Despite the key role of γ-aminobutyric acid (GABA) neurons in the modulation of cerebral cortical output, little is known about their development in the human cortex. We analyzed several GABAergic ...parameters in standardized regions of the cerebral cortex and white matter in a total of 38 human fetuses and infants from 19 gestational weeks to 2.7 postnatal years using immunocytochemistry, Western blotting, tissue autoradiography, and computer-based cellular quantitation. At least 20% of GABAergic neurons in the white matter migrated toward the cortex over late gestation. After term, migration declined and ended within 6 postnatal months. In parallel, the GABAergic neuronal density increased in the cortex over late gestation, also with a peak at term. From midgestation to infancy, the pattern of GABAA receptor binding changed from uniformly low across all cortical layers to high levels concentrated in the middle laminae; glutamic acid decarboxylase (GAD65 and GAD67) levels differentially increased. Thus, the second half of gestation is a period of rapid development of the cortical GABAergic system that continues into early infancy. This period corresponds to the peak window of vulnerability to perinatal hypoxia-ischemia in which GABAergic neurons are potentially developmentally susceptible, including in the preterm infant.
Purpose
Online Adaptive Radiation Therapy (oART) follows a different treatment paradigm than conventional radiotherapy, and because of this, the resources, implementation, and workflows needed are ...unique. The purpose of this report is to outline our institution's experience establishing, organizing, and implementing an oART program using the Ethos therapy system.
Methods
We include resources used, operational models utilized, program creation timelines, and our institutional experiences with the implementation and operation of an oART program. Additionally, we provide a detailed summary of our first year's clinical experience where we delivered over 1000 daily adaptive fractions. For all treatments, the different stages of online adaption, primary patient set‐up, initial kV‐CBCT acquisition, contouring review and edit of influencer structures, target review and edits, plan evaluation and selection, Mobius3D 2nd check and adaptive QA, 2nd kV‐CBCT for positional verification, treatment delivery, and patient leaving the room, were analyzed.
Results
We retrospectively analyzed data from 97 patients treated from August 2021–August 2022. One thousand six hundred seventy seven individual fractions were treated and analyzed, 632(38%) were non‐adaptive and 1045(62%) were adaptive. Seventy four of the 97 patients (76%) were treated with standard fractionation and 23 (24%) received stereotactic treatments. For the adaptive treatments, the generated adaptive plan was selected in 92% of treatments. On average(±std), adaptive sessions took 34.52 ± 11.42 min from start to finish. The entire adaptive process (from start of contour generation to verification CBCT), performed by the physicist (and physician on select days), was 19.84 ± 8.21 min.
Conclusion
We present our institution's experience commissioning an oART program using the Ethos therapy system. It took us 12 months from project inception to the treatment of our first patient and 12 months to treat 1000 adaptive fractions. Retrospective analysis of delivered fractions showed that the average overall treatment time was approximately 35 min and the average time for the adaptive component of treatment was approximately 20 min.
During uphill running limb muscles must perform net mechanical work to increase the body's potential energy, while during level running the net mechanical work required is negligible as long as speed ...is constant. The increased demands for work as running incline increases might be met by an increase in power output at all joints, or only a subset of joints. We used inverse dynamics to determine which joints modulate net work output in humans running uphill. We measured joint kinematics and ground reaction force during moderate speed running at 0 degrees , 6 degrees and 12 degrees inclines. Muscle force, joint power and work per step were determined at the ankle, knee and hip using inverse dynamics calculations. We found that virtually all of the increase in work output with increasing incline resulted from increases in net work done at the hip (-0.25+/-0.23 J kg(-1), level, vs 0.88+/-0.10 J kg(-1), 12 degrees incline), while the knee and ankle performed similar functions at all inclines. The increase in work output at the hip resulted primarily from a large increase in average net muscle moment during stance (2.07+/-17.84 Nm, level, vs 87.30+/-13.89 Nm, 12 degrees incline); joint excursion increased by only 20% (41.22+/-3.41 degrees , level, vs 49.22+/-2.35 degrees , 12 degrees incline). The increase in hip muscle moment and power was associated with a poorer mechanical advantage for producing force against the ground. The increase in hip moment with running incline allows for the production of the power necessary to lift the body. This power may be developed by hip extensors or by transfer of power from muscles at other joints via biarticular muscles.
CONTEXT Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities ...of serotonin (5-hydroxytryptamine 5-HT) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS. OBJECTIVE To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme (tryptophan hydroxylase TPH2), or both. DESIGN, SETTING, AND PARTICIPANTS Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT1A receptor binding. The data set was accrued between 2004 and 2008 and consisted of 41 infants dying from SIDS (cases), 7 infants with acute death from known causes (controls), and 5 hospitalized infants with chronic hypoxia-ischemia. MAIN OUTCOME MEASURES Serotonin and metabolite tissue levels in the raphé obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphé obscurus; and 5-HT1A binding density in 5 medullary nuclei that contain 5-HT neurons and 5 medullary nuclei that receive 5-HT projections. RESULTS Serotonin levels were 26% lower in SIDS cases (n = 35) compared with age-adjusted controls (n = 5) in the raphé obscurus (55.4 95% confidence interval {CI}, 47.2-63.6 vs 75.5 95% CI, 54.2-96.8 pmol/mg protein, P = .05) and the PGCL (31.4 95% CI, 23.7-39.0 vs 40.0 95% CI, 20.1-60.0 pmol/mg protein, P = .04). There was no evidence of excessive 5-HT degradation assessed by 5-HIAA levels, 5-HIAA:5-HT ratio, or both. In the raphé obscurus, TPH2 levels were 22% lower in the SIDS cases (n = 34) compared with controls (n = 5) (151.2% of standard 95% CI, 137.5%-165.0% vs 193.9% 95% CI, 158.6%-229.2%, P = .03). 5-HT1A receptor binding was 29% to 55% lower in 3 medullary nuclei that receive 5-HT projections. In 4 nuclei, 3 of which contain 5-HT neurons, there was a decrease with age in 5-HT1A receptor binding in the SIDS cases but no change in the controls (age × diagnosis interaction). The profile of 5-HT and TPH2 abnormalities differed significantly between the SIDS and hospitalized groups (5-HT in the raphé obscurus: 55.4 95% CI, 47.2-63.6 vs 85.6 95% CI, 61.8-109.4 pmol/mg protein, P = .02; 5-HT in the PGCL: 31.4 95% CI, 23.7-39.0 vs 71.1 95% CI, 49.0-93.2 pmol/mg protein, P = .002; TPH2 in the raphé obscurus: 151.2% 95% CI, 137.5%-165.0% vs 102.6% 95% CI, 58.7%-146.4%, P = .04). CONCLUSION Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.
CONTEXT The serotonergic (5-hydroxytryptamine 5-HT) neurons in the medulla oblongata project extensively to autonomic and respiratory nuclei in the brainstem and spinal cord and help regulate ...homeostatic function. Previously, abnormalities in 5-HT receptor binding in the medullae of infants dying from sudden infant death syndrome (SIDS) were identified, suggesting that medullary 5-HT dysfunction may be responsible for a subset of SIDS cases. OBJECTIVE To investigate cellular defects associated with altered 5-HT receptor binding in the 5-HT pathways of the medulla in SIDS cases. DESIGN, SETTING, AND PARTICIPANTS Frozen medullae from infants dying from SIDS (cases) or from causes other than SIDS (controls) were obtained from the San Diego Medical Examiner's office between 1997 and 2005. Markers of 5-HT function were compared between SIDS cases and controls, adjusted for postconceptional age and postmortem interval. The number of samples available for each analysis ranged from 16 to 31 for SIDS cases and 6 to 10 for controls. An exploratory analysis of the correlation between markers and 6 recognized risk factors for SIDS was performed. MAIN OUTCOME MEASURES 5-HT neuron count and density, 5-HT1A receptor binding density, and 5-HT transporter (5-HTT) binding density in the medullary 5-HT system; correlation between these markers and 6 recognized risk factors for SIDS. RESULTS Compared with controls, SIDS cases had a significantly higher 5-HT neuron count (mean SD, 148.04 51.96 vs 72.56 52.36 cells, respectively; P<.001) and 5-HT neuron density (P<.001), as well as a significantly lower density of 5-HT1A receptor binding sites (P≤.01 for all 9 nuclei) in regions of the medulla involved in homeostatic function. The ratio of 5-HTT binding density to 5-HT neuron count in the medulla was significantly lower in SIDS cases compared with controls (mean SD, 0.70 0.33 vs 1.93 1.25 fmol/mg, respectively; P = .001). Male SIDS cases had significantly lower 5-HT1A binding density in the raphé obscurus compared with female cases (mean SD, 16.2 2.0 vs 29.6 16.5 fmol/mg, respectively; P = .04) or with male and female controls combined (mean SD, 53.9 19.8 fmol/mg; P = .005). No association was found between 5-HT neuron count or density, 5-HT1A receptor binding density, or 5-HTT receptor binding density and other risk factors. CONCLUSIONS Medullary 5-HT pathology in SIDS is more extensive than previously delineated, potentially including abnormal 5-HT neuron firing, synthesis, release, and clearance. This study also provides preliminary neurochemical evidence that may help explain the increased vulnerability of boys to SIDS.
Objective:The study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects.Method:EHR data were obtained from a health care ...system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis.Results:The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses.Conclusions:Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent ...a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
The rate of the sudden infant death syndrome (SIDS) among American Indian infants in the Northern Plains is almost 6 times higher than in U.S. white infants. In a study of infant mortality among ...Northern Plains Indians, we tested the hypothesis that receptor binding abnormalities to the neurotransmitter serotonin (5-HT) in SIDS cases, compared with autopsied controls, occur in regions of the medulla oblongata that contain 5-HT neurons and that are critical for the regulation of cardiorespiration and central chemosensitivity during sleep, i.e. the medullary 5-HT system. Tritiated-lysergic acid diethylamide binding to 5-HT1A-D and 5-HT2 receptors was measured in 19 brainstem nuclei in 23 SIDS and 6 control infants using tissue receptor autoradiography. Binding in the arcuate nucleus, a part of the medullary 5-HT system along the ventral surface, in the SIDS infants (mean age-adjusted binding 7.1 ± 0.8 fmol/mg tissue, n = 23) was significantly lower than in controls (mean age-adjusted binding 13.1 ± 1.6 fmol/mg tissue, n = 5) (p = 0.003). Binding also demonstrated significant diagnosis × age interactions (p < 0.04) in 4 other nuclei that are components of the 5-HT system. These data suggest that medullary 5-HT dysfunction can lead to sleep-related, sudden death in affected SIDS infants, and confirm the same binding abnormalities reported by us in a larger dataset of non-American Indian SIDS and control infants. This study also links 5-HT abnormalities in the arcuate nucleus with exposure to adverse prenatal exposures, i.e. cigarette smoking (p = 0.011) and alcohol (p = 0.075), during the periconceptional period or throughout pregnancy. Prenatal exposure to cigarette smoke and/or alcohol may contribute to abnormal fetal medullary 5-HT development in SIDS infants.
Periventricular leukomalacia (PVL) involves free radical injury to developing oligodendrocytes (OLs), resulting from ischemia/reperfusion, particularly between 24 and 32 gestational weeks. Using ...immunocytochemistry and Western blots, we tested the hypothesis that this vulnerability to free radical toxicity results, in part, from developmental lack of superoxide dismutases (SOD)-1 and -2, catalase, and glutathione peroxidase (GPx) in the telencephalic white matter of the human fetus. During the period of greatest PVL risk and through term (≥37 weeks), expression of both SODs (for conversion of O2 to H2O2) significantly lagged behind that of catalase and GPx (for breakdown of H2O2), which, in contrast, superseded adult levels by 30 gestational weeks. Our data indicate that a developmental “mismatch” in the sequential antioxidant enzyme cascade likely contributes to the vulnerability to free radical toxicity of the immature cerebral white matter, which is “unprepared” for the transition from a hypoxic intrauterine to an oxygen-rich postnatal environment. All enzymes, localized to astrocytes and OLs, had higher-than-adult expression at 2 to 5 postnatal months (peak of myelin sheath synthesis), suggesting an adaptive mechanism to protect against lipid peroxidation during myelin sheath (lipid) synthesis. The previously unrecognized dissociation between the expression of the SODs and that of catalase and GPx in the fetal period has potential implications for future antioxidant therapy in PVL.
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by ...limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10
), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10
). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10
) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10
). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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