Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome.

We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist for participants with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤400/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. Primary endpoint was time (hours) above ANC threshold ≥500/µL (TATANC; over 24 hours). Secondary endpoints included TAT absolute lymphocyte count ≥1000/µL (TATALC; defined similar to TATANC); absolute changes in white blood cell (WBC), ANC, and ALC from baseline; annualized infection rate; infection duration and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n=14; placebo, n=17), mavorixafor least squares (LS) mean TATANC was 15.0 hours, placebo 2.8 hours (P<0.001). Mavorixafor LS mean TATALC was 15.8 hours, placebo 4.6 hours (P<0.001). Higher absolute WBC, ANC, and ALC levels were seen with mavorixafor than placebo at each timepoint assessed. Annualized infection rates were 60% lower with mavorixafor versus placebo (LS mean 1.7 versus 4.2; nominal P=0.007) and total infection scores were 40% lower (7.4 [95% CI, 1.6-13.2] versus 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor-treated participants showed significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration. Mavorixafor was well tolerated in participants with WHIM syndrome. Trial was registered at ClinicalTrials.gov NCT03995108.

The Digital Navigator: Standardizing Human Technology Support in App-Integrated Clinical Care.

Background: Mental health apps offer scalable care, yet clinical adoption is hindered by low user engagement and integration challenges into clinic workflows. Human support staff called digital navigators, trained in mental health technology, could enhance care access and patient adherence and remove workflow burdens from clinicians. While the potential of this role is clear, training staff to become digital navigators and assessing their impact are primary challenges. Methods: We present a detailed manual/framework for implementation of the Digital Navigator within a short-term, cognitive-behavioral therapy-focused hybrid clinic. We analyze patient engagement, satisfaction, and digital phenotyping data quality outcomes. Data from 83 patients, for the period spanning September 2022 to September 2023, included Digital Navigator satisfaction, correlated with demographics, mindLAMP app satisfaction, engagement, and passive data quality. Additionally, average passive data across 33 clinic patients from November 2023 to January 2024 were assessed for missingness. Results: Digital Navigator satisfaction averaged 18.8/20. Satisfaction was not influenced by sex, race, gender, or education. Average passive data quality across 33 clinic patients was 0.82 at the time this article was written. Digital Navigator satisfaction scores had significant positive correlation with both clinic app engagement and perception of that app. Conclusions: Results demonstrate preliminary support and patient endorsement for the Digital Navigator role and positive outcomes around digital engagement and digital phenotyping data quality. Through sharing training resources and standardizing the role, we aim to enable clinicians and researchers to adapt and utilize the Digital Navigator for their own needs.

Eosinophils restrain humoral alloimmunity after lung transplantation.

While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils' role in alloimmunity. Due to their prevalence in the lung, and their defined role in other pulmonary pathologies such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody-secreting cell differentiation and resulted in de novo generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4+Foxp3-Bcl6+CXCR5+PD-1+ T follicular helper (Tfh) cells, which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh cell generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naive CD4+ T cells. Our data thus describe what we believe is a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggest that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.

Dysregulation of alternative splicing in spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1. We found that the diverse splicing events occurred in a predominantly cell autonomous manner. A majority of the transcripts with misregulated alternative splicing events were previously unknown, thus allowing us to identify overall new biological pathways that are distinctive to those affected by differential gene expression in spinocerebellar ataxia type 1. We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo. Together, this study provides novel molecular mechanistic insight into the pathogenesis of spinocerebellar ataxia type 1 and identifies potential therapeutic strategies for spinocerebellar ataxia type 1.

Comparison of two sedation protocols, with and without analgesia, in pigs: Assessment of sedation end points and propofol requirements.

OBJECTIVE: To compare the effects of intramuscular premedication with a novel nonanalgesic [alfaxalone-midazolam-acepromazine (AMA)] and an analgesic [ketamine-midazolam-detomidine (KMD)] protocol on sedation end points and propofol requirements for induction of anesthesia in swine. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of 27 Yorkshire cross gilts weighing approximately 30 kg. METHODS: Two sedation protocols, AMA and KMD, were compared. Time from intramuscular injection to ataxia, recumbency and nonresponsiveness to tactile stimulation was recorded. The propofol dose requirement for induction of general anesthesia and tracheal intubation, and any adverse events (paddling, twitching), were recorded. Data were tested for normality using a Shapiro-Wilk test. Propofol requirements were compared using a Student's t test. Times from injection to sedation end points were compared using a Mood's test, and significance was confirmed using a Kaplan-Meier curve with Wilcoxon test survival analysis. RESULTS: Sedation end points were reached significantly faster with KMD than with AMA. Nonresponsiveness occurred in 5 (0-16) and 9.5 (5-36) minutes for KMD and AMA, respectively (p = 0.011). No significant difference (p = 0.437) was found between propofol doses used in either group (KMD; 64.38 ± 5.98 mg, AMA; 72.00 ± 7.57 mg). More adverse events were noted with AMA (11/16 pigs) than with KMD (1/11 pigs). CONCLUSIONS AND CLINICAL RELEVANCE: In pigs, AMA can be used as a reliable sedation protocol. Frequency of adverse events and time to reach sedation end points between AMA and KMD differed, but the dose of propofol needed to induce general anesthesia was not significantly different.

Personal and community-level exposure to air pollution and daily changes in respiratory symptoms and oxygen saturation among adults with COPD.

Background: Air pollution exposure is associated with hospital admissions for Chronic Obstructive Pulmonary Disease (COPD). Few studies have investigated whether daily personal exposure to air pollutants affects respiratory symptoms and oxygenation among COPD patients. Methodology: We followed 30 former smokers with COPD for up to 4 non-consecutive 30-day periods in different seasons. Participants recorded worsening of respiratory symptoms (sub-categorized as breathing or bronchitis symptoms) by daily questionnaire, and oxygen saturation by pulse oximeter. Personal and community-level exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) were measured by portable air quality monitors and stationary monitors in the Boston area. We used generalized and multi-level linear mixed-effects models to estimate associations of the 24-hour average of each pollutant in the previous day with changes in respiratory symptoms and oxygen saturation. Results: Higher community-level exposure to air pollutants was associated with worsening respiratory symptoms. An interquartile range (IQR) higher community-level O3 was associated with a 1.35 (95%CI: 1.07-1.70) higher odds of worsening respiratory symptoms. The corresponding ORs for community-level PM2.5 and NO2 were 1.18 (95%CI: 1.02-1.37) and 1.06 (95%CI: 0.90-1.25), respectively. Community-level NO2 was associated with worsening bronchitis symptoms (OR=1.25, 95%CI: 1.00-1.56), but not breathing symptoms. Personal PM2.5 exposure was associated with lower odds of worsening respiratory symptoms (OR=0.91; 95%CI: 0.81-1.01). Personal exposure to NO2 was associated with 0.11% lower oxygen saturation (95%CI: -0.22, 0.00) per IQR. Conclusions: In this COPD population, there was a pattern of worsening respiratory symptoms associated with community-level exposure to O3 and PM2.5, and worsening oxygenation associated with personal exposure to NO2.

How Has Statistical Testing in Orthopedics Changed Over Time? An Assessment of High Impact Journals Over 25 Years.

BACKGROUND: It is important for physicians to be familiar with statistical techniques commonly used in published medical research. Statistical errors in medical literature are common, and there is a reported lack of understanding regarding statistical knowledge necessary for data interpretation and journal reading. As study design has become increasingly complex, peer-reviewed literature poorly addresses and explains the most common statistical methods utilized across leading orthopedic journals. METHODS: Articles from 5 leading general and subspecialty orthopedic journals were compiled from 3 distinct time periods. After exclusions were applied, 9521 remained, and a random 5% sampling of these articles, balanced across journals and years, was conducted yielding 437 articles after additional exclusions. Information regarding the number of statistical tests used, power/sample size calculation, type of statistical tests used, level of evidence (LOE), study type, and study design was collected. RESULTS: The mean number of statistical tests across all 5 orthopedic journals increased from 1.39 to 2.29 by 2018 (p = 0.007). The percentage of articles that reported power/sample size analyses was not found to differ by year, but the value has increased from 2.6% in 1994 to 21.6% in 2018 (p = 0.081). The most commonly used statistical test was the t-test which was present in 20.5% of articles, followed by chi-square test (13%), Mann-Whitney analysis (12.6%) and analysis of variance (ANOVA, 9.6%). The mean number of tests was generally greater in articles from higher impact factor journals (p = 0.013). Studies with a LOE of I used the highest mean number of statistical tests (3.23) compared to studies with lower LOE ratings (range 1.66-2.69, p < 0.001). Randomized control trials used the highest mean number of statistical test (3.31), while case series used the lowest mean number of tests (1.57, p < 0.001). CONCLUSIONS: The mean number of statistical tests used per article has increased over the past 25 years with the t-test, chi-square test, Mann-Whitney analysis, and ANOVA being the most used statistical tests in leading orthopedic journals. Despite an increase in statistical tests it should be noted that there was a paucity in advance statistical testing within the orthopedic literature. This study displays important trends in data analysis and can serve as a guide to help clinicians and trainees better understand the statistics used in literature as well as identifying deficits within the literature that should be addressed to help progress the field of orthopedics.

Neural stem and progenitor cells support and protect adult hippocampal function via vascular endothelial growth factor secretion.

Adult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses broadly throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs.

Differences of sexual development: genetic counseling considerations in the prenatal setting.

PURPOSE OF REVIEW: With the rapid adoption of noninvasive prenatal screening (NIPS), predictive fetal sex information is available early in pregnancy. This information can conflict with the results of other prenatal tests such as fetal ultrasound or diagnostic testing and raise the possibility of a fetal difference of sexual development (DSD). In this review, we describe recent studies examining the counseling and outcomes of prenatally suspected DSD. RECENT FINDINGS: Discordance in prenatal genetic testing results can cause confusion and anxiety in families as expectations of testing are not often discussed in detail prior to testing. There are no established guidelines for the counseling or management of such situations. SUMMARY: We present case vignettes to highlight relevant counseling points and considerations to aid in the development of guidelines and best practices in the management of DSD in the prenatal setting.

Physical Activity, Air Pollution Exposure, and Lung Function Interactions Among Adults with COPD.

Rationale: Although physical activity is strongly encouraged for patients with chronic obstructive pulmonary disease (COPD), it is unknown if physical activity affects daily exposure to air pollution, or whether it attenuates or exacerbates the effects of pollution on the airways among adults with COPD. Methods: Thirty former smokers with moderate-to-severe COPD in Boston were followed for 4 non-consecutive months in different seasons. We assessed daily lung function (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), prior-day personal pollutant exposure measured by portable air quality monitors (fine particulate matter [PM2.5] nitrogen oxide [NO2], and ozone [O3]), and daily step count. We constructed multi-level linear mixed-effects models with random intercepts for person and person-observation month, adjusting for demographic/seasonal covariates to test if step count was associated with daily pollution exposure, and if associations between prior-day pollution and lung function differed based on prior-day step count. Where effect modification was found, we performed stratified analyses by tertile of step count. Results: Higher daily step count was associated with higher same-day personal exposure to PM2.5, and O3 but not NO2. Each interquartile range (IQR) increment in step count was associated with 0.97 µg/m3 (95%CI: 0.30, 1.64) higher exposure to PM2.5 and 0.15 parts per billion (95% CI: -0.05, 0.35) higher exposure to O3 in adjusted models. We observed an interaction between prior-day NO2 and step count on FEV1 and FVC (Pinteraction<0.05) in which the negative associations between NO2 and lung function were reduced or absent at higher levels of daily activity. For example, FEV1 was 28.5mL (95%CI: -41.0, -15.9) lower per IQR of NO2 in the lowest tertile of step count, but there was no association in the highest tertile of step count (-1.6mL, 95% CI: -18.4, 15.2). Conclusions: Higher physical activity was associated with modestly higher daily exposure to PM2.5 and O3 and may attenuate the association between NO2 exposure and lung function.

Precipitation and Adolescent Respiratory Health in the Northeast United States.

Rationale: With more frequent and intense precipitation events across the globe due to a changing climate, there is a need to understand the relationship between precipitation and respiratory health. Precipitation may trigger asthma exacerbations, but little is known about how precipitation affects lung function and airway inflammation in early adolescents. Objectives: To determine if short-term precipitation exposure is associated with lung function and airway inflammation in early adolescents and if ever having a diagnosis of asthma modifies associations of precipitation with lung function and airway inflammation. Methods: In a prospective prebirth cohort, Project Viva, that included 1,019 early adolescents born in the northeastern United States, we evaluated associations of 1-, 2-, 3-, and 7-day moving averages of precipitation in the preceding week and forced expiratory volume in 1 second, forced vital capacity, and fractional exhaled nitric oxide (FeNO) using linear regression. We used log-transformed FeNO with effect estimates presented as percentage change. We adjusted for maternal education and household income at enrollment; any smoking in the home in early adolescence; child sex, race/ethnicity, and ever asthma diagnosis; and age, height, weight, date, and season (as sine and cosine functions of visit date) at the early adolescent visit and moving averages for mean daily temperature (same time window as exposure). Results: In fully adjusted linear models, 3- and 7-day moving averages for precipitation were positively associated with FeNO but not lung function. Every 2-mm increase in the 7-day moving average for precipitation was associated with a 4.0% (95% confidence interval, 1.1, 6.9) higher FeNO. There was evidence of effect modification by asthma status: Precipitation was associated with lower forced vital capacity and higher FeNO among adolescents with asthma. We also found that outdoor aeroallergen sensitization (immunoglobulin E against common ragweed, oak, ryegrass, or silver birch) modified associations of precipitation with FeNO, with higher FeNO in sensitized adolescents compared with nonsensitized adolescents. The associations of precipitation with FeNO were not explained by relative humidity or air pollution exposure. Conclusions: We found that greater short-term precipitation may trigger airway inflammation in adolescents, particularly among those with asthma.

Associations between greenness and predicted COVID-19-like illness incidence in the United States and the United Kingdom.

Green spaces may be protective against COVID-19 incidence. They may provide outdoor, ventilated, settings for physical and social activities and therefore decrease transmission risk. We examined the association between neighborhood greenness and COVID-19-like illness incidence using individual-level data. Methods: The study population includes participants enrolled in the COVID Symptom Study smartphone application in the United Kingdom and the United States (March-November 2020). All participants were encouraged to report their current health condition and suspected risk factors for COVID-19. We used a validated symptom-based classifier that predicts COVID-19-like illness. We estimated the Normalized Difference Vegetation Index (NDVI), for each participant's reported neighborhood of residence for each month, using images from Landsat 8 (30 m2). We used time-varying Cox proportional hazards models stratified by age, country, and calendar month at study entry and adjusted for the individual- and neighborhood-level risk factors. Results: We observed 143,340 cases of predicted COVID-19-like illness among 2,794,029 participants. Neighborhood NDVI was associated with a decreased risk of predicted COVID-19-like illness incidence in the fully adjusted model (hazard ratio = 0.965, 95% confidence interval = 0.960, 0.970, per 0.1 NDVI increase). Stratified analyses showed protective associations among U.K. participants but not among U.S. participants. Associations were slightly stronger for White individuals, for individuals living in rural neighborhoods, and for individuals living in high-income neighborhoods compared to individuals living in low-income neighborhoods. Conclusions: Higher levels of greenness may reduce the risk of predicted COVID-19-like illness incidence, but these associations were not observed in all populations.

The effect of IV ketamine in patients with major depressive disorder and elevated features of borderline personality disorder.

BACKGROUND: Comorbid borderline personality disorder and major depressive disorder is common and often not adequately responsive to standard antidepressant therapies. Ketamine is a potentially life-saving option. METHODS: 153 adult patients with MDD were assessed with the Personality Assessment Inventory (PAI) Borderline Subscale. Data was normally distributed with a mean + SD of 38.95 + 11.54. Patients >1 SD above the mean were assigned to the MDD + BF group. All others were assigned to the MDD-BF group. Patients were administered IV ketamine 0.5 mg/kg of ketamine over 40 min. Mood was assessed using the Beck Depression Inventory-II at baseline, 3 and 24 h post-ketamine. Scores between the MDD + BF and MDD-BF group at each time point were compared using t-test or analysis of covariance (ANCOVA) model. The primary outcome was response at 24 h. RESULTS: The LS mean change in BDI at 24 h was -23.8 (15.3) for MDD + BF and -21.0 (13.5) for MDD-BF (F [1151] = 0.043, p = 0.51). The LS mean change in BDI at 3 h was -21.3 (13.2) for MDD + BF and -19.6 (13.2) for MDD-BF (F[1151] = 0.045, p = 0.83). The LS mean change in BDI at 14 days was -23.2 (15.3) for MDD + BF and -15.3 (15.2) for MDD-BF (F[1130] = 4.24, p = 0.04). LIMITATIONS: People in the MDD + BF group were not necessarily diagnosable with borderline personality disorder. CONCLUSIONS: These data indicate that IV ketamine is effective in MDD patients with and without elevated borderline features. This can provide clinicians some reassurance about using ketamine in this population.

Geomagnetic disturbances reduce heart rate variability in the Normative Aging Study.

BACKGROUND: Solar and geomagnetic activity (GA) have been linked to increased cardiovascular (CVD) events. We hypothesize that heart rate variability (HRV) may be the biological mechanism between increased CVD risk and intense geomagnetic disturbances (GMD). METHODS: To evaluate the impact of GA and intense GMD on HRV in 809 elderly men [age mean 74.5 (SD = 6.8)] enrolled in the Normative Aging Study (Greater Boston Area), we performed repeated-measures using mixed-effects regression models. We evaluated two HRV outcomes: the square root of the mean squared differences of successive normal-to-normal intervals (r-MSSD) and the standard deviation of normal-to-normal heartbeat intervals (SDNN) in milliseconds (ms). We also compared the associations between Kp and HRV in patients with and without comorbidities such as diabetes and coronary heart diseases (CHD). We used data on global planetary K-Index (Kp) from middle latitudes as a GA and GMD (>75th Kp) parameters from the National Oceanic and Atmospheric Agency's Space Weather Prediction Center. RESULTS: We found a near immediate effect of continuous and higher Kp on reduced HRV for exposures up to 24 h prior to electrocardiogram recording. A 75th percentile increase in 15-hour Kp prior the examination was associated with a -14.7 ms change in r-MSSD (95 CI: -23.1, -6.3, p-value = 0.0007) and a -8.2 ms change in SDNN (95 CI: -13.9, -2.5, p-value = 0.006). The associations remained similar after adjusting the models for air pollutants over the exposure window prior to the event. In periods of intense GMD, the associations were stronger in patients with CHD and non-diabetes. CONCLUSIONS: This is the first study to demonstrate the potential adverse effects of geomagnetic activity on reduced heart rate variability in a large epidemiologic cohort over an extended period, which may have important clinical implications among different populations.

Mitigating the effects of choroidal hyper- and hypo-transmission defects on choroidal vascularity index assessments using optical coherence tomography.

Background: Changes in choroidal vascularity index (CVI) are associated with multiple choroid-related ocular diseases. CVI is calculated as the area/volume ratio of vessels in the choroid, which could be affected by alterations in regional signal intensities due to hypo-transmission defects (hypoTDs) caused by drusen and retinal pigment epithelium (RPE) detachments, and hyper-transmission defects (hyperTDs) caused by the absence of RPE. To develop a simulation model to verify the CVI assessments in eyes with hyper/hypoTDs and demonstrate that accurate CVIs can be achieved after attenuation correction on swept-source optical coherence tomography (SS-OCT). Methods: A simulation model was developed on 6×6 mm macular scans from normal subjects. Signal intensity in a cylindrical region below RPE was altered to mimic hyper/hypoTDs. CVIs were compared inside and outside the simulated regions before and after attenuation correction. CVI assessments of OCT scans from patients with hyperTDs due to geographic atrophy (GA) and from patients with hypoTDs due to drusen that subsequently resolved with the disappearance of the hypoTDs were compared with and without attenuation correction. Results: Ten normal eyes were recruited to generate the hyper/hypoTD simulation model. In eyes with hypoTDs, CVIs were overestimated, and in eyes with hyperTDs, the CVIs were underestimated (P<0.001). After attenuation correction, the uneven distribution of signal intensity was eliminated and the resulting CVI showed no significant difference compared with the 'ground truth', which is measured from the original scans. Attenuation correction successfully eliminated the influence of hyperTDs caused by GA on CVI measurements (n=38). Quantitatively, no significant difference was found in the CVIs of eyes before and after drusen collapse with attenuation correction (n=8). Conclusions: The simulation model could reveal the impact of hypo/hyperTDs on CVI quantification in eyes with choroid-involved ocular diseases. The importance of attenuation correction to ensure accuracy in choroidal vessel segmentation was demonstrated by analyzing eyes with GA or drusen.

A reengineered common chain cytokine augments CD8+ T cell-dependent immunotherapy.

Cytokine therapy is limited by undesirable off-target side effects as well as terminal differentiation and exhaustion of chronically stimulated T cells. Here, we describe the signaling properties of a potentially unique cytokine by design, where T cell surface binding and signaling are separated between 2 different families of receptors. This fusion protein cytokine, called OMCPmutIL-2, bound with high affinity to the cytotoxic lymphocyte-defining immunoreceptor NKG2D but signaled through the common γ chain cytokine receptor. In addition to precise activation of cytotoxic T cells due to redirected binding, OMCPmutIL-2 resulted in superior activation of both human and murine CD8+ T cells by improving their survival and memory cell generation and decreasing exhaustion. This functional improvement was the direct result of altered signal transduction based on the reorganization of surface membrane lipid rafts that led to Janus kinase-3-mediated phosphorylation of the T cell receptor rather than STAT/AKT signaling intermediates. This potentially novel signaling pathway increased CD8+ T cell response to low-affinity antigens, activated nuclear factor of activated T cells transcription factors, and promoted mitochondrial biogenesis. OMCPmutIL-2 thus outperformed other common γ chain cytokines as a catalyst for in vitro CD8+ T cell expansion and in vivo CD8+ T cell-based immunotherapy.

Synthesis and Characterization of Core-Shell Cu-Ru, Cu-Rh, and Cu-Ir Nanoparticles.

Optimizing the use of expensive precious metals is critical to developing sustainable and low-cost processes for heterogeneous catalysis or electrochemistry. Here, we report a synthesis method that yields core-shell Cu-Ru, Cu-Rh, and Cu-Ir nanoparticles with the platinum-group metals segregated on the surface. The synthesis of Cu-Ru, Cu-Rh, and Cu-Ir particles allows maximization of the surface area of these metals and improves catalytic performance. Furthermore, the Cu core can be selectively etched to obtain nanoshells of the platinum-group metal components, leading to a further increase in the active surface area. Characterization of the samples was performed with X-ray absorption spectroscopy, X-ray powder diffraction, and ex situ and in situ transmission electron microscopy. CO oxidation was used as a reference reaction: the three core-shell particles and derivatives exhibited promising catalyst performance and stability after redox cycling. These results suggest that this synthesis approach may optimize the use of platinum-group metals in catalytic applications.

Interocular asymmetry of choroidal thickness and vascularity index measurements in normal eyes assessed by swept-source optical coherence tomography.

BACKGROUND: To investigate the symmetry of interocular choroidal thickness and vascularity index measurements in normal eyes using swept-source optical coherence tomography (SS-OCT). Cross-sectional and observational study. This study included 244 eyes of 122 normal adults with ages uniformly distributed from 19 to 89 years. METHODS: SS-OCT imaging was performed using a scanning pattern of 12×12 mm. Mean choroidal thickness (MCT) and choroidal vascularity index (CVI) measurements in the entire scanning region were obtained using a validated and published automatic method. The correlation and differences (including signed and absolute differences) between bilateral MCT and CVI measurements were analyzed at the following 6 regions: 3 concentric circles centered on the fovea with diameters of 2.5, 5, and 11 mm; the inner rim from 2.5 to 5 mm circle; the outer rim from 5 to 11 mm circle; and the entire 12×12-mm scan region, respectively. Comparison of interocular MCT and CVI measurements. RESULTS: MCT measurements in right and left eyes were strongly correlated in all regions [all intraclass correlation (ICC) >0.73], but MCT measurements in right eyes were significantly thicker than in left eyes. CVI measurements in right and left eyes were moderately correlated in all regions (all ICC >0.46), but CVI measurements in right eyes were significantly smaller than that in left eyes in the macular subregions (2.5 mm circle, 5 mm circle, and the inner rim). Neither signed nor absolute interocular differences in MCT were correlated with corresponding CVI interocular differences. CONCLUSIONS: Choroidal differences exist between normal fellow eyes in adults in the absence of obvious pathology. This study is useful in assisting clinicians and researchers in distinguishing asymmetric changes that are to be expected in normal eyes versus changes that could be associated with diseases.