Electrochemically driven cross-electrophile coupling of alkyl halides.

Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp3 carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of carbon(sp3)-carbon(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective3-5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp3)-carbon(sp3) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.

The DNA Structure-Specific Endonuclease MUS81 Mediates DNA Sensor STING-Dependent Host Rejection of Prostate Cancer Cells.

Self-DNA is present in the cytosol of many cancer cells and can promote effective immune rejection of tumor cells, but the mechanisms leading to the presence of cytosolic DNA are unknown. Here, we report that the cleavage of genomic DNA by DNA structure-specific endonuclease MUS81 and PARP-dependent DNA repair pathways leads to the accumulation of cytosolic DNA in prostate cancer cells. The number of nuclear MUS81 foci and the amount of cytosolic dsDNA increased in tandem from hyperplasia to clinical stage II prostate cancers and decreased at stage III. Cytosolic DNA generated by MUS81 stimulated DNA sensor STING-dependent type I interferon (IFN) expression and promoted phagocytic and T cell responses, resulting in type I and II IFN-mediated rejection of prostate tumor cells via mechanisms that partly depended on macrophages. Our results demonstrate that the tumor suppressor MUS81 alerts the immune system to the presence of transformed host cells.

Contemporary Care and Outcomes of Critically-ill Children With Clinically Diagnosed Myocarditis.

PURPOSE: To describe contemporary management and outcomes in children with myocarditis who are admitted to a cardiac intensive care unit (CICU) and to identify the characteristics associated with mortality. METHODS: All patients in the Pediatric Cardiac Critical Care Consortium (PC4) registry between August 2014 and June 2021 who were diagnosed with myocarditis were included. Univariable analyses and multivariable logistic regression evaluated the factors associated with in-hospital mortality. RESULTS: There were 847 CICU admissions for myocarditis in 51 centers. The median age was 12 years (IQR 2.7-16). In-hospital mortality occurred in 53 patients (6.3%), and 60 (7.1%) had cardiac arrest during admission. Mechanical ventilation was required in 339 patients (40%), and mechanical circulatory support (MCS) in 177 (21%); extracorporeal membrane oxygenation (ECMO)-only in 142 (16.7%), ECMO-to-ventricular assist device (VAD) in 20 (2.4%), extracorporeal cardiac resuscitation in 43 (5%), and VAD-only in 15 (1.8%) patients. MCS was associated with in-hospital mortality; 20.3% receiving MCS died compared to 2.5% without MCS (P < 0.001). Mortality rates were similar in ECMO-only, ECMO-to-VAD and VAD-only groups. The median time from CICU admission to ECMO was 2.0 hours (IQR 0-9.4) and to VAD, it was 9.9 days (IQR 6.3-16.8). Time to MCS was not associated with mortality. In multivariable modeling of patients' characteristics, smaller body surface area (BSA) and low eGFR were independently associated with mortality, and after including critical therapies, mechanical ventilation and ECMO were independent predictors of mortality. CONCLUSION: This contemporary cohort of children admitted to CICUs with myocarditis commonly received high-resource therapies; however, most patients survived to hospital discharge and rarely received VAD. Smaller patient size, acute kidney injury and receipt of mechanical ventilation or ECMO were independently associated with mortality.

Uncovering the magnitude of African pangolin poaching with extensive nanopore DNA genotyping of seized scales.

Trade in pangolins is illegal, and yet tons of their scales and products are seized at various ports. These large seizures are challenging to process and comprehensively genotype for upstream provenance tracing and species identification for prosecution. We implemented a scalable DNA barcoding pipeline in which rapid DNA extraction and MinION sequencing were used to genotype a substantial proportion of pangolin scales subsampled from 2 record shipments seized in Singapore in 2019 (37.5 t). We used reference sequences to match the scales to phylogeographical regions of origin. In total, we identified 2346 cytochrome b (cytb) barcodes of white-bellied (Phataginus tricuspis) (from 1091 scales), black-bellied (Phataginus tetradactyla) (227 scales), and giant (Smutsia gigantea) (1028 scales) pangolins. Haplotype diversity was higher for P. tricuspis scales (121 haplotypes, 66 novel) than that for P. tetradactyla (22 haplotypes, 15 novel) and S. gigantea (25 haplotypes, 21 novel) scales. Of the novel haplotypes, 74.2% were likely from western and west-central Africa, suggesting potential resurgence of poaching and newly exploited populations in these regions. Our results illustrate the utility of extensively subsampling large seizures and outline an efficient molecular approach for rapid genetic screening that should be accessible to most forensic laboratories and enforcement agencies.

Revelación de la magnitud de la caza furtiva del pangolín africano mediante el genotipo extenso de nanoporos de ADN de escamas incautadas Resumen Aunque el mercado de pangolines es ilegal, se incautan toneladas de sus escamas y productos derivados en varios puertos comerciales. Es un reto procesar estas magnas incautaciones y obtener el genotipo completo para usarlo en la trazabilidad logística ascendente e identificación de la especie y así imponer sanciones. Implementamos una canalización escalable del código de barras de ADN en el cual usamos la extracción rápida de ADN y la secuenciación MinION para obtener el genotipo de una proporción sustancial de las escamas de pangolín submuestreadas en dos cargamentos incautados en 2019 en Singapur (37.5 t). Usamos secuencias referenciales para emparejar las escamas con las regiones filogeográficas de origen. Identificamos en total 2,346 códigos de citocromo b (cytb) del pangolín de vientre blanco (Phataginus tricuspis) (de 1,091 escamas), de vientre negro (P. tetradactyla) (227 escamas) y del pangolín gigante (Smutsia gigantea) (1,028 escamas). La diversidad de haplotipos fue mayor en las escamas de P. tricuspis (121 haplotipos, 66 nuevos) que en las de P. tetradactyla (22 haplotipos, 15 nuevos) y S. gigantea (25 haplotipos, 21 nuevos). De los haplotipos nuevos, el 74.2% probablemente provenía del occidente y centro­occidente de África, lo que sugiere un resurgimiento potencial de la caza furtiva y poblaciones recién explotadas en estas regiones. Nuestros resultados demuestran la utilidad de submuestrear extensivamente las grandes incautaciones y esboza una estrategia molecular eficiente para un análisis genético rápido que debería ser accesible para la mayoría de los laboratorios forenses y las autoridades de aplicación.

Efficacy and safety of apremilast in pediatric patients with moderate-to-severe plaque psoriasis: 16-week results from SPROUT, a randomized controlled trial.

BACKGROUND: Approved systemic treatment options are limited for pediatric patients with moderate to severe plaque psoriasis. OBJECTIVE: To assess the efficacy and safety of apremilast over 16 weeks in pediatric patients with plaque psoriasis. METHODS: SPROUT (NCT03701763) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study of apremilast in patients aged 6-17 years with moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] ≥12, body surface area ≥10%, static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy. Patients were stratified by age group and randomized (2:1) to apremilast (20 or 30 mg BID based on weight) or placebo for 16 weeks, followed by apremilast extension to 52 weeks. RESULTS: Of 245 patients randomized (apremilast: 163; placebo: 82), 221 (90%) completed the double-blind phase (apremilast: 149; placebo: 72). Significantly more patients achieved sPGA response and ≥75% reduction in PASI with apremilast than placebo, regardless of baseline age, weight, or disease severity. No new safety signals were observed. LIMITATIONS: Sample size of subgroup analyses. CONCLUSIONS: Improvements in global disease activity and skin involvement were significantly greater in pediatric patients treated with apremilast versus placebo. Adverse events were consistent with the known apremilast safety profile.

Three-Component Cross-Electrophile Coupling: Regioselective Electrochemical Dialkylation of Alkenes.

The cross-electrophile dialkylation of alkenes enables the formation of two C(sp3)-C(sp3) bonds from readily available starting materials in a single transformation, thereby providing a modular and expedient approach to building structural complexity in organic synthesis. Herein, we exploit the disparate electronic and steric properties of alkyl halides with varying degrees of substitution to accomplish their selective activation and addition to alkenes under electrochemical conditions. This method enables regioselective dialkylation of alkenes without the use of a transition-metal catalyst and provides access to a diverse range of synthetically useful compounds.

Electrochemical Preparation of Sm(II) Reagent Facilitated by Weakly Coordinating Anions.

Samarium diiodide (SmI2 ) is widely used as a strong one-electron reducing agent and is often employed to form C-C bonds in complex systems. Despite their utility, SmI2 and related salts suffer from several drawbacks that render the use of Sm reducing agents in large-scale synthesis impractical. Here, we report factors influencing the electrochemical reduction of Sm(III) to Sm(II), towards the goal of electrocatalytic Sm(III) reduction. We probe the effect of supporting electrolyte, electrode material, and Sm precursor on Sm(II)/(III) redox and on the reducing power of the Sm species. We find that the coordination strength of the counteranion of the Sm salt affects the reversibility and redox potential of the Sm(II)/(III) couple and establish that the counteranion primarily determines the reducibility of Sm(III). Electrochemically generated SmI2 performs similarly to commercial SmI2 solutions in a proof-of-concept reaction. The results will provide fundamental insight to facilitate the development of Sm-electrocatalytic reactions.

An in vitro and in vivo study on extracorporeal transducer optimization for high-intensity focused ultrasound to improve the safety and efficacy of breast tumor ablation.

OBJECTIVE: To observe the characteristics of a new extracorporeal high intensity focused ultrasound transducer, titled Haifu system JCQ-B, and to compare its safety and efficacy for breast ablation with the standard Haifu system JC transducer. MATERIALS AND METHODS: Ox liver with pig skin and pork ribs were prepared in a semi-sphere shape, served as in vitro acoustic model. The udders of female goats were used as in vivo acoustic model. Both in vitro and in vivo models were ablated by either JCQ-B or JC transducer. The morphology of biological focal region (BFR), the coagulative necrosis volume, and the temperature increase were observed and compared. RESULTS: The BFR morphology of JCQ-B transducer was circular both in vitro and in vivo, with a length-width ratio close to one. Under the same sonication parameters (sonication power, time and depth in tissue), coagulation necrosis volume caused by JCQ-B transducer was larger than that caused by JC transducer both in vitro and in vivo. The increase in temperature in the near and far acoustic pathways with JCQ-B transducer was significantly lower than that of JC transducer in vitro. After receiving high sonication energy during in vivo experimentation, there were no complications observed after the ablation of JCQ-B transducer, while small skin damage was observed after the ablation of JC transducer. CONCLUSIONS: The JCQ-B transducer improved the safety and efficacy of treatment by optimizing BFR morphology and ablation efficiency, which could be applied in the treatment of breast tumor.

Screening for Social Determinants of Health Among Medicare Beneficiaries in Primary Care During the Covid-19 Pandemic in Prince George's County, Maryland.

Primary care providers in Prince George's County, Maryland reported inconsistencies in their ability to identify and refer patients with social care needs. This project aimed to improve health outcomes of Medicare beneficiaries by implementing social determinant of health (SDOH) screening to identify unmet needs and improve rates of referral to appropriate services. Buy-in was achieved from providers and frontline staff via stakeholder meetings at a private primary care group practice. The Health Leads questionnaire was modified and integrated into the electronic health record. Medical assistants (MA) were trained to conduct screening and initiate care plan referrals prior to visits with the medical provider. During implementation, 96.25% of patients (n = 231) agreed to screening. Of these, 13.42% (n = 31) screened positive for at least one SDOH need, and 48.39% (n = 15) reported multiple social needs. Top needs included social isolation (26.23%), literacy (16.39%), and financial concerns (14.75%). All patients screening positive for one or more social needs were provided referral resources. Patients who identified as being of Mixed or Other race had significantly higher rates of positive screens (p = 0.032) compared to Caucasians, African Americans, and Asians. Patients were more likely to report SDOH needs during in-person visits (17.22%) compared to telehealth visits (p = 0.020). Screening for SDOH needs is feasible and sustainable and can improve the identification of SDOH needs and resource referrals. A limitation of this project was the lack of follow-up to determine whether patients with positive SDOH screens had been successfully linked to resources after initial referral.

Elevated body mass index in modified natural cycle frozen euploid embryo transfers is not associated with live birth rate.

PURPOSE: To assess the impact of elevated BMI on the success of modified natural cycle frozen embryo transfers (mNC-FET) of euploid embryos. METHODS: This retrospective cohort study at a single academic institution reviewed mNC-FET involving single euploid blastocysts from 2016 to 2020. Comparison groups were divided by pre-pregnancy BMI (kg/m2) category: normal weight (18.5-24.9), overweight (25-29.9) or obese (≥ 30). Underweight BMI (< 18.5) was excluded from the analysis. The primary outcome was live birth rate (LBR) and secondary outcome was clinical pregnancy rate (CPR), defined as presence of fetal cardiac activity on ultrasound. Absolute standardized differences (ASD) were calculated to compare descriptive variables and p-values and multivariable logistic regressions with generalized estimating equations (GEE) were used to compare pregnancy outcomes. RESULTS: 562 mNC-FET cycles were completed in 425 patients over the study period. Overall, there were 316 transfers performed in normal weight patients, 165 in overweight patients, and 81 in obese weight patients. There was no statistically significant difference in LBR across all BMI categories (55.4% normal weight, 61.2% overweight, and 64.2% obese). There was also no difference for the secondary outcome, CPR, across all categories (58.5%, 65.5%, and 66.7%, respectively). This was confirmed in GEE analysis when adjusting for confounders. CONCLUSION: While increased weight has commonly been implicated in poor pregnancy outcomes, the effect of BMI on the success of mNC-FET remains debated. Across five years of data from a single institution using euploid embryos in mNC-FET cycles, elevated BMI was not associated with reduced LBR or CPR.

Pregnancy and neonatal outcomes of letrozole versus natural cycle frozen embryo transfer of autologous euploid blastocyst.

PURPOSE: To investigate the pregnancy and neonatal outcomes of letrozole-stimulated frozen embryo transfer (LTZ-FET) cycles compared with natural FET cycles (NC-FET). METHODS: Our retrospective cohort included all LTZ-FET (n = 161) and NC-FET (n = 575) cycles that transferred a single euploid autologous blastocyst from 2016 to 2020 at Stanford Fertility Center. The LTZ-FET protocol entailed 5 mg of daily letrozole for 5 days starting on cycle day 2 or 3. Outcomes were compared using absolute standardized differences (ASD), in which a larger ASD signifies a larger difference. Multivariable regression models adjusted for confounders: maternal age, BMI, nulliparity, embryo grade, race, infertility diagnosis, and endometrial thickness. RESULTS: The demographic and clinical characteristics were overall similar. A greater proportion of the letrozole cohort was multiparous, transferred high-graded embryos, and had ovulatory dysfunction. The cohorts had similar pregnancy rates (67.1% LTZ vs 62.1% NC; aOR 1.31, P = 0.21) and live birth rates (60.9% LTZ vs 58.6% NC; aOR 1.17, P = 0.46). LTZ-FET neonates on average were born 5.7 days earlier (P < 0.001) and had higher prevalence of prematurity (18.6% vs. 8.0%NC, ASD = 0.32) and low birth weight (10.4% vs. 5.0%, ASD = 0.20). Both cohorts' median gestational ages (38 weeks and 1 day for LTZ; 39 weeks and 0 day for NC) were full term. CONCLUSION: There were similar rates of pregnancy and live birth between LTZ-FET and NC-FET cycles. However, there was a higher prevalence of prematurity and low birth weight among LTZ-FET neonates. Reassuringly, the median gestational age in both cohorts was full term, and while the difference in gestational length of almost 6 days does not appear to be clinically significant, this warrants larger studies.

Coxiella burnetii Virulent Phase I and Avirulent Phase II Variants Differentially Manipulate Autophagy Pathway in Neutrophils.

Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes Q fever in humans. The virulent C. burnetii Nine Mile phase I (NMI) strain causes disease in animal models, while the avirulent NM phase II (NMII) strain does not. In this study, we found that NMI infection induces severe splenomegaly and bacterial burden in the spleen in BALB/c mice, while NMII infection does not. A significantly higher number of CD11b+ Ly6G+ neutrophils accumulated in the liver, lung, and spleen of NMI-infected mice than in NMII-infected mice. Thus, neutrophil accumulation correlates with NMI and NMII infection-induced inflammatory responses. In vitro studies also demonstrated that although NMII exhibited a higher infection rate than NMI in mouse bone marrow neutrophils (BMNs), NMI-infected BMNs survived longer than NMII-infected BMNs. These results suggest that the differential interactions of NMI and NMII with neutrophils may be related to their ability to cause disease in animals. To understand the molecular mechanism underlying the differential interactions of NMI and NMII with neutrophils, global transcriptomic gene expressions were compared between NMI- and NMII-infected BMNs by RNA sequencing (RNA-seq) analysis. Interestingly, several genes involved in autophagy-related pathways, particularly membrane trafficking and lipid metabolism, are upregulated in NMII-infected BMNs but downregulated in NMI-infected BMNs. Immunofluorescence and immunoblot analyses indicate that compared to NMI-infected BMNs, vacuoles in NMII-infected-BMNs exhibit increased autophagic flux along with phosphatidylserine translocation in the cell membrane. Similar to neutrophils, NMII activated LC3-mediated autophagy in human macrophages. These findings suggest that the differential manipulation of autophagy of NMI and NMII may relate to their pathogenesis.

Prevalence and incidence of hepatitis C infection amongst men who have sex with men in a population-based pre-exposure prophylaxis program in British Columbia, Canada.

BACKGROUND: Men who have sex with men (MSM) are at risk for sexually-transmitted hepatitis C (HCV). Evidence for HCV infection in the context of pre-exposure prophylaxis (PrEP) use in North America is limited. We sought to characterize baseline HCV prevalence and incidence in MSM receiving PrEP in British Columbia (BC), Canada. METHODS: We followed individuals in the BC PrEP program from January 2018 to August 2019. We evaluated baseline prevalence and incident seroconversions (newly positive HCV antibody). A multivariable logistic regression model was performed in MSM for factors associated with HCV prevalence at enrollment, including reported prior sexually transmitted infection (STI), HIV Incidence Risk Index for MSM score, PrEP use because of a partner living with HIV, and location of residence. RESULTS: The median age of the cohort was 33 years, 98.3% male, with 3058 person years (PY) of follow-up. Baseline HCV prevalence was 0.82% (31/3907 MSM enrollees) and HCV incidence (n = 3) was 0.15 per 100 PY (95% confidence interval [CI] 0.03-0.45). In multivariable analysis, initiating PrEP because of a partner living with HIV (adjusted odds ratio [aOR] 5.02; 95% CI 1.87-13.47) and prior STI (aOR 2.34; 95% CI 1.04-5.24) were associated with positive HCV status. CONCLUSIONS: Baseline HCV prevalence and incidence was low amongst MSM in a population-based PrEP program in BC, Canada. HCV was associated with bridging from populations living with HIV and evidence of a reported prior STI as a PrEP indicator condition amongst MSM. PrEP initiation may be an opportunity for linkage to HCV screening and treatment.

The impact of euploid blastocyst morphology and maternal age on pregnancy and neonatal outcomes in natural cycle frozen embryo transfers.

PURPOSE: To evaluate whether morphology impacts the pregnancy and neonatal outcomes of euploid blastocysts, and whether maternal age still affects outcomes when top-graded, euploid blastocysts are used. METHODS: This retrospective cohort study included all natural-cycle frozen embryo transfers (NC-FET) using an autologous, euploid blastocyst from June 2016 to June 2020 (n = 610). There were five groups based on embryo grade: AA, AB, BA, BB, and "any C". For analysis of only AA-graded embryos, there were three maternal age groups: < 35, 35-39, and 40 + years. The main outcomes measured were clinical pregnancy and live birth rates, while the secondary outcomes included neonatal outcomes such as gestational age at delivery and birthweight. Multivariable logistic regression models were performed to adjust for confounders. RESULTS: Euploid blastocysts with poorer morphology had lower odds of pregnancy and live birth; specifically, embryos with inner cell mass (ICM) graded as "C" had statistically significant decreased odds of pregnancy (aOR 0.33, p = 0.04) and live birth (aOR 0.32, p = 0.03) compared with ICM grade "A". The differences in pregnancy rate between trophectoderm grades were not statistically significant. Even in cycles that transferred a top-graded (AA) euploid embryo, maternal age at transfer was independently associated with outcomes. Embryo grade and maternal age, however, did not significantly impact neonatal outcomes such as prematurity and birthweight. CONCLUSION: The morphology of euploid blastocysts and maternal age at NC-FET both independently impact pregnancy outcomes. Neonatal outcomes were similar across embryo morphology and maternal age groups, suggesting that lower morphology euploid embryos not be discounted as viable options for transfer.

Interprofessional Education and Older Adults in the Shared Virtual Classroom: Lessons Learned During the COVID-19 Pandemic.

The current article provides an overview of an interprofessional service-learning course that became virtual in the setting of the coronavirus disease 2019 pandemic. Telehealth video technologies were used to build an intergenerational, virtual classroom and increase engagement of older adults with interdisciplinary health professional students. The virtual classroom involved group health education sessions, individualized Medicare wellness visits, and a clinical huddle. The course addressed the public health need for reliable health information during the early days of the pandemic, social connection, and meeting the educational goals for health care students and older adults in a novel virtual setting. Lessons learned for the interdisciplinary team and for engaging older adults included the need for preparation reading, team building exercises, training videos, and telehealth competency checklists. Beyond the pandemic, adoption of virtual methods enables hybrid approaches to interprofessional education and builds competencies for delivery of telehealth and computer-based visits in professional practice settings. [Journal of Gerontological Nursing, 48(8), 52-56.].

ERP CORE: An open resource for human event-related potential research.

Event-related potentials (ERPs) are noninvasive measures of human brain activity that index a range of sensory, cognitive, affective, and motor processes. Despite their broad application across basic and clinical research, there is little standardization of ERP paradigms and analysis protocols across studies. To address this, we created ERP CORE (Compendium of Open Resources and Experiments), a set of optimized paradigms, experiment control scripts, data processing pipelines, and sample data (N = 40 neurotypical young adults) for seven widely used ERP components: N170, mismatch negativity (MMN), N2pc, N400, P3, lateralized readiness potential (LRP), and error-related negativity (ERN). This resource makes it possible for researchers to 1) employ standardized ERP paradigms in their research, 2) apply carefully designed analysis pipelines and use a priori selected parameters for data processing, 3) rigorously assess the quality of their data, and 4) test new analytic techniques with standardized data from a wide range of paradigms.

Anatomic thermochromic tissue-mimicking phantom of the lumbar spine for pre-clinical evaluation of MR-guided focused ultrasound (MRgFUS) ablation of the facet joint.

OBJECTIVE: To develop a thermochromic tissue-mimicking phantom (TTMP) with an embedded 3D-printed bone mimic of the lumbar spine to evaluate MRgFUS ablation of the facet joint and medial branch nerve. MATERIALS AND METHODS: Multiple 3D-printed materials were selected and characterized by measurements of speed of sound and linear acoustic attenuation coefficient using a through-transmission technique. A 3D model of the lumbar spine was segmented from a de-identified CT scan, and 3D printed. The 3D-printed spine was embedded within a TTMP with thermochromic ink color change setpoint at 60 °C. Multiple high energy sonications were targeted to the facet joints and medial branch nerve anatomical location using an ExAblate MRgFUS system connected to a 3T MR scanner. The phantom was dissected to assess sonication targets and the surrounding structures for color change as compared to the expected region of ablation on MR-thermometry. RESULTS: The measured sound attenuation coefficient and speed of sound of gypsum was 240 Np/m-MHz and 2471 m/s, which is the closest to published values for cortical bone. Following sonication, dissection of the TTMP revealed good concordance between the regions of color change within the phantom and expected areas of ablation on MR-thermometry. No heat deposition was observed in critical areas, including the spinal canal and nerve roots from either color change or MRI. CONCLUSION: Ablated regions in the TTMP correlated well with expected ablations based on MR-thermometry. These findings demonstrate the utility of an anatomic spine phantom in evaluating MRgFUS sonication for facet joint and medial branch nerve ablations.

Pharmacokinetics and safety of apremilast in pediatric patients with moderate to severe plaque psoriasis: Results from a phase 2 open-label study.

BACKGROUND: No oral systemic treatments are approved for pediatric patients with psoriasis. OBJECTIVE: To evaluate the pharmacokinetics and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in pediatric patients with psoriasis. METHODS: This phase 2, multicenter, open-label study enrolled pediatric patients with moderate to severe plaque psoriasis. Patients received apremilast twice daily without titration for 2 weeks (group 1 [age, 12-17 years; weight, ≥35 kg]: apremilast 20 or 30 mg; group 2 [age, 6-11 years; weight, ≥15 kg]: apremilast 20 mg), followed by a 48-week extension. Primary endpoints were pharmacokinetics and safety. Other endpoints were taste/acceptability and change from baseline in score on the Psoriasis Area and Severity Index. RESULTS: A total of 42 enrolled patients (21 adolescents [age, 12-17 years] and 21 children [age, 6-11 years]) received apremilast. Pharmacokinetics modeling and noncompartmental analyses showed that weight-based dosing with apremilast 20 mg twice daily in children or apremilast 20 or 30 mg twice daily in adolescents provides exposure (area under the concentration-time curve from time 0 to 12 hours after the dose) that is comparable to that achieved with apremilast 30 mg twice daily in adults. The safety profile was generally similar to that in adults. Most study participants liked the taste of the tablet. Improvements from baseline in mean Psoriasis Area and Severity Index score were 68% for adolescents (overall) and 79% for children. LIMITATIONS: No children weighing less than 20 kg were enrolled. CONCLUSIONS: This first-time-in-children phase 2 study supports weight-based apremilast dosing for future phase 3 studies of pediatric plaque psoriasis.

Vascular Health of Children Conceived via In Vitro Fertilization.

OBJECTIVE: To evaluate whether in vitro fertilization (IVF) has an effect on the cardiovascular health of offspring. STUDY DESIGN: This was a cross-sectional pilot study. We performed vascular health assessment for 17 children aged 10-14 years who were conceived via IVF with autologous oocytes at Stanford University. Carotid artery ultrasound evaluated intima-media thickness and stiffness, carotid-femoral pulse wave velocity determined segmental arterial stiffness, and endothelial pulse amplitude testing assessed endothelial function. We compared IVF offspring with control adolescents assessed in the same laboratory, with all comparisons adjusted for age, sex, and race/ethnicity. RESULTS: All participants had normal body mass index and blood pressure. Compared with controls, IVF children had thicker common carotid artery intima-media thickness (0.44 ± 0.03 mm vs 0.38 ± 0.03 mm; P < .01), higher elastic modulus (395.29 ± 185.33 mm Hg vs 242.79 ± 37.69 mm Hg; P = .01), higher ßstiffness (2.65 ± 0.38 vs 2.28 ± 0.23; P < .01), and higher peak velocity (142.29 ± 31.62 cm/s vs 117.71 ± 32.69 cm/s; P = .04). The mean endothelial pulse amplitude testing reactive hyperemia index was not significantly different between IVF and controls. The mean pulse wave velocity was 4.69 ± 0.51 m/s compared with the controls 4.60 ± 0.57 m/s (P = .11), with 8 (47%) having abnormal values. CONCLUSION: In an assessment of endothelial function and arterial properties of children conceived via IVF, we found that children conceived via IVF seem to have evidence of abnormal vascular health. Further studies with larger sample size and long-term follow-up are warranted.

Accumulation of Multiple Mutations In Vivo Confers Cross-Resistance to New and Existing Integrase Inhibitors.

Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance to the approved integrase inhibitors raltegravir (RAL) and elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient-derived RNA extracts for resistance phenotype for a panel of viruses containing G140S/Q148H with additional accessory substitutions. The accumulation of multiple integrase substitutions confers high-level resistance to all 5 integrase inhibitors. There is extensive cross-resistance between DTG, BIC, and CAB (r = 0.96-0.97).