RESUMEN
BACKGROUND: Neurological symptoms associated with coronavirus disease 2019 (COVID-19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post-COVID-19 timeframe. PURPOSE: To determine whether adults who experienced flu-like symptoms due to COVID-19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu-like symptoms but tested negative for COVID-19. STUDY TYPE: Prospective observational. POPULATION: A total of 39 adults who previously self-isolated at home due to COVID-19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu-like symptoms but had a negative COVID-19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis). FIELD STRENGTH AND SEQUENCES: A 3.0 T; T1-weighted magnetization-prepared rapid gradient and echo-planar turbo gradient-spin echo arterial spin labeling sequences. ASSESSMENT: Arterial spin labeling was used to estimate CBF. A self-reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID-19 and control groups and between those with (n = 11) and without self-reported ongoing fatigue (n = 28) within the COVID-19 group. STATISTICAL TESTS: Between-group and within-group comparisons of CBF were performed in a voxel-wise manner, controlling for age and sex, at a family-wise error rate of 0.05. RESULTS: Relative to controls, the COVID-19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t-statistic = 5.21). Within the COVID-19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self-reported on-going fatigue. DATA CONCLUSION: These cross-sectional data revealed regional CBF decreases in the COVID-19 group, suggesting the relevance of brain physiology in the post-COVID-19 timeframe. This research may help elucidate the heterogeneous symptoms of the post-COVID-19 condition. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.
Asunto(s)
COVID-19 , Adulto , Femenino , Humanos , Masculino , Circulación Cerebrovascular/fisiología , COVID-19/diagnóstico por imagen , Prueba de COVID-19 , Estudios Transversales , Fatiga/diagnóstico por imagen , Imagen por Resonancia Magnética , Marcadores de Spin , Persona de Mediana EdadRESUMEN
BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.
Asunto(s)
Trastorno Bipolar , Trastorno Depresivo Resistente al Tratamiento , Adulto , Humanos , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/tratamiento farmacológico , Óxido Nitroso/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Antidepresivos/uso terapéutico , Neuroimagen , Midazolam , Resultado del Tratamiento , Método Doble CiegoRESUMEN
White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.
Asunto(s)
Leucoaraiosis , Sustancia Blanca , Vasos Coronarios , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Leucoaraiosis/patología , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
Unlimited self renewal capacity and differentiation potential make human pluripotent stem cells (PSC) a promising source for the ex vivo manufacture of red blood cells (RBCs) for safe transfusion. Current methods to induce erythropoiesis from PSC suffer from low yields of RBCs, most of which are immature and contain embryonic and fetal rather than adult hemoglobins. We have previously shown that homodimerization of the intracellular component of MPL (ic-MPL) induces erythropoiesis from human cord blood progenitors. The goal of this study was to investigate the potential of ic-MPL dimerization to induce erythropoiesis from human embryonic stem cells (hESCs) and to identify the signaling pathways activated by this strategy. We present here the evidence that ic-MPL dimerization induces erythropoietin (EPO)-independent erythroid differentiation from hESC by inducing the generation of erythroid progenitors and by promoting more efficient erythroid maturation with increased RBC enucleation as well as increased gamma:epsilon globin ratio and production of beta-globin protein. ic-MPL dimerization is significantly more potent than EPO in inducing erythropoiesis, and its effect is additive to EPO. Signaling studies show that dimerization of ic-MPL, unlike stimulation of the wild type MPL receptor, activates AKT in the absence of JAK2/STAT5 signaling. AKT activation upregulates GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis, modulation of cell cycle, and enhanced maturation of erythroid cells. These findings open up potential new targets for the generation of therapeutically relevant RBC products from hPSC.
Asunto(s)
Células Madre Embrionarias/citología , Células Madre Embrionarias/enzimología , Eritropoyesis , Eritropoyetina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Ciclo Celular , Diferenciación Celular , Línea Celular , Proliferación Celular , Supervivencia Celular , Células Precursoras Eritroides/citología , Células Precursoras Eritroides/metabolismo , Humanos , Megacariocitos/citología , Megacariocitos/metabolismo , Multimerización de Proteína , Estructura Terciaria de Proteína , Receptores de Trombopoyetina/química , Receptores de Trombopoyetina/metabolismoRESUMEN
BACKGROUND: The optimal empiric antibiotic regimen for non-ventilator-associated hospital-acquired pneumonia (HAP) is uncertain. OBJECTIVES: To compare the effectiveness and safety of alternative empiric antibiotic regimens in HAP using a network meta-analysis. DATA SOURCES: Medline, EMBASE, Cochrane CENTRAL, Web of Science, and CINAHL from database inception to July 06, 2023. STUDY ELIGIBILITY CRITERIA: RCTs. PARTICIPANTS: Adults with clinical suspicion of HAP. INTERVENTIONS: Any empiric antibiotic regimen vs. another, placebo, or no treatment. ASSESSMENT OF RISK OF BIAS: Paired reviewers independently assessed risk of bias using a modified Cochrane tool for assessing risk of bias in randomized trials. METHODS OF DATA SYNTHESIS: Paired reviewers independently extracted data on trial and patient characteristics, antibiotic regimens, and outcomes of interest. We conducted frequentist random-effects network meta-analyses for treatment failure and all-cause mortality and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Thirty-nine RCTs proved eligible. Thirty RCTs involving 4807 participants found low certainty evidence that piperacillin-tazobactam (RR compared to all cephalosporins: 0.65; 95% CI: 0.42, 1.01) and carbapenems (RR compared to all cephalosporins: 0.77; 95% CI: 0.53, 1.11) might be among the most effective in reducing treatment failure. The findings were robust to the secondary analysis comparing piperacillin-tazobactam vs. antipseudomonal cephalosporins or antipseudomonal carbapenems vs. antipseudomonal cephalosporins. Eleven RCTs involving 2531 participants found low certainty evidence that ceftazidime and linezolid combination may not be convincingly different from cephalosporin alone in reducing all-cause mortality. Evidence on other antibiotic regimens is very uncertain. Data on other patient-important outcomes including adverse events was sparse, and we did not perform network or pairwise meta-analysis. CONCLUSIONS: For empiric antibiotic therapy of adults with HAP, piperacillin-tazobactam might be among the most effective in reducing treatment failure. Empiric methicillin-resistant Staphylococcus aureus coverage may not exert additional benefit in reducing mortality. REGISTRATION: PROSPERO (CRD 42022297224).
RESUMEN
Youth with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit an increased prevalence of obesity, early adiposity rebound, and increased abdominal adiposity compared to unaffected youth. Current obesity management in CAH largely focuses on lifestyle modifications. There is evidence that topiramate therapy is effective in reducing body mass index (BMI), as well as visceral adipose tissue (VAT), in unaffected adolescents with exogenous obesity. However, little is known about the efficacy of topiramate in patients with classical CAH. We report on a 17-year-old female with severe obesity and salt-wasting CAH due to 21-hydroxylase deficiency, who demonstrated reductions in BMI, as well as abdominal visceral and subcutaneous adipose tissue (SAT) while on topiramate therapy. The patient was diagnosed with classical CAH as a newborn with a 17-hydroxyprogesterone 11,000 ng/dL. She had a BMI over the 95th percentile at 3 years of age, followed by unremitting obesity. At 17 years old, she was started on topiramate to treat chronic migraines. Following three years of topiramate therapy, her BMI z-score decreased from +2.6 to +2.1. After four years of therapy, her waist circumference decreased from 110 to 101 cm, abdominal VAT decreased substantially by 34.2%, and abdominal SAT decreased by 25.6%. Topiramate therapy was associated with effective weight loss and reduced central adiposity in an adolescent with classical CAH and severe obesity, without any side effects. Further study is warranted regarding topiramate therapy in obese youth with classical CAH and increased central adiposity, who are at higher risk for significant morbidity.
RESUMEN
INTRODUCTION: Patients with classical congenital adrenal hyperplasia (CAH) have prenatal and postnatal hormonal imbalances. To characterize the ontogeny of reported brain and behavior changes in older children with CAH, we aimed to study the brain structure in infants with CAH compared to healthy controls. METHODS: We performed neuroimaging in 16 infants with classical CAH due to 21-hydroxylase deficiency (8 males, gestational age 38.2 ± 1.7 weeks, post-conceptional age [PCA] 42.2 ± 3.0 weeks) and 14 control infants (9 males, gestational age 38.5 ± 1.8 weeks, PCA 42.5 ± 2.4 weeks) utilizing 3-Tesla magnetic resonance imaging. Regional brain volumes were adjusted for PCA and sex, along with an additional adjustment for total brain volume (TBV), for group comparisons by regression analyses (mean, 95% confidence interval [CI]). The degree to which each brain region was differentiated between CAH and control infants was examined by relaimpo analyses, adjusting for all other brain regions, PCA, and sex. RESULTS: Infants with CAH had significantly smaller thalamic volumes (8,606 mm3, 95% CI [8,209, 9,002]) compared to age-matched control infants (9,215 mm3, 95% CI [8,783, 9,647]; ß = -609; p = 0.02) which remained smaller after further adjustment for TBV. Upon further adjustment for TBV, the temporal lobe was larger in infants with CAH (66,817 mm3, CI [65,957, 67,677]) compared to controls (65,616 mm3, CI [64,680, 66,551]; ß = 1,202, p = 0.03). The brain regions most differentiated between CAH versus controls were the thalamus (22%) and parietal lobe (10%). CONCLUSIONS: Infants with CAH exhibit smaller thalamic regions from early life, suggesting a prenatal influence on brain development in CAH. Thalamic emergence at 8-14 weeks makes the region particularly vulnerable to changes in the intrauterine environment, with potential implications for later maturing brain regions. These changes may take time to manifest, meriting longitudinal study through adolescence in CAH.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Masculino , Niño , Embarazo , Femenino , Adolescente , Humanos , Lactante , Hiperplasia Suprarrenal Congénita/diagnóstico por imagen , Estudios Longitudinales , Tálamo/diagnóstico por imagen , Edad Gestacional , Imagen por Resonancia MagnéticaRESUMEN
We report a case of a fetus with a prenatal diagnosis of classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Although CAH is typically assessed postnatally, this fetal case had multiple prenatal clinical assessments made feasible by an interdisciplinary CAH center. The approach facilitated the development and delivery of comprehensive and earlier care for the fetus, and the family living with this complex, congenital condition, with perinatology, endocrinology, genetic counseling, psychology, and urology involvement. As well, the addition of fetal MRI to standard ultrasound revealed significant deficits in the biparietal diameter, occipitofrontal diameter, and total intracranial volume of the fetal CAH brain. These early anomalies in the brain suggest that neurological comorbidities observed in older children and adults with CAH should be studied as early as prenatally, with the addition of fetal MRI to ultrasound potentially being useful for identifying and understanding prenatal anomalies in CAH.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/diagnóstico por imagen , Hiperplasia Suprarrenal Congénita/genética , Adulto , Encéfalo/diagnóstico por imagen , Niño , Femenino , Humanos , Embarazo , Diagnóstico PrenatalRESUMEN
INTRODUCTION: Youth with classical congenital adrenal hyperplasia (CAH) have higher prevalence of cardiometabolic risk factors such as obesity, abdominal adiposity, and hypertension. Patients with CAH also exhibit an earlier adiposity rebound (AR) compared to normative populations. However, the predictive relationship between AR and cardiometabolic risk factors needs to be better understood. METHODS: We performed a retrospective cohort study at a US tertiary pediatric center in youth with classical CAH due to 21-hydroxylase deficiency. AR was determined by cubic polynomial modeling. A subset of participants had fasting analytes, whole-body dual-energy X-ray absorptiometry, and magnetic resonance imaging as adolescents. RESULTS: In 42 youth with CAH (45.2% female, 54.8% Hispanic, and 90.5% salt-wasting form), the average age at AR was 3.4 ± 1.3 years. AR differed by BMI-z, with youth with obesity having an earlier AR (2.8 ± 1.0 years) compared to lean youth (4.1 ± 1.3 years, p = 0.001). However, AR did not differ by either CAH form or sex. Earlier AR predicted higher BMI-z at 7 and 12 years of age. In addition, earlier AR predicted increased central obesity (as measured by waist circumference, subcutaneous adipose tissue, and trunk fat) and total body fat in adolescence. AR was negatively correlated with bone age, and its relationships with HDL and hypertension were trending towards significance. CONCLUSIONS: AR in youth with classical CAH could serve as a useful clinical marker to identify those patients who are at higher risk for developing cardiometabolic risk factors during childhood and adolescence.