN RESULTS: We included 291 studies involving 45,846 participants with the full spectrum of eczema severity, mainly conducted in high-income countries in secondary care settings. Most studies included adults, with only 31 studies limited to children aged < 12 years. Studies usually included male and female participants, multiple ethnic groups but predominantly white populations. Most studies were industry-funded (68%) or did not report their funding sources/details. Treatment duration and trial participation were a median of 21 and 28 days (ranging from 7 days to 5 years), respectively. Interventions used were topical corticosteroids (TCS) (172), topical calcineurin inhibitors (TCI) (134), phosphodiesterase-4 (PDE-4) inhibitors (55), janus kinase (JAK) inhibitors (30), aryl hydrocarbon receptor activators (10), or other topical agents (21). Comparators included vehicle (170) or other anti-inflammatory treatments. The risk of bias was high in 242 of the 272 (89.0%) trials contributing to data analyses, most commonly due to concerns about selective reporting. Network meta-analysis (NMA) was only possible for short-term outcomes. Patient-reported symptoms NMA of 40 trials (6482 participants) reporting patient-reported symptoms as a binary outcome ranked tacrolimus 0.1% (OR 6.27, 95% CI 1.19 to 32.98), potent TCS (OR 5.99, 95% CI 2.83 to 12.69), and ruxolitinib 1.5% (OR 5.64, 95% CI 1.26 to 25.25) as the most effective, all with low confidence. Mild TCS, roflumilast 0.15%, and crisaborole 2% were the least effective. Class-level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and was more effective than mild TCI and PDE-4 inhibitors. NMA of 29 trials (3839 participants) reporting patient-reported symptoms as a continuous outcome ranked very potent TCS (SMD -1.99, 95% CI -3.25 to -0.73; low confidence) and tacrolimus 0.03% (SMD -1.57, 95% CI -2.42 to -0.72; moderate confidence) the highest. Direct information for tacrolimus 0.03% was based on one trial of 60 participants at high risk of bias. Roflumilast 0.15%, delgocitinib 0.25% or 0.5%, and tapinarof 1% were the least effective. Class-level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors and mild/moderate TCS was less effective than mild TCI. A further 50 trials (9636 participants) reported patient-reported symptoms as a continuous outcome but could not be included in NMA. Clinician-reported signs NMA of 32 trials (4121 participants) reported clinician signs as a binary outcome and ranked potent TCS (OR 8.15, 95% CI 4.99, 13.57), tacrolimus 0.1% (OR 8.06, 95% CI 3.30, 19.67), ruxolitinib 1.5% (OR 7.72, 95% CI 4.92, 12.10), and delgocitinib 0.5% (OR 7.61, 95% CI 3.72, 15.58) as most effective, all with moderate confidence. Mild TCS, roflumilast 0.15%, crisaborole 2%, and tapinarof 1% were the least effective. Class-level sensitivity analysis found potent/very potent TCS more effective than potent TCI, mild TCI, JAK inhibitors, PDE-4 inhibitors; and mild TCS and PDE-4 inhibitors had similar effectiveness. NMA of 49 trials (5261 participants) reported clinician signs as a continuous outcome and ranked tacrolimus 0.03% (SMD -2.69, 95% CI -3.36, -2.02) and very potent TCS (SMD -1.87, 95% CI -2.69, -1.05) as most effective, both with moderate confidence; roflumilast 0.15%, difamilast 0.3% and tapinarof 1% were ranked as least effective. Direct information for tacrolimus 0.03% was based on one trial in 60 participants with a high risk of bias. For some sensitivity analyses, potent TCS, tacrolimus 0.1%, ruxolitinib 1.5%, delgocitinib 0.5% and delgocitinib 0.25% became some of the most effective treatments. Class-level analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors, and moderate/mild TCS was more effective than mild TCI. A further 100 trials (22,814 participants) reported clinician signs as a continuous outcome but could not be included in NMA. Investigator Global Assessment NMA of 140 trials (23,383 participants) reported IGA as a binary outcome and ranked ruxolitinib 1.5% (OR 9.34, 95% CI 4.8, 18.18), delgocitinib 0.5% (OR 10.08, 95% CI 2.65, 38.37), delgocitinib 0.25% (OR 6.87, 95% CI 1.79, 26.33), very potent TCS (OR 8.34, 95% CI 4.73, 14.67), potent TCS (OR 5.00, 95% CI 3.80, 6.58), and tacrolimus 0.1% (OR 5.06, 95% CI 3.59, 7.13) as most effective, all with moderate confidence. Mild TCS, crisaborole 2%, pimecrolimus 1%, roflumilast 0.15%, difamilast 0.3% and 1%, and tacrolimus 0.03% were the least effective. In a sensitivity analysis of low risk of bias information (12 trials, 1639 participants), potent TCS, delgocitinib 0.5% and delgocitinib 0.25% were most effective, and pimecrolimus 1%, roflumilast 0.15%, difamilast 1% and difamilast 0.3% least effective. Class-level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors and were more effective than PDE-4 inhibitors; mild/moderate TCS were less effective than potent TCI and had similar effectiveness to mild TCI. Longer-term outcomes over 6 to 12 months showed a possible increase in effectiveness for pimecrolimus 1% versus vehicle (4 trials, 2218 participants) in a pairwise meta-analysis, and greater treatment success with mild/moderate TCS than pimecrolimus 1% (based on 1 trial of 2045 participants). Local adverse effects NMA of 83 trials (18,992 participants, 2424 events) reporting application-site reactions ranked tacrolimus 0.1% (OR 2.2, 95% CI 1.53, 3.17; moderate confidence), crisaborole 2% (OR 2.12, 95% CI 1.18, 3.81; high confidence), tacrolimus 0.03% (OR 1.51, 95%CI 1.10, 2.09; low confidence), and pimecrolimus 1% (OR 1.44, 95% CI 1.01, 2.04; low confidence) as most likely to cause site reactions. Very potent, potent, moderate, and mild TCS were least likely to cause site reactions. NMA of eight trials (1786 participants, 3 events) reporting pigmentation changes found no evidence for increased pigmentation changes with TCS and crisaborole 2%, with low confidence for mild, moderate or potent TCS and moderate confidence for crisaborole 2%. NMA of 25 trials (3691 participants, 36 events) reporting skin thinning found no evidence for increased skin thinning with short-term (median 3 weeks, range 1-16 weeks) use of mild TCS (OR 0.72, 95% CI 0.12, 4.31), moderate TCS (OR 0.91, 95% CI 0.16, 5.33), potent TCS (OR 0.96, 95% CI 0.21, 4.43) or very potent TCS (OR 0.88, 95% CI 0.31, 2.49), all with low confidence. Longer-term outcomes over 6 to 60 months showed increased skin thinning with mild to potent TCS versus TCI (3 trials, 4069 participants, 6 events with TCS). AUTHORS' CONCLUSIONS: Potent TCS, JAK inhibitors and tacrolimus 0.1% were consistently ranked as amongst the most effective topical anti-inflammatory treatments for eczema and PDE-4 inhibitors as amongst the least effective. Mild TCS and tapinarof 1% were ranked amongst the least effective treatments in three of five efficacy networks. TCI and crisaborole 2% were ranked most likely to cause local application-site reactions and TCS least likely. We found no evidence for increased skin thinning with short-term TCS but an increase with longer-term TCS.
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Anti-Inflamatórios , Eczema , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Eczema/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Criança , Viés , Adulto , Administração Tópica , Feminino , Qualidade de Vida , Emolientes/uso terapêutico , Corticosteroides/uso terapêutico , Corticosteroides/administração & dosagemRESUMO
BACKGROUND: Subtypes of atopic dermatitis (AD) have been derived from the Avon Longitudinal Study of Parents and Children (ALSPAC) based on presence and severity of symptoms reported in questionnaires (Severe-Frequent, Moderate-Frequent, Moderate-Declining, Mild-Intermittent, Unaffected/Rare). Good agreement between ALSPAC and linked electronic health records (EHRs) would increase trust in the clinical validity of these subtypes and allow inferring subtypes from EHRs alone, which would enable their study in large primary care databases. OBJECTIVES: 1. Explore if presence and number of AD records in EHRs agrees with AD symptom and severity reports from ALSPAC; 2. Explore if EHRs agree with ALSPAC-derived AD subtypes; 3. Construct models to classify ALSPAC-derived AD subtype using EHRs. METHODS: We used data from the ALSPAC prospective cohort study from 11 timepoints until age 14 years (1991-2008), linked to local general practice EHRs. We assessed how far ALSPAC questionnaire responses and derived subtypes agreed with AD as established in EHRs using different AD definitions (e.g., diagnosis and/or prescription) and other AD-related records. We classified AD subtypes using EHRs, fitting multinomial logistic regression models tuning hyperparameters and evaluating performance in the testing set (ROC AUC, accuracy, sensitivity, and specificity). RESULTS: 8,828 individuals out of a total 13,898 had both been assigned an AD subtype and had linked EHRs. The number of AD-related codes in EHRs generally increased with severity of AD subtype, however not all with the Severe-Frequent subtypes had AD in EHRs, and many with the Unaffected/Rare subtype did have AD in EHRs. When predicting ALSPAC AD subtype using EHRs, the best tuned model had ROC AUC of 0.65, sensitivity of 0.29 and specificity of 0.83 (both macro averaged); when different sets of predictors were used, individuals with missing EHR coverage excluded, and subtypes combined, sensitivity was not considerably improved. CONCLUSIONS: ALSPAC and EHRs disagreed not just on AD subtypes, but also on whether children had AD or not. Researchers should be aware that individuals considered as having AD in one source may not be considered as having AD in another.
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INTRODUCTION: Understanding the correlates of problematic gambling among emerging adult university students is crucial for developing effective approaches to minimise harm. METHODS: This cross-sectional survey study reports on 397 18-25 year old emerging adults studying at Irish universities who completed an online survey about problematic gambling and a range of biopsychosocial variables. Chi-square and binary logistic regression analyses explored the relationships between problematic gambling and the biopsychosocial variables measured. RESULTS: Chi-square analyses showed that being male, having an online gambling account, having a mobile gambling app, novelty seeking (impulsivity), harm avoidance (fear of uncertainty), and high alcohol volume consumption were significantly associated with problematic gambling. Regression analyses showed that individuals were more likely to report problematic gambling if they were male (OR = 9.57 times), had an online gambling account (OR = 17.05 times), had a mobile gambling app (OR = 20.37 times), scored high in impulsivity (OR = 7.79 times), and reported high alcohol volume consumption (OR = 4.66 times). Individuals were less likely to report problematic gambling if they scored high in fear of uncertainty (OR = 0.26 times). CONCLUSIONS: A high rate of problematic gambling was observed among the current study sample. Participants were more likely to reported problematic gambling if they were male, had online gambling accounts, mobile gambling apps, scored high in impulsivity, scored low in fear of uncertainty, or consumed high volumes of alcohol in typical drinking sessions. These findings have implications for Irish legislation and policy-makers, Irish higher education institutions, and young adult Irish university students.
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AIMS AND OBJECTIVES: To map out the primary research studies relating to how virtual reality (VR) has been used to distract children and young people with long-term conditions from pain or pruritus. BACKGROUND: Pharmacologic treatment of chronic pain and pruritus may have side effects; hence, non-invasive non-pharmacological treatments are being sought. DESIGN: The scoping review followed the methodology recommended by the Joanna Briggs Institute, PAGER framework and PRISMA-ScR checklist. The protocol was registered with the Open Science Registration on 14 February 2022 https//doi.org/10.17605/OSF.IO/K2R93. METHODS: Five databases (Medline, CINAHL, PsycINFO, Web of Science and Scopus) were searched. Data were extracted from primary research studies published between 2000 and 2022 involving children and adolescent populations (<21 years) with a long-term condition that had an element of enduring pruritus and/or pain. RESULTS: Of 464 abstracts screened, 35 full-text papers were assessed with 5 studies meeting the eligibility criteria. Three main themes emerged from the included studies: (1) Improvements in pain and daily functioning; (2) positive perceptions of VR and (3) accessibility and feasibility of VR. No papers were found on the effect of VR on alleviating pruritus. CONCLUSION: VR is feasible, acceptable, and safe for children and adolescents with chronic pain in a range of long-term conditions and offers promise as an adjunctive treatment for improving chronic pain and quality of life. No studies were identified that targeted pruritis or measured pruritis outcomes; thus, the effects of VR for pruritis are unknown. There is a need for rigorously designed, randomised controlled trials to test the clinical and cost-effectiveness of VR interventions for chronic pain and pruritis in children and adolescents. The use of the PAGER (Patterns, Advances, Gaps, Evidence for Practice and Research Recommendations) framework for scoping reviews helped to structure analysis and findings and identify research gaps. RELEVANCE TO CLINICAL PRACTICE: VR interventions offer promise in improving chronic pain related to long-term conditions.
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Dor Crônica , Prurido , Realidade Virtual , Adolescente , Criança , Humanos , Dor Crônica/terapia , Prurido/terapia , Qualidade de VidaRESUMO
BACKGROUND: Studies have shown a significant reduction in breast cancer-related lymphedema (BCRL) rates in patients undergoing complete axillary lymph node dissection (cALND) combined with immediate lymphatic reconstruction (ILR) using lymphovenous bypass (LVB).The purpose of this study was to determine if ILR with LVB at the time of cALND results in a decreased incidence of BCRL and its impact on patient quality of life (QOL). METHODS: In this prospective cohort study, patients ≥ 18 years requiring cALND underwent ILR from 2019 to 2021. The primary outcome was bilateral upper limb volumes measured by Brørson's truncated cone formula and the Pero-System (3D Körper Scanner). The secondary outcome was QOL measured by the Lymphedema Quality of Life (LYMQOL) arm patient-reported outcome measurement. RESULTS: Forty-two patients consented to ILR using LVB. ILR was completed in 41 patients with a mean of 1.9 ± 0.9 lymphovenous anastomosis performed. Mean age of patients was 52.4 ± 10.5 years with a mean body mass index of 27.5 ± 4.9 kg/m2. All patients (n = 39, 100%) received adjuvant therapy after ILR. Mean follow-up was 15.2 ± 5.1 months. Five patients met criteria for lymphedema throughout the duration of the study (12.8%), with two patients having resolution, with an overall incidence of 7.7% by the end of the study period. Patients with lymphedema were found to have statistically significant lower total LYMQOL values at 18 months (8.44 ± 1.17 vs. 3.23 ± 0.56, p < 0.001). A mean increase of 0.73 ± 3.5 points was observed for overall QOL average for upper limb function at 18 months compared with 3 months (t = 0.823, p = 0.425). CONCLUSION: This study showed an incidence of 7.7% lymphedema development throughout the duration of study. We also showed that ILR has the potential to reduce the significant long-term adverse outcomes of lymphedema and improve QOL for patients undergoing cALND.
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Background: The American Heart Association has a call to action to reduce hospital acquired venous thromboembolism (HA-VTE) by 20% by the year 2030. There is increasing recognition that quality improvement initiatives for VTE reduction should focus on reducing potentially preventable HA-VTE. The objective of our study was to determine what proportion of HA-VTE events are potentially preventable. Methods: This was a retrospective, single center pilot study of 50 patients with HA-VTE. Seven preventability factors were identified with a focus on VTE prescription and administration. Data were extracted through chart review using a systematic data collection form. The primary endpoint was the proportion of patients with potentially preventable HA-VTE. Descriptive statistics were used. Results: The median age was 66 years with an admission VTE risk level of moderate-high in 94%. Potentially preventable HA-VTE was found in 40% of cases. Missed doses occurred in 29.8% with a median of 2 missed doses and a range of 1 to 20. Patient refusal was the most common reason for missed doses in 71%. Delays in initiation occurred in 12.7%. Sixty percent of those on mechanical prophylaxis only had nonadherence. Conclusion: Forty percent of HA-VTE cases were potentially preventable. Missed doses was the most common preventability factor identified with patient refusal accounting for most missed doses.
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A terminal diagnosis can diminish an individual's sense of agency and identity. Leading change appears to restore a sense of agential self. The first phase of this literature review explores factors influencing patient-led change across the palliative care ecosystem. The second phase illuminates how storytelling can support palliative care patients in leading ecosystem-wide change. 35 studies were identified in Phase 1 and 36 in Phase 2. This research highlights the need to situate patient leadership activity within a palliative care ecosystem to understand factors likely to support or hinder patient leadership activity within it. The evidence indicates the potential use of storytelling to support patients with a life-limiting illness to lead change across the palliative care ecosystem. This challenges current conceptualisations of such patients and offers them instead as an additional source of palliative care support.
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Prefrontal circuits are thought to underlie aberrant emotion contributing to relapse in abstinence; however, the discrete cell-types and mechanisms remain largely unknown. Corticotropin-releasing factor and its cognate type-1 receptor, a prominent brain stress system, is implicated in anxiety and alcohol use disorder (AUD). Here, we tested the hypothesis that medial prefrontal cortex CRF1-expressing (mPFCCRF1+) neurons comprise a distinct population that exhibits neuroadaptations following withdrawal from chronic ethanol underlying AUD-related behavior. We found that mPFCCRF1+ neurons comprise a glutamatergic population with distinct electrophysiological properties and regulate anxiety and conditioned rewarding effects of ethanol. Notably, mPFCCRF1+ neurons undergo unique neuroadaptations compared to neighboring neurons including a remarkable decrease in excitability and glutamatergic signaling selectively in withdrawal, which is driven in part by the basolateral amygdala. To gain mechanistic insight into these electrophysiological adaptations, we sequenced the transcriptome of mPFCCRF1+ neurons and found that withdrawal leads to an increase in colony-stimulating factor 1 (CSF1) in this population. We found that selective overexpression of CSF1 in mPFCCRF1+ neurons is sufficient to decrease glutamate transmission, heighten anxiety, and abolish ethanol reinforcement, providing mechanistic insight into the observed mPFCCRF1+ synaptic adaptations in withdrawal that drive these behavioral phenotypes. Together, these findings highlight mPFCCRF1+ neurons as a critical site of enduring adaptations that may contribute to the persistent vulnerability to ethanol misuse in abstinence, and CSF1 as a novel target for therapeutic intervention for withdrawal-related negative affect.
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Alcoolismo , Síndrome de Abstinência a Substâncias , Humanos , Receptores de Hormônio Liberador da Corticotropina/genética , Etanol/farmacologia , Alcoolismo/genética , Hormônio Liberador da Corticotropina , Neurônios , AnsiedadeRESUMO
BACKGROUND: There is a lack of well-conducted randomized controlled trials evaluating the effectiveness of theory-based online interventions for eczema. To address these deficiencies, we previously developed and demonstrated the effectiveness of two online behavioural interventions: Eczema Care Online for parents/carers of children with eczema, and Eczema Care Online for young people with eczema. OBJECTIVES: To explore the views and experiences of people who have used the Eczema Care Online interventions to provide insights into how the interventions worked and identify contextual factors that may impede users' engagement with the interventions. METHODS: Qualitative semistructured interviews were conducted with 17 parents/carers of children with eczema and 17 young people with eczema. Participants were purposively sampled from two randomized controlled trials of the interventions and recruited from GP surgeries in England. Transcripts were analysed using inductive thematic analysis, and intervention modifications were identified using the person-based approach table of changes method. RESULTS: Both young people and parents/carers found the interventions easy to use, relatable and trustworthy, and perceived that they helped them to manage their eczema, thus suggesting that Eczema Care Online may be acceptable to its target groups. Our analysis suggested that the interventions may reduce eczema severity by facilitating empowerment among its users, specifically through improved understanding of, and confidence in, eczema management, reduced treatment concerns, and improved treatment adherence and management of irritants/triggers. Reading about the experiences of others with eczema helped people to feel 'normal' and less alone. Some (mainly young people) expressed firmly held negative beliefs about topical corticosteroids, views that were not influenced by the intervention. Minor improvements to the design and navigation of the Eczema Care Online interventions and content changes were identified and made, ready for wider implementation. CONCLUSIONS: People with eczema and their families can benefit from reliable information, specifically information on the best and safest ways to use their eczema treatments early in their eczema journey. Together, our findings from this study and the corresponding trials suggest wider implementation of Eczema Care Online (EczemaCareOnline.org.uk) is justified.
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Eczema , Intervenção Baseada em Internet , Humanos , Criança , Adolescente , Cuidadores , Eczema/terapia , Terapia Comportamental , Pais , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Alcohol Use Disorder (AUD) is a chronic, relapsing syndrome diagnosed by a heterogeneous set of behavioral signs and symptoms. There are no laboratory tests that provide direct objective evidence for diagnosis. Microarray and RNA-Seq technologies enable genome-wide transcriptome profiling at low costs and provide an opportunity to identify biomarkers to facilitate diagnosis, prognosis, and treatment of patients. However, access to brain tissue in living patients is not possible. Blood contains cellular and extracellular RNAs that provide disease-relevant information for some brain diseases. We hypothesized that blood gene expression profiles can be used to diagnose AUD. We profiled brain (prefrontal cortex, amygdala, and hypothalamus) and blood gene expression levels in C57BL/6J mice using RNA-seq one week after chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. We found a high degree of preservation (rho range: [0.50, 0.67]) between blood and brain transcript levels. There was small overlap between blood and brain DEGs, and considerable overlap of gene networks perturbed after CIE related to cell-cell signaling (e.g., GABA and glutamate receptor signaling), immune responses (e.g., antigen presentation), and protein processing / mitochondrial functioning (e.g., ubiquitination, oxidative phosphorylation). Blood gene expression data were used to train classifiers (logistic regression, random forest, and partial least squares discriminant analysis), which were highly accurate at predicting alcohol dependence status (maximum AUC: 90.1%). These results suggest that gene expression profiles from peripheral blood samples contain a biological signature of alcohol dependence that can discriminate between CIE and Air subjects.
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Consumo de Bebidas Alcoólicas/genética , Etanol/administração & dosagem , Expressão Gênica , Animais , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The lipid phosphatase PTEN (phosphatase and tensin homologue on chromosome 10) is a key tumour suppressor gene and an important regulator of neuronal signalling. PTEN mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intellectual disability, and epilepsy. PTEN enzymatic activity is regulated by a cluster of phosphorylation sites at the C-terminus of the protein. Here, we focused on the role of PTEN T366 phosphorylation and generated a knock-in mouse line in which Pten T366 was substituted with alanine (PtenT366A/T366A). We identify that phosphorylation of PTEN at T366 controls neuron size and connectivity of brain circuits involved in sensory processing. We show in behavioural tests that PtenT366/T366A mice exhibit cognitive deficits and selective sensory impairments, with significant differences in male individuals. We identify restricted cellular overgrowth of cortical neurons in PtenT366A/T366A brains, linked to increases in both dendritic arborization and soma size. In a combinatorial approach of anterograde and retrograde monosynaptic tracing using rabies virus, we characterize differences in connectivity to the primary somatosensory cortex of PtenT366A/T366A brains, with imbalances in long-range cortico-cortical input to neurons. We conclude that phosphorylation of PTEN at T366 controls neuron size and connectivity of brain circuits involved in sensory processing and propose that PTEN T366 signalling may account for a subset of autism-related functions of PTEN.
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PTEN Fosfo-Hidrolase , Treonina , Animais , Camundongos , Masculino , Treonina/metabolismo , Tensinas/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neurônios/metabolismo , Alanina/metabolismo , LipídeosRESUMO
BACKGROUND: It is unclear if ambient temperature changes affect eczema. It is also unclear if people with worse disease are more susceptible to weather-related flares, or specific types of emollient offer protection. OBJECTIVES: To investigate the effect of short-term temperature variations on eczema symptoms in children. METHODS: Data from a UK cohort of 519 children with eczema were combined with data from the Hadley Centre's Integrated Surface Database. Hot and cold weeks were defined by average regional temperature > 75th or < 25th percentile, January 2018 to February 2020. Eczema flares were defined as ≥ 3-point change in Patient-Oriented Eczema Measure (POEM). Random-effects logistic regression models were used to estimate the odds ratios of flares in hot and cold weeks (reference group: temperate weeks). RESULTS: The baseline mean age was 4.9â years (SD 3.2) and the POEM score was 9.2 (SD 5.5). From the 519 participants, there were 6796 consecutively paired POEMs and 1082 flares. Seasonal variation in POEM scores was observed, suggesting symptoms worsening in winter and improving in summer. Odds ratios of flares were: 1.15 [95% confidence interval (CI) 0.96-1.39, P = 0.14] in cold weeks and 0.85 (95% CI 0.72-1.00, P = 0.05) in hot weeks. The likelihood ratio test showed no evidence of this differing by disease severity (P = 0.53) or emollient type used (P = 0.55). CONCLUSIONS: Our findings are consistent with previous studies demonstrating either improvements in eczema symptoms or reduced flares in hot weather. Worse disease and different emollient types did not increase susceptibility or provide protection against temperature changes. Further work should investigate the role of sunlight, humidity, pollution and other environmental factors.