Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial.

Importance: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist used for the treatment of type 2 diabetes. Efficacy and safety of adding tirzepatide vs prandial insulin to treatment in patients with inadequate glycemic control with basal insulin have not been described. Objective: To assess the efficacy and safety of tirzepatide vs insulin lispro as an adjunctive therapy to insulin glargine. Design, Setting, and Participants: This open-label, phase 3b clinical trial was conducted at 135 sites in 15 countries (participants enrolled from October 19, 2020, to November 1, 2022) in 1428 adults with type 2 diabetes taking basal insulin. Interventions: Participants were randomized (in a 1:1:1:3 ratio) to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708). Main Outcomes and Measures: Outcomes included noninferiority of tirzepatide (pooled cohort) vs insulin lispro, both in addition to insulin glargine, in HbA1c change from baseline at week 52 (noninferiority margin, 0.3%). Key secondary end points included change in body weight and percentage of participants achieving hemoglobin A1c (HbA1c) target of less than 7.0%. Results: Among 1428 randomized participants (824 [57.7%] women; mean [SD] age, 58.8 [9.7] years; mean [SD] HbA1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA1c with tirzepatide (pooled cohort) was -2.1% vs -1.1% with insulin lispro, resulting in mean HbA1c levels of 6.7% vs 7.7% (estimated treatment difference, -0.98% [95% CI, -1.17% to -0.79%]; P < .001); results met noninferiority criteria and statistical superiority was achieved. Estimated mean change from baseline in body weight was -9.0 kg with tirzepatide and 3.2 kg with insulin lispro (estimated treatment difference, -12.2 kg [95% CI, -13.4 to -10.9]). The percentage of participants reaching HbA1c less than 7.0% was 68% (483 of 716) with tirzepatide and 36% (256 of 708) with insulin lispro (odds ratio, 4.2 [95% CI, 3.2-5.5]). The most common adverse events with tirzepatide were mild to moderate gastrointestinal symptoms (nausea: 14%-26%; diarrhea: 11%-15%; vomiting: 5%-13%). Hypoglycemia event rates (blood glucose level <54 mg/dL or severe hypoglycemia) were 0.4 events per patient-year with tirzepatide (pooled) and 4.4 events per patient-year with insulin lispro. Conclusions and Relevance: In people with inadequately controlled type 2 diabetes treated with basal insulin, weekly tirzepatide compared with prandial insulin as an additional treatment with insulin glargine demonstrated reductions in HbA1c and body weight with less hypoglycemia. Trial Registration: ClinicalTrials.gov Identifier: NCT04537923.

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.

INTRODUCTION: 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.

Patient-Reported Outcomes of Breast Reconstruction: Does the Quality of Decisions Matter?

BACKGROUND: Little is known about how the quality of decisions influences patient-reported outcomes (PROs). We hypothesized that higher decision quality for breast reconstruction would be independently associated with better PROs. METHODS: We conducted a prospective cohort study of patients undergoing mastectomy with or without reconstruction. Patients were enrolled before surgery and followed for 18 months. We used BREAST-Q scales to measure PROs and linear regression models to explore the relationship between decision quality (based on knowledge and preference concordance) and PROs. Final models were adjusted for baseline BREAST-Q score, radiation, chemotherapy, and major complications. RESULTS: The cohort included 101 patients who completed baseline and 18-month surveys. Breast reconstruction was independently associated with higher satisfaction with breasts (ß = 20.2, p = 0.0002), psychosocial well-being (ß = 14.4, p = 0.006), and sexual well-being (ß = 15.7, p = 0.007), but not physical well-being. Patients who made a high-quality decision had similar PROs as patients who did not. Among patients undergoing mastectomy with reconstruction, higher decision quality was associated with lower psychosocial well-being (ß = -14.2, p = 0.01). CONCLUSIONS: Breast reconstruction was associated with better PROs in some but not all domains. Overall, making a high-quality decision was not associated with better PROs. However, patients who did not have reconstruction had a trend toward better well-being after making a high-quality decision, whereas patients who did have reconstruction had poorer well-being after making a high-quality decision. Additional research on the relationship between decision quality and PROs is needed.

THUNDER: A reference-free deconvolution method to infer cell type proportions from bulk Hi-C data.

Hi-C data provide population averaged estimates of three-dimensional chromatin contacts across cell types and states in bulk samples. Effective analysis of Hi-C data entails controlling for the potential confounding factor of differential cell type proportions across heterogeneous bulk samples. We propose a novel unsupervised deconvolution method for inferring cell type composition from bulk Hi-C data, the Two-step Hi-c UNsupervised DEconvolution appRoach (THUNDER). We conducted extensive simulations to test THUNDER based on combining two published single-cell Hi-C (scHi-C) datasets. THUNDER more accurately estimates the underlying cell type proportions compared to reference-free methods (e.g., TOAST, and NMF) and is more robust than reference-dependent methods (e.g. MuSiC). We further demonstrate the practical utility of THUNDER to estimate cell type proportions and identify cell-type-specific interactions in Hi-C data from adult human cortex tissue samples. THUNDER will be a useful tool in adjusting for varying cell type composition in population samples, facilitating valid and more powerful downstream analysis such as differential chromatin organization studies. Additionally, THUNDER estimated contact profiles provide a useful exploratory framework to investigate cell-type-specificity of the chromatin interactome while experimental data is still rare.

Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial.

Importance: The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described. Objective: To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control. Design, Setting, and Participants: Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin. Interventions: Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. Main Outcomes and Measures: The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels. Results: Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%). Conclusions and Relevance: Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04039503.

Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia.

Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.

SAME-clustering: Single-cell Aggregated Clustering via Mixture Model Ensemble.

Clustering is an essential step in the analysis of single cell RNA-seq (scRNA-seq) data to shed light on tissue complexity including the number of cell types and transcriptomic signatures of each cell type. Due to its importance, novel methods have been developed recently for this purpose. However, different approaches generate varying estimates regarding the number of clusters and the single-cell level cluster assignments. This type of unsupervised clustering is challenging and it is often times hard to gauge which method to use because none of the existing methods outperform others across all scenarios. We present SAME-clustering, a mixture model-based approach that takes clustering solutions from multiple methods and selects a maximally diverse subset to produce an improved ensemble solution. We tested SAME-clustering across 15 scRNA-seq datasets generated by different platforms, with number of clusters varying from 3 to 15, and number of single cells from 49 to 32 695. Results show that our SAME-clustering ensemble method yields enhanced clustering, in terms of both cluster assignments and number of clusters. The mixture model ensemble clustering is not limited to clustering scRNA-seq data and may be useful to a wide range of clustering applications.

SAFE-clustering: Single-cell Aggregated (from Ensemble) clustering for single-cell RNA-seq data.

MOTIVATION: Accurately clustering cell types from a mass of heterogeneous cells is a crucial first step for the analysis of single-cell RNA-seq (scRNA-Seq) data. Although several methods have been recently developed, they utilize different characteristics of data and yield varying results in terms of both the number of clusters and actual cluster assignments. RESULTS: Here, we present SAFE-clustering, single-cell aggregated (From Ensemble) clustering, a flexible, accurate and robust method for clustering scRNA-Seq data. SAFE-clustering takes as input, results from multiple clustering methods, to build one consensus solution. SAFE-clustering currently embeds four state-of-the-art methods, SC3, CIDR, Seurat and t-SNE + k-means; and ensembles solutions from these four methods using three hypergraph-based partitioning algorithms. Extensive assessment across 12 datasets with the number of clusters ranging from 3 to 14, and the number of single cells ranging from 49 to 32, 695 showcases the advantages of SAFE-clustering in terms of both cluster number (18.2-58.1% reduction in absolute deviation to the truth) and cluster assignment (on average 36.0% improvement, and up to 18.5% over the best of the four methods, measured by adjusted rand index). Moreover, SAFE-clustering is computationally efficient to accommodate large datasets, taking <10 min to process 28 733 cells. AVAILABILITY AND IMPLEMENTATION: SAFEclustering, including source codes and tutorial, is freely available at https://github.com/yycunc/SAFEclustering. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Accuracy of Predictions of Patients With Breast Cancer of Future Well-being After Immediate Breast Reconstruction.

Importance: Making a good decision about breast reconstruction requires predicting how one would feel after the procedure, but people tend to overestimate the impact of events on future well-being. Objective: To assess how well patients predict future well-being after mastectomy, with or without immediate reconstruction, with the following a priori hypotheses: Patients will overestimate the negative impact of mastectomy and positive impact of reconstruction, and prediction accuracy will be associated with decision satisfaction and decision regret. Design, Setting, and Participants: This prospective cohort survey study was conducted at a single, multidisciplinary academic oncology clinic from July 2012 to February 2014. Adult women undergoing mastectomy for stage 1, 2, or 3 invasive ductal or lobular breast cancer, ductal carcinoma in situ, or prophylaxis were invited to participate. Data analysis was conducted from September 2015 to October 2017. Exposures: Mastectomy only or mastectomy with immediate reconstruction. Main Outcomes and Measures: Preoperative measures predicted were 12-month happiness (Cantril Ladder) and quality of life, predicted satisfaction with breasts, sexual attractiveness, breast numbness, and pain (measured with BreastQ single items). Measures at 12 months postoperative added the Decision Regret Scale and Satisfaction With Decisions Scale. Results: Of 214 eligible patients, 182 consecutive patients were approached, and 145 enrolled (80%). Of these 145 patients, 131 returned surveys (72%) and 111 of these remained at 12 months (88%). Fifteen who had delayed reconstruction were excluded from analysis, leaving a final cohort of 96 women; 54 had not had reconstruction and 42 had had reconstruction. The mean (SD) age of the cohort was 53.9 (12.1) years; 73 (76%) were white; 50 (52%) were college graduates; 54 (56%) were privately insured; 69 (72%) had disease at stages 0, 1, or 2; and 31 (32%) received adjuvant radiation. Patients having mastectomy without reconstruction underestimated future well-being in all domains. Differences were significant for quality of life scores (mean predicted, 68 vs mean actual, 74; t50, -2.47; P = .02) and satisfaction with breasts-clothed (mean predicted, 2.4 vs mean actual, 2.8; t49, -2.11; P = .04). Patients undergoing mastectomy with reconstruction overestimated future well-being in all but 1 domain. Differences were significant for satisfaction with breasts-unclothed (mean predicted, 3.1 vs mean actual, 2.6; t41, 2.70; P = .01); sexual attractiveness-clothed (mean predicted, 3.7 vs mean actual, 3.3; t39, 2.29; P = .03); sexual attractiveness-unclothed (mean predicted, 3.3 vs mean actual, 2.3; t40, 5.57; P < .001). Both groups experienced more numbness than predicted (mean predicted, 2.79 and 2.72 for mastectomy only and mastectomy with reconstruction groups, respectively; mean actual, 3.52 and 3.56, respectively; t47, -3.4 and t38, -2.9, respectively; P < .01). Patients who were less happy (ß = 6.3; P = .02) or had greater pain (ß = 8.7; P < .001) than predicted had greater regret. Conclusions and Relevance: Patients underestimated future well-being after mastectomy and overestimated well-being after reconstruction. Misprediction was associated with regret. Decision support for breast reconstruction should address expectations about well-being.

Quality of Patient Decisions About Breast Reconstruction After Mastectomy.

IMPORTANCE: Breast reconstruction has the potential to improve a person's body image and quality of life but has important risks. Variations in who undergoes breast reconstruction have led to questions about the quality of patient decisions. OBJECTIVE: To assess the quality of patient decisions about breast reconstruction. DESIGN, SETTING, AND PARTICIPANTS: A prospective, cross-sectional survey study was conducted from June 27, 2012, to February 28, 2014, at a single, academic, multidisciplinary oncology clinic among women planning to undergo mastectomy for stage I to III invasive ductal or lobular breast cancer, ductal carcinoma in situ, or prophylaxis. EXPOSURES: Mastectomy only and mastectomy with reconstruction. MAIN OUTCOME AND MEASURES: Knowledge, as ascertained using the Decision Quality Instrument; preference concordance, based on rating and ranking of key attributes; and decision quality, defined as having knowledge of 50% or more and preference concordance. RESULTS: During the 20-month period, 214 patients were eligible, 182 were approached, and 32 missed. We enrolled 145 patients (79.7% enrollment rate), and received surveys from 131 patients (72.0% participation rate). Five participants became ineligible. The final study population was 126 patients. Among the 126 women in the study (mean [SD] age, 53.2 [12.1] years), the mean (SD) knowledge score was 58.5% (16.2%) and did not differ by treatment group (mastectomy only, 55.2% [15.0%]; mastectomy with reconstruction, 60.5% [16.5%]). A total of 82 of 123 participants (66.7%) had a calculated treatment preference of mastectomy only; 39 of these women (47.6%) underwent mastectomy only. A total of 41 participants (32.5%) had a calculated treatment preference of mastectomy with reconstruction; 36 of these women (87.8%) underwent mastectomy with reconstruction. Overall, 52 of 120 participants (43.3%) made a high-quality decision. In multivariable analysis, white race/ethnicity (odds ratio [OR], 2.72; 95% CI, 1.00-7.38; P = .05), having private insurance (OR, 1.61; 95% CI, 1.35-1.93; P < .001), having a high school education or less (vs some college) (OR, 4.84; 95% CI, 1.22-19.21; P = .02), having a college degree (vs some college) (OR, 1.95; 95% CI, 1.53-2.49; P < .001), and not having a malignant neoplasm (eg, BRCA carriers) (OR, 3.13; 95% CI, 1.25-7.85; P = .01) were independently associated with making a high-quality decision. CONCLUSIONS AND RELEVANCE: A minority of patients undergoing mastectomy in a single academic center made a high-quality decision about reconstruction. Shared decision making is needed to support decisions about breast reconstruction.

Stream-dependent development of higher visual cortical areas.

Multiple cortical areas contribute to visual processing in mice. However, the functional organization and development of higher visual areas are unclear. Here we used intrinsic signal optical imaging and two-photon calcium imaging to map visual responses in adult and developing mice. We found that visually driven activity was well correlated among higher visual areas within two distinct subnetworks resembling the dorsal and ventral visual streams. Visual response magnitude in dorsal stream areas slowly increased over the first 2 weeks of visual experience. By contrast, ventral stream areas exhibited strong responses shortly after eye opening. Neurons in a dorsal stream area showed little change in their tuning sharpness to oriented gratings while those in a ventral stream area increased stimulus selectivity and expanded their receptive fields significantly. Together, these findings provide a functional basis for grouping subnetworks of mouse visual areas and revealed stream differences in the development of receptive field properties.