Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. ...Left ventricular hypertrophy and coronary artery calcification are potent risk factors for mortality in CKD, and FGFs have been implicated in the pathogenesis of both myocardial hypertrophy and atherosclerosis. We conducted a cross-sectional study to test the hypothesis that elevated FGF-23 concentrations are associated with left ventricular hypertrophy and coronary artery calcification in patients with CKD.
In this study, 162 subjects with CKD underwent echocardiograms and computed tomography scans to assess left ventricular mass index and coronary artery calcification; echocardiograms also were obtained in 58 subjects without CKD. In multivariable-adjusted regression analyses in the overall sample, increased log FGF-23 concentrations were independently associated with increased left ventricular mass index (5% increase per 1-SD increase in log FGF-23; P=0.01) and risk of left ventricular hypertrophy (odds ratio per 1-SD increase in log FGF-23, 2.1; 95% confidence interval, 1.03 to 4.2). These associations strengthened in analyses restricted to the CKD subjects (11% increase in left ventricular mass index per 1-SD increase in log FGF-23; P=0.01; odds ratio of left ventricular hypertrophy per 1-SD increase in log FGF-23, 2.3; 95% confidence interval, 1.2 to 4.2). Although the highest tertile of FGF-23 was associated with a 2.4-fold increased risk of coronary artery calcification > or =100 versus <100 U compared with the lowest tertile (95% confidence interval, 1.1 to 5.5), the association was no longer significant after multivariable adjustment.
FGF-23 is independently associated with left ventricular mass index and left ventricular hypertrophy in patients with CKD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy in CKD requires further study.
Monogenic conditions that disrupt proper development and/or function of the immune system are termed inborn errors of immunity (IEIs), also known as primary immunodeficiencies. Patients with IEIs ...often suffer from other manifestations in addition to infection, and allergic inflammation is an increasingly recognized feature of these conditions.
We performed a retrospective analysis of IEIs presenting with allergic inflammation as reported in the USIDNET registry. Our inclusion criteria comprised of patients with a reported monogenic cause for IEI where reported lab eosinophil and/or IgE values were available for the patient prior to them receiving potentially curative therapy. Patients were excluded if we were unable to determine the defective gene underlying their IEI. Patients were classified as having eosinophilia or elevated IgE when their record included at least 1 eosinophil count or IgE value that was greater than the age stratified upper limit of normal. We compared the proportion of patients with eosinophilia or elevated IgE with the proportion of samples in a reference population that fall above the upper limit of normal (2.5%).
The query submitted to the USIDNET registry identified 1409 patients meeting inclusion criteria with a monogenic cause for their IEI diagnosis, of which 975 had eosinophil counts and 645 had IgE levels obtained prior to transplantation or gene therapy that were available for analysis. Overall, 18.8% (183/975) of the patients evaluated from the USIDNET registry had eosinophilia and 20.9% (135/645) had an elevated IgE. IEIs caused by defects in 32 genes were found to be significantly associated with eosinophilia and/or an elevated IgE level, spanning 7 of the 10 IEI categories according to the International Union of Immunological Societies classification.
Type 2 inflammation manifesting as eosinophilia or elevated IgE is found in a broad range of IEIs in the USIDNET registry. Our findings suggest that allergic immune dysregulation may be more widespread in IEIs than previously reported.
There is considerable interest in therapeutically engaging human γδ T cells. However, due to the unique TCRs of human γδ T cells, studies from animal models have provided limited directly applicable ...insights, and human γδ T cells from key immunological tissues remain poorly characterized. In this study, we investigated γδ T cells from human spleen tissue. Compared to blood, where Vδ2+Vγ9+ T cells are the dominant subset, splenic γδ T cells included a variety of TCR types, with Vδ1+ T cells typically being the most frequent. Intracellular cytokine staining revealed that IFN-γ was produced by a substantial fraction of splenic γδ T cells, IL-17A by a small fraction, and IL-4 was minimal. Primary splenic γδ T cells frequently expressed NKG2D (NK group 2 member D) and CD16, whereas expression of DNAM-1 (DNAX accessory molecule 1), CD28, PD-1, TIGIT, and CD94 varied according to subset, and there was generally little expression of natural cytotoxicity receptors, TIM-3, LAG-3, or killer Ig-like receptors. In vitro expansion was associated with marked changes in expression of these activating and inhibitory receptors. Analysis of functional responses of spleen-derived Vδ2+Vγ9+, Vδ1+Vγ9+, and Vδ1+Vγ9- T cell lines to recombinant butyrophilin BTN2A1 and BTN3A1 demonstrated that both Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells were capable of responding to the extracellular domain of BTN2A1, whereas the addition of BTN3A1 only markedly enhanced the responses of Vδ2+Vγ9+ T cells. Conversely, Vδ1+Vγ9+ T cells appeared more responsive than Vδ2+Vγ9+ T cells to TCR-independent NKG2D stimulation. Thus, despite shared recognition of BTN2A1, differential effects of BTN3A1 and coreceptors may segregate target cell responses of Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells.
Given the paucity of level 1 evidence, the optimal regimen to control oral mucositis pain remains unclear. Although national guidelines allow consideration of prophylactic gabapentin, prior trials ...showed improved pain control with venlafaxine among patients with diabetic neuropathy. We sought to investigate the role of prophylactic high-dose gabapentin with venlafaxine to reduce oral mucositis pain among patients with head and neck cancer.
We performed a single-institution, phase 2 randomized trial on nonmetastatic squamous cell carcinoma of the head and neck treated with chemoradiation. Patients were randomized to either prophylactic gabapentin (3600 mg daily) with or without venlafaxine (150 mg daily). Primary endpoint was differences in pain levels at the end of chemoradiation. Secondary endpoint was toxicity profiles, quality of life changes, opioid use, and feeding tube placement. Differences between the 2 arms at multiple time points were evaluated using a generalized linear mixed regression model with Sidak correction.
Between May 2018 and March 2021, a total of 62 patients were enrolled and evaluable for analysis (n = 32 for the gabapentin alone arm, n = 30 for the gabapentin + venlafaxine arm). Over 90% of patients tolerated gabapentin well. Head and neck pain level showed a mean value of 45 (standard deviation, 23) and 43 (standard deviation, 21) for the gabapentin alone and the gabapentin + venlafaxine arms, respectively (P = .65). No statistically significant differences were observed in adverse events, opioid use, feeding tube placement, or quality of life.
The addition of venlafaxine to prophylactic gabapentin did not result in improvements in pain control and quality of life among patients with head and neck cancer.
Age-related macular degeneration (AMD) is a major blinding disease, affecting over 14% of the elderly. Risk for AMD is related to age, diet, environment, and genetics. Dietary modulation of AMD risk ...is a promising treatment modality, but requires appropriate animal models to demonstrate advantages of diet. Mice lacking the antioxidant transcription factor Nrf2 (Nfe2l2) develop age-related retinopathy relevant to human AMD. Here we evaluated the effect of consuming high glycemic (HG) or low glycemic (LG) diets until 18-months of age on development of features relevant to AMD in Nrf2-null mice. Nrf2-null mice that consumed HG diets developed atrophic AMD, characterized by photoreceptor degeneration, retinal pigment epithelium (RPE) atrophy and pigmentary abnormalities, basal laminar deposits, and loss of the choriocapillaris. In contrast, Nrf2-null-mice that consumed LG diets did not develop retinal disease phenotypes. Consumption of HG diets was associated with accumulation of advanced glycation end-products in the RPE and systemically, whereas consumption of the LG diet was associated with increased levels of anti-glycative and anti-oxidative detoxification machinery. Together our data indicate that the Nrf2-null HG mouse is a good model for atrophic AMD studies and that the LG diet can activate protective pathways to prevent AMD, even in a genetically predisposed animal.
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•Nrf2-null mice fed high glycemic diets develop features relevant to dry AMD.•AMD-relevant features include degeneration of RPE, photoreceptors, and choriocapillaris.•Nrf2-null mice fed low glycemic diets do not develop AMD-releveant features.•Advanced glycation end-products are increased in the RPE by high glycemic diet.•Low glycemic diet-fed mice have increased levels of antioxidant enzymes in the RPE.
Medication for opioid use disorder (MOUD) is the gold standard treatment for opioid use disorder. Traditionally, "success" in MOUD treatment is measured in terms of program retention, adherence to ...MOUD, and abstinence from opioid and other drug use. While clinically meaningful, these metrics may overlook other aspects of the lives of people with opioid use disorder (OUD) and surprisingly do not reflect the diagnostic criteria for OUD.
Authors identified items for a pilesorting task to identify participant-driven measures of MOUD treatment success through semi-structured interviews. Interviews were transcribed verbatim and coded in Nvivo using directed and conventional content analysis to identify measures related to treatment success and quality of life goals. Participants of a low-threshold MOUD program were recruited and asked to rank identified measures in order of importance to their own lives. Multidimensional scaling (MDS) compared the similarity of items while non-metric MDS in R specified a two-dimensional solution. Descriptive statistics of participant demographics were generated in SPSS.
Sixteen semi-structured interviews were conducted between June and August 2020 in Philadelphia, PA, USA, and 23 measures were identified for a pilesorting activity. These were combined with 6 traditional measures for a total list of 29 items. Data from 28 people were included in pilesorting analysis. Participants identified a combination of traditional and stakeholder-defined recovery goals as highly important, however, we identified discrepancies between the most frequent and highest ranked items within the importance categories. Measures of success for participants in MOUD programs were complex, multi-dimensional, and varied by the individual. However, some key domains such as emotional well-being, decreased drug use, and attendance to basic functioning may have universal importance. The following clusters of importance were identified: emotional well-being, decreased drug use, and human functioning.
Outcomes from this research have practical applications for those working to provide services in MOUD programs. Programs can use aspects of these domains to both provide patient-centered care and to evaluate success. Specifics from the pilesorting results may also inform approaches to collaborative goal setting during treatment.
Aim
To assess the predictive validity of developmental screenings in children with sickle cell disease (SCD) for academic outcomes and stroke risk.
Method
Parent questionnaires and medical record ...data were collected for a cohort receiving developmental screenings between September 2004 and May 2008 as toddlers or early school age. Screening outcomes were dichotomized (positive, negative) by a priori criteria. Questionnaires assessed school and social functioning, services received, and quality of life. Medical record data assessed general SCD morbidity and stroke risk.
Results
Forty‐one toddlers (mean age 2y 5mo; 25 males, 16 females) and 49 early school‐age children (mean age 6y 5mo; 26 males, 23 females) completed follow‐up. The mean follow‐up period was 8 years 6 months (range 6.1–10.8y). For toddlers, positive screenings for language delays predicted lower academic performance (p=0.023). For older children, positive screenings for cognitive delays predicted more frequent academic/attentional problems at school (p<0.001), grade retention (p=0.007), and lower academic performance (p=0.001). Positive screenings were associated with an earlier onset of school problems and lower quality of life. Positive screenings for language/cognitive delays predicted increased stroke risk (both p<0.05).
Interpretation
Screening for language or cognitive development in young children with SCD predicts academic outcomes and stroke risk.
What this paper adds
Developmental screening predicts academic outcomes in sickle cell disease.
Children with concerning language/cognitive screenings have early‐onset school difficulties.
Developmental screenings may help predict cerebrovascular complications.
Resumen
Validez predictiva de la pesquisa del desarrollo en niños pequeños con anemia falciforme: un estudio de seguimiento longitudinal
Objetivo
Evaluar la validez predictiva de las pruebas de pesquisa del desarrollo en niños con Anemia Falciformes (AF) para el aprendizaje académicos y el riesgo de accidente cerebrovascular (ACV).
Método
Se recolectaron datos usando cuestionarios para padres e historias médicas de una cohorte de niños que recibieron pruebas de pesquisa del desarrollo entre Septiembre del 2004 y Mayo del 2008, a la de edad prescolar o al inicio de la edad escolar. Los resultados de la detección fueron dicotomizados (positivos, negativos) según criterios elegidos a priori. Los cuestionarios evaluaron el funcionamiento escolar y social, los servicios recibidos y la calidad de vida. Datos de registros médicos: morbilidad relacionada con AF y riesgo de ACV.
Resultados
Cuarenta y un niños de edad prescolar (edad media de 2 años, 5 meses, 25 varones, 16 mujeres) y 49 niños en edad escolar (edad media de 6 años, 5 meses, 26 varones, 23 mujeres) completaron el seguimiento. El período de seguimiento medio fue de 8 años y 6 meses (rango 6.1‐10.8 años). Para los niños pequeños, las evaluaciones positivas para retrasos en el lenguaje predijeron un menor rendimiento académico (p = 0.023). En los niños mayores, las pesquisas positivas para retrasos cognitivos predijeron mayor frecuencia de problemas académicos / atencionales en la escuela (p = 0,0003), retención de grado (p = 0,007) y un rendimiento académico más bajo (p = 0,001). Las pesquisas positivas se asociaron con un inicio más temprano de problemas escolares y una menor calidad de vida. Los exámenes positivos para el retraso del lenguaje / cognitivo predijeron un riesgo de ACV más alto (ambos p <0.05).
Interpretación
Pruebas de pesquisa de retraso en el lenguaje o desarrollo cognitivo en niños pequeños con AF pueden predecir problemas académicos o riesgo de ACV.
Resumo
Validade preditiva do rastreio do desenvolvimento em crianças pequenas com anemia falciforme: estudo longitudinal de seguimento
Objetivo
Avaliar a validade preditivo de avaliações de rastreio de desenvolvimento em crianças com anemia falciforme (AF) para resultados acadêmicos e para risco de acidente vascular encefálico (AVE).
Método
Foram coletados questionários respondidos pelos pais e dados de registros médicos de uma coorte composta por pré‐escolares e por crianças em idade escolar precoce que foram submetidas a avaliações de rastreio de desenvolvimento entre setembro de 2004 e maio de 2008. Os resultados da triagem foram dicotomizados (positivos, negativos) por critérios estabelecidos a priori. Os questionários avaliaram o funcionamento escolar e social, os serviços recebidos e a qualidade de vida. Os dados dos registros médicos avaliaram a morbidade em geral e o risco de AVE.
Resultados
Quarenta e um pré‐escolares (média de idade de 2 anos e 5 meses; 25 do sexo masculino, 16 do sexo feminino) e 49 crianças com idade escolar precoce (média de idade de 6 anos e 5 meses; 26 do sexo masculino e 23 do sexo feminino) completaram o seguimento. O período médio de seguimento foi de 8 anos e 6 meses (6,1‐10,8 anos). Para os pré‐escolares, avaliações positivas para atrasos de linguagem previram menor desempenho acadêmico (p = 0,023). Para crianças mais velhas, avaliações positivas para atrasos cognitivos previram problemas acadêmicos / atencionais mais frequentes na escola (p = 0,0003), retenção de série (p = 0,007) e menor desempenho acadêmico (p = 0,001). As avaliações positivas foram associados com um início precoce de problemas escolares e com menor qualidade de vida. As avaliações positivas para atrasos linguísticos / cognitivos previram aumento do risco de acidente vascular encefálico (ambos p <0,05).
Interpretação
O rastreio do desenvolvimento linguístico ou cognitivo em crianças pequenas com AF prevê resultados acadêmicos e risco de acidente vascular cerebral.
What this paper adds
Developmental screening predicts academic outcomes in sickle cell disease.
Children with concerning language/cognitive screenings have early‐onset school difficulties.
Developmental screenings may help predict cerebrovascular complications.
This article is commented on by King on pages 443–444 of this issue.
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Objective
To evaluate the presence of tau deposition and pathologic features of chronic traumatic encephalopathy (CTE) in young adult patients treated with focal cortical resections for ...drug‐resistant epilepsy.
Methods
Sixty consecutive patients who had undergone surgical treatment for drug‐resistant focal epilepsy between 18 and 45 years of age were identified (2010‐2017). Medical records were reviewed to determine clinical factors, including history of head trauma, age at seizure onset, age at surgical resection, seizure type(s) and frequency, imaging findings, and surgical outcome. All formalin‐fixed, paraffin‐embedded blocks from the surgical specimens from each subject were sectioned and stained with hematoxylin and eosin and antibodies to tau (Thermo Fisher Scientific Clone AT8), and examined blindly for tau pathology, including lesions characteristic of CTE.
Results
The median age at resection was 29.5 years (range = 19‐45). A history of head trauma was reported in 19 patients. Although none of the patients had pathological findings characteristic of CTE, 23 patients (38%) demonstrated tau‐immunoreactive lesions, including neurites, neurofibrillary pretangles, neurofibrillary tangles, subpial tau, and/or glial tau. In 4 of the 23 patients (7% of the cohort; 17% of those with tau pathology), substantial tau burden was identified. Three of these 4 patients had no significant history of head trauma; 1 patient had multiple sports‐related concussions. No specific clinical factors correlated with the presence of tau pathology.
Significance
Tau‐immunoreactive lesions were found in 38% of 60 patients who underwent a focal cortical resection for drug‐resistant focal epilepsy. Diagnostic features of CTE were not detected in any patient; however, the pathological evaluation for CTE was limited to a surgical specimen. The prominent and excessive tau deposition in 23 patients (38%) is abnormal in this age group and warrants further investigation.
Like all herpesviruses, the roseoloviruses (HHV6A, -6B, and -7) establish lifelong infection within their host, requiring these viruses to evade host antiviral responses. One common host-evasion ...strategy is the downregulation of host-encoded, surface-expressed glycoproteins. Roseoloviruses have been shown to evade the host immune response by downregulating NK-activating ligands, class I MHC, and the TCR/CD3 complex. To more globally identify glycoproteins that are differentially expressed on the surface of HHV6A-infected cells, we performed cell surface capture of N-linked glycoproteins present on the surface of T cells infected with HHV6A, and compared these to proteins present on the surface of uninfected T cells. We found that the protein tyrosine phosphatase CD45 is downregulated in T cells infected with HHV6A. We also demonstrated that CD45 is similarly downregulated in cells infected with HHV7. CD45 is essential for signaling through the T cell receptor and, as such, is necessary for developing a fully functional immune response. Interestingly, the closely related betaherpesviruses human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) have also separately evolved unique mechanisms to target CD45. While HCMV and MCMV target CD45 signaling and trafficking, HHV6A acts to downregulate CD45 transcripts.
Human herpesviruses-6 and -7 infect essentially 100% of the world's population before the age of 5 and then remain latent or persistent in their host throughout life. As such, these viruses are among the most pervasive and stealthy of all viruses. Host immune cells rely on the presence of surface-expressed proteins to identify and target virus-infected cells. Here, we investigated the changes that occur to proteins expressed on the cell surface of T cells after infection with human herpesvirus-6A. We discovered that HHV-6A infection results in a reduction of CD45 on the surface of infected T cells and impaired activation in response to T cell receptor stimulation.
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