Long-term trends in the burden of breast cancer in China over three decades: a joinpoint regression and age-period-cohort analysis based on Global Burden of Disease 2021.

We analyzed the trends in breast cancer (BC) morbidity, prevalence, and mortality among Chinese residents from 1990 to 2021. We then used joinpoint regression to further assess BC morbidity and mortality. We screened the morbidity, mortality, and prevalence of BC in Chinese residents (1990-2021) from the Global Burden of Disease.

Osteoporosis prediction in lumbar spine X-ray images using the multi-scale weighted fusion contextual transformer network.

Osteoporosis is a bone-related disease characterized by decreased bone density and mass, leading to brittle fractures. Osteoporosis assessment from radiographs using a deep learning algorithm has proven a low-cost alternative to the golden standard DXA. Due to the considerable noise and low contrast, automated diagnosis of osteoporosis in X-ray images still poses a significant challenge for traditional diagnostic methods.

Robust Vascular Segmentation for Raw Complex Images of Laser Speckle Contrast Based on Weakly Supervised Learning.

Laser speckle contrast imaging (LSCI) is widely used for in vivo real-time detection and analysis of local blood flow microcirculation due to its non-invasive ability and excellent spatial and temporal resolution. However, vascular segmentation of LSCI images still faces a lot of difficulties due to numerous specific noises caused by the complexity of blood microcirculation's structure and irregular vascular aberrations in diseased regions. In addition, the difficulties of LSCI image data annotation have hindered the application of deep learning methods based on supervised learning in the field of LSCI image vascular segmentation.

Robust vessel segmentation in laser speckle contrast images based on semi-weakly supervised learning.

The goal of this study is to develop a robust semi-weakly supervised learning strategy for vessel segmentation in laser speckle contrast imaging (LSCI), addressing the challenges associated with the low signal-to-noise ratio, small vessel size, and irregular vascular aberration in diseased regions, while improving the performance and robustness of the segmentation method.For the training dataset, the healthy vascular images denoted as normal-vessel samples were manually labeled, while the diseased LSCI images involving tumor or embolism were denoted as abnormal-vessel samples and annotated as pseudo labels by the traditional semantic segmentation methods. In the training phase, the pseudo labels were constantly updated to improve the segmentation accuracy based on DeepLabv3+.

Neurog2 directly converts astrocytes into functional neurons in midbrain and spinal cord.

Conversion of astrocytes into neurons in vivo offers an alternative therapeutic approach for neuronal loss after injury or disease. However, not only the efficiency of the conversion of astrocytes into functional neurons by single Neurog2, but also the conundrum that whether Neurog2-induced neuronal cells (Neurog2-iNs) are further functionally integrated into existing matured neural circuits remains unknown. Here, we adopted the AAV(2/8) delivery system to overexpress single factor Neurog2 into astrocytes and found that the majority of astrocytes were successfully converted into neuronal cells in multiple brain regions, including the midbrain and spinal cord.

Molecular Mechanisms Underlying Ascl1-Mediated Astrocyte-to-Neuron Conversion.

Direct neuronal reprogramming potentially provides valuable sources for cell-based therapies. Proneural gene Ascl1 converts astrocytes into induced neuronal (iN) cells efficiently both in vitro and in vivo. However, the underlying mechanisms are largely unknown.

Combined-Indications Significance Level of Multiple Related Indications Developed Simultaneously.

Background: Typically, regulatory requirements include 2 confirmatory studies, each at a 1-sided .025 significance level, for a medicine to be approved for a specific indication. When the same medicine has been approved in related indications, 1 confirmatory study at a 1-sided .

Reducing Patient Burden in Clinical Trials Through the Use of Historical Controls: Appropriate Selection of Historical Data to Minimize Risk of Bias.

Historical data have been used to augment or replace control arms in some rare disease and pediatric clinical trials. With greater availability of historical data and new methodology such as dynamic borrowing, the inclusion of historical data in clinical trials is an increasingly appealing approach for larger disease areas as well, as this can result in increased power and precision and can minimize the burden on patients in clinical trials. However, sponsors must assess whether the potential biases incurred with this approach outweigh the benefits and discuss this trade-off with the regulatory agencies.

Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design.

Introduction: Nonalcoholic steatohepatitis (NASH) is a sub-classification of nonalcoholic fatty liver disease (NAFLD) characterized by increased risk of progressive liver fibrosis. Cenicriviroc (CVC) is a novel, orally administered, potent chemokine 2 and 5 receptor antagonist currently in development for the treatment of liver fibrosis in adults with NASH.

Methods And Analysis: Efficacy and safety of CVC will be comprehensively evaluated in a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled study (AURORA, NCT03028740) of subjects with NASH and Stage F2 or F3 fibrosis.

Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons.

Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to convert non-neuronal cells into NA neurons.

Design of randomized controlled confirmatory trials using historical control data to augment sample size for concurrent controls.

This paper deals with the methods to augment concurrent controls (CC) in a randomized controlled trial with available historical data in clinical studies. In their article, , Stuart and Rubin proposed a matching method where the primary/local control and the secondary/non-local control are both included in the propensity score estimates. The authors discuss a similar approach taking the CC as the primary and the historical control as the secondary, and find that this approach does not save the sample size of the randomized trial compared to the traditional randomized design without supplementation of historical data.

Seamless phase IIa/IIb adaptive design with the same primary endpoint for proof of concept and dose finding.

This paper considers combining a proof of concept (POC) study and a dose finding (DF) study where the POC and the DF share the same primary endpoint. An example based on real study conditions shows that compared to a conventional design the proposed adaptive design tests more active doses, with a smaller sample size and a shorter overall duration leading to a budget saving of 30% in study operations.

Minimizing Patient Burden Through the Use of Historical Subject-Level Data in Innovative Confirmatory Clinical Trials: Review of Methods and Opportunities.

The goal of clinical trial research is to deliver safe and efficacious new treatments to patients in need in a timely and cost-effective manner. There is precedent in using historical control data to reduce the number of concurrent control subjects required in developing medicines for rare diseases and other areas of unmet need. The purpose of this paper is to provide a review for a regulatory and industry audience of the current state of relevant statistical methods, and of the uptake of these approaches and the opportunities for broader use of historical data in confirmatory clinical trials.

Clinical Study Design to Assess Both Short- and Long-term Efficacy in Addition to Group Sequential Test on Safety.

In clinical studies for disorders such as rheumatoid arthritis, type 2 diabetes mellitus, multiple sclerosis, osteoporosis, etc, sometimes the developers need to address safety concerns (eg, cardiovascular risk) in the phase III development, so that a large long-term safety study is needed before registration. This article does not contain any studies with human or animal subjects performed by any of the authors. Aiming for potential regulatory approval with a single confirmatory study, the authors suggest a design that assesses short-term efficacy (eg, signs or symptoms) and long-term efficacy (eg, structure or imaging), as well as safety (eg, major adverse cardiac events), for which a group sequential test is performed applying an alpha spending function.

Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis.

Background: In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients.

Methods: In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo.

Seamless Phase IIa/IIb and enhanced dose-finding adaptive design.

In drug development, when the drug class has a relatively well-defined path to regulatory approval and the enrollment is slow with certain patient populations, one may want to consider combining studies of different phases. This article considers combining a proof of concept (POC) study and a dose-finding (DF) study with a control treatment. Conventional DF study designs sometimes are not efficient, or do not have a high probability to find the optimal dose(s) for Phase III trials.

Ascl1 Converts Dorsal Midbrain Astrocytes into Functional Neurons In Vivo.

In vivo induction of non-neuronal cells into neurons by transcription factors offers potential therapeutic approaches for neural regeneration. Although generation of induced neuronal (iN) cells in vitro and in vivo has been reported, whether iN cells can be fully integrated into existing circuits remains unclear. Here we show that expression of achaete-scute complex homolog-like 1 (Ascl1) alone is sufficient to convert dorsal midbrain astrocytes of mice into functional iN cells in vitro and in vivo.

Sample Size Calculation for Bioequivalence Studies Assessing Drug Effect and Food Effect at the Same Time With a 3-Treatment Williams Design.

The US Food and Drug Administration issued a guidance in 2002, "Food-Effect Bioavailability and Fed Bioequivalence Studies," in which it states "in addition to a BE [bioequivalence] study under fasting conditions, we recommend a BE study under fed conditions for all orally administered immediate-release drug products" for abbreviated new drug applications. This statement involves 3 studies: a BE study under fasting status, a food-effect (FE) study, and a BE study under fed status. In practice, when it is known that there is no FE with a reference ( R) formulation, a sponsor may choose to run a BE study that assesses the drug effect and food effect with a test ( T) formulation in a single study that includes 3 treatments: R formulation at fasting status, T formulation at fasting status, and T formulation at fed status.