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BACKGROUND: Racial and ethnic disparities in life expectancy in the United States have been widely documented. To date, there remains a paucity of similar data in patients with inborn errors of immunity (IEIs). OBJECTIVE: Our aim was to examine racial and ethnic differences in mortality due to an IEI in the United States. METHODS: We analyzed National Center for Health Statistics national mortality data from 2003 to 2018. We quantified age-adjusted death rate and age-specific death rate as a result of an IEI for each major racial and ethnic group in the United States and examined the association of race and ethnicity with death at a younger age. RESULTS: From 2003 to 2018, IEIs were reported as the underlying or contributing cause of death in 14,970 individuals nationwide. The age-adjusted death rate was highest among Black patients (4.25 per 1,000,000 person years), compared with 2.01, 1.71, 1.50, and 0.92 per 1,000,000 person years for White, American Indian/Alaska Native, Hispanic, and Asian/Pacific Islander patients, respectively. The odds of death before age 65 years were greatest among Black patients (odds ratio [OR] = 5.15 [95% CI = 4.61-5.76]), followed by American Indian/Alaska Native patients (OR = 3.58 [95% CI = 2.30-5.82]), compared with White patients. The odds of death before age 24 years were greater among Hispanic patients than among non-Hispanic patients (OR = 3.60 [95% CI = 3.08-4.18]). CONCLUSION: Our study highlights racial and ethnic disparities in mortality due to an IEI and the urgent need to further identify and systematically remove barriers in care for historically marginalized patients with IEIs.
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Etnicidade , Disparidades nos Níveis de Saúde , Doenças do Sistema Imunitário , Grupos Raciais , Humanos , Estados Unidos/epidemiologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/mortalidadeRESUMO
BACKGROUND: Prior studies have reported that renal insufficiency occurs in a small percentage of patients with predominantly antibody deficiency (PAD) and in about 2% of patients with common variable immunodeficiency. OBJECTIVE: The goal of our study was to understand and evaluate the prevalence and type of renal complications in patients with PAD in the United States Immunodeficiency Network (USIDNET) cohort. We hypothesized that there is an association between certain renal complications and severity of immunophenotype in patients with PAD. METHODS: We performed a query of patients with PAD from the USIDNET cohort with renal complications. Patients with documented renal disease such as chronic kidney disease (CKD), nephrolithiasis, nephritis, and renal failure syndrome were included. We compared immunophenotype, flow cytometry findings, and immunoglobulin levels of patients with PAD accompanied by renal complications with those of the total USIDNET cohort of patients with PAD. RESULTS: We determined that 140 of 2071 patients with PAD (6.8%) had renal complications. Of these 140 patients, 50 (35.7%) had CKD, 46 (32.9%) had nephrolithiasis, 18 (12.9 %) had nephritis, and 50 (35.7%) had other renal complications. Compared with the total USIDNET cohort of patients with PAD, patients with CKD had lower absolute lymphocyte counts, CD3+ T-cell counts, CD4+ T-cell counts, CD19+ B-cell counts, CD20+ B-cell counts, and CD27+IgD- B-cell counts (P < .05 for all). Patients with nephritis had lower absolute lymphocyte counts, CD19+ B-cell counts, CD27+ B-cell counts, and IgE levels (P < .05 for all) than patients with PAD without renal disease. CONCLUSIONS: We determined that 6.8% of the USIDNET cohort of patients with PAD had a documented renal complication. Compared with the overall cohort of patients with PAD, those patients with nephritis and CKD had a more severe immunophenotype.
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Síndromes de Imunodeficiência , Humanos , Masculino , Feminino , Estados Unidos/epidemiologia , Adulto , Pessoa de Meia-Idade , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/complicações , Nefropatias/imunologia , Nefropatias/etiologia , Nefropatias/epidemiologia , Prevalência , Adolescente , Imunofenotipagem , Adulto Jovem , Idoso , Estudos de Coortes , CriançaRESUMO
Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. "Fair or poor" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoimmune and inflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported "fair or poor" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD.
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Qualidade de Vida , Humanos , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Inquéritos e Questionários , Nível de Saúde , Idoso , Adulto Jovem , Síndromes de Imunodeficiência/epidemiologia , Estados Unidos/epidemiologia , AdolescenteRESUMO
Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.
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Artrite , Síndrome de Behçet , Produtos Biológicos , Doenças Inflamatórias Intestinais , Masculino , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Artralgia , Proteínas de Ligação a DNA , Fatores de Transcrição/genéticaRESUMO
Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.
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BACKGROUND: Predominantly antibody deficiency (PAD) is associated with noninfectious inflammatory gastrointestinal disease. Population estimates of celiac disease (CeD) risk in those with PAD are limited. OBJECTIVE: To estimate population risk of PAD in individuals with CeD. METHODS: We conducted a nationwide case-control study in Swedish individuals who received a diagnosis of CeD between 1997 and 2017 (n = 34,980), matched to population comparators by age, sex, calendar year, and county. The CeD was confirmed through the Epidemiology Strengthened by histopathology Reports in Sweden study, which provided information on biopsy specimens from each of Sweden's pathology departments. PAD was identified using International Classification of Diseases, 10th Revision coding and categorized according to the International Union of Immunologic Societies. Logistic regression was used to calculate adjusted odds ratios (aORs) and 95% CIs. RESULTS: PAD was more prevalent in CeD than in population controls (n = 105 [0.3%] vs n = 57 [0.033%], respectively). This translated to an aOR of 8.23 (95% CI 5.95-11.48). The association was strongest with common variable immunodeficiency (aOR 17.25; 95% CI 6.86-52.40), and slightly lower in other PAD (aOR 8.39; 95% CI 5.79-12.32). The risk of CeD remained increased at least 5 years after diagnosis of PAD (aOR 4.79; 95% CI 2.89-7.97, P-heterogeneity ≤ 0.001). CONCLUSION: PAD was associated with an increased risk of CeD. A particularly strong association was seen in those with CVID, although this should be interpreted cautiously given the limited understanding of the mechanisms of histopathologic changes in these patients.
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Doença Celíaca , Humanos , Doença Celíaca/epidemiologia , Doença Celíaca/imunologia , Doença Celíaca/complicações , Suécia/epidemiologia , Estudos de Casos e Controles , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Adolescente , Adulto Jovem , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/complicações , Prevalência , Lactente , Razão de Chances , Fatores de RiscoRESUMO
PURPOSE : Predominant antibody deficiency (PAD) disorders, including common variable immunodeficiency (CVID), have been linked to increased risk of gastrointestinal infections and inflammatory bowel diseases. However, there are limited data on the relationship between PAD, specifically CVID, and risk of microscopic colitis (MC). METHODS: We performed a nationwide case-control study of Swedish adults with MC diagnosed between 1997 and 2017 (n = 13,651). Data on biopsy-verified MC were retrieved from all of Sweden's pathology departments through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) study. We defined predominant antibody deficiency using International Union of Immunologic Societies (IUIS) phenotypic classification. Individuals with MC were matched to population controls by age, sex, calendar year, and county. We used logistic regression to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: The prevalence of PAD in MC was 0.4% as compared to 0.05% in controls. After adjustment for potential confounders, this corresponded to an aOR of 7.29 (95%CI 4.64-11.63). The magnitude of the association was higher for CVID (aOR 21.01, 95% 5.48-137.44) compared to other antibody deficiencies (aOR 6.16, 95% CI 3.79-10.14). In exploratory analyses, the association between PAD and MC was particularly strong among males (aOR 31.73, 95% CI 10.82-135.04). CONCLUSION: In this population-based study, predominant antibody deficiency was associated with increased risk of MC, particularly among males. Clinicians who encounter these patients should consider a detailed infectious history and screening for antibody deficiency.
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Colite Microscópica , Doenças Inflamatórias Intestinais , Adulto , Masculino , Humanos , Estudos de Casos e Controles , Suécia/epidemiologia , Fatores de Risco , Colite Microscópica/epidemiologia , Colite Microscópica/patologiaRESUMO
Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. "Fair or poor" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoinflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported "fair or poor" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD.
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Background: Patients with predominantly antibody deficiency (PAD) have lower anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody levels after initial 2-dose SARS-CoV-2 vaccination than healthy controls do; however, the anti-spike antibody responses and neutralization function in patients with PAD following subsequent immunizations remain understudied. Objective: We sought to characterize anti-spike antibody responses in adults with PAD over the course of 5 SARS-CoV-2 vaccine doses and identify diagnostic and immunophenotypic risk factors for low antibody response. Methods: We evaluated anti-spike antibody levels in 117 adult patients with PAD and 192 adult healthy controls following a maximum of 5 SARS-CoV-2 immunizations. We assessed neutralization of the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant and analyzed infection outcomes. Results: The patients with PAD had significantly lower mean anti-spike antibody levels after 3 SARS-CoV-2 vaccine doses than the healthy controls did (1,439.1 vs 21,890.4 U/mL [P < .0001]). Adults with secondary PAD, severe primary PAD, and high-risk immunophenotypes had lower mean anti-spike antibody levels following vaccine doses 2, 3, and/or 4 but not following vaccine dose 5. Compared with patients with mild and moderate PAD, patients with severe PAD had a higher rate of increase in anti-spike antibody levels over 5 immunizations. A strong positive correlation was observed between anti-spike antibody levels and neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Most infections were managed on an outpatient basis. Conclusions: In all of the patients with PAD, anti-spike antibody levels increased with successive SARS-CoV-2 immunizations and were correlated with neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Secondary PAD, severe primary PAD, and high-risk immunophenotypes were correlated with lower mean anti-spike antibody levels following vaccine doses 2 through 4. Patients with severe PAD had the highest rate of increase in anti-spike antibody levels over 5 immunizations. These data suggest a clinical benefit to sequential SARS-CoV-2 immunizations, particularly among high-risk patients with PAD.
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GOALS: To determine whether patients with celiac disease (CD) and low vitamin D levels also have a higher prevalence of other autoimmune diseases (AD) as compared with patients with normal vitamin D levels. BACKGROUND: Patients with CD carry a higher risk of other autoimmune disorders. Because of its immunoregulatory properties, vitamin D deficiency has been proposed in the pathogenesis of a variety of AD. Whether low vitamin D levels in patients with CD can predict concomitant AD is unknown. STUDY: A retrospective cross-sectional study of 530 adult patients with CD and a 25-hydroxyvitamin D level on record at Columbia University Medical Center. RESULTS: One hundred thirty-three patients (25%) had vitamin D deficiency. The prevalence of AD was similar among those with normal vitamin D levels (11%), insufficiency (9%), and deficiency (12%, P=0.66). On multivariate analysis, adjusting for age of CD diagnosis and sex, vitamin D deficiency was not associated with AD (odds ratio, 1.35; 95% confidence interval, 0.62-2.95). The risk of psoriasis was higher in patients with vitamin D deficiency (7% vs. 3%, P=0.04). Vitamin D deficiency was more common in those who presented with anemia (39%) than in those who did not (23% P=0.002). CONCLUSIONS: Vitamin D deficiency in CD is common but does not predict AD. The risk of psoriasis is increased in vitamin D-deficient CD patients. Assessment of vitamin D seems to be a high-yield practice, especially in those CD patients who present with anemia.
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Doenças Autoimunes/sangue , Doenças Autoimunes/etiologia , Doença Celíaca/sangue , Doença Celíaca/complicações , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/epidemiologia , Autoimunidade , Doença Celíaca/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Vitamina D/sangue , Adulto JovemRESUMO
OBJECTIVES: Clinical inference suggests the prevalence of non-celiac gluten sensitivity is substantially higher than that of celiac disease in the USA. Unfortunately, there are currently no data supporting these claims. The authors analyzed nationally representative data to estimate the prevalence of adherence to a gluten-free diet among participants without celiac disease and also to characterize the demographics and general health status of these participants. STUDY DESIGN AND SETTING: The Continuous National Health and Nutrition Examination Survey (NHANES) 2009-2010 enrolled 7762 individuals representing the civilian, non-institutionalized, US population free of celiac disease. Participants responded to interviewer administered questionnaires regarding current adherence to a gluten-free diet. Prevalence estimates were computed using SAS survey procedures. RESULTS: There were 49 individuals who reported current adherence to a gluten-free diet reflecting a weighted prevalence of 0.548% (95% CI 0.206-0.889). The prevalence of a gluten-free diet was higher in females (0.58%) than males (0.37%), although this was not statistically significant (p = 0.34). Participants reporting a gluten-free diet were older (46.6 vs. 40.5 years, p = 0.005), had higher high-density lipoprotein, lower iron and lower body mass index. CONCLUSIONS: The estimated national prevalence of non-celiac gluten sensitivity is 0.548%, approximately half that of celiac disease. Future studies are merited in order to better understand the population burden of non-celiac gluten sensitivity.
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Dieta Livre de Glúten/estatística & dados numéricos , Proteínas Alimentares/efeitos adversos , Hipersensibilidade Alimentar/dietoterapia , Glutens/efeitos adversos , Cooperação do Paciente/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Celíaca , Estudos Transversais , Feminino , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/etiologia , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Prevalência , Autorrelato , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: The Game of Dice Task (GDT) captures probabilistic risk-taking, which is an important feature of addictions and integral to gambling disorder (GD). No research appears to have assessed effects of gambling-specific priming manipulations or the pharmacological basis of such effects on the GDT. AIMS: To investigate effects of slot machine gambling (Slots) and d-amphetamine (AMPH; 20 mg) on risk-taking in people with GD and healthy controls (HCs) (n = 30/group). The role of dopamine (DA) was assessed by pre-treating participants with the D2 receptor (D2R)-preferring antagonist, haloperidol (HAL; 3-mg) or mixed D1R-D2R antagonist, fluphenazine (FLU; 3-mg). HYPOTHESES: Slots and AMPH will each increase risk-taking based on fewer (less probable) possible outcomes selected (POS) and poorer net monetary outcomes (NMO; gains minus losses) on the GDT, with stronger effects in Group GD. If DA mediates these effects, outcomes will vary with pre-treatment. METHOD: Participants attended a pre-experimental baseline session and 4 test sessions. Antagonist Group (HAL, FLU) was manipulated between-participants. Pre-treatment (antagonist, placebo) was manipulated within-participants and counterbalanced over sessions for Slots and AMPH test phases. Moderator/mediator effects of trait and neuropsychological factors and GD severity (South Oaks Gambling Screen; SOGS) were explored via covariance. RESULTS: AMPH led to an escalation in risky POS over trial blocks in both groups, regardless of pre-treatment. Cognitive inflexibility (high perseveration-proneness) moderated this effect in Group HC. In Group GD, SOGS selectively predicted riskier POS on AMPH sessions. Group GD achieved poorer NMO vs. Group HC on the pre-experimental baseline and Placebo-Slots sessions. Group HC selectively displayed poorer NMO on the Antagonist-Slots session. CONCLUSIONS: The GDT can detect behavioral and pharmacological priming effects. Cognitive inflexibility and symptom severity moderate AMPH-induced risk-taking in HC and GD participants, respectively. Sensitization-related "wanting" of risk may contribute to the latter effect in people with GD.
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Anfetamina , Jogo de Azar , Humanos , Anfetamina/efeitos adversos , Jogo de Azar/psicologia , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Dextroanfetamina , Flufenazina , Dopamina , Assunção de RiscosRESUMO
Data regarding response to SARS-CoV-2 immunization in pediatric patients with predominantly antibody deficiency (PAD) is limited. We evaluated SARS-CoV-2 immunization response by anti-SARS-CoV-2-spike antibody level in 15 pediatric PAD patients. These data were compared to a published cohort of adult PAD patients (n=62) previously analyzed following SARS-CoV-2 immunization at our single center institution. We evaluated demographics, clinical characteristics, immunophenotype, infection history, and past medication use by chart review. Following a two-dose monovalent initial series SARS-CoV-2 immunization, mean anti-SARS-CoV-2-spike antibody levels were significantly higher in pediatric PAD patients compared to adult PAD patients (2,890.7 vs. 140.1 U/mL; p<0.0001). Pediatric PAD patients with low class-switched memory B-cells, defined as <2% of total CD19+ B-cells, had significantly lower mean anti-SARS-CoV-2-spike antibody levels than those without (p=0.02). Following a third-dose monovalent SARS-CoV-2 immunization, the mean anti-SARS-CoV-2-spike antibody levels in pediatric PAD patients significantly increased (2,890.7 to 18,267.2 U/mL; p<0.0001). These data support Centers for Disease Control guidelines regarding three-part SARS-CoV-2 vaccine series, including in the pediatric PAD patient demographic.
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COVID-19 , Doenças da Imunodeficiência Primária , Vacinas , Adulto , Humanos , Criança , Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2 , Vacinação , Anticorpos AntiviraisRESUMO
Nodular regenerative hyperplasia (NRH) is associated with high morbidity and mortality in patients with common variable immunodeficiency (CVID). While liver biopsy is the gold standard for NRH diagnosis, a non-invasive technique could facilitate early disease recognition, monitoring, and/or immune intervention. We performed a cross-sectional analysis of ultrasound-based transient elastography (TE) in patients with CVID to evaluate liver stiffness and compared this between patients with (N = 12) and without (N = 6) biopsy-proven NRH. Additionally, these data were compared to a cohort followed at our institution for non-alcoholic fatty liver disease (NAFLD) (N = 527), a disease for which TE has routine diagnostic use. Clinical and pathologic features of NRH were evaluated as correlates of liver stiffness, and receiver operating characteristic curves were used to define a liver stiffness cutoff with diagnostic utility for NRH among CVID patients. CVID patients with NRH had a more severe disease presentation compared to those without. This included increased autoinflammatory disease comorbidities, combined B-cell and T-cell dysfunction, and abnormal liver biochemistries (specifically an increased mean alkaline phosphatase level [proximal to TE, 250 vs. 100 U/L; p = 0.03; peak, 314 vs. 114 U/L; p = 0.02). Results of TE demonstrated a significantly elevated liver stiffness in CVID patients with NRH (mean 13.2 ± 6.2 kPa) as compared to both CVID patients without NRH (mean 4.6 ± 0.9 kPa) and non-CVID patients with NAFLD (mean 6.9 ± 5.5 kPa) (p < 0.01). No single or composite histopathologic feature of NRH correlated with liver stiffness including nodule size, nodule density, sinusoidal dilation, fibrosis, and/or lymphocytosis. In contrast, liver stiffness by TE was significantly correlated with clinical parameters of portal hypertension, including an elevated hepatic venous pressure gradient, an increased splenic longitudinal diameter, presence of varices, and presence of peripheral edema. A liver stiffness of greater than or equal to 6.2 kPa was a clinically significant cutoff for NRH in CVID patients. We propose that TE has diagnostic utility in CVID, particularly in the presence of immunophenotypic features such as combined B-cell and T-cell dysfunction, autoinflammatory comorbidities, and/or abnormal liver tests. Elevated liver stiffness by TE should raise suspicion for NRH in patients with CVID and prompt expedited evaluation by hepatology.
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Imunodeficiência de Variável Comum , Técnicas de Imagem por Elasticidade , Hipertensão Portal , Hepatopatia Gordurosa não Alcoólica , Imunodeficiência de Variável Comum/complicações , Estudos Transversais , Técnicas de Imagem por Elasticidade/métodos , Humanos , Hiperplasia , Hipertensão Portal/diagnóstico por imagem , Hipertensão Portal/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagemRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with predominant antibody deficiency (PAD) is associated with high morbidity, yet data regarding the response to SARS-CoV-2 immunization in PAD patients, including additional dose vaccine, are limited. OBJECTIVE: To characterize antibody response to SARS-CoV-2 vaccine in PAD patients and define correlates of vaccine response. METHODS: We assessed the levels and function of anti-SARS-CoV-2 antibodies in 62 PAD patients compared with matched healthy controls at baseline, at 4 to 6 weeks after the initial series of immunization (a single dose of Ad26.COV2.S [Janssen] or two doses of BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]), and at 4 to 6 weeks after an additional dose immunization, if received. RESULTS: After the initial series of SARS-CoV-2 vaccination, PAD patients had lower mean anti-spike antibody levels compared with matched healthy controls (140.1 vs 547.3 U/mL; P = .02). Patients with secondary PAD (eg, B-cell depletion therapy was used) and those with severe primary PAD (eg, common variable immunodeficiency with autoinflammatory complications) had the lowest mean anti-spike antibody levels. Immune correlates of a low anti-spike antibody response included low CD4+ T helper cells, low CD19+ total B cells, and low class-switched memory (CD27+IgD/M-) B cells. In addition, a low (<100 U/mL) anti-spike antibody response was associated with prior exposure to B-cell depletion therapy, both at any time in the past (odds ratio = 5.5; confidence interval, 1.5-20.4; P = .01) and proximal to vaccination (odds ratio = 36.4; confidence interval, 1.7-791.9; P = .02). Additional dose immunization with an mRNA vaccine in a subset of 31 PAD patients increased mean anti-spike antibody levels (76.3 U/mL before to 1065 U/mL after the additional dose; P < .0001). CONCLUSIONS: Patients with secondary and severe primary PAD, characterized by low T helper cells, low B cells, and/or low class-switched memory B cells, were at risk for low antibody response to SARS-CoV-2 immunization, which improved after an additional dose vaccination in most patients.
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COVID-19 , Vacinas Virais , Ad26COVS1 , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , Vacinas Sintéticas , Vacinas de mRNARESUMO
Background: An adequate understanding of the relationship between breast-feeding practices and infant food allergy is essential for clinicians. Although there is evidence of an education gap in general breast-feeding concepts, little is known about the pediatric trainee knowledge and practice with regard to breast-feeding, maternal diet, and potential allergy outcomes. Objective: To assess pediatric residents' knowledge, describe practices, and evaluate a module designed to provide evidence-based education about breast-feeding, food allergy, and food avoidance to inform future resources on the topic of breast-feeding and allergic outcomes. Methods: Pediatric residents completed a survey to assess the knowledge and comfort with regard to maternal dietary restriction, breast-feeding, and infant food allergy. Residents then viewed an online educational module about evidence-based breast-feeding and infant food allergy guidelines, and, after 1 month, completed the online questionnaire again. Results: Among respondents (N = 68), only 8% and 5%, felt knowledgeable and comfortable with current maternal diet during breast-feeding and infant food allergy recommendations, respectively. Eighty-seven percent had not received formal training on the topic, and a large percentage relied on mentor teaching (49%) or anecdotal evidence (19%) as opposed to available guidelines (32%) for guidance. Most respondents (61-93%) correctly answered questions with regard to guidelines on primary and secondary food allergy prevention in relation to maternal diet. The upper-level residents answered more questions correctly about allergic proctocolitis compared with the interns (p < 0.05); no differences were noted for other topics. The majority (63%) did not believe that a mother's nutritional status could be adversely affected by dietary allergen restriction. A review of the pre- and posttest scores showed the educational module had little impact on knowledge. Conclusion: Pediatric residents reported low comfort and perceived that they had little knowledge about maternal diet and infant food allergy, yet their actual performance suggested the opposite. Those who completed the educational module did not demonstrate knowledge improvement, which highlighted the need for the development of robust educational resources.
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BACKGROUND: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear. AIMS: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects. METHODS: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design. RESULTS: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble. CONCLUSIONS: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.
Assuntos
Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Jogo de Azar/tratamento farmacológico , Jogo de Azar/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Anfetamina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Método Duplo-Cego , Feminino , Flufenazina/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Reforço PsicológicoRESUMO
This study investigated the role of dopamine, and specifically the D1 receptor (D1R), in the reinforcing effects of a slot-machine game in healthy volunteers ( n=30). To compare gambling and drug effects, subjects received the prototypic psychostimulant drug d-amphetamine (AMPH; 20 mg) in a multi-session, placebo-controlled design. To isolate D1R, half the subjects were pretreated with the preferential D2 receptor antagonist haloperidol (HAL; 3 mg), and the other half with the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg) before the game (Phase I) and AMPH (Phase II). HAL decreased and FLU increased the post-game desire to gamble and post-AMPH desire to take AMPH again, as well as amphetamine scale ratings on the Addiction Research Center Inventory after gambling and AMPH. The effects of the antagonists on desire to gamble and to take AMPH again were significantly intercorrelated. HAL increased and FLU decreased the salience of negative affective words on a rapid reading task after both reinforcers. HAL also decreased the salience of gambling words after AMPH. Both reinforcers increased diastolic blood pressure equally under antagonists and placebo. Results indicate that D1R plays a parallel role in the psychostimulant-like, incentive-motivational, and salience-enhancing effects of gambling and AMPH. Moderate D1R activation appears to optimize these effects in healthy subjects.
Assuntos
Anfetamina/farmacologia , Comportamento Aditivo/metabolismo , Jogo de Azar/metabolismo , Receptores de Dopamina D1/metabolismo , Adulto , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Feminino , Haloperidol/farmacologia , Voluntários Saudáveis , Humanos , Masculino , Motivação/efeitos dos fármacos , Reforço PsicológicoRESUMO
OBJECTIVES: Early-onset colorectal cancer (CRC) incidence rates are rising. This group is susceptible to heritable conditions (i.e., Lynch syndrome (LS)) and inflammatory bowel disease (IBD) with high metachronous CRC rates after segmental resection. Hence, extended colonic resection (ECR) is often performed and considered generally in young patients. As there are no population-based studies analyzing resection extent in early-onset CRC, we used CDC Comparative Effectiveness Research (CER) data to assess state-wide operative practices. METHODS: Using CER and Louisiana Tumor Registry data, all CRC patients aged ≤50 years, diagnosed in Louisiana in 2011, who underwent surgery in 2011-2012 were retrospectively analyzed. Prevalence of, and the factors associated with operation type (ECR including subtotal/total/proctocolectomy vs. segmental resection) were evaluated. RESULTS: Of 2,427 CRC patients, 274 were aged ≤50 years. In all, 234 underwent surgery at 53 unique facilities and 6.8% underwent ECR. Statistically significant ECR-associated factors included age ≤45 years, polyposis, synchronous/metachronous LS-associated cancers, and IBD. Abnormal microsatellite instability (MSI) was not ECR-associated. ECR was not performed in sporadic CRC. CONCLUSIONS: ECR is performed in the setting of clinically obvious associated high-risk features (polyposis, IBD, synchronous/metachronous cancers) but not in isolated/sporadic CRC. However, attention must be paid to patients with seemingly lower risk characteristics (isolated CRC, no polyposis), as LS can still be present. In addition, the presumed sporadic group requires further study as metachronous CRC risk in early-onset sporadic CRC has not been well-defined, and some may harbor undefined/undiagnosed hereditary conditions. Abnormal MSI (LS risk) is not associated with ECR; abnormal MSI results often return postoperatively after segmental resection has already occurred, which is a contributing factor.