Sequential monitoring of response-adaptive randomized clinical trials

Clinical trials are complex and usually involve multiple objectives such as controlling type I error rate, increasing power to detect treatment difference, assigning more patients to better treatment, and more. In literature, both response-adaptive randomization (RAR) procedures (by changing randomization procedure sequentially) and sequential monitoring (by changing analysis procedure sequentially) have been proposed to achieve these objectives to some degree. In this paper, we propose to sequentially monitor response-adaptive randomized clinical trial and study it's properties. We prove that the sequential test statistics of the new procedure converge to a Brownian motion in distribution. Further, we show that the sequential test statistics asymptotically satisfy the canonical joint distribution defined in Jennison and Turnbull (\citeyearJT00). Therefore, type I error and other objectives can be achieved theoretically by selecting appropriate boundaries. These results open a door to sequentially monitor response-adaptive randomized clinical trials in practice. We can also observe from the simulation studies that, the proposed procedure brings together the advantages of both techniques, in dealing with power, total sample size and total failure numbers, while keeps the type I error. In addition, we illustrate the characteristics of the proposed procedure by redesigning a well-known clinical trial of maternal-infant HIV transmission.Comment: Published in at http://dx.doi.org/10.1214/10-AOS796 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Studies of hypervalent organotin complexes and organotin clusters

(119)Sn, (31)P and (13)C variable temperature NMR spectroscopies have been used to examine the effective coordination spheres in solution of a series of hypervalent organotin(IV) dithiolate compounds RnSnXm(S-S)4-n-m where R = Ph, Me, nBu, tBu; X = Cl, Br; (S-S) = S2CNR\u272, S2COR\u27, S2P(OR\u27)2 (R\u27 = Me, Et, iPr) and n = 1, 2, 3; m = 0,1,2. Stereochemical nonrigidity is a common phenomenon found for these hypervalent compounds. On the basis of heteronuclear NMR data and X-ray crystallographic data, dynamic behaviors of these hypervalent compounds have been established. The system of hypervalent organotin(IV) fluoride complexes has also been investigated by variable temperature heteronuclear NMR techniques. A series of monomeric pentacoordinate complexes [RnSnC1mF5-n-m]-(R = Ph, Me, nBu, tBu; n = 2, 3; m - 0, 1, 2, 3) and dimeric complexes [(Me3SnX)F(Me3SnX\u27)]- (X = F, Cl; X\u27 = F, Cl) and hexacoordinate complexes [RnSnClmF6-n.m]2- (R = Ph, Me, nBu; n = 1, 2; m = (X 1, 2, 3,4) are identified in solution. The fluoride is of higer affinite to tin than the chloride. The stereochemistry and dynamic behavior of these complexes in solution has been studied. Fluoride ion may induce phenyl group disproportionation of phenyhin(IV) compounds. It is also found that in pentacoordinate diorganotin complexes, such as [Ph2SnCl2F]- and [Ph2SnClF2]- fluorine can be less apicophilic than chlorine. Studies of stereochemistry and dynamic behavior of bi-functional Lewis acid bis(haloorganosiannes) have also been carried out. The bis(haloorganostannes) exhibit strong chelate ability towards halide, with high selectivity on fluoride, forming heterocyclic chelating rings, the stability of which depend on the ring size. In further exploration of the Lewis acidity of organotin(IV) halides, complexation of organotin(IV) halides with bis(tertiary phosphinc) ligands has been studied by 119Sn and 31P NMR spectroscopy and X-ray crystallography. The phenyl group disproportionation is often observed in the complexation reaction. Furthermore, organotin(IV) clusters such as [(RSn)12O14(OH)6]Cl2-2H2O (R = iPr, nBu) have been successfully prepared by base hydrolysis of RSnCl3. These clusters contain 12 tin atoms in one molecule and the cores of the clusters are dications. Other organotin clusters such as [nBuSn(O)O2CCH3]6 and [(nBuSn(OH)O2PPh2)3][O2PPh2) are readily formed by reaction of the 12-tin-atom cluster with an appropriate acid. The reactivity of and interconversion between organotin(FV) clusters have also been studied

Structural evolution and characterization of organic-rich shale from macroscopic to microscopic resolution: The significance of tectonic activity

Shale gas exploration and development have taken significant strides in the relatively straightforward intra-basin stability zone and intra-basin weak deformation zone of marine shale in the Sichuan Basin, South China. In addition, the extra-basin strong tectonic modification zones have been actively explored. However, the results have been limited, which reveals the complexity of shale gas formation and preservation conditions in the context of multi-scale geological processes. These tectonic geological conditions have a significant impact on the shale gas content, while it has been difficult to figure out how tectonic deformation modifies reservoir structure and what specific mechanism causes shale gas content anomalies. Based on subjecting geologic samples to combined high-temperature and high-pressure experiments, this study summarizes the tectonic constraint mechanism of shale petrophysical structure evolution and its impact on shale gas storage, reveals the intrinsic connection and mechanism of shale pore-fracture and organic matter, inorganic mineral particle structure evolution and tectonic stress, and identifies the remodeling mechanism of the shale reservoir physical property change. The findings contribute to the theory of shale deformation and gas accumulation, as well as offer a scientific foundation for the exploration of marine shale gas in the complex tectonic zones outside the Sichuan Basin.Document Type: PerspectiveCited as: Gao, J., Li, X., Cheng, G., Luo, H., Zhu, H. Structural evolution and characterization of organic-rich shale from macroscopic to microscopic resolution: The significance of tectonic activity. Advances in Geo-Energy Research, 2023, 10(2): 84-90. https://doi.org/10.46690/ager.2023.11.0

Convergence Rates of Stochastic Gradient Descent under Infinite Noise Variance

Recent studies have provided both empirical and theoretical evidence illustrating that heavy tails can emerge in stochastic gradient descent (SGD) in various scenarios. Such heavy tails potentially result in iterates with diverging variance, which hinders the use of conventional convergence analysis techniques that rely on the existence of the second-order moments. In this paper, we provide convergence guarantees for SGD under a state-dependent and heavy-tailed noise with a potentially infinite variance, for a class of strongly convex objectives. In the case where the $p$-th moment of the noise exists for some $p\in [1,2)$, we first identify a condition on the Hessian, coined '$p$-positive (semi-)definiteness', that leads to an interesting interpolation between positive semi-definite matrices ($p=2$) and diagonally dominant matrices with non-negative diagonal entries ($p=1$). Under this condition, we then provide a convergence rate for the distance to the global optimum in $L^p$. Furthermore, we provide a generalized central limit theorem, which shows that the properly scaled Polyak-Ruppert averaging converges weakly to a multivariate $\alpha$-stable random vector. Our results indicate that even under heavy-tailed noise with infinite variance, SGD can converge to the global optimum without necessitating any modification neither to the loss function or to the algorithm itself, as typically required in robust statistics. We demonstrate the implications of our results to applications such as linear regression and generalized linear models subject to heavy-tailed data

Day Re-construction: Understanding How College Students Manage Their Time Through Self-monitoring

With a plethora of possibilities for new social experiences, activities, and other prospects, college students may find it challenging to balance their time. To facilitate their awareness of and reflection upon time expenditures regarding the three pillars of a balanced life: work, personal maintenance and leisure. We designed and evaluated a web app called LifeLogger. This application harnesses semi-automated, self-tracking, and visualization features to support awareness and reflection of time use. We invited 13 participants to interact with the prototype for a week, and followed up with semi-structured interviews to understand their experiences of the application. We find that LifeLogger increases participants awareness and encourages self-reflection on time use, which could facilitate participants in comprehend- ing their time expenditures. We conclude by discussing potential design strategies for time management

Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden

Over 80% of women diagnosed with advanced-stage ovarian cancer die as a result of disease recurrence due to failure of chemotherapy treatment. In this study, using two distinct ovarian cancer cell lines (epithelial OVCA 433 and mesenchymal HEY) we demonstrate enrichment in a population of cells with high expression of CSC markers at the protein and mRNA levels in response to cisplatin, paclitaxel and the combination of both. We also demonstrate a significant enhancement in the sphere forming abilities of ovarian cancer cells in response to chemotherapy drugs. The results of these in vitro findings are supported by in vivo mouse xenograft models in which intraperitoneal transplantation of cisplatin or paclitaxel-treated residual HEY cells generated significantly higher tumor burden compared to control untreated cells. Both the treated and untreated cells infiltrated the organs of the abdominal cavity. In addition, immunohistochemical studies on mouse tumors injected with cisplatin or paclitaxel treated residual cells displayed higher staining for the proliferative antigen Ki67, oncogeneic CA125, epithelial E-cadherin as well as cancer stem cell markers such as Oct4 and CD117, compared to mice injected with control untreated cells. These results suggest that a short-term single treatment of chemotherapy leaves residual cells that are enriched in CSC-like traits, resulting in an increased metastatic potential. The novel findings in this study are important in understanding the early molecular mechanisms by which chemoresistance and subsequent relapse may be triggered after the first line of chemotherapy treatment

The effects of solvent extraction on nanoporosity of marine-continental coal and mudstone

Coal and organic-rich mudstone develop massive nanopores, which control the storage of adsorbed and free gas, as well as fluid flows. Generation and retention of bitumen and hydrocarbons of oil window reservoirs add more uncertainty to the nanoporosity. Solvent extraction is a traditional way to regain unobstructed pore networks but may cause additional effects due to interactions with rocks, such as solvent adsorbing on clay surfaces or absorbing in kerogens. Selected marine-continental coal and mudstone in Eastern Ordos Basin were studied to investigate how pore structures are affected by these in-situ-sorptive compounds (namely residual bitumen and hydrocarbons) and altered by solvent extractions. Solvent extraction was performed to obtain bitumen-free subsamples. Organic petrology, bulk geochemical analyses and gas chromatography were used to characterize the samples and the extracts. Low-pressure argon and carbon dioxide adsorptions were utilized to characterize the nanopore structures of the samples before and after extraction. The samples, both coal and mudstone, are in oil windows, with vitrinite reflectance ranging from 0.807 to 1.135%. The coals are strongly affected by marine organic input, except for the sample C-4; the mudstones are sourced by either marine or terrestrial organic input, or their mixture. As for the coals affected by marine organic input, residual bitumen and hydrocarbons occupying or blocking pores <10 nm becomes weak with thermal maturation. Bitumen derived from terrestrial organic matter mainly affects small pores, since coal asphaltene molecules are much smaller than petroleum asphaltene molecules. The mudstone M-2 with high extract production showed an increase of nanopores after extraction, due to the exposure of the filled or blocked pores. However, most transitional mudstones saw decreases of the pores because pore shrinkage caused by solvents adsorbing on and swelling clay minerals (mainly kaolinite and illite/smectite mixed layers) counteracts the released pore spaces. Solvent extractions on the coals significantly increased the micropores <0.6 nm, since the heat of sorption of alkanes reaches the peak in the pores within 0.4–0.5 nm. By contrast, solvent extractions on the mudstones decreased the micropores ∼0.35 nm, which is perhaps caused by evaporative drying of solvent displacing residual water in clay

Organic matter provenance and depositional environment of marine-to-continental mudstones and coals in eastern Ordos Basin, China—Evidence from molecular geochemistry and petrology

Cyclothems, composed of interbedded mudstone, coal and sandstone layers, make up the Taiyuan and Shanxi Formations in the Late Carboniferous to Early Permian in North China under a marine-to-continental depositional environment. The cyclothems act as important fossil energy hosts, such as coalbeds, hydrocarbon source rocks and unconventional natural gas reservoirs. Organic geochemistry and petrology of mudstones and coals in the Taiyuan and Shanxi Formations in the eastern Ordos Basin were studied to reveal the organic matter sources and paleoenvironments. Total organic carbon (TOC) contents vary from 1.1 wt% (mudstone) to 72.6 wt% (coal). The samples are mainly within the oil window, with the Tmax values ranging from 433 to 469 °C. Organic petrology and source biomarkers indicate that the mudstones were sourced from a mixed organic matter input, and terrigenous organic matter predominates over aquatic organic matter. The coals are mostly sourced by terrigenous organic matter inputs. High concentrations of hopanes argue for a strong bacterial input. Some m/z 217 mass chromatograms have peaks at the hopanes' retention times as a result of high hopane to sterane ratios. These hopane-derived peaks do not interfere the identification of the steranes because the hopanes and the steranes have different retention times. Maturity-dependent biomarkers demonstrate that the samples have been thermally mature, which agree with the Tmax values. Anomalously low C29 20S/(20S + 20R) and C29 ββ/(ββ + αα) sterane ratios are present in all the samples, and are interpreted as due to the terrigenous organic matter input or the coal-related depositional environment. In addition, biomarkers and iron sulfide morphology indicate that the organic matter of the mudstones deposited in a proximal setting with shallow, brackish/fresh water bodies. With consideration of preservation of organic matter, the redox conditions are dysoxic. Redox oscillations resulted in the records of oxic conditions in some samples. Finally, the coals and the mudstones mainly generate gas and have poor oil generative potential

Assessing protocol adherence in a clinical trial with ordered treatment regimens: Quantifying the pragmatic, randomized optimal platelet and plasma ratios (PROPPR) trial experience

AbstractBackgroundMedication dispensing errors are common in clinical trials, and have a significant impact on the quality and validity of a trial. Therefore, the definition, calculation and evaluation of such errors are important for supporting a trial’s conclusions. A variety of medication dispensing errors can occur. In this paper, we focus on errors in trials where the intervention includes multiple therapies that must be given in a pre-specified order that varies across treatment arms and varies in duration.MethodsThe Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was a Phase III multi-site, randomized trial to compare the effectiveness and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with a 1:1:2 ratio. In this trial, these three types of blood products were to be transfused in a pre-defined order that differed by treatment arm. In this paper, we present approaches from the PROPPR trial that we used to define and calculate the occurrence of out of order blood transfusion errors. We applied the proposed method to calculate protocol adherence to the specified order of transfusion in each treatment arm.ResultsUsing our proposed method, protocol adherence was greater in the 1:1:1 group than in the 1:1:2 group (96% vs 93%) (p<0.0001), although out of order transfusion errors in both groups were low. Final transfusion ratios of plasma to platelets to red blood cells for the 1:1:1 ratio group was 0.93:1.32:1, while the transfusion ratio for the 1:1:2 ratio group was 0.48:0.48:1.ConclusionsOverall, PROPPR adherence to blood transfusion order pre-specified in the protocol was high, and the required order of transfusions for the 1:1:2 group was more difficult to achieve. The approaches proposed in this manuscript were useful in evaluating the PROPPR adherence and are potentially useful for other trials where a specific treatment orders with varying durations must be maintained

Cine magnetic resonance urography as a new approach for postoperative evaluation of the reconstructed upper urinary tract: a multicenter study

PURPOSETo evaluate the feasibility and usefulness of cine magnetic resonance urography (cine MRU) as a novel postoperative examination after upper urinary tract reconstruction surgery.METHODSNinety-six patients underwent cine MRU for postoperative evaluation between August 2015 and August 2020. The morphological observations included regular peristalsis, anastomosis, urine flow signals, and reflux. The quantitative evaluations included luminal diameter, peristaltic amplitude, contraction ratio, peristaltic waves, and ureteric jets. The surgical outcomes were classified as success, gray area, or failure by combining the results of cine MRU, symptoms, and the degree of hydronephrosis.RESULTSThere was no obvious stenosis of the anastomosis in 83 patients (86.46%). Regular peristalsis of the ureter and signals of urination was observed in 85 (88.54%) and 84 patients (87.50%), respectively. In addition, three patients (3.13%) showed urine reflux. The patients in both the success group and the gray area group showed significantly different creatinine levels (success 86.2 ± 22.3 μmol/L vs. failure 110.7 ± 8.2 μmol/L, P = 0.016; gray area 81.0 ± 20.0 μmol/L vs. failure 110.7 ± 8.2 μmol/L, P = 0.009) and estimated glomerular filtration rate (success: 88.5 ± 23.1 mL/min·1.73 m2, failure: 61.6 ± 14.1 mL/min·1.73 m2, P = 0.014; gray area: 94.7 ± 24.6 mL/min·1.73 m2, failure: 61.6 ± 14.1 mL/min·1.73 m2, P = 0.007) compared to those in the failure group. The ipsilateral split renal function was 33.6 ± 15.0, 24.5 ± 13.4, and 20.1 ± 0.4 mL/min in the success, gray area, and failure groups, respectively (P = 0.354).CONCLUSIONCine MRU demonstrates the morphology and function of the reconstructed upper urinary tract. The results of cine MRU can be used to evaluate the surgical effect, providing guidance for further treatment