2 Minute Medicine Rewind March 16, 2020

Estimation of Glomerular Filtration Rate With vs Without Including Patient Race

1. The exclusion of patient race from glomerular filtration rate (GFR) estimation resulted in systematic error that significantly underestimated GFR in African American individuals more so than non-African Americans.

Evidence Rating Level: 2 (Good)

Glomerular filtration rate (GFR), an integral component of establishing drug dosing, prognosis, and treatment of patients with kidney disease, is often measure indirectly through serum creatinine levels to develop an estimate (eGFR). This estimation is adjusted by height, weight, age, sex, and race due to the susceptibility of serum creatinine to muscle mass, diet, and GFR. This investigation of a pooled data set from 10 studies of individuals with and without chronic kidney disease sought to determine whether or not removal of the race variable from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation would impact accurate outcomes. The major concern and impetus for this research question was that race is a social construct that is often more complicated than one single category. In these cases, eGFR could potentially be inaccurate. A total of 8,254 individuals were included in the development data set (mean [SD] age = 47 [15] years, mean [SD] GFR = 68 [40] mL/min/1.73 m2). Of this group, 31.5% were African American and 43.6% were women. When the race coefficient was removed from the CKD-EPI equation, significant systematic error resulted in the evaluation of African American GFR, such that values were underestimated. Non-African Americans were less impacted by this alteration. The inclusion of variables such as height and weight did not adequately decrease the association of eGFRcr and race (coefficient 1.16 vs 1.15). This study highlights not only the importance of race in these estimates but also suggests that a construct deemed socially-derived rather than biological is still necessary in estimating GFR in those with chronic kidney disease.

Safety, Tolerability, and Immunogenicity of Influenza Vaccination With a High-Density Microarray Path: Results From a Randomized, Controlled Phase I Clinical Trial

1. High-density microarray patches (HD-MAPs) for influenza vaccination were well-tolerated and resulted in similar or improved immune response at one-sixth the standard dose compared to intramuscular injection of commercial quadrivalent influenza vaccine.

Evidence Rating Level: 2 (Good)

Microarray patches (MAPs) are advantageous compared to needle injection of vaccination due to greater acceptability, ease of use, and vaccine thermostability. This randomized, partially-blind, placebo-controlled Phase I clinical trial investigated the safety, tolerability, and immunogenicity of the Vaxxas high-density MAP (HD-MAP) in delivering a monovalent influenza vaccine. A total of 60 healthy adults from Melbourne, Australia aged 18 to 35 years were enrolled in this study. HD-MAPs had monovalent, split inactivated vaccine coating containing A/Singapore/GP1908/2015 H1N1 haemagglutinin (HA). Participants were randomly assigned to one of the following: 1) HD-MAPs delivering 15μg of A/Singapore/GP1908/2015 H1N1 HA antigen (A-Sing) to volar forearm (FA); 2) uncoated HD-MAPs; 3) intramuscular (IM) injection of commercial quadrivalent influenza vaccine (QIV) containing A-Sing at 15μg/dose; or, 4) IM injection of H1N1 HA antigen at 15μg/dose. After a 22-day follow-up to assess safety, there was enrollment of 150 adult participants randomized to one of nine total treatment groups. These groups were HD-MAPs at doses of 15, 10, 5, 2.5, or 0 μg of HA to the FA, the same vaccinations in the upper arm (UA, or IM injection of QIV. Researchers found that vaccines coated with HD-MAPs were antigenically stable at 40ºC for a minimum of 12 months. HD-MPA was also safe and well-tolerated with limited mild-to-moderate adverse effects including myalgia and headache. HD-MAP resulted in improved humoral responses compared with IM injection with higher HAI geometric mean titers (GMTs) at Day 8 in the MAP-UA-15 group (GMT 437.1, 95% CI 133.2 to 441.5), MAP-FA-15 (GMT 218.6, 95% CI 111.0 to 427.0), and MAP-FA-10 (GMT 437.1, 95% CI 254.3 to 751.3) compared to IM-QIV-15 (GMT 82.8, 95% CI 42.4 to 161.8. Significance levels for MAP-UA-15, MAP-FA-15, and MAP-FA-10 were 0.02, 0.04, and <0.001, respectively. Higher titers were noted at Day 22 in the MAP-FA-10 (GMT 485.0, 95% CI 301.5 to 780.2) and MAP-UA-15 (GMT 367.6, 95% CI 197.9 to 682.7) groups compared to the IM-QIV-15 group (GMT 139.3, 95% CI 79.3 to 244.5). Overall, Vaxxas HD-MAP resulted in immune responses equivalent to or higher than those resulting from IM-QIV injection. Further, HD-MAP required one-sixth the standard dose – 2.5μg induced HAI and MN titers to achieve the same results as 15μg HA-IM.

Association of Childhood Obesity With Risk of Early All-Cause and Cause-Specific Mortality: A Swedish Prospective Cohort Study

1. Children with obesity were at greater risk of mortality in early adulthood than a population-based comparison group, suggesting that risks begin earlier than later adulthood.

2. Deaths due to suicide and self-injury are also common in this group, warranting clinical consideration at a primary care level.

Evidence Rating Level: 2 (Good)

The impacts of obesity on premature mortality and further health are ubiquitous. However, limited research has focused on when this risk begins and whether or not young adults are at risk if they were obese during childhood. This prospective cohort study conducted in Sweden investigated individuals between the ages of 3 and 17.9 years through the Swedish Childhood Obesity Treatment Register. A control group was matched by sex, birth year, and area of residence. All-cause and cause-specific mortality were evaluated with Cox proportional hazard ratios adjusted for parental socioeconomic status, Nordic origin, sex, and group. Across 190,752 person-years of follow-up (median = 3.6 years), 104 deaths occurred (median [IQR] age at death = 22.0 [20.0-24.5] years). These deaths were comprised of 39 children (0.55%) in the obesity group and 65 in the comparison group (0.19%; p<0.001). Greater than 25% of obesity-group deaths had obesity reported as the primary or contributing cause. Interestingly, low parental socioeconomic status and male sex were associated with premature all-cause mortality – the main causes of death in this group were suicide and self-harm with unknown intent. The most notable difference between the obesity and non-obesity groups was that children who had a history of obesity treatment experienced a mortality rate ratio 4.04 (95% CI 2.00 to 8.17) compared to the control group (p<0.001). This study suggests that children with obesity are not only at increased risk of morality in early adulthood but that suicide and self-harm are also clinical concerns that should be confronted in primary care. Low socioeconomic status and male sex should be considered risk factors.

An Extended Swedish National Adoption Study of Bipolar Disorder Illness and Cross-Generational Familial Association With Schizophrenia and Major Depression

1. Cross-generational transmission between bipolar disorder and schizophrenia was predominantly based on genetics, while transmission between bipolar disorder and major depression was equally influenced by genetics and child-rearing practices.

Evidence Rating Level: 1 (Excellent)

Cross-generational transmission of bipolar disorder is less well-known, with specific gaps related to whether parental bipolar disorder translates to schizophrenia and major depression in their children. This national, Swedish cohort study sought to determine the degree to which these transmissions were a result of genetics, parental rearing, or a combination thereof. A total of 2,417,105 parents and offspring born between 1960-1990 (median [range] age = 41 [25-60] years, 48.2% female) included four family types: 1) intact (offspring n = 2,175,259), 2) not-lived-with biological father (offspring n = 152,436), 3) lived-with stepfather (offspring n = 73,785), and 4) adoptive (offspring n = 15,624). Schizophrenia was a broad category of unaffected, nonaffective psychosis, and schizophrenia. Resemblance of parent-child dyads were determined primarily by tetrachoric correlation. Tetrachoric correlations were statistically homogeneous across family type for rearing only (0.07, 95% CI -001 to 0.15), genes only (0.22, 95% CI 0.18 to 0.26), and rearing plus genes (0.25, 95% CI 0.24 to 0.26). Parallel ORs were calculated for these groups: 1.63 (95% CI 0.96 to 2.78), 3.66 (95% CI 2.97 to 4.51), and 5.20 (95% CI 4.91 to 5.50), respectively. Importantly, cross-disorder tetrachoric correlations for bipolar disorder and schizophrenia were for rearing only (-0.03, 95% CI 0.11 to 0.04), genes only (0.12, 95% CI 0.09 to 0.14), and rearing plus genes (0.12, 95% CI 0.11 to 0.13), with parallel ORs of 0.76, 2.04, and 1.95, respectively. For bipolar disorder and major depression, tetrachoric correlations were for rearing only (0.05, 95% CI 0.01 to 0.08), genes only (0.04, 95% CI 0.01 to 0.07), and rearing plus genes (0.09, 95% CI 0.07 to 0.10). Parallel ORs were 1.25, 1.23, and 1.53, respectively. Genetics-based correlations between bipolar disorder and broad schizophrenia were estimated to be 0.572 (95% CI 0.560 to 0.589) and 0.302 (95% CI 0.001 to 0.523) between bipolar disorder and major depression, with an overall bipolar disorder heritability estimate of 0.44 (95% CI 0.36 to 0.48). Overall, this study highlights the role of genetics in cross-generational transmission of bipolar disorder. The transmission between bipolar disorder and major depression, however, seems to be equally influenced by child-rearing practices. Further research is warranted on what these child-rearing practices should be to attenuate this genetic predisposition.

Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell-Derived Cerebral Organoids in Schizophrenia

1. In this study of 3-dimensional cerebral organoids of schizophrenia patients and healthy controls, differences were found in mitochrondrial function, response to stimulation and depolarization, ATP production, and overall pathway and neuronal generation deficits.

Evidence Rating Level: 2 (Good)

Patient-derived induced pluripotent stem cells (iPSCs) come from somatic cells through
cellular reprogramming methods, allowing for the genesis of new cells and tissues. iPSCs further allow for the study of cells associated with disease-specific genetic
predispositions, particularly ex vivo models of psychiatric conditions. Most studies of this
type are two-dimensional, while the current study undertook a three-dimensional
approach to iPSC-derived brain organoids. Specifically, this case-control study at
Massachusetts General Hospital sought to determine functional characteristics and
transcriptomic profiles of these cerebral organoids in individuals with Schizophrenia
using genome-wide association study (GWAS) information. A total of 16 participants
were selected, half of whom were diagnosed with Schizophrenia and the remaining half
were healthy controls (M [SD] age = 38.8 [12.0] years, 31.3% female). Significant gene
ontology processes such as neurogenesis, nervous system development, and neuronal
generation were downregulated in Schizophrenia patients, while antigen processing,
extracellular matrix organization, and cellular response to chemical stimulus were
upregulated in this group. Gene expression appeared to be significantly dysregulated in
genes associated with mitochondrial functioning as well as both inhibitory and excitatory
pathways. Mitochondrial respiration analyses suggested lower adenosine triphosphate
production, proton leak, basal consumption rate, and non-mitochondrial oxygen
consumption in schizophrenia cerebral organoids. No differences were noted in
baseline electrical activity in schizophrenia organoids following microelectrode array studies, but there was a notable reduction in response to depolarization and stimulation. Overall, this study of schizophrenia-related cerebral organoids suggests significant
dysregulation of several pathways, mitochondrial functionality, and response to
depolarization and stimulation.

Image: PD

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