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Background To evaluate patient-reported outcomes with ramucirumab plus docetaxel, a regimen which improved progression-free survival in platinum-refractory advanced urothelial carcinoma (aUC). Methods RANGE—a randomized, double-blinded, phase 3 trial in patients with platinum-refractory aUC. Ramucirumab (10 mg/kg) plus docetaxel (75 mg/m 2 ) or placebo plus docetaxel were administered every 21 days until disease progression or unacceptable toxicity. Patients received maximum 10 cycles of docetaxel. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EuroQoL five-dimensions (EQ-5D-5L) were administered at baseline, start of each cycle, and 30-day follow-up visit. A ≥ 10-point change in QLQ-C30 scores was considered meaningful. Rates of improved/stable scores were compared between treatment arms using Fisher’s exact test. Time to deterioration (TtD) was estimated and compared using Kaplan–Meier estimation and log-rank test. Results Of the 530 patients, ~ 97% patients in each arm provided baseline QLQ-C30 data. On-treatment compliance was ≥ 88% for first 8 cycles. Mean baseline QLQ-C30 scores were similar between arms, with global quality of life (QoL), fatigue, pain, and insomnia having greatest impairment. Postbaseline rates of improved/stable QLQ-C30 scores were similar between treatment arms except for greater improvement in pain score with ramucirumab. TtD of QLQ-C30 scales favored ramucirumab arm. Baseline EQ-5D-5L index and visual analogue scale scores were similar between arms, followed by relatively stable on-treatment scores. EQ-5D-5L scores worsened at post-discontinuation follow-up visit. Conclusions Ramucirumab plus docetaxel did not negatively impact QoL compared with docetaxel alone in platinum-refractory aUC. Improved TtD and tumor associated rates of pain favored ramucirumab treatment. Clinical trail registration NCT02426125. https://clinicaltrials.gov/ct2/show/NCT02426125 . Date of registration: April 24th 2015

Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone. We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834. From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of −1·91% (−21 mmol/mol) with tirzepatide 5 mg, −1·93% (−21 mmol/mol) with tirzepatide 10 mg, and −2·11% (−23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87–92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81–86% vs 10%) and 31–52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12–18% vs 6%), diarrhoea (12–14% vs 8%), and vomiting (2–6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group. Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. Eli Lilly and Company.

Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes. This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7–10% (53–86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003. Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was –12·8% (SE 0·6) and –14·7% (0·5), respectively, and –3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of –9·6% percentage points (95% CI –11·1 to –8·1) with tirzepatide 10 mg and –11·6% percentage points (–13·0 to –10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79–83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator. In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management. Eli Lilly and Company.

Abstract Context Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes (T2D). SURPASS-1, a phase 3 trial of tirzepatide monotherapy in people with early T2D, enables evaluating effects of tirzepatide on pancreatic beta-cell function and insulin sensitivity (IS) without other background antihyperglycemic medications. Objective Explore changes in biomarkers of beta-cell function and IS with tirzepatide monotherapy. Design Post hoc analyses of fasting biomarkers with analysis of variance and mixed model repeated measures. Setting Forty-seven sites in 4 countries. Patients Four hundred seventy-eight T2D participants. Intervention Tirzepatide (5, 10, 15 mg), placebo. Main Outcome Measure(s) Analyze biomarkers of beta-cell function and IS at 40 weeks. Results At 40 weeks, markers of beta-cell function improved with tirzepatide monotherapy vs placebo with reductions from baseline in fasting proinsulin levels (49-55% vs −0.6%) and in intact proinsulin/C-peptide ratios (47-49% vs −0.1%) (P < .001, all doses vs placebo). Increases from baseline in homeostatic model assessment for beta-cell function (computed with C-peptide) (77-92% vs −1.4%) and decreases in glucose-adjusted glucagon levels (37-44% vs +4.8%) were observed with tirzepatide vs placebo (P < .001, all doses vs placebo). IS improved as indicated by reductions from baseline in homeostatic model assessment for insulin resistance (9-23% vs +14.7%) and fasting insulin levels (2-12% vs +15%), and increases in total adiponectin (16-23% vs −0.2%) and insulin-like growth factor binding protein 2 (38-70% vs +4.1%) with tirzepatide vs placebo at 40 weeks (P ≤ .031, all doses vs placebo, except for fasting insulin levels with tirzepatide 10 mg). Conclusions As monotherapy for early T2D, tirzepatide achieved significant improvements in biomarkers of both pancreatic beta-cell function and IS.

Propensity score has been increasingly used to control for confounding in observational studies. The inverse probability weighting (IPW) is widely used to estimate the average treatment effect (ATE). The excessively large IPW weights caused by lack of overlap in the propensity score distributions between groups can cause numeric instability in estimation. In Chapter 2, we studied a class of modified IPW estimators that can be used to avoid this problem. These weights cause the estimand to deviate from ATE. We provided justification for the deviation from the perspective of treatment effect discovery. We showed that in the presence of lack of overlap, the modified IPWs may achieve substantial gain in statistical power compared with IPW and other relevant propensity score methods. We developed analytical variance estimation that properly adjusts for the sampling variability of estimated propensity scores, and augment the modified IPW estimator with outcome models for improved efficiency. The proposed methodology was illustrated with a blood cell transfusion study. We provided open source software to implement the proposed methodology. The modified IPWs in Chapter 2 has not been studied in the context of survival data, and we investigated this problem in Chapter 3. We considered estimands of average survival time, restricted average survival time, survival probability, survival quantile effect, and the marginal hazard ratio in the two-sample context. We proposed a unified analytic framework to obtain the point and variance estimators. Simulations showed that the point and variance estimators possess desired finite sample properties, and demonstrate better numerical performance than some existing weighting and matching methods commonly used in the literature. The proposed methodology was illustrated with data from a breast cancer study. Like weighting methods studied in previous two chapters, regression adjustment is frequently used for treatment effect estimation and it can be highly efficient when the relationship between outcome and propensity score is correctly specified, but can lead to biased estimation when model assumption is violated. To address this issue, we proposed a flexible regression approach that allows for nonlinear association between outcome and propensity score in Chapter 4. The flexible approach has connections to other commonly used propensity score methods. We developed a penalized spline based method to obtain point and variance estimators that properly adjust for the estimated propensity scores. Simulations showed that the proposed approach demonstrates satisfactory numerical properties, and are at least comparable with other propensity score methods. The proposed methodology was further illustrated with a right heart catheterization study. In summary, this dissertation added to current propensity score literature by considering modified IPW weights for treatment effect discovery and in studies with survival outcome, addressing limitations in regression adjustment, and providing software for convenient implementation. These advances would promote its application in public health research where observational data is commonly encountered for intervention effect evaluation and subsequent decision making.

Allelic frequency difference across population can provide valuable insight into population differentiation in a variety of ways, and it is becoming increasingly popular nowadays with easy access to genome-wide allele frequency data. Using the 1000 Genomes Project phase I single nucleotide polymorphism (SNP) data, the fixation index was estimated to be 0.0308 for 14 populations sampled from 4 geographical regions. Relationship among populations was also examined by distinct allelic richness and private allelic richness for single population and population combination. We found that African populations have higher distinct and private allelic richness than populations outside Africa. In addition, ADD and ADD-DEL simulation studies identified that rare variants influence population parameter estimation by decreasing fixation index and distinct allelic richness, while increasing private allelic richness.

Bacillus subtilis bacteriophage ϕ29 packages double-stranded DNA (dsDNA) into a preformed viral shell, or procapsid, and serves as a model system for studying genome packaging in eukaryotic dsDNA viruses such as poxviruses, herpesviruses and adenoviruses. Encapsidation of bacteriophage ϕ29 DNA is driven by a phage-encoded molecular motor. This motor is powered by an oligomeric ATPase, gp16, or gene product 16, that converts energy obtained from ATP hydrolysis into translocation of dsDNA. In this study, we solved the gp16 ATPase structure via X-ray crystallography. The resultant monomeric structure indicated that gp16 ATPase adopts a modified Rossmann fold (Rossmann et al., 1974), in which six conserved β-strands form a central β-sheet, and adjacent β-strands are linked by intervening α-helices, and that the protein is a member of the ancient P-loop additional strand catalytic E (ASCE) NTPase superfamily. The active site responsible for ATP hydrolysis is located on one side of the central β-sheet. Superposition of our structure on related ring-forming members of the ASCE superfamily indicated that residue Arg148 protrudes from the other side of the β-sheet and is well-positioned to insert its side chain into the active site of a neighboring ATPase to trigger sequential ATP hydrolysis events around an oligomeric ATPase ring.

Double-stranded DNA viruses use ATP-powered molecular motors to package their genomes. To do so, these motors must efficiently transition between initiation, translocation, and termination modes. Here, we report structural and biophysical analyses of the C-terminal domain of the bacteriophage phi29 ATPase (CTD) that suggest a structural basis for these functional transitions. Sedimentation experiments show that the inter-domain linker in the full-length protein promotes dimerization and thus may play a role in assembly of the functional motor. The NMR solution structure of the CTD indicates it is a vestigial nuclease domain that likely evolved from conserved nuclease domains in phage terminases. Despite the loss of nuclease activity, fluorescence binding assays confirm the CTD retains its DNA binding capabilities and fitting the CTD into cryoEM density of the phi29 motor shows that the CTD directly binds DNA. However, the interacting residues differ from those identified by NMR titration in solution, suggesting that packaging motors undergo conformational changes to transition between initiation, translocation, and termination.