RESUMO
The tissue microenvironment is a major driver in imprinting tissue-specific macrophage functions in various mammalian tissues. As monocytes are recruited into the gastrointestinal (GI) tract at steady state and inflammation, they rapidly adopt a tissue-specific and distinct transcriptome. However, the GI tract varies significantly along its length, yet most studies of intestinal macrophages do not directly compare the phenotype and function of these macrophages in the small and large intestine, thus leading to disparities in data interpretations. This review highlights differences along the GI tract that are likely to influence macrophage function, with a specific focus on diet and microbiota. This analysis may fuel further investigation regarding the interplay between the intestinal immune system and GI tissue microenvironments, ideally providing unique therapeutic targets to modulate specific intestinal macrophage populations and/or functions.
Assuntos
Trato Gastrointestinal , Microbiota , Animais , Intestinos , Macrófagos , MonócitosRESUMO
Over 100 genes are associated with monogenic forms of inflammatory bowel disease (IBD). These genes affect the epithelial barrier function, innate and adaptive immunity in the intestine, and immune tolerance. We provide an overview of newly discovered monogenic IBD genes and illustrate how a recently proposed taxonomy model can integrate phenotypes and shared pathways. We discuss how functional understanding of genetic disorders and clinical genomics supports personalised medicine for patients with monogenic IBD.
Assuntos
Doenças Inflamatórias Intestinais , Medicina de Precisão , Humanos , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Intestinos , FenótipoRESUMO
Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.
Assuntos
Defeitos Congênitos da Glicosilação , Hiperinsulinismo , Doenças Inflamatórias Intestinais , Doenças Renais Policísticas , Humanos , Hiperplasia/genéticaRESUMO
BACKGROUND: Prognostic uncertainty is frequently cited as a barrier to communication between physicians and patients and is particularly burdensome for surrogate decision-makers, who must make choices on behalf of their incapacitated family members. The Conceptual Taxonomy of Uncertainty is one model through which physician and surrogate communication can be analyzed to identify strategies for reducing uncertainty in surrogate decision-making. Our objective was to examine themes of uncertainty in physician communication of prognosis and surrogate goals-of-care decision-making for critically ill patients with traumatic brain injury (TBI). METHODS: We performed a secondary analysis of a previous qualitative study that involved semistructured interviews of 16 surrogates of critically ill patients with TBI from two level 1 trauma centers and 20 TBI expert physicians from seven trauma centers. Open-ended questions about prognostic uncertainty were asked. We identified major themes with an inductive approach. The Conceptual Taxonomy of Uncertainty was applied to further characterize these themes as data-centered, system-centered, and patient-centered issues of uncertainty. RESULTS: Nearly all surrogates (15 of 16) and physicians (19 of 20) recognized the emotional burden of uncertainty in the decision-making process for surrogates. More than three quarters of surrogates (13 of 16) described instances in which a lack of information regarding their loved one's disease or prognosis created uncertainty in their decision-making process, identifying both positive and negative instances of prognostic communication by physicians. We found that physicians used one of three strategies to communicate prognostic uncertainty to surrogates: leaving no room for uncertainty, honesty about uncertainty, and range of possibilities. These strategies did not meet the communication preferences of the majority of surrogates, with more than a third of decision-makers (6 of 15) being frustrated by too much ambiguity about prognosis as well as the failure to acknowledge the existence of uncertainty. CONCLUSIONS: We found that physician communication strategies rarely addressed surrogate needs regarding uncertainty adequately, suggesting an urgent need for future research into improved communication of prognostic uncertainty.
Assuntos
Lesões Encefálicas Traumáticas , Estado Terminal , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/terapia , Tomada de Decisões , Humanos , Unidades de Terapia Intensiva , Prognóstico , IncertezaRESUMO
Flight polyphenisms naturally occur as discrete or continuous traits in insects. Discrete flight polyphenisms include winged and wingless morphs, whereas continuous flight polyphenisms can take the form of short- or long-distance fliers. The mountain pine beetle (Dendroctonus ponderosae) exhibits polyphenic variation in flight distance but the consequences of this flight variation on life history strategies of beetles is unknown. This study assessed the effect of flight on two particular aspects of beetle biology: (1) an energetic trade-off between flight distance and host colonisation capacity; and (2) the relationship between flight distance and pheromone production. A 23 h flight treatment was applied to a subset of beetles using computer-linked flight mills. After flight treatment, both flown and unflown (control) beetles were given the opportunity to colonise bolts of host trees, and beetles that entered hosts were aerated to collect pheromone. A trade-off occurred between initiation of host colonisation and percentage body mass lost during flight, which indicates energy use during flight affects host acceptance in female mountain pine beetles. Furthermore, production of the aggregation pheromone trans-verbenol by female beetles was influenced by both percentage body mass lost during flight and flight distance. Male production of exo-brevicomin was affected by beetle condition following flight but not by the energy used during flight. These novel results give new insight into the polyphenic flight behaviour of mountain pine beetles. Flight variation is adaptive by acting to maintain population levels through safe and risky host colonisation strategies. These findings suggest mechanisms that facilitate the extremities of the continuous flight polyphenism spectrum. These opposing mechanisms appear to maintain the high variation in flight exhibited by this species.
Assuntos
Besouros , Casca de Planta , Animais , Besouros/genética , Feminino , Masculino , Feromônios , ÁrvoresRESUMO
Emerging technologies research often covers various perspectives in disciplines and research areas ranging from hard sciences, engineering, policymaking, and sociology. However, the interrelationship between these different disciplinary domains, particularly the physical and social sciences, often occurs many years after a technology has matured and moved towards commercialization. Synthetic biology may serve an exception to this idea, where, since 2000, the physical and the social sciences communities have increasingly framed their research in response to various perspectives in biological engineering, risk assessment needs, governance challenges, and the social implications that the technology may incur. This paper reviews a broad collection of synthetic biology literature from 2000-2016, and demonstrates how the co-development of physical and social science communities has grown throughout synthetic biology's earliest stages of development. Further, this paper indicates that future co-development of synthetic biology scholarship will assist with significant challenges of the technology's risk assessment, governance, and public engagement needs, where an interdisciplinary approach is necessary to foster sustainable, risk-informed, and societally beneficial technological advances moving forward.
Assuntos
Bioengenharia/tendências , Política Pública/tendências , Sociologia/tendências , Biologia Sintética/tendências , Humanos , Pesquisa/tendências , Ciências SociaisRESUMO
The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub-Saharan Africa describe an endemic vitamin D-independent form that responds to dietary calcium enrichment. The extent to which calcium-deficiency rickets is the dominant form across sub-Saharan Africa and in other low-latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25-hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p = .001), phosphate (p < .001), 25-hydroxyvitamin D (p = .049), and 1,25-dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear.
Assuntos
Desnutrição/complicações , Raquitismo/etiologia , Deficiência de Vitamina D/complicações , Cálcio/sangue , Cálcio/deficiência , Cálcio da Dieta/administração & dosagem , Pré-Escolar , Suplementos Nutricionais , Feminino , Humanos , Lactente , Quênia , Masculino , Fosfatos/sangue , Fosfatos/deficiência , Raquitismo/diagnóstico , Raquitismo/tratamento farmacológico , População Urbana , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Síndrome de Emaciação/sangue , Síndrome de Emaciação/etiologiaRESUMO
BACKGROUND: Hyperbilirubinaemia is a major cause of neonatal morbidity. Early identification of those infants most at risk might allow the development of targeted primary preventative therapy and follow-up. The objective of this study was to assess whether arterial umbilical cord bilirubin (aUCB) level at delivery predicts the development of neonatal jaundice in term deliveries. METHODS: Retrospective analysis of hospital biochemistry records identified term deliveries with recorded aUCB. Infant medical records were reviewed to identify those who developed neonatal hyperbilirubinaemia (requiring treatment according to UK NICE guidelines) with/without a positive direct antiglobulin test (DAT). RESULTS: Of 1411 term deliveries with a clearly recorded aUCB, 30 infants developed clinically-significant jaundice (2.7%), of whom 8 were DAT + ve (0.6%) mostly due to ABO incompatibility. aUCB strongly predicted the development of DAT + ve jaundice (area under the ROC curve = 0.996), as well as all-cause jaundice (area under the ROC curve = 0.74). However, this effect was critically dependent on maternal blood group. Amongst infants at risk of ABO incompatibility (maternal blood groups O + ve/O-ve, 39.7%) the predictive value of aUCB for all cause jaundice was strengthened (area under the ROC curve = 0.88). Amongst those not at risk (defined maternal blood group not O + ve/O-ve, 51.0%) it disappeared completely (area under the ROC curve = 0.46). A cutoff of 35 µmol/l for mothers with blood group O + ve/O-ve increased the pre-test probability for all-cause jaundice of 4% to a post-test probability of 30%. CONCLUSIONS: For infants of mothers with blood group O, aUCB predicts development of neonatal jaundice. There was no evident utility for infants of mothers with other blood groups. Estimation of aUCB should be considered as a strategy for early identification of those at risk of neonatal haemolytic jaundice.
Assuntos
Bilirrubina/sangue , Sangue Fetal/metabolismo , Icterícia Neonatal/diagnóstico , Biomarcadores/sangue , Feminino , Humanos , Recém-Nascido , Icterícia Neonatal/sangue , Modelos Logísticos , Masculino , Curva ROC , Estudos RetrospectivosRESUMO
Ready-to-use therapeutic foods (RUTFs) are a key component of a life-saving treatment for young children who present with uncomplicated severe acute malnutrition in resource limited settings. Increasing recognition of the role of balanced dietary omega-6 and omega-3 polyunsaturated fatty acids (PUFA) in neurocognitive and immune development led two independent groups to evaluate RUTFs. Jones et al. (BMC Med 13:93, 2015), in a study in BMC Medicine, and Hsieh et al. (J Pediatr Gastroenterol Nutr 2015), in a study in the Journal of Pediatric Gastroenterology and Nutrition, reformulated RUTFs with altered PUFA content and looked at the effects on circulating omega-3 docosahexaenoic acid (DHA) status as a measure of overall omega-3 status. Supplemental oral administration of omega-3 DHA or reduction of RUTF omega-6 linoleic acid using high oleic peanuts improved DHA status, whereas increasing omega-3 alpha-linolenic acid in RUTF did not. The results of these two small studies are consistent with well-established effects in animal studies and highlight the need for basic and operational research to improve fat composition in support of omega-3-specific development in young children as RUTF use expands.
Assuntos
Suplementos Nutricionais , Fast Foods , Ácidos Graxos Ômega-3/administração & dosagem , Óleos de Peixe/administração & dosagem , Desnutrição/dietoterapia , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. METHODS: This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. RESULTS: Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrollment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. CONCLUSIONS: PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT01593969. Registered 4 May 2012.
Assuntos
Suplementos Nutricionais , Fast Foods , Ácidos Graxos Ômega-3/administração & dosagem , Óleos de Peixe/administração & dosagem , Desnutrição/dietoterapia , Doença Aguda , Pré-Escolar , Ácidos Docosa-Hexaenoicos , Método Duplo-Cego , Ácido Eicosapentaenoico , Ácidos Graxos Insaturados/sangue , Feminino , Humanos , Lactente , Quênia , Lipídeos/sangue , MasculinoRESUMO
BACKGROUND: Environmental enteric dysfunction (EED) refers to an incompletely defined syndrome of inflammation, reduced absorptive capacity, and reduced barrier function in the small intestine. It is widespread among children and adults in low- and middle-income countries. Understanding of EED and its possible consequences for health is currently limited. OBJECTIVE: A narrative review of the current understanding of EED: epidemiology, pathogenesis, therapies, and relevance to child health. METHODS: Searches for key papers and ongoing trials were conducted using PUBMED 1966-June 2014; ClinicalTrials.gov; the WHO Clinical Trials Registry; the Cochrane Library; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. RESULTS: EED is established during infancy and is associated with poor sanitation, certain gut infections, and micronutrient deficiencies. Helicobacter pylori infection, small intestinal bacterial overgrowth (SIBO), abnormal gut microbiota, undernutrition, and toxins may all play a role. EED is usually asymptomatic, but it is important due to its association with stunting. Diagnosis is frequently by the dual sugar absorption test, although other biomarkers are emerging. EED may partly explain the reduced efficacy of oral vaccines in low- and middle-income countries and the increased risk of serious infection seen in children with undernutrition. CONCLUSIONS: Despite its potentially significant impacts, it is currently unclear exactly what causes EED and how it can be treated or prevented. Ongoing trials involve nutritional supplements, water and sanitation interventions, and immunomodulators. Further research is needed to better understand this condition, which is of likely crucial importance for child health and development in low- and middle-income settings.
Assuntos
Meio Ambiente , Inflamação , Enteropatias/fisiopatologia , Síndromes de Malabsorção/fisiopatologia , Adulto , Infecções Bacterianas , Síndrome da Alça Cega , Pré-Escolar , Transtornos do Crescimento/etiologia , Humanos , Lactente , Enteropatias/epidemiologia , Enteropatias/etiologia , Intestinos/microbiologia , Síndromes de Malabsorção/epidemiologia , Síndromes de Malabsorção/etiologia , Pobreza , SaneamentoRESUMO
BACKGROUND: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. METHODS: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. RESULTS: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone--insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. CONCLUSIONS: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. TRIAL REGISTRATION: Registered at Clinicaltrials.gov NCT01841099.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças Inflamatórias Intestinais , Desnutrição/tratamento farmacológico , Mesalamina/administração & dosagem , Serviços de Saúde da Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Habitação , Humanos , Lactente , Masculino , Desnutrição/patologia , Projetos Piloto , Pobreza , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Undernutrition in childhood is estimated to cause 3.1 million child deaths annually through a potentiating effect on common infectious diseases, such as pneumonia and diarrhea. In turn, overt and subclinical infections, and inflammation, especially in the gut, alter nutrient intake, absorption, secretion, diversion, catabolism, and expenditure. OBJECTIVE: A narrative overview of the current understanding of infections, inflammation, and antimicrobials in relation to childhood malnutrition. METHODS: Searches for pivotal papers were conducted using PUBMED 1966-January 2013; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. RESULTS: Although the epidemiological evidence for increased susceptibility to life-threatening infections associated with malnutrition is strong, we are only just beginning to understand some of the mechanisms involved. Nutritional status and growth are strongly influenced by environmental enteric dysfunction (EED), which is common among children in developing countries, and by alterations in the gut microbiome. As yet, there are no proven interventions against EED. Antibiotics have long been used as growth promoters in animals. Trials of antibiotics have shown striking efficacy on mortality and on growth in children with uncomplicated severe acute malnutrition (SAM) or HIV infection. Antibiotics act directly by preventing infections and may act indirectly by reducing subclinical infections and inflammation. We describe an ongoing multicenter, randomized, placebo-controlled trial of daily cotrimoxazole prophylaxis to prevent death in children recovering from complicated SAM. Secondary outcomes include growth, frequency and etiology of infections, immune activation and function, the gut microbiome, and antimicrobial resistance. The trial is expected to be reported in mid-2014. CONCLUSIONS: As well as improving nutritional intake, new case management strategies need to address infection, inflammation, and microbiota and assess health outcomes rather than only anthropometry.
Assuntos
Anti-Infecciosos/uso terapêutico , Infecções/complicações , Inflamação/complicações , Desnutrição/complicações , Desnutrição/terapia , Animais , Pré-Escolar , Humanos , Lactente , Controle de Infecções , Inflamação/prevenção & controle , Intestinos/microbiologia , Quênia , Microbiota , Estado Nutricional , Ensaios Clínicos Controlados Aleatórios como Assunto , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
We compared the blood RNA transcriptome of children hospitalized with influenza A H1N1/09, respiratory syncytial virus (RSV) or bacterial infection, and healthy controls. Compared to controls, H1N1/09 patients showed increased expression of inflammatory pathway genes and reduced expression of adaptive immune pathway genes. This was validated on an independent cohort. The most significant function distinguishing H1N1/09 patients from controls was protein synthesis, with reduced gene expression. Reduced expression of protein synthesis genes also characterized the H1N1/09 expression profile compared to children with RSV and bacterial infection, suggesting that this is a key component of the pathophysiological response in children hospitalized with H1N1/09 infection.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/genética , Biossíntese de Proteínas/genética , Adolescente , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Criança , Análise por Conglomerados , Humanos , Influenza Humana/imunologia , Influenza Humana/metabolismo , Reprodutibilidade dos Testes , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sincicial Respiratório Humano , Transdução de SinaisRESUMO
Due to the pervasiveness of trauma, it is likely that many children and families seen in pediatric health settings have incurred traumatic experiences. These experiences can lead to a variety of negative medical, psychological, and social health outcomes. Therefore, a provider's focus on supporting resilience is integral. The use of trauma-informed care (TIC) is one way providers can work toward promoting a family's resilience. TIC is considered an organizational, attitudinal shift to understanding the broad impacts of trauma. This shift can contribute to changes in policies and procedures to make each system more welcoming to all those accessing the health system. This review will discuss the current pervasiveness of trauma, its associated impacts, the importance of TIC, and practical applications of TIC based on guiding principles provided by the Substance Abuse and Mental Health Services Administration. [Pediatr Ann. 2024;53(8):e299-e304.].
Assuntos
Resiliência Psicológica , Humanos , Criança , Adolescente , Família/psicologia , Pacientes Internados/psicologia , Pediatria/métodosRESUMO
Recent evidence supports the implementation of massed delivery of disorder-specific treatments in the military service member and veteran population. However, many treatment settings serve patients with a wide range of diagnoses, and often patients present with comorbid conditions. Growing evidence suggests transdiagnostic cognitive behavioral treatments are effective for a wide range of emotional disorders and may reduce barriers to access. Little is known about the feasibility and outcomes of the massed delivery of transdiagnostic treatments. The present study examined real-world outcomes of a 2-week intensive outpatient program using the Unified Protocol for emotional disorders (UP-IOP). The sample included military service members and veterans diagnosed with a range of emotional disorders, namely trauma- and stressor-related disorders, unipolar depressive disorders, and anxiety disorders. The present study examined outcomes of UP-IOP (depression, trauma-related symptom severity, and emotion dysregulation). Participants included all patients who sought UP-IOP in its first 15 months of operation (N = 117). A diagnosis of posttraumatic stress disorder (PTSD) was an exclusion criterion because the site had an established PTSD-specific IOP treatment option. Findings indicate UP-IOP was feasible, had 94% patient retention, and was effective in reducing symptom severity (Cohen's d = 0.76 for depression symptom severity, Cohen's d = 0.80 for trauma-related symptom severity). There was no observed reduction in emotion dysregulation over the 2-week course of treatment. The intensive transdiagnostic approach resulted in effective symptom reduction in an accelerated timeframe while minimizing patient attrition. These findings indicate massed delivery of transdiagnostic cognitive behavioral therapy (CBT) treatments should continue to be explored, especially for this population. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Assuntos
Assistência Ambulatorial , Militares , Veteranos , Humanos , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Estudos de Viabilidade , Transtorno Depressivo/terapia , Protocolos Clínicos , Regulação Emocional , Pacientes Ambulatoriais , Adulto Jovem , Transtornos Relacionados a Trauma e Fatores de Estresse/terapia , Transtornos de Estresse Pós-Traumáticos/terapiaRESUMO
The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.
Assuntos
COVID-19 , Humanos , Citocinas/metabolismo , SARS-CoV-2 , Estudos Prospectivos , Fezes , Anticorpos AntiviraisRESUMO
BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numerical and structural chromosomal abnormalities. METHODS: We performed a systematic literature search of databases PubMed and Embase; and analysed gnomAD, Clinvar, the 100 000 Genomes Project, and DECIPHER databases. Further, we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility. RESULTS: A meta-analysis suggests that monosomy X [Turner syndrome] is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% confidence interval [CI] 1.48 to 2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low [<2.6%]. CONCLUSIONS: Turner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.
Assuntos
Doenças Inflamatórias Intestinais , Síndrome de Turner , Humanos , Variações do Número de Cópias de DNA , Síndrome de Turner/complicações , Doenças Inflamatórias Intestinais/genética , Aberrações Cromossômicas , Inflamação/complicaçõesRESUMO
BACKGROUND: Therapeutic options for paediatric inflammatory bowel disease (IBD) are limited, especially for younger children. Unlike in adults, vedolizumab and ustekinumab are not licensed for paediatric use in the UK. We aimed to understand the real-world access to, and use of, these therapies in the paediatric population. METHODS: We surveyed UK IBD centres to assess the incident use of vedolizumab and ustekinumab from 1 January 2021 to 31 December 2021. We collected information on funding, dose escalations and therapeutic drug monitoring. RESULTS: 18 of 21 centres responded, covering an estimated 5260 patients. One hundred and thirteen were started on vedolizumab, prescription incidence 2.2%, median prescriptions per centre was 4 (range 1-20). Considering ustekinumab, 73 patients were commenced, prescription incidence 1.4%. Median prescription per centre was 3.5 (range 1-13). Prescription rates at each centre were not predicted by patient number cared for at that centre (p=0.2). Dose escalation was common in vedolizumab (66.7% centres) and ustekinumab (55.5%).Funding strategies varied substantially, and multiple funding sources were used; 12 of 18 centres (66.7%) reported funding through routine National Health Service (NHS) England/Scottish arrangements. There was local NHS trust funding in 8 of 18 centres (44.4%). Individual funding requests (IFRs) were used in 5 of 18 (27.8%), although IFRs are reserved for patients with unique additional characteristics. Four centres were unable to achieve funding in pre-pubescent children. CONCLUSIONS: There is widespread use of vedolizumab and ustekinumab across the UK, although practice is highly variable. Access to therapy appeared to differ substantially. There is a growing disparity between international guidelines and real-world practice. Establishing early and effective therapy in all patients remains a priority.
Assuntos
Doenças Inflamatórias Intestinais , Ustekinumab , Adulto , Humanos , Criança , Ustekinumab/uso terapêutico , Medicina Estatal , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inglaterra/epidemiologia , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient's history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities.