Bulletin of Computer Science and Electrical Engineering (BCSEE)
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Time to Reach Glycaemic and Body Weight Loss Thresholds with Tirzepatide in Patients with Type 2 Diabetes: A Pre-planned Exploratory Analysis of SURPASS-2 and SURPASS-3
No full textINTRODUCTION: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, provides clinically meaningful improvements in glycaemic control and body weight loss in people with type 2 diabetes. The early efficacy profile of tirzepatide after treatment initiation is of interest. In this exploratory pre-planned analysis, we evaluated the time to achieve glycaemic control and body weight loss thresholds with tirzepatide. METHODS: In two randomised studies, we compared time to achieve HbA1c (< 7.0% and ≤ 6.5%) and weight loss (≥ 5%, SURPASS-2 only) thresholds among people treated with tirzepatide (5, 10, and 15 mg), semaglutide 1 mg in SURPASS-2, and titrated insulin degludec in SURPASS-3. Longitudinal logistic regression models were used to explore the proportion of participants achieving HbA1c and body weight loss thresholds at 4, 12, and 24 weeks. The time to achieve these thresholds was analysed and compared between groups using the Cox proportional-hazards model. RESULTS: Overall, greater proportions of participants achieved the HbA1c and body weight loss thresholds at 4, 12, and 24 weeks with tirzepatide compared with semaglutide 1 mg and insulin degludec. The median time to achieve HbA1c < 7.0% (8.1 weeks with each tirzepatide dose, 12.0 weeks with semaglutide 1 mg, and 12.1 weeks with insulin degludec) and ≤ 6.5% (12.1, 15.7, and 24.1 weeks, respectively) was faster with tirzepatide than semaglutide 1 mg and insulin degludec. In SURPASS-2, the median time to first achieve a body weight loss of ≥ 5% was faster with tirzepatide 5 mg (16.0 weeks) and 10 and 15 mg (12.4 weeks) than with semaglutide 1 mg (24.0 weeks). CONCLUSION: Analyses of data from SURPASS-2 and -3 revealed that tirzepatide treatment enabled more people with type 2 diabetes to achieve glycaemic thresholds and these were achieved faster than with semaglutide 1 mg or insulin degludec. Tirzepatide-treated participants also achieved a body weight loss of ≥ 5% significantly faster with tirzepatide than with semaglutide 1 mg. TRIAL REGISTRATION NUMBERS: NCT03987919; NCT03882970
Sex-biased T cell exhaustion drives differential immune responses in glioblastoma
No full textSex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8 + T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response. SIGNIFICANCE: Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM.</p
Remarks on the size of apparent horizons
No full textMarginally outer trapped surfaces (also referred to as apparent horizons)that are stable in 3-dimensional initial data sets obeying the dominant energycondition strictly are known to satisfy an area bound. The main purpose of thisnote is to show (in several ways) that such surfaces also satisfy a diameterbound
Retinopathy of Prematurity Related Late Rhegmatogenous Retinal Detachment - Chapter 35
No full textRetinopathy of prematurity is a neovascular disease of premature infants and the natural history of this disease has been extensively described. Long term sequelae and complications has been less investigated. Retinal detachment is vision threating in these patients; tractional and exudative retinal detachments are usually presented earlier in age; rhegmatogenous detachments tent to occur more commonly later in life secondary to abnormal vitreoretinal interface changes. Different surgical approaches can be used to treat this complication. Either vitrectomy, scleral buckle or combination of both techniques are recommended depending on the case
Day-of-the-Week and Time-of-the-Day Patterns of Sedentary Behavior in the Hispanic Community Health Study / Study of Latinos
No full textPURPOSEExisting sedentary behavior interventions have largely achieved mixed results. Conventionally, interventions have attempted to reduce sedentary behavior using a full-day approach. An alternative strategy may be to target specific periods during the day and/or week. This study examined the day-of-the-week (Monday to Sunday) and time-of-the-day patterns (3-hr and 6-hr periods) of sedentary behavior among U.S. Hispanics/Latinos adults. METHODSParticipants (n = 12,241) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multi-site community-based prospective cohort study of Hispanic/Latino adults, were studied. Sedentary behavior was assessed for one week using a hip-mounted accelerometer through total sedentary time, sedentary time in bouts ≥60 minutes, and total number of sedentary breaks. The temporal patterns of sedentary behavior metrics were evaluated using linear mixed effect models accounting for HCHS/SOL complex survey design. RESULTSThere were statistically significant variations in temporal patterns across day-of-the-week and time-of-the-day periods for all three metrics (p < .001). Adults were more sedentary on weekends than on weekdays, and most sedentary on Sundays. The time-of-the-day patterns had a U-curve pattern wherein adults were most sedentary late at night, became less sedentary throughout the day, reached peak activeness around noon, then gradually became more sedentary into the evening. These patterns were largely robust across seasonality and most sociodemographic characteristics including age, employment status, work shift schedule, acculturation, and field center. CONCLUSIONSOur findings suggest that early mornings, evenings, and weekends were the more sedentary periods in this cohort of Hispanic/Latino adults, characterized by higher volumes of sedentary time, higher volumes of time in prolonged sedentary bouts, and fewer number of sedentary breaks than other time periods, highlighting important windows of opportunity to reduce sedentary behavior
Co-targeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells
No full textNeurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.</p
Engagement in the preschool classroom: Brief measures for use with children from ethno-racially diverse and low-income backgrounds
No full text•Two new measures of children's engagement were developed and tested for use in preschool classrooms– a teacher rating scale and an independent observation instrument.•Findings revealed initial construct validity evidence for the two measures, which were found to be reliable and to relate modestly with one another as well as to an external criterion measure of children's science knowledge.•Findings also revealed significant relations between preschool children's engagement and child and family demographic characteristics, perhaps attributable to the unique context of Head Start. For example, teachers rated children whose home language was not English as higher in engagement compared with children whose home language was English.
Children's behavioral engagement in preschool is a strong predictor of their academic achievement both concurrently and into the later school years across socioeconomic and ethnic groups (Chien et al., 2010; Fuhs et al., 2013; Hamre & Pianta, 2001; Kim & Suarez-Orozco, 2015; Ladd & Dinella, 2009). The present measurement development study was conducted within the context of a larger intervention research program in partnership with an urban Head Start program in the northeastern United States. Forty-one teachers and 456 children participated. Two new measures were developed and tested for use in preschool classrooms– a teacher rating scale and an independent observation instrument. Although many of the assessments that result from commonly employed systematic observation methods provide a detailed and nuanced description of children's engagement in the classroom, they often require intensive training and are costly to implement. The present study sought to provide the early childhood education field with two brief and more cost-effective measures. Findings revealed initial construct validity evidence for the two measures, which were found to be reliable and to relate modestly with one another as well as to an external criterion measure of children's science knowledge, which was the focus of the larger intervention. Findings also revealed significant relations between children's engagement and child and family demographic characteristics, perhaps attributable to the unique context of Head Start
Retinopathy of Prematurity Outcomes of Neonates Meeting only a Single Screening Criterion: Proposal of the TWO-ROP Algorithm: Single Screening Criterion for Retinopathy of Prematurity
No full textTo assess the rates of retinopathy of prematurity (ROP) and treatment-warranted ROP in a modern set of patients meeting zero or one of the current ROP screening criteria.
Retrospective cohort study.
Single-center study of 9,350 infants screened for ROP from 2009-2019. Rates of ROP and treatment-warranted ROP were evaluated in group 1 (BW < 1500g and GA ≥ 30weeks), group 2 (BW ≥ 1500g and GA < 30 weeks), and group 3 (BW ≥ 1500g and GA ≥ 30weeks).
Out of 7,520 patients with reported BW and GA, 1,612 (21.4%) patients met the inclusion criteria. The number of patients in group 1, 2, and 3 was 466 (6.19%), 23 (0.31%), and 1123 (14.93%) respectively. The number of patients diagnosed with ROP was 20 (4.29%) in group 1, 1 (4.35%) in group 2, and 12 (1.07%) in group 3, P < .001. Mean interval between birth and ROP diagnosis was 36.25 days (range 12 - 75) in group 1, 47 days in group 2 and 23.33 days (range 10 - 39) in group 3 (P = .05). No cases of stage 3, zone 1 or plus disease were recorded. No patient met the treatment criteria.
Patients meeting one screening criterion had a low rate of ROP (<5%), with no stage 3, zone 1, or plus disease. No patients required treatment. We propose a possible algorithm (TWO-ROP) in appropriate NICUs, with an amendment in screening protocol for this low-risk population to include only an outpatient screening exam within 1 week of discharge, or at 40 weeks if inpatient, to decrease the inpatient ROP screening burden while maintaining safety. Further external validation of this protocol would be required
136 Evaluating the ten-year progression of the Miami CTSI Mentored Translational Research Scholars (KL2) Program Awards
No full textOBJECTIVES/GOALS: The goal of Miami CTSI’s Mentored Translational Research Scholars (KL2) Program is to identify outstanding early-stage investigators and prepare them to become the next generation of highly skilled independent researchers who translate fundamental knowledge and new technologies from the laboratory to the clinic and to the community. METHODS/STUDY POPULATION: Evaluation of the KL2 program focused on assessing progress in the following areas: 1) scholar productivity during and after graduating from the program; 2) continued engagement of KL2 program graduates in clinical and translational research; scholar productivity during and after graduating from the program; 3) outcomes such as establishing independent research careers, obtaining research funding, and establishing collaborations; and 4) research impact. We used a developmental evaluation approach and benefits-framework model to conduct program evaluation, incorporating both in a program-specific logic model. Bi-annual surveys were used to measure scholar feedback and progress, and utilization of CTSI services. RESULTS/ANTICIPATED RESULTS: Since 2013, the KL2 program has trained 21 scholars,17 of whom have completed training, and four are still in the program. Of the 21 scholars, 52% are female and 38% are underrepresented minorities (URM)–significantly higher than the 12% URM for overall CTSA KL2 scholars. Scholars have 176 total publications related to their KL2 projects and have received $52.4m in total research funding. In addition, 50% of the projects focused on health disparities. Overall, 48% of KL2 scholars have received large subsequent federal awards including three NIH K awards and six NIH R awards. Scholars actively utilized CTSI services during and after graduation. Programmatic enhancements such as adding institutional scholars and using scholar feedback to improve program resources were also implemented. DISCUSSION/SIGNIFICANCE: Miami CTSI’s KL2 program has demonstrated success in fulfilling its program goals. The process and outcome evaluation has provided a better understanding of program performance and progress and has demonstrated alignment with CTSI’s overall goals on addressing health disparities and its commitment to diversity and equity
Addressing key issues in HIV self-test program implementation for Black and Latino sexual minority men in the Southern United States: a multiphase study protocol
No full textBlack and Latino sexual minority men in the Southern United States have the highest HIV infection rates in the country. Increased HIV testing can help decrease onward HIV transmission through detecting previously undiagnosed infections. HIV self-testing is an evidence-based strategy to increase HIV testing among sexual minority men, but the implementation of this intervention in the Southern United States is limited. One implementation barrier is the lack of knowledge of Black and Latino sexual minority men's preferences for various HIV self-testing program characteristics and their willingness to pay for these preferences. In addition, little is known about facilitators and barriers to initiating HIV self-testing programs from the perspectives of HIV prevention implementation decision-makers in this region.
We will conduct an online discrete choice experiment among Black and Latino sexual minority men in the Southern United States (n = 300) to estimate this population's preferences for the following HIV self-testing program characteristics: delivery strategy (home delivery, peer delivery, clinic pickup); delivery speed (same day, next day, 3 days, and 5 days); support (instructions only, during test, and 1 week after delivery); and price (20, 50, $60). We will also use this choice data to generate willingness-to-pay estimates for each program characteristic. Guided by the Consolidated Framework for Implementation Research, we will then conduct semi-structured interviews (n = 30) with HIV prevention program decision-makers at various health organizations serving Black and Latino sexual minority men in the region to further understand facilitators and barriers to implementation of the most preferred HIV self-testing program design.
By gaining perspectives on HIV self-testing implementation from patients and providers, this project will build a roadmap for the initiation of HIV self-testing programs to decrease HIV incidence among one of the most disproportionately impacted populations in the USA