Bayesian Methods for Information Borrowing in Basket Trials: An Overview.

Basket trials allow simultaneous evaluation of a single therapy across multiple cancer types or subtypes of the same cancer. Since the same treatment is tested across all baskets, it may be desirable to borrow information across them to improve the statistical precision and power in estimating and detecting the treatment effects in different baskets. We review recent developments in Bayesian methods for the design and analysis of basket trials, focusing on the mechanism of information borrowing. We explain the common components of these methods, such as a prior model for the treatment effects that embodies an assumption of exchangeability. We also discuss the distinct features of these methods that lead to different degrees of borrowing. Through simulation studies, we demonstrate the impact of information borrowing on the operating characteristics of these methods and discuss its broader implications for drug development. Examples of basket trials are presented in both phase I and phase II settings.

The effect of femoral component valgus/varus angle on the mid-term efficacy of unicondylar knee arthroplasty.

OBJECTIVE: To investigate the effect of femoral component valgus/varus angle (FCVA) on the mid-term outcome after unicondylar knee arthroplasty. METHODS: Patients who underwent unicompartmental knee replacement in the Department of Bone and Joint Surgery, were retrospectively analyzed. According to the postoperative femoral prosthesis internal and external rotation angle, patients were divided into six groups the postoperative femoral prosthesis internal and external rotation angle: standard group, mildly abnormal group. The patients were followed up for 12 months, and complications were recorded during the follow-up period. The Range of motion (ROM), visual analog scale (VAS), and Knee society score (KSS) were compared between the six groups. RESULTS: One hundred twenty-four patients with 124 knees were included in this study. There were no statistical differences in age, gender, body mass index, preoperative ROM, or preoperative VAS, KSS-C, and KSS-F scores among the six groups. Comparison of postoperative outcomes and efficacy grades showed that: (1) the differences in ROM grades, as well as VAS, KSS-C, and KSS-F efficacy at 12 months postoperatively were statistically significant in all six groups by rank sum test; and patients in the normal group had better ROM grades and KSS-F grades than those in the mild and severe abnormality groups; (2) During the follow-up, no patient records had other serious complications such as periprosthetic infection, prosthetic loosening, periprosthetic fracture, and spacer dislocation. CONCLUSION: Controlling the femoral prosthetic internal rotation angle between 6° and 0° in unicompartmental knee replacements can lead to better mid-term outcomes for patients.

Hydrogen Sulfide Promotes Osteogenesis by Modulating Macrophage Polarization.

Macrophages, a versatile subset of immune cells, are essential for successful bone repair. Hydrogen sulfide (H2S) is a gasotransmitter associated with tissue development and repair. Emerging evidence demonstrates that H2S is involved in bone formation under physiology condition and bone regeneration under pathology condition. However, whether hydrogen sulfide mediates osteogenesis by influencing macrophages is unknown. Here, we aimed to investigate the effects of hydrogen sulfide on macrophage polarization and the subsequent impact on bone regeneration. In the present study, we found that the H2S-donor GYY4137 stimulated M0/M1 macrophages to express high level of CD-206 and IL-10 but decreased the levels of i-NOS and TNF-α in M1 macrophages. Furthermore, coculture of GYY4137-treated M0 macrophages with pro-osteoblastic MC3T3-E1 cells significantly increased the viability of the MC3T3-E1 cells. Importantly, the formation of mineralized particles in MC3T3-E1 cells was significantly promoted following coculture with IL-4-treated and GYY4137-treated M0 macrophages. Collectively, our study demonstrated that hydrogen sulfide increased macrophages M2 polarization and subsequently promoted bone regeneration.

m6 A demethylase ALKBH5 drives denervation-induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling.

BACKGROUND: Skeletal muscle atrophy is a common clinical manifestation of various neurotrauma and neurological diseases. In addition to the treatment of primary neuropathies, it is a clinical condition that should be investigated. FoxO3 activation is an indispensable mechanism in denervation-induced muscle atrophy; however, upstream factors that control FoxO3 expression and activity have not been fully elucidated. N6 -methyladenosine (m6 A) methylation is a novel mode of epitranscriptional gene regulation that affects several cellular processes. However, the biological significance of m6 A modification in FoxO3-dependent atrophy is unknown. METHODS: We performed gain-of-function and loss-of-function experiments and used denervation-induced muscle atrophy mouse model to evaluate the effects of m6 A modification on muscle mass control and FoxO3 activation. m6 A-sequencing and mass spectrometry analyses were used to establish whether histone deacetylase 4 (HDAC4) is a mediator of m6 A demethylase ALKBH5 regulation of FoxO3. A series of cellular and molecular biological experiments (western blot, immunoprecipitation, half-life assay, m6 A-MeRIP-qPCR, and luciferase reporter assays among others) were performed to investigate regulatory relationships among ALKBH5, HDAC4, and FoxO3. RESULTS: In skeletal muscles, denervation was associated with a 20.7-31.9% decrease in m6 A levels (P < 0.01) and a 35.6-115.2% increase in demethylase ALKBH5 protein levels (P < 0.05). Overexpressed ALKBH5 reduced m6 A levels, activated FoxO3 signalling, and induced excess loss in muscle wet weight (-10.3% for innervation and -11.4% for denervation, P < 0.05) as well as a decrease in myofibre cross-sectional areas (-35.8% for innervation and -33.3% for denervation, P < 0.05) during innervation and denervation. Specific deletion of Alkbh5 in the skeletal muscles prevented FoxO3 activation and protected mice from denervation-induced muscle atrophy, as evidenced by increased muscle mass (+16.0%, P < 0.05), size (+50.0%, P < 0.05) and MyHC expression (+32.6%, P < 0.05). Mechanistically, HDAC4 was established to be a crucial central mediator for ALKBH5 in enhancing FoxO3 signalling in denervated muscles. ALKBH5 demethylates and stabilizes Hdac4 mRNA. HDAC4 interacts with and deacetylates FoxO3, resulting in a significant increase in FoxO3 expression (+61.3-82.5%, P < 0.01) and activity (+51.6-122.0%, P < 0.001). CONCLUSIONS: Our findings elucidate on the roles and mechanisms of ALKBH5-mediated m6 A demethylation in the control of muscle mass during denervation and activation of FoxO3 signalling by targeting HDAC4. These results suggest that ALKBH5 is a potential therapeutic target for neurogenic muscle atrophy.

Incorporating external data into the analysis of clinical trials via Bayesian additive regression trees.

Most clinical trials involve the comparison of a new treatment to a control arm (eg, the standard of care) and the estimation of a treatment effect. External data, including historical clinical trial data and real-world observational data, are commonly available for the control arm. With proper statistical adjustments, borrowing information from external data can potentially reduce the mean squared errors of treatment effect estimates and increase the power of detecting a meaningful treatment effect. In this article, we propose to use Bayesian additive regression trees (BART) for incorporating external data into the analysis of clinical trials, with a specific goal of estimating the conditional or population average treatment effect. BART naturally adjusts for patient-level covariates and captures potentially heterogeneous treatment effects across different data sources, achieving flexible borrowing. Simulation studies demonstrate that BART maintains desirable and robust performance across a variety of scenarios and compares favorably to alternatives. We illustrate the proposed method with an acupuncture trial and a colorectal cancer trial.

RoBoT: a robust Bayesian hypothesis testing method for basket trials.

A basket trial in oncology encompasses multiple "baskets" that simultaneously assess one treatment in multiple cancer types or subtypes. It is well-recognized that hierarchical modeling methods, which adaptively borrow strength across baskets, can improve over simple pooling and stratification. We propose a novel Bayesian method, RoBoT (Robust Bayesian Hypothesis Testing), for the data analysis and decision-making in phase II basket trials. In contrast to most existing methods that use posterior credible intervals to determine the efficacy of the new treatment, RoBoT builds upon a formal Bayesian hypothesis testing framework that leads to interpretable and robust inference. Specifically, we assume that the baskets belong to several latent subgroups, and within each subgroup, the treatment has similar probabilities of being more efficacious than controls, historical, or concurrent. The number of latent subgroups and subgroup memberships are inferred by the data through a Dirichlet process mixture model. Such model specification helps avoid type I error inflation caused by excessive shrinkage under typical hierarchical models. The operating characteristics of RoBoT are assessed through computer simulations and are compared with existing methods. Finally, we apply RoBoT to data from two recent phase II basket trials of imatinib and vemurafenib, respectively.

The design of an "H" joystick for closed reduction and its application in segmental and comminuted femoral shaft fractures: an innovative technique.

BACKGROUND: Closed reduction and locked intramedullary nailing has become a common surgical method in the treatment of femoral shaft fractures. Overlap and rotation displacements can usually be corrected through the use of an orthopedic traction table. However, lateral displacement and angulation persist. METHODS: In this paper, we describe a joystick that can be used in the closed reduction of a fracture. It can correct lateral displacement and angulation, and has the advantage of multi-direction reduction. The device described in this paper includes two parallel horizontal joysticks, one vertical main joystick and four assistant rods. Moreover, there are many specific spacing holes in the two parallel horizontal joysticks and a groove structure in the vertical main joystick. When the main "H" joystick is pressed, it can adjust lateral displacements and angulation because of the lever principle. The distance between parallel horizontal joysticks and assistant rods can be adjusted to the fracture position and body mass index of different patients. RESULTS: The study participants consisted of 11 males and 5 females with a mean age of 31.0 years. All participants had good closed reduction and achieved bony union without any complications such as infection, nerve injury, non-union, malunion, and limb length discrepancy. By using an "H" joystick, closed femoral shaft fracture reduction and locked intramedullary nailing becomes simpler and faster. CONCLUSION: Based on the use of this instrument, we can easily and conveniently obtain the correct reduction situation, which leads to better surgical results. This device can be applied in the reduction of clinical femoral fractures and gradually extended to the reduction of other fractures.

A BAYESIAN NONPARAMETRIC MODEL FOR RECONSTRUCTING TUMOR SUBCLONES BASED ON MUTATION PAIRS.

We present a feature allocation model to reconstruct tumor subclones based on mutation pairs. The key innovation lies in the use of a pair of proximal single nucleotide variants (SNVs) for the subclone reconstruction as opposed to a single SNV. Using the categorical extension of the Indian buffet process (cIBP) we define the subclones as a vector of categorical matrices corresponding to a set of mutation pairs. Through Bayesian inference we report posterior probabilities of the number, genotypes and population frequencies of subclones in one or more tumor sample. We demonstrate the proposed methods using simulated and real-world data. A free software package is available at http://www.compgenome.org/pairclone.

[Semicircular decompression for the treatment of old thoracolumbar fractures and intractable neuropathic pain].

OBJECTIVE: To investigate the clinical outcomes of semicircular decompression in treating old thoracolumbar fractures and intractable neuropathic pain. METHODS: From September 2009 to September 2013, 21 patients with old thoracolumbar fracture and intractable neuropathic pain were treated with semicircular decompression. Among initial surgery, posterior pedicle screw fixation was used in these patients, with or without laminectomy. All patients were male, range in age from 20 to 28 years old with an average of (25.00±2.38) years. Vertebral body residual bone block resulted in intra-spinal placeholder more than 50%. All patients were complete spinal cord injury (ASIA grade) or cauda equina injury. VAS scores was from 6 to 10 points with the mean of 7.14±0.91. In these patients, MRI, CT, X-rays were performed; denomination and dosage of analgesics were recorded; nerve function and pain status were respectively evaluated by ASIA grade and VAS score before and after operation. RESULTS: All patients were followed up from 8 to 32 months with an average of (17.29±6.02) months. All bone fragments of spinal canal were removed and spinal cord decompressions were achieved. At final follow-up, VAS scores were from 0 to 8 points with an average of (2.43±2.46) points, and were obviously reduced than peroperative data (P<0.05). Eleven cases of them stopped analgesic intake and 7 cases reduced using. Three patients' symptoms and VAS scores were not improved. CONCLUSION: Old thoracolumbar fractures and intractable neuropathic pain need receive imaging examination as soon as possible and consider semicircular decompression therapy if bone fragments were in vertebral canal and spinal canal stenosis existed. This therapy can effectively relieve pain and profit nerve functional recovery.

[Median nerve constrictive operation combined with tendon transfer to treat brain paralysis convulsive deformity of hand].

OBJECTIVE: To evaluate the effectiveness of the median nerve constrictive operation combined with tendon transfer to treat the brain paralysis convulsive deformity of the hand. METHODS: The clinical data from 21 cases with brain paralysis convulsive deformity of the hand were analyzed retrospectively between August 2009 and April 2012. Of them, there were 13 males and 8 females with an average age of 15 years (range, 10-29 years). The causes of the convulsive cerebral palsy included preterm deliveries in 11 cases, hypoxia asphyxia in 7, traumatic brain injury in 2, and encephalitis sequela in 1. The disease duration was 2-26 years (mean, 10.6 years). All the 21 patients had cock waists, crooking fingers, and contracture of adductors pollicis, 12 had the forearm pronation deformity. According to Ashworth criteria, there were 2 cases at level I, 5 cases at level II, 8 cases at level III, 4 cases at level IV, and 2 cases at level V. All patients had no intelligence disturbances. The forearm X-ray film showed no bone architectural changes before operation. The contraction of muscle and innervation was analyzed before operation. The median nerve constrictive operation combined with tendon transfer was performed. The functional activities and deformity improvement were evaluated during follow-up. RESULTS: After operation, all the patients' incision healed by first intension, without muscle atrophy and ischemic spasm. All the 21 cases were followed up 1.5-4.5 years (mean, 2.3 years). No superficial sensory loss occurred. The effectiveness was excellent in 13 cases, good in 6 cases, and poor in 2 cases, with an excellent and good rate of 90.4% at last follow-up. CONCLUSION: The median nerve constrictive operation combined with tendon transfer to treat brain paralysis convulsive deformity of the hand can remove and prevent the recurrence of spasm, achieve the orthopedic goals, to assure the restoration of motor function and the improvement of the life quality.

[Distribution characteristics of polycyclic aromatic hydrocarbons in runoff from the middle line source area of south-to-north water diversion project].

The distribution characteristics of polycyclic aromatic hydrocarbons in runoff from the middle line source area of south-to-north water diversion project were studied. Five groups of artificial runoff fields were established to collect runoff based on the different types of land-use, the contents of 16 USEPA priority PAHs in the runoff were determined using GC/MS method. The results showed that the average concentrations of PAHs of the aqueous phase in the collected runoff samples of different land-use types decreased in the order:cultivated land (26.53 ng x L(-1)) > oak forest (20.91 ng x L(-1)) > orchard (17.59 ng x L(-1)), and the average concentrations of PAHs of the particle phase were cultivated land (1 073.72 ng x g(-1)) > orchard (652.29 ng x g(-1)) > oak forest (385.46 ng x g(-1)). The high carcinogenic components Bap were detected in both run off of cultivated land and orchard with a detected rate of 30%. According to National Recommended Water Quality Standards of priority toxic pollutants (2006 USEPA), it was found that Chr exceed standard 40%, with a detected rate of 100%. It was also found that the runoff volume and the total PAHs content in runoff increase with the slope, and PAHs loss and slope were closely related in same land-use types. Based on the Molecular Markers Indicative Law, it can be concluded that the dominant source of PAHs in runoff of study area was combustion of coal, and a small amount came from vehicle exhaust emissions. There is a certain degree of ecological risk about runoff PAHs pollution in the study area, which is worth further attention.

[Total hip replacement for patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip].

OBJECTIVE: To investigate the surgical techniques and clinical outcomes of total hip replacement for patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip. METHODS: From May 2004 to March 2008, a total of 36 total hip replacements were performed in 32 patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip. The acetabulum cup was reconstructed in the corresponding anatomical position in all cases. Cemented components were used in 16 hips, and cementless components in the other 20 hips. The mean follow-up was 31.3 months. Clinical outcomes were determined with Harris hip score. Radiographs were taken after the surgery and in every follow-up examination for further reference. RESULTS: All patients postoperatively gained a limb lengthening with an average of (3.4+/-1.3) cm. Three patients had complications, 2 had nondisplaced fractures of the proximal part of the femur,and 1 sciatic nerve palsy which disappeared after 3 months. There was no infection, dislocation and symptomatic deep vein thrombosis. Compared with preoperation, the mean Harris hip scores on the 3rd day, the 14th day after the operation and at the last follow-up were all improved significantly (all P<0.05). There was no loosening, migration, heterotopic ossification radiographically, and no revision during the follow-up. CONCLUSION: Total hip replacement is an effective treatment for patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip. The key is to place the acetabulum cup in the corresponding anatomical position, and choose proper prosthesises during the surgery.

[Distribution characteristics of organochlorine pesticides in surface water and sediments from the Mengjin wetland].

The surface water and sediments from the Mengjin wetland were collected. After seperated and concentrated by solid phase extraction and Soxhlet extraction, twenty kinds of organochlorine pesticides (OCPs) in the samples from the Mengjin wetland were analyzed by gas chromatography. In the surface water, 7 kinds of OCPs (incluing alpha-HCH, beta-HCH, gamma-HCH, delta-HCH, 4,4-DDT, heptachor and aldrin) were detected, with the detected ratio of 4.2% -62.5% and the content range of ND-12.21 ng/L. In the sediments, 4,4-DDE and 4,4-DDT were detected, with the detected ratio of 50%-75% and the content range of ND-64.58 ng/g. HCHs and DDTs in the surface water were both lower than the limited value defined by Environmental Quality Standards for Surface Water in China, while the surface sediments in the Mengjin wetland pose a bit high risk comparing with ERL and ERM value of risk evaluation. Distribution characteristics of OCPs components showed that HCHs usually had higher residue levels in surface water, while sediment was the fate of DDTs in the transfer process of materials from water to sediment. OCPs content in the surface water and sediments both decreased in the order of high water period > level water period > low water period. OCPs in the low water seasons were mainly the early residue, but OCPs in the high seasons had some new input in near term in the surface water and sediments. The results suggested that non-point source was one of the important sources of OCPs entering Mengjin wetland.