Edetate Disodium-Based Chelation for Patients With a Previous Myocardial Infarction and Diabetes: TACT2 Randomized Clinical Trial.

Importance: In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)-based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI). Objective: To replicate the finding of TACT in individuals with diabetes and previous MI. Design, Setting, and Participants: A 2 × 2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons. Interventions: Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study. Main Outcomes and Measures: The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion. Results: Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P = .53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 µg/L at baseline to 3.46 µg/L at infusion 40 (P < .001). Corresponding levels in the placebo group were 9.3 µg/L and 8.7 µg/L, respectively. Conclusions and Relevance: Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI. Trial Registration: ClinicalTrials.gov Identifier: NCT02733185.

The association between vitamin D deficiency and multiple sclerosis: an updated systematic review and meta-analysis.

BACKGROUND: Although there is evidence of a link between vitamin D status and risk of multiple sclerosis (MS), there has been no systematic review where the exposure measure was vitamin D deficiency rather than 25 hydroxy vitamin D (25(OH)D) concentration. We conducted an updated systematic review and meta-analysis to estimate the association between vitamin D deficiency, defined in most studies as a serum 25(OH)D concentration of < 50 nmol L-1, and MS. METHODS: We searched the MEDLINE, EMBASE, and CINAHL databases to identify relevant publications. We estimated the pooled odds ratio (OR) using a random effects model for the association between vitamin D deficiency and MS, overall and stratified by several factors, including whether or not studies included participants who were taking vitamin D supplements. We also analysed the association between mean 25(OH)D concentration and MS, and used meta-regression to assess the effects of vitamin D supplementation, latitude, age, ethnicity, vitamin D definition and seasonality on the OR estimates. The Newcastle-Ottawa Scale was used to assess study quality. RESULTS: Results were pooled across 14 case-control studies published between 2007 and 2021 (n = 4130 cases, n = 4604 controls). Persons with vitamin D deficiency had a 54 % higher risk of multiple sclerosis than those with sufficient vitamin D status (OR 1.54; 95 % CI 1.05, 2.24). In studies that excluded participants taking vitamin D supplements (N = 7), the OR was 2.19 (95 % CI: 1.44, 3.35), whereas, in studies that did not exclude participants taking supplements, there was no increase in risk (OR 0.82; 95 % CI: 0.43, 1.58). Mean age (R2 = 27.4 %) and inclusion/exclusion of participants taking supplements (R2 = 33.4 %) contributed most to variability in the OR of vitamin D deficiency and MS. CONCLUSION: Vitamin D deficiency is associated with an increased likelihood of multiple sclerosis. Maintaining sufficient vitamin D may be an important modifiable risk factor for MS.

Associations between Positive Childhood Experiences (PCEs), Discrimination, and Internalizing/Externalizing in Pre-Adolescents.

OBJECTIVE: This study aimed to investigate the relationships between four types of perceived discrimination (based on race and ethnicity, nationality/country of origin, gender identity, weight/body size), individually and cumulatively; positive childhood experiences (PCEs); and behavioral symptoms among pre-adolescent youth. METHODS: This study was a secondary analysis of data from the Adolescent Brain Cognitive Development (ABCD) Study, a US-based cohort study of pre-adolescent youth in the United States (N = 10,915). Our outcome was emotional/behavioral symptoms measured by the Child Behavior Checklist. Primary exposures were four types of discrimination, a count of 0-5 PCEs, and other adverse childhood experiences (ACEs). Multiple logistic regression models were used to estimate the relationship between perceived discrimination and clinical-range behavioral symptoms, including the role of PCEs and ACEs. RESULTS: Weight discrimination was the most frequent exposure (n = 643, 5.9%). Race and weight perceived discrimination were associated with clinical-range externalizing and internalizing symptoms, respectively, but these associations were non significant once other ACEs were added to models. Cumulative discrimination was associated with clinical-range Child Behavior Checklist (CBCL) scores, even when accounting for other ACEs (aOR=1.47, 95% CI=1.2-1.8). PCEs slightly reduced the strength of this relationship and were independently associated with reduced symptoms (aOR=0.82, 95% CI=0.72-0.93). CONCLUSIONS: Results of this national study suggest cumulative discrimination can exert emotional/behavioral health harm among youth. PCEs were independently associated with reduced behavioral symptoms. There is a need for further research on how to prevent discrimination and bolster PCEs by targeting upstream social inequities in communities.

Steroid-induced mania in a patient with previously well-controlled organic bipolar 1-like affective disorder secondary to acquired brain injury: case report and literature review.

Steroid-induced neuropsychiatric sequelae are common, and pose significant risks to people usually receiving glucocorticoids in the context of physical illness. Steroid-induced mania and hypomania are the most common of the acute complications, yet despite great progress in understandings in neurophysiology there are no recent studies which review the factors which might predict who will experience this severe complication, nor are there consensus guidelines on management. We report the unusual case of a woman in her 50s admitted to a psychiatric unit with steroid-induced mania despite compliance with two mood stabilisers, several days after the administration of a Dexamethasone and Docetaxel chemotherapy regime adjunctive to lumpectomy for breast cancer. She had previously been diagnosed with an organic affective disorder (with classical bipolar 1 pattern) following severe ventriculitis related to ventricular drain insertion for obstructive hydrocephalus secondary to a colloid cyst. She had no psychiatric illness before this brain injury, but has a maternal history of idiopathic bipolar 1 affective disorder. Her episode of steroid-induced mania resolved following use of sedative medications, continuation of her existing mood stabilisers, and reductions of the steroid dosing in collaboration with her oncology team, which also protected her from further manic relapses during continued chemotherapy. Established mental illness, a family history, and acquired brain injury may reflect risk factors for steroid-induced mania through currently unclear pathways. Future epidemiological studies could better confirm these observations, and basic neuroscience may look to further explore the role of extrinsic glucocorticoids in the pathophysiology of affective disorders.

Balancing the risks and benefits of sun exposure: A revised position statement for Australian adults.

OBJECTIVE: To describe the development of a new position statement regarding balancing the risks and benefits of sun exposure for Australian adults. METHODS: We conducted a Sun Exposure Summit in March 2021, with presentations from invited experts and a workshop including representation from academic, clinical, policy, and patient stakeholder organisations. The group considered advice about balancing the risks and benefits of sun exposure for Australian adults and developed a revised consensus position statement. RESULTS: The balance of risks and benefits of sun exposure is not the same for everybody. For people at very high risk of skin cancer, the risks of exposure likely outweigh the benefits; sun protection is essential. Conversely, people with deeply pigmented skin are at low risk of skin cancer but at high risk of vitamin D deficiency; routine sun protection is not recommended. For those at intermediate risk of skin cancer, sun protection remains a priority, but individuals may obtain sufficient sun exposure to maintain adequate vitamin D status. CONCLUSIONS: The new position statement provides sun exposure advice that explicitly recognises the differing needs of Australia's diverse population. IMPLICATIONS FOR PUBLIC HEALTH: Mass communication campaigns should retain the focus on skin cancer prevention. The new position statement will support the delivery of personalised advice.

Racial and Ethnic Disparities in Receipt of Pediatric Mental Health Care.

BACKGROUND: Studies suggest increasing mental health care needs among children but limited capacity to meet those needs, potentially leaving some needs unmet. There are no recent national studies examining the receipt of mental health treatment among children. We sought to identify the correlates of treatment receipt in a nationally representative sample of children in the United States. METHODS: We conducted a cross-sectional analysis of the 2019 National Health Interview Survey. Parents reported on their child's sociodemographic characteristics, general health care engagement, mental health using the Strengths and Difficulties Questionnaire, and whether their child received therapy or medication in the prior year. Weighted logistic regressions tested associations among child characteristics and receipt of mental health treatment while controlling for parental report of child mental health symptoms. RESULTS: Among 7168 children surveyed, 1044 (15%) received mental health treatment, equating to over 7 million US children. Hispanic children (adjusted odds ratio [AOR]: 0.46 [95% confidence interval (CI): 0.34-0.62]) and non-Hispanic Black children (AOR: 0.35 [95% CI: 0.23-0.54]) had lower odds of receiving treatment compared to non-Hispanic White children, controlling for mental health symptoms. Children with a well-child visit in the last year (AOR: 2.05 [95% CI: 1.20-3.52]) and whose usual place of care was a doctor's office (AOR 2.10 [95% CI: 1.33-3.34]) had higher odds of treatment receipt. CONCLUSIONS: Racially and ethnically minoritized children and those without primary care access have disproportionately low levels of receipt of mental health treatment. Interventions to meet the needs of these groups should be prioritized to reduce mental health disparities.

Adding α,α-disubstituted and ß-linked monomers to the genetic code of an organism.

The genetic code of living cells has been reprogrammed to enable the site-specific incorporation of hundreds of non-canonical amino acids into proteins, and the encoded synthesis of non-canonical polymers and macrocyclic peptides and depsipeptides1-3. Current methods for engineering orthogonal aminoacyl-tRNA synthetases to acylate new monomers, as required for the expansion and reprogramming of the genetic code, rely on translational readouts and therefore require the monomers to be ribosomal substrates4-6. Orthogonal synthetases cannot be evolved to acylate orthogonal tRNAs with non-canonical monomers (ncMs) that are poor ribosomal substrates, and ribosomes cannot be evolved to polymerize ncMs that cannot be acylated onto orthogonal tRNAs-this co-dependence creates an evolutionary deadlock that has essentially restricted the scope of translation in living cells to α-L-amino acids and closely related hydroxy acids. Here we break this deadlock by developing tRNA display, which enables direct, rapid and scalable selection for orthogonal synthetases that selectively acylate their cognate orthogonal tRNAs with ncMs in Escherichia coli, independent of whether the ncMs are ribosomal substrates. Using tRNA display, we directly select orthogonal synthetases that specifically acylate their cognate orthogonal tRNA with eight non-canonical amino acids and eight ncMs, including several ß-amino acids, α,α-disubstituted-amino acids and ß-hydroxy acids. We build on these advances to demonstrate the genetically encoded, site-specific cellular incorporation of ß-amino acids and α,α-disubstituted amino acids into a protein, and thereby expand the chemical scope of the genetic code to new classes of monomers.

Making the sunshine vitamin - How much sun exposure is needed to maintain 25-hydroxy vitamin D concentration?

Our objective was to calculate the time in the sun necessary to maintain existing 25-hydroxyvitamin D (25(OH)D) concentration at locations across Australia and New Zealand. We used a microsimulation model to estimate changes in monthly 25(OH)D concentration using data on standard erythemal dose, solar zenith angle, and climatological ozone. We estimated the number of standard vitamin D doses per 10-min interval and used a dose-response equation to determine the average time in the sun to maintain existing 25(OH)D concentration according to month and time of day. Across all locations in summer, 5-10 min outdoors between 8 a.m. and 4 p.m. on most days of the week, with 35% of the body surface area exposed, is sufficient to maintain existing 25(OH)D concentration. In winter, at mid-to-high latitudes, time outdoors during the middle of the day is required. In winter, with 10% of the body surface area exposed, greater than 45 min in the middle of the day is required in most locations to maintain existing 25(OH)D concentration. These data can be used to inform guidelines regarding maintaining vitamin D via sun exposure and may help health practitioners identify patients who may be vitamin D deficient.

Structural Factors in Health Care Associated With the Mental Health Needs of Black Women in California During the Perinatal Period.

OBJECTIVE: To identify structural factors associated with the receipt of mental health care treatment among Black women in California during pregnancy and after childbirth. DESIGN: Secondary analysis of data from the population-based Listening to Mothers in California survey. PARTICIPANTS: The sample included 194 non-Latina Black women in the postpartum period. METHODS: We used descriptive statistics, including differences between means and logistic regression, to conduct a series of bivariate analyses. RESULTS: Most respondents (84.4%, n = 163) reported symptoms of perinatal mood and anxiety disorders prenatally, and half (50% n = 97) reported symptoms of perinatal mood and anxiety disorders in the postpartum period. Only 12.3% to 14.6% of those who reported symptoms received mental health care treatment. Furthermore, 21.2% (n = 38) of respondents were not screened for postpartum depression. Respondents with private insurance coverage were more likely to report receipt of mental health care after childbirth (OR = 4.6; 95% confidence interval [1.5, 13.5]) compared to respondents with public insurance coverage. CONCLUSION: Our results suggest a high prevalence of unmet mental health needs among non-Latina Black women who lived in California during the perinatal period. Practitioners in clinical settings may be more likely to make referrals to mental health care for women with private insurance coverage in the postpartum period.

Implementing quantum dimensionality reduction for non-Markovian stochastic simulation.

Complex systems are embedded in our everyday experience. Stochastic modelling enables us to understand and predict the behaviour of such systems, cementing its utility across the quantitative sciences. Accurate models of highly non-Markovian processes - where the future behaviour depends on events that happened far in the past - must track copious amounts of information about past observations, requiring high-dimensional memories. Quantum technologies can ameliorate this cost, allowing models of the same processes with lower memory dimension than corresponding classical models. Here we implement such memory-efficient quantum models for a family of non-Markovian processes using a photonic setup. We show that with a single qubit of memory our implemented quantum models can attain higher precision than possible with any classical model of the same memory dimension. This heralds a key step towards applying quantum technologies in complex systems modelling.

Impact of a Low-Carbohydrate Compared with Low-Fat Breakfast on Blood Glucose Control in Type 2 Diabetes: A Randomized Trial.

BACKGROUND: In type 2 diabetes (T2D), consuming carbohydrates results in a rapid and large increase in blood glucose, particularly in the morning when glucose intolerance is highest. OBJECTIVES: We investigated if a low-carbohydrate (LC) breakfast (∼465 kcal: 25 g protein, 8 g carbohydrates, and 37 g fat) could improve glucose control in people with T2D when compared with a low-fat control (CTL) breakfast (∼450 kcal:20 g protein, 56 g carbohydrates, and 15 g fat). METHODS: Participants with T2D (N = 121, 53% women, mean age 64 y) completed a remote 3-month parallel-group randomized controlled trial comparing a LC with standard low-fat guideline CTL breakfast. The change in HbA1c was the prespecified primary outcome. Continuous glucose monitoring, self-reported anthropometrics, and dietary information were collected for an intention-to-treat analysis. RESULTS: HbA1c was reduced (-0.3%; 95% CI: -0.4%, -0.1%) after 12 wks of a LC breakfast, but the between-group difference in HbA1c was of borderline statistical significance (-0.2; 95% CI: -0.4, 0.0; P = 0.06). Self-reported total daily energy (-242 kcal; 95% CI: -460, -24 kcal; P = 0.03) and carbohydrate (-73 g; 95% CI: -101, -44 g; P < 0.01) intake were lower in the LC group but the significance of this difference is unclear. Mean and maximum glucose, area under the curve, glycemic variability, standard deviation, and time above range were all significantly lower, and time in the range was significantly higher, in the LC group compared with CTL (all P < 0.05). CONCLUSIONS: Advice and guidance to consume a LC breakfast appears to be a simple dietary strategy to reduce overall energy and carbohydrate intake and improve several continuous glucose monitoring variables when compared with a CTL breakfast in persons living with T2D. The trial was registered at clinicaltrials.gov as NCT04550468.

Cell-of-origin-specific proteomics of extracellular vesicles.

The ability to assign cellular origin to low-abundance secreted factors in extracellular vesicles (EVs) would greatly facilitate the analysis of paracrine-mediated signaling. Here, we report a method, named selective isolation of extracellular vesicles (SIEVE), which uses cell type-specific proteome labeling via stochastic orthogonal recoding of translation (SORT) to install bioorthogonal reactive groups into the proteins derived from the cells targeted for labeling. We establish the native purification of intact EVs from a target cell, via a bioorthogonal tetrazine ligation, leading to copurification of the largely unlabeled EV proteome from the same cell. SIEVE enables capture of EV proteins at levels comparable with those obtained by antibody-based methods, which capture all EVs regardless of cellular origin, and at levels 20× higher than direct capture of SORT-labeled proteins. Using proteomic analysis, we analyze nonlabeled cargo proteins of EVs and show that the enhanced sensitivity of SIEVE allows for unbiased and comprehensive analysis of EV proteins from subpopulations of cells as well as for cell-specific EV proteomics in complex coculture systems. SIEVE can be applied with high efficiency in a diverse range of existing model systems for cell-cell communication and has direct applications for cell-of-origin EV analysis and for protein biomarker discovery.

Genetically programmed cell-based synthesis of non-natural peptide and depsipeptide macrocycles.

The direct genetically encoded cell-based synthesis of non-natural peptide and depsipeptide macrocycles is an outstanding challenge. Here we programme the encoded synthesis of 25 diverse non-natural macrocyclic peptides, each containing two non-canonical amino acids, in Syn61Δ3-derived cells; these cells contain a synthetic Escherichia coli genome in which the annotated occurrences of two sense codons and a stop codon, and the cognate transfer RNAs (tRNAs) and release factor that normally decode these codons, have been removed. We further demonstrate that pyrrolysyl-tRNA synthetase/tRNA pairs from distinct classes can be engineered to direct the co-translational incorporation of diverse alpha hydroxy acids, with both aliphatic and aromatic side chains. We define 49 engineered mutually orthogonal pairs that recognize distinct non-canonical amino acids or alpha hydroxy acids and decode distinct codons. Finally, we combine our advances to programme Syn61Δ3-derived cells for the encoded synthesis of 12 diverse non-natural depsipeptide macrocycles, which contain two non-canonical side chains and either one or two ester bonds.

Engagement, Use, and Impact of Digital Mental Health Resources for Diverse Populations in COVID-19: Community-Partnered Evaluation.

BACKGROUND: The COVID-19 pandemic increased disparities for communities burdened by structural barriers such as reduced affordable housing, with mental health consequences. Limited data are available on digital resources for public mental health prevention during the COVID-19 pandemic. OBJECTIVE: The study aim was to evaluate engagement in and impact of free digital resources on the Together for Wellness/Juntos por Nuestro Bienestar (T4W/Juntos) website during COVID-19 in California. METHODS: A pilot evaluation of T4W/Juntos was performed, with partner agencies inviting providers, clients, and partners to visit the website and complete surveys at baseline (September 20, 2021, to April 4, 2022) and at 4-6-week follow-up (October 22, 2021, to May 17, 2022). Website use was assessed by three engagement items (ease of use, satisfaction, relevance), comfort in use, and use of six resource categories. Primary outcomes at follow-up were depression and anxiety (scores≥3 on Patient Health Questionnaire-2 item [PHQ2] and Generalized Anxiety Disorder-2 item [GAD2] scales). Secondary outcomes were post-pre differences in PHQ2 and GAD2 scores, and use of behavioral health hotlines and services the month before follow-up. RESULTS: Of 366 eligible participants, 315 (86.1%) completed baseline and 193 (61.3%) completed follow-up surveys. Of baseline participants, 72.6% identified as female, and 21.3% identified as lesbian, gay, bisexual, transgender, queer/questioning, and others (LGBTQ+). In terms of ethnicity, 44.0% identified as Hispanic, 17.8% as African American, 26.9% as non-Hispanic white, and 11.4% as other ethnicity. Overall, 32.7% had moderate anxiety or depression (GAD2/PHQ2≥3) at baseline. Predictors of baseline website engagement included being Hispanic versus other race/ethnicity (ß=.27, 95% CI .10-.44; P=.002) and number of COVID-19-related behavior changes (ß=.09, 95% CI .05-.13; P<.001). Predictors of comfort using the website were preferring English for website use (odds ratio [OR] 5.57, 95% CI 2.22-13.96; P<.001) and COVID-19-related behavior changes (OR 1.37, 95% CI 1.12-1.66; P=.002); receiving overnight behavioral health treatment in the prior 6 months (OR 0.15, 95% CI 0.03-0.69, P=.015) was associated with less comfort in website use. The main predictor of depression at follow-up (PHQ2≥3) was baseline depression (OR 6.24, 95% CI 2.77-14.09; P<.001). Engagement in T4W/Juntos was associated with lower likelihood of depression (OR 0.54, 95% CI 0.34-0.86; P=.01). Website use the month before follow-up was associated with a post-pre reduction in PHQ2 score (ß=-.62, 95% CI -1.04 to -0.20; P=.004). The main predictor of GAD2≥3 at follow-up was baseline GAD2≥3 (OR 13.65, 95% CI 6.06-30.72; P<.001). Greater baseline website engagement predicted reduced hotline use (OR 0.36, 95% CI 0.18-0.71; P=.004). CONCLUSIONS: Ethnicity/language and COVID-19-related behavior changes were associated with website engagement; engagement and use predicted reduced follow-up depression and behavioral hotline use. Findings are based on participants recommended by community agencies with moderate follow-up rates; however, significance was similar when weighting for nonresponse. This study may inform research and policy on digital mental health prevention resources.

FcMBL magnetic bead-based MALDI-TOF MS rapidly identifies paediatric blood stream infections from positive blood cultures.

Rapid identification of potentially life-threatening blood stream infections (BSI) improves clinical outcomes, yet conventional blood culture (BC) identification methods require ~24-72 hours of liquid culture, plus 24-48 hours to generate single colonies on solid media suitable for identification by mass spectrometry (MS). Newer rapid centrifugation techniques, such as the Bruker MBT-Sepsityper® IVD, replace culturing on solid media and expedite the diagnosis of BCs but frequently demonstrate reduced sensitivity for identifying clinically significant Gram-positive bacterial or fungal infections. This study introduces a protocol that utilises the broad-range binding properties of an engineered version of mannose-binding lectin linked to the Fc portion of immunoglobulin (FcMBL) to capture and enrich pathogens combined with matrix-assisted laser desorption-ionisation time-of-flight (MALDI-TOF) MS for enhanced infection identification in BCs. The FcMBL method identified 94.1% (64 of 68) of clinical BCs processed, with a high sensitivity for both Gram-negative and Gram-positive bacteria (94.7 and 93.2%, respectively). The FcMBL method identified more patient positive BCs than the Sepsityper® (25 of 25 vs 17 of 25), notably with 100% (3/3) sensitivity for clinical candidemia, compared to only 33% (1/3) for the Sepsityper®. Additionally, during inoculation experiments, the FcMBL method demonstrated a greater sensitivity, identifying 100% (24/24) of candida to genus level and 9/24 (37.5%) top species level compared to 70.8% (17/24) to genus and 6/24 to species (25%) using the Sepsityper®. This study demonstrates that capture and enrichment of samples using magnetic FcMBL-conjugated beads is superior to rapid centrifugation methods for identification of BCs by MALDI-TOF MS. Deploying the FcMBL method therefore offers potential clinical benefits in sensitivity and reduced turnaround times for BC diagnosis compared to the standard Sepsityper® kit, especially for fungal diagnosis.

Refactored genetic codes enable bidirectional genetic isolation.

The near-universal genetic code defines the correspondence between codons in genes and amino acids in proteins. We refactored the structure of the genetic code in Escherichia coli and created orthogonal genetic codes that restrict the escape of synthetic genetic information into natural life. We developed orthogonal and mutually orthogonal horizontal gene transfer systems, which permit the transfer of genetic information between organisms that use the same genetic code but restrict the transfer of genetic information between organisms that use different genetic codes. Moreover, we showed that locking refactored codes into synthetic organisms completely blocks invasion by mobile genetic elements, including viruses, which carry their own translation factors and successfully invade organisms with canonical and compressed genetic codes.

Cross-sectional Comparison of Disparities by Race Using White vs Hispanic as Reference Among Children and Youths With Developmental Disabilities Referred for Speech Therapy.

Importance: Health care research on racial disparities among children and youths has historically used the White race as a reference category with which other racial and ethnic groups are compared, which may inadvertently set up Whiteness as a standard for health. Objective: To compare 2 interpretations of an analysis of racial disparities in speech therapy receipt among children and youths with developmental disabilities: a traditional, White-referenced analysis and a Hispanic majority-referenced analysis. Design, Setting, and Participants: This cross-sectional study used multiple logistic regression to analyze speech therapy referrals for children, adolescents, and transition age youths in an integrated health care system in Southern California from 2017 to 2020. Eligible participants were children and youths up to age 26 years with 1 or more diagnosed intellectual or developmental disability (eg, autism spectrum disorder, speech or language delay, developmental delay, Down syndrome, and others). Exposures: Child or youth race and ethnicity as reported by parents or caregivers (Asian, Black and African American, Hispanic and Latinx, American Indian or Alaskan Native, Native Hawaiian or Pacific Islander, White, multiple, and other). Main Outcomes and Measures: Receipt of speech therapy within 1 year of referral. Results: A total 66 402 referrals were included; 65 833 referrals (99.1%) were for children under age 17 years, 47 323 (71.3%) were for boys, and 39 959 (60.2%) were commercially insured. A majority of participants were identified as Hispanic (36 705 [55.3%]); 6167 (9.3%) were identified as Asian, 4810 (7.2%) as Black, and 14 951 (22.5%) as White. In the traditional racial disparities model where the reference category was White, referrals of children and youths who identified as Hispanic, Black, Pacific Islander, and other had lower odds of actual receipt of speech therapy compared with referrals for White children and youths (Hispanic: OR, 0.79; 95% CI, 0.75-0.83; Black: OR, 0.72; 95% CI, 0.66-0.78; Pacific Islander: OR, 0.74; 95% CI, 0.57-0.98). When using the majority race group (Hispanic) as the reference category, referrals for children and youths who identified as White (OR, 1.26; 95% CI, 1.20-1.30), Asian (OR, 1.21; 95% CI, 1.12-1.30), and multiracial (OR, 1.35; 95% CI, 1.08-1.71) had higher odds of resulting in actual service receipt in comparison with referrals for Hispanic children and youths. Conclusions and Relevance: The cross-sectional study demonstrates the value of decentering Whiteness in interpreting racial disparities research and considering racial differences against multiple referents. Racial disparities researchers should consider investigating multiple between-group differences instead of exclusively using White as the default reference category.

Early cost-utility analysis of genetically guided therapy for patients with drug-resistant epilepsy.

OBJECTIVE: Existing gene panels were developed to understand the etiology of epilepsy, and further benefits will arise from an effective pharmacogenomics panel for personalizing therapy and achieving seizure control. Our study assessed the cost-effectiveness of a pharmacogenomics panel for patients with drug-resistant epilepsy, compared with usual care. METHODS: A cost-utility analysis was employed using a discrete event simulation model. The microsimulation model aggregated the costs and benefits of genetically guided treatment versus usual care for 5000 simulated patients. The 10-year model combined data from various sources including genomic databases on prevalence of variants, population-level pharmaceutical claims on antiseizure medications, published long-term therapy retention rates, patient-level cost data, and systematic reviews. Incremental cost per quality-adjusted life-year (QALY) gained was computed. Deterministic and probabilistic sensitivity analyses were undertaken to address uncertainty in model parameters. RESULTS: The mean cost of the genetically guided treatment option was AU$98 199 compared with AU$95 386 for usual care. Corresponding mean QALYs were 4.67 compared with 4.28 for genetically guided and usual care strategies, respectively. The incremental cost per QALY gained was AU$7381. In probabilistic sensitivity analyses, the incremental cost per QALY gained was AU$6321 (95% uncertainty interval = AU$3604-AU$9621), with a 100% likelihood of being cost-effective in the Australian health care system. The most influential drivers of the findings were the monthly health care costs associated with reduced seizures, costs when seizures continued, and the quality-of-life estimates under genetically guided and usual care strategies. SIGNIFICANCE: This early economic evaluation of a pharmacogenomics panel to guide treatment for drug-resistant epilepsy could potentially be cost-effective in the Australian health care system. Clinical trial evidence is necessary to confirm these findings.

From clinic to community: A randomized controlled trial of a peer support model for adults with type 2 diabetes from specialty care settings in British Columbia.

AIMS: To examine the impact of a 12-month peer-led diabetes self-management support intervention delivered via telephone amongst adults with type 2 diabetes (T2D) from specialty care settings in British Columbia (BC). METHODS: One-hundred ninety-six adults with T2D were randomly assigned to either a 12-month Peer-Led, Empowerment-based, Approach, to Self-management Efforts in Diabetes (PLEASED) intervention or a usual care condition. PLEASED involved weekly telephone contacts from a peer leader (PL) in the first 3 months followed by bi-weekly telephone contacts in the last 9 months. Assessments were conducted at baseline, 3 and 12 months. The primary outcome was HbA1c ; secondary outcomes included diabetes distress (DD), ApoB, systolic and diastolic blood pressure (BP), body mass index, waist circumference and depressive symptoms. RESULTS: No within or between group changes were observed for HbA1c at 3 or 12 months. However, amongst participants with HbA1c  ≥ 69 mmol/mol (8.5%), the PLEASED group significantly lowered their HbA1c at 12 months [-11.7 mmol/mol (-1.07%); 95% CI: -20.7, -2.5 (-1.89, -0.23); p = 0.016] compared to usual care. Amongst secondary outcomes, within-group improvements in overall DD were found at 3 months (-0.21; 95% CI: -0.35, -0.08; p = 0.002) for the PLEASED group and at 12 months for both groups (PLEASED: -0.35; 95% CI: -0.49, -0.21; p < 0.001 and control: -0.33; 95% CI: -0.47, -0.19; p < 0.001), however, no between-group differences were observed. The PLEASED group improved systolic BP at 12 months (-5.4 mm Hg; 95% CI: -10.0, -0.8; p = 0.023) compared to usual care. CONCLUSIONS: Participation in a peer support intervention in diabetes delivered via telephone leads to long-term improvements in HbA1c amongst high-risk adults with T2D living in BC. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NT02804620).

The trial to assess chelation therapy 2 (TACT2): Rationale and design.

BACKGROUND: Intravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design. METHODS: TACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are followed for 2.5 to 5 years. The primary endpoint is time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial has >;85% power to detect a 30% relative reduction in the primary endpoint. TACT2 also includes a Trace Metals and Biorepository Core Lab, to test whether benefits of treatment, if present, are due to chelation of lead and cadmium from patients. Design features of TACT2 were chosen to replicate selected features of the first TACT, which demonstrated a significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. RESULTS: Results are expected in 2024. CONCLUSION: TACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants.