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BACKGROUND & AIMS: The pathophysiology of Crohn's-like disease of the ileal pouch-anal anastomosis (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single cell analyses. METHODS: Endoscopic samples were collected from pouch body and pre-pouch ileum (pouch/ileum) of 50 patients with an IPAA. Single-cell RNA sequencing (scRNA-seq) was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, as well as those with familial adenomatous polyposis (FAP) after pouch formation. Findings were independently validated using immunohistochemistry. RESULTS: The cell populations/states in pouch body differed from those in pre-pouch ileum, likely secondary to increased microbial burden. Compared to FAP pouch, UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in Th17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of Th17-inducing cytokine genes such as IL23, IL1B and IL6 by mononuclear phagocytes (MNPs). Ligand-receptor analysis further revealed a stromal-MNP-lymphocyte circuit in CDP. Integrated analysis showed that upregulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum (ER) stress across all major cell compartments. CONCLUSIONS: CDP likely represents a distinct entity of inflammatory bowel disease with heightened ER stress in both immune and non-immune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.
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BACKGROUND AND AIM: Walled-off pancreatic necrosis (WON) frequently develops after necrotizing pancreatitis. Endoscopic drainage has become the preferred modality for symptomatic or infected WON. The aim of the present study was to assess health-related quality of life (HR-QOL) and long-term outcomes in patients undergoing endoscopic drainage for WON. METHODS: Patients undergoing endoscopic drainage of WON from January 2006 to May 2016 were identified. Data recorded included demographic information, and the incidence of long-term sequelae including pancreatic endocrine and exocrine insufficiency. Attempts were made to contact all patients. HR-QOL was assessed using the SF-36 questionnaire. RESULTS: Eighty patients were analyzed, 41 (51.3%) of whom completed the SF-36. One-year all-cause mortality was 6.2%, and disease-related mortality was 3.7%. A notable proportion of patients developed exocrine insufficiency (32.5%), endocrine insufficiency (27.7%), and long-term opiate use (42.5%). Development of exocrine insufficiency was predictive of lower total SF-36 scores (P = 0.016). Patients with WON had better HR-QOL compared with cohorts of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). In patients developing exocrine insufficiency versus healthy controls, poorer scores in the physical role (P < 0.001), general health (P < 0.001), vitality (P = 0.001), and emotional role (P = 0.029) domains were observed. Exocrine insufficiency patients had better HR-QOL than the IBS and IBD cohorts, although these differences were less pronounced. CONCLUSION: After undergoing endoscopic drainage for WON, patients have relatively preserved HR-QOL. The subset of patients that develop exocrine insufficiency have significantly poorer HR-QOL compared to healthy controls, although not to the degree of chronic gastrointestinal disorders such as IBS and IBD.
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Drenagem , Endoscopia , Pancreatite Necrosante Aguda/cirurgia , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite Necrosante Aguda/complicações , Pancreatite Necrosante Aguda/mortalidade , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: It is not clear whether digital single-operator cholangioscopy (D-SOC) with electrohydraulic and laser lithotripsy is effective in removal of difficult biliary stones. We investigated the safety and efficacy of D-SOC with electrohydraulic and laser lithotripsy in an international, multicenter study of patients with difficult biliary stones. METHODS: We performed a retrospective analysis of 407 patients (60.4% female; mean age, 64.2 years) who underwent D-SOC for difficult biliary stones at 22 tertiary centers in the United States, United Kingdom, or Korea from February 2015 through December 2016; 306 patients underwent electrohydraulic lithotripsy and 101 (24.8%) underwent laser lithotripsy. Univariate and multivariable analyses were performed to identify factors associated with technical failure and the need for more than 1 D-SOC electrohydraulic or laser lithotripsy session to clear the bile duct. RESULTS: The mean procedure time was longer in the electrohydraulic lithotripsy group (73.9 minutes) than in the laser lithotripsy group (49.9 minutes; P < .001). Ducts were completely cleared (technical success) in 97.3% of patients (96.7% of patients with electrohydraulic lithotripsy vs 99% patients with laser lithotripsy; P = .31). Ducts were cleared in a single session in 77.4% of patients (74.5% by electrohydraulic lithotripsy and 86.1% by laser lithotripsy; P = .20). Electrohydraulic or laser lithotripsy failed in 11 patients (2.7%); 8 patients were treated by surgery. Adverse events occurred in 3.7% patients and the stone was incompletely removed from 6.6% of patients. On multivariable analysis, difficult anatomy or cannulation (duodenal diverticula or altered anatomy) correlated with technical failure (odds ratio, 5.18; 95% confidence interval, 1.26-21.2; P = .02). Procedure time increased odds of more than 1 session of D-SOC electrohydraulic or laser lithotripsy (odds ratio, 1.02; 95% confidence interval, 1.01-1.03; P < .001). CONCLUSIONS: In a multicenter, international, retrospective analysis, we found D-SOC with electrohydraulic or laser lithotripsy to be effective and safe in more than 95% of patients with difficult biliary stones. Fewer than 5% of patients require additional treatment with surgery and/or extracorporeal shockwave lithotripsy to clear the duct.
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Endoscopia Gastrointestinal/efeitos adversos , Endoscopia Gastrointestinal/métodos , Cálculos Biliares/terapia , Litotripsia/efeitos adversos , Litotripsia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: A major complication of using medical devices is the development of biofilm-associated infection caused by Staphylococcus epidermidis where polysaccharide intercellular adhesin (PIA) is a major mechanism of biofilm accumulation. PIA affects innate and humoral immunity in isolated cells and animal models. Few studies have examined these effects in prosthetic joint infection (PJI). METHODS: This study used ex vivo whole blood modelling in controls together with matched-serum and staphylococcal isolates from patients with PJI. RESULTS: Whole blood killing of PIA positive S. epidermidis and its isogenic negative mutant was identical. Differences were unmasked in immunosuppressed whole blood pre-treated with dexamethasone where PIA positive bacteria showed a more resistant phenotype. PIA expression was identified in three unique patterns associated with bacteria and leukocytes, implicating a soluble form of PIA. Purified PIA reduced whole blood killing while increasing C5a levels. In clinically relevant staphylococcal isolates and serum samples from PJI patients; firstly complement C5a was increased 3-fold compared to controls; secondly, the C5a levels were significantly higher in serum from PJI patients whose isolates preferentially formed PIA-associated biofilms. CONCLUSIONS: These data demonstrate for the first time that the biological effects of PIA are mediated through C5a in patients with PJI.
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Artrite/microbiologia , Atividade Bactericida do Sangue , Complemento C5a/metabolismo , Interações Hospedeiro-Patógeno , Polissacarídeos Bacterianos/metabolismo , Infecções Relacionadas à Prótese/microbiologia , Staphylococcus epidermidis/fisiologia , Humanos , Staphylococcus epidermidis/crescimento & desenvolvimento , Staphylococcus epidermidis/isolamento & purificação , Staphylococcus epidermidis/metabolismoRESUMO
Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.
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Hematúria/terapia , Nefrite Hereditária/terapia , Diagnóstico Diferencial , Prova Pericial , Família , Feminino , Genes Recessivos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Testes Genéticos , Hematúria/diagnóstico , Hematúria/genética , Humanos , Transplante de Rim , Masculino , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Guias de Prática Clínica como AssuntoRESUMO
We present clinical practice recommendations for the treatment of children with Alport syndrome who are not enrolled in clinical trials. Our goal is to promote early initiation of a standard therapeutic approach that will facilitate assessment of the safety and efficacy of the protocol. The treatment protocol is based on the reduction of proteinuria, intraglomerular pressure, and renal fibrosis via interference with the renin-angiotensin-aldosterone system.
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Nefrite Hereditária/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , Nefrite Hereditária/genética , Nefrite Hereditária/fisiopatologiaRESUMO
Irreducible posterolateral knee dislocations are rare and complex injuries that are often difficult to treat. Prompt recognition and appropriate early management are vital to the successful long-term outcome for the patient. In this case report, we highlight a single patient presenting with an irreducible posterolateral knee dislocation following a high-energy trauma. Evaluation and management included careful history and physical examination, appropriate imaging studies, and formulation of an early operative plan, leading to a safe and successful knee reduction for this patient. We review the best available evidence to guide orthopedic surgeons in their evaluation and management of the irreducible knee dislocation.
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Luxação do Joelho/etiologia , Luxação do Joelho/cirurgia , Acidentes de Trânsito , Adulto , Braquetes , Humanos , Imobilização , Instabilidade Articular/etiologia , Instabilidade Articular/terapia , Articulação do Joelho/cirurgia , Ligamentos Articulares/lesões , Ligamentos Articulares/cirurgia , Imageamento por Ressonância Magnética , Masculino , Manipulação Ortopédica/efeitos adversos , Motocicletas , RecidivaRESUMO
BACKGROUND: Formal economic evaluation using a model-based approach is playing an increasingly important role in health care decision making. OBJECTIVE: To develop a model by using an objective measure of lung function-- prebronchodilator FEV(1) as a percent of predicted (FEV(1)% predicted)--as the primary independent factor to predict the frequency of adverse events related to the exacerbation of asthma on a population level. METHODS: We developed a Markov simulation model of childhood asthma by using data from the Childhood Asthma Management Program. The primary outcomes were the result of asthma exacerbations defined as hospitalizations, emergency department (ED) visits, and the need for oral corticosteroid therapy. Predicted monthly frequencies for each acute event were based on negative binomial regression equations estimated from the placebo arm of the Childhood Asthma Management Program with covariates of age, prebronchodilator FEV(1)% predicted, time in study, prior hospitalizations, and prior nocturnal awakenings. RESULTS: Simulated versus observed mean number of acute events were similar within the placebo and treatment groups. While the trial demonstrated treatment effects of 48% reduction in hospitalizations, 46% reduction in ED visits, and 44% reduction in the need for oral corticosteroid therapy at 48 months, the model simulated similar reductions of 49% in hospitalizations, 41% in ED visits, and 46% in the need for oral corticosteroid therapy. CONCLUSIONS: Our findings suggest that longitudinal intervention effects may be modeled through FEV(1)% predicted to estimate hospitalizations, ED visits, and need for oral corticosteroid therapy in childhood asthma for planning and evaluation purposes.
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Asma/tratamento farmacológico , Asma/fisiopatologia , Simulação por Computador , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Pulmão/fisiopatologia , Administração Oral , Corticosteroides/uso terapêutico , Criança , Técnicas de Apoio para a Decisão , Progressão da Doença , Feminino , Humanos , Masculino , Modelos Biológicos , Estudos Multicêntricos como Assunto , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Testes de Função Respiratória , Estados UnidosRESUMO
Background: Invasive fungal infections are a devastating complication of inflammatory bowel disease (IBD) treatment. We aimed to determine the incidence of fungal infections in IBD patients and examine the risk with tumor necrosis factor-alpha inhibitors (anti-TNF) compared with corticosteroids. Methods: In a retrospective cohort study using the IBM MarketScan Commercial Database we identified US patients with IBD and at least 6 months enrollment from 2006 to 2018. The primary outcome was a composite of invasive fungal infections, identified by ICD-9/10-CM codes plus antifungal treatment. Tuberculosis (TB) infections were a secondary outcome, with infections presented as cases/100 000 person-years (PY). A proportional hazards model was used to determine the association of IBD medications (as time-dependent variables) and invasive fungal infections, controlling for comorbidities and IBD severity. Results: Among 652 920 patients with IBD, the rate of invasive fungal infections was 47.9 cases per 100 000 PY (95% CI 44.7-51.4), which was more than double the TB rate (22 cases [CI 20-24], per 100 000 PY). Histoplasmosis was the most common invasive fungal infection (12.0 cases [CI 10.4-13.8] per 100 000 PY). After controlling for comorbidities and IBD severity, corticosteroids (hazard ratio [HR] 5.4; CI 4.6-6.2) and anti-TNFs (HR 1.6; CI 1.3-2.1) were associated with invasive fungal infections. Conclusions: Invasive fungal infections are more common than TB in patients with IBD. The risk of invasive fungal infections with corticosteroids is more than double that of anti-TNFs. Minimizing corticosteroid use in IBD patients may decrease the risk of fungal infections.
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BACKGROUND: The diagnostic algorithm for most cancers includes the assessment of a tissue specimen by a surgical pathologist, but if specimen provenance is uncertain, the diagnostic and therapeutic process carries significant risk to the patient. Over the last decade, short tandem repeat (STR) analysis has emerged as a DNA-based method with clinical applicability for specimen identity testing (also known as specimen provenance testing). Although the clinical utility of identity testing using STR-based analysis has been demonstrated in many studies, its economic value has not been established. METHODS: We developed a decision-analytic model of the application of STR-based provenance testing of transrectal prostate biopsy specimens obtained as part of routine clinical care to rule out the presence of adenocarcinoma of the prostate, as compared with no STR-based testing. Using parameter values drawn from the published literature, the cost-effectiveness of STR-based testing was quantified by calculating the incremental cost-effectiveness ratio per quality-adjusted life-year gained. RESULTS: In comparison to the current standard practice of no identity testing, identity testing by STR-based analysis has an incremental cost-effectiveness ratio of $65,570 per quality-adjusted life-year gained at a testing cost of $618 per person. At a cost of $515 per person, identity testing would meet the conservative standard of $50,000 per quality-adjusted life-year. At a test cost of $290 per person, identity testing would be cost saving. CONCLUSION: Given the rapidly declining pricing of STR-based identity testing, it is likely that testing to confirm the identity of positive prostate biopsy samples will be a cost-effective method for preventing treatment errors stemming from misidentification. Studies to formally establish the frequency of specimen provenance errors in routine clinical practice would therefore seem justified.
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Biópsia por Agulha/métodos , Repetições de Microssatélites/genética , Modelos Teóricos , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Análise Custo-Benefício , Técnicas e Procedimentos Diagnósticos/economia , Testes Diagnósticos de Rotina/economia , Humanos , MasculinoRESUMO
BACKGROUND: Artificial intelligence-based technology systems offer an alternative solution for diabetic retinopathy (DR) screening compared with standard, in-office dilated eye examinations. We performed a cost-effectiveness analysis of Automated Retinal Image Analysis System (ARIAS)-based DR screening in a primary care medicine clinic that serves a low-income patient population. METHODS: A model-based, cost-effectiveness analysis of two DR screening systems was created utilizing data from a recent study comparing adherence rates to follow-up eye care among adults ages 18 or older with a clinical diagnosis of diabetes. In the study, the patients were prescreened with an ARIAS-based, nonmydriatic (undilated), point-of-care tool in the primary care setting and were compared with patients with diabetes who were referred for dilated retinal screening without prescreening, as is the current standard of care. Using a Markov model with microsimulation resulting in a total of 600 000 simulated patient experiences, we calculated the incremental cost-utility ratio (ICUR) of the two screening approaches, with regard to five-year cost-effectiveness of DR screening and treatment of vision-threatening DR. RESULTS: At five years, ARIAS-based screening showed similar utility as the standard of care screening systems. However, ARIAS reduced costs by 23.3%, with an ICUR of $258 721.81 comparing the current practice to ARIAS. CONCLUSIONS: Primary care-based ARIAS DR screening is cost-effective when compared with standard of care screening methods.
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Diabetes Mellitus , Retinopatia Diabética , Adolescente , Adulto , Inteligência Artificial , Análise Custo-Benefício , Retinopatia Diabética/diagnóstico , Humanos , Programas de Rastreamento/métodos , Atenção Primária à SaúdeRESUMO
Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.
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Autoantígenos/genética , Colágeno Tipo IV/genética , Testes Genéticos/normas , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Nefrite Hereditária/terapia , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P < 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5' end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3' end; P < 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5; end of the gene. These strong genotype-phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.
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Colágeno Tipo IV/genética , Genótipo , Mutação , Nefrite Hereditária/genética , Fenótipo , Adulto , Idade de Início , Oftalmopatias Hereditárias/genética , Glicina/genética , Perda Auditiva/genética , Humanos , Masculino , Nefrite Hereditária/complicações , Nefrite Hereditária/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch's postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell-specific type 1 interferon-CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.
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Doença de Crohn/microbiologia , Doença de Crohn/patologia , Debaryomyces/isolamento & purificação , Debaryomyces/fisiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Anfotericina B/farmacologia , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Quimiocina CCL5/metabolismo , Colo/microbiologia , Colo/patologia , Doença de Crohn/imunologia , Debaryomyces/crescimento & desenvolvimento , Feminino , Microbioma Gastrointestinal , Vida Livre de Germes , Humanos , Íleo/microbiologia , Íleo/patologia , Inflamação , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.
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Consenso , Testes Genéticos/métodos , Nefrite Hereditária/genética , Guias de Prática Clínica como Assunto , Autoantígenos/genética , Colágeno Tipo IV/genética , Testes Genéticos/normas , Humanos , Nefrite Hereditária/diagnóstico , FenótipoRESUMO
BACKGROUND: An association between inflammatory bowel disease (IBD) and obesity has been observed. Little is known about the effect of weight loss on IBD course. Our aim was to determine the impact of bariatric surgery on long-term clinical course of obese patients with IBD, either Crohn's disease (CD) or ulcerative colitis (UC). METHODS: Patients with IBD who underwent bariatric surgery subsequent to IBD diagnosis were identified from 2 tertiary IBD centers. Complications after bariatric surgery were recorded. Patients were matched 1:1 for age, sex, IBD subtype, phenotype, and location to patients with IBD who did not undergo bariatric surgery. Controls started follow-up at a time point in their disease similar to the disease duration in the matched case at the time of bariatric surgery. Inflammatory bowel disease medication usage and disease-related complications (need for corticosteroids, hospitalizations, and surgeries) among cases and controls were compared. RESULTS: Forty-seven patients met inclusion criteria. Appropriate matches were found for 25 cases. Median follow-up among cases (after bariatric surgery) and controls was 7.69 and 7.89 years, respectively. Median decrease in body mass index after bariatric surgery was 12.2. Rescue corticosteroid usage and IBD-related surgeries were numerically less common in cases than controls (24% vs 52%; odds ratio [OR], 0.36; 95% confidence interval [CI], 0.08-1.23; 12% vs 28%; OR, 0.2; 95% CI, 0.004-1.79). Two cases and 1 control were able to discontinue biologics during follow-up. CONCLUSIONS: Inflammatory bowel disease patients with weight loss after bariatric surgery had fewer IBD-related complications compared with matched controls. This observation requires validation in a prospective study design.
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Cirurgia Bariátrica , Colite Ulcerativa/fisiopatologia , Doença de Crohn/fisiopatologia , Doenças Inflamatórias Intestinais/fisiopatologia , Obesidade/cirurgia , Adulto , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Progressão da Doença , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento , Redução de PesoRESUMO
BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk for pneumonia, and corticosteroids are reported to amplify this risk. Less is known about the impact of corticosteroid-sparing IBD therapies on pneumonia risk or the efficacy of pneumococcal vaccination in reducing all-cause pneumonia in real-world IBD cohorts. METHODS: We performed a population-based study using an established Veterans Health Administration cohort of 29,957 IBD patients. We identified all patients who developed bacterial pneumonia. Cox survival analysis was used to determine the association of corticosteroids at study entry and as a time-varying covariate, corticosteroid-sparing agents (immunomodulators and antitumor necrosis-alpha [TNF] inhibitors), and pneumococcal vaccination with the development of all-cause pneumonia. RESULTS: Patients with IBD who received corticosteroids had a greater risk of pneumonia when controlling for age, gender, and comorbidities (hazard ratio [HR] 2.21; 95% confidence interval [CI], 1.90-2.57 for prior use; HR = 3.42; 95% CI, 2.92-4.01 for use during follow-up). Anti-TNF inhibitors (HR 1.52; 95% CI, 1.02-2.26), but not immunomodulators (HR 0.91; 95% CI, 0.77-1.07), were associated with a small increase in pneumonia. A history of pneumonia was strongly associated with subsequent pneumonia (HR = 4.41; 95% CI, 3.70-5.27). Less than 15% of patients were vaccinated against pneumococcus, and this was not associated with a reduced risk of pneumonia (HR = 1.02; 95% CI, 0.80-1.30) in this cohort. CONCLUSION: In a large US cohort, corticosteroids were confirmed to increase pneumonia risk. Tumor necrosis-alpha inhibitors were associated with a smaller increase in the risk of pneumonia. Surprisingly, pneumococcal vaccination did not reduce all-cause pneumonia in this population, though few patients were vaccinated.
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Corticosteroides/efeitos adversos , Doenças Inflamatórias Intestinais/complicações , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Vacinas Pneumocócicas/administração & dosagem , Pneumonia/prevenção & controle , Fatores de Risco , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Estados Unidos/epidemiologia , Saúde dos VeteranosRESUMO
According to the docking studies and the analysis of a co-crystal structure of GW4064 with FXR, a series of 3-aryl heterocyclic isoxazole analogs were designed and synthesized. N-Oxide pyridine analog (7b) was identified as a promising FXR agonist with potent binding affinity and good efficacy, supporting our hypothesis that through an additional hydrogen bond interaction between the pyridine substituent of isoxazole analogs and Tyr373 and Ser336 of FXR, binding affinity and functional activity could be improved.
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Química Farmacêutica/métodos , Isoxazóis/síntese química , Sítios de Ligação , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Isoxazóis/química , Isoxazóis/farmacologia , Ligantes , Modelos Químicos , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/química , Serina/química , Tirosina/químicaRESUMO
BACKGROUND: Alport syndrome (AS) is a progressive renal disease with cochlear and ocular involvement. The majority of AS cases are X-linked (XLAS) and due to mutations in the COL4A5 gene. Although the disease may appear early in life and progress to end stage renal disease (ESRD) in young adults, in other families ESRD occurs in middle age. Few of the more than four hundred mutations described in COL4A5 are associated with adult type XLAS, but the families may be very large. METHODS: We classified adult type AS mutation by prevalence in the US and we developed a molecular assay using a set of hybridization probes that identify the three most common adult type XLAS mutations; C1564S, L1649R, and R1677Q. RESULTS: The test was validated on samples previously determined to contain one or none of these mutations. In the US, the test's clinical specificity and sensitivity are estimated to be higher than 99% and 75% respectively. Analytical specificity and sensitivity are above 99%. CONCLUSION: This test may be useful for presymptomatic and carrier testing in families with one of the mutations and in the diagnosis of unexplained hematuria or chronic kidney disease.
Assuntos
Colágeno Tipo IV/genética , Colágeno Tipo V/genética , Triagem de Portadores Genéticos/métodos , Nefrite Hereditária/genética , Adulto , Fatores Etários , Substituição de Aminoácidos/genética , Sondas de DNA/genética , Feminino , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/epidemiologia , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Dialysis is an effective treatment for end-stage renal disease, but it is available to only approximately half of those who need it in the world. METHODS: Two prototype passive-flow dialysate delivery systems were constructed. RESULTS: Each dialysate delivery system provided a flow of dialysate in the range of 200-300 mL/minute. In one example, flow regulation was good, but ultrafiltration could not be monitored. The second prototype could monitor and regulate ultrafiltration but required repeated manual adjustment to maintain nearly constant dialysate flow. Approaches to the remaining obstacles to a fully passive dialysis system are outlined, but these will require further work to prove feasibility. CONCLUSION: In principle, costs of providing hemodialysis could be reduced and equipment created to function without electricity by exploiting passive-flow techniques.