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Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed.Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2–4.1 h; mean half-life was 5–12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months.MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.

Treatment of osteoporosis with medications like teriparatide, a parathyroid hormone, is known to improve bone density and reduce the risk of osteoporotic vertebral fractures. Anecdotal and limited surgical series have described the utility of this treatment for osteoporotic patients prior to spinal fusion surgery, but there is variability in adoption of this strategy as well as consensus regarding optimal treatment duration before and after surgery. In this study, the clinical results of the use of teriparatide for this application are reviewed and critically examined. We conducted a systematic review of electronic databases using different MeSH terms from 1980 to 2020. Pooled and subgroup analyses were performed using fixed and random effect models based upon the heterogeneity (I2). The results were reported as either mean difference (MD) or odds ratio (OR) with 95% confidence interval (CI). A total of 771 patients from 12 studies were identified. Three hundred seventy-seven patients (90.8% females) were treated with teriparatide. Lumbar spinal fusion rates were significantly higher among patients who received teriparatide compared to the non-teriparatide group (OR 2.15, 95%CI 1.56–2.97, p

The increasing prevalence of Alzheimer disease (AD), higher risk among certain ethnoracial groups, and lack of effective therapies highlights the need to recruit and enroll diverse populations in prospective, observational studies and clinical trials. However, there is little known about the effectiveness of traditional media vs. social media outreach on recruitment in aging study studies. This study retrospectively examined the effectiveness and differences in using both traditional and social media materials for the recruitment of African American (AA) versus non-Hispanic white (NHW) participants for a prospective, longitudinal study examining preclinical AD and driving outcomes. Participants needed to be at least 65 years old, drive at least an average of once weekly, own a vehicle that was manufactured in 1996 or later, and agree to cognitive testing, psychometric testing, brain magnetic resonance imaging (MRI), brain amyloid positron emission tomography (PET), and cerebrospinal fluid collection via lumbar puncture. A total of 546 individuals contacted the study coordinator by phone or email. Of those individuals, 97 enrolled and 192 were not contacted secondary to filling enrollment capacity. Sixteen participants (16.5%) were AA and the remainder were NHW. Of the 354 individuals whom the coordinator contacted back, approximately 73% declined or did not return calls. Social media was more effective with recruiting NHW participants, while traditional advertisement (newspaper) was more successful in recruiting AA participants in this urban setting. Prospective studies should balance participant burden and enrollment with a targeted, multi-tiered recruitment plan and sufficient budget to reach the population of interest.

Sierra Leone has invested in education after the civil war but it is unclear if persons with disabilities have benefited from this effort. In 2009, we conducted a household field survey in 17 randomly selected localities of Sierra Leone. Findings show that persons disabled before school-going age, those with multiple disabilities, girls, elderly children, the poorest, and those residing in rural areas were less likely to participate in primary and secondary education. The same predictors were associated with lower odds of being literate except the age of disability onset. Our findings indicate that quality and equity in learning require policy that prioritize vulnerable groups especially in post-conflict context.

Our objective was to identify functional brain changes that associate with driving behaviors in older adults. Within a cohort of 64 cognitively normal adults (age 60+), we compared naturalistic driving behavior with resting state functional connectivity using machine learning. Functional networks associated with the ability to interpret and respond to external sensory stimuli and the ability to multi-task were associated with measures of route selection. Maintenance of these networks may be important for continued preservation of driving abilities.

Optical imaging through diffuse media is a challenging issue and has attracted applications in many fields such as biomedical imaging, non-destructive testing, and computer-assisted surgery. However, light interaction with diffuse media leads to multiple scattering of the photons in the angular and spatial domain, severely degrading the image reconstruction process. In this article, a novel method to image through diffuse media using multiple modes of vortex beams and a new deep learning network named “LGDiffNet” is derived. A proof-of-concept numerical simulation is conducted using this method, and the results are experimentally verified. In this technique, the multiple modes of Gaussian and Laguerre-Gaussian beams illuminate the displayed digits dataset number, and the beams are then propagated through the diffuser before being captured on the beam profiler. Furthermore, we investigated whether imaging through diffuse media using multiple modes of vortex beams instead of Gaussian beams improves the imaging system's imaging capability and enhances the network's reconstruction ability. Our results show that illuminating the diffuser using vortex beams and employing the “LGDiffNet” network provides enhanced image reconstruction compared to existing modalities. When employing vortex beams for image reconstruction, the best NPCC is − 0.9850. However, when using Gaussian beams for imaging acquisition, the best NPCC is − 0.9837. An enhancement of 0.62 dB, in terms of PSNR, is achieved using this method when a highly scattering diffuser of grit 220 and width 2 mm (7.11 times the mean free path) is used. No additional optimizations or reference beams were used in the imaging system, revealing the robustness of the “LGDiffNet” network and the adaptability of the imaging system for practical applications in medical imaging.

Tranexamic acid (TXA) is an effective and commonly used hemostatic agent for perioperative blood loss in various surgical specialties. It is being increasingly used in spinal deformity surgery. We aimed to evaluate the safety and efficacy of topical TXA (tTXA) compared to both placebo and/or intravenous (IV) TXA in patients undergoing spinal deformity surgery. We conducted a systematic review of the electronic databases using different MeSH terms from January 1970 to August 2019. Pooled and subgroup analysis was performed using fixed and random-effect model based upon the heterogeneity (I2). A total of 609 patients (tTXA: n = 258, 42.4%) from 8 studies were included. We found that there was a statistically significant difference in terms of (i) postoperative blood loss [mean difference (MD) − 147.1, 95% CI − 189.5 to − 104.8, p

OBJECTIVE: To examine the effect of race in driving performance and behavior prospectively among cognitively normal older adults. METHODS: Cognitively normal participants (Clinical Dementia Rating 0), ≥ 65 years of age (n=177) were selected from prospective, longitudinal studies at the Knight Alzheimer’s Disease Research Center at Washington University. Self-reported driving behavior (Driving Habits Questionnaire (DHQ)) and driving performance (road test) were annually assessed. Daily driving behavior data were collected using the Driving Real World In-Vehicle Evaluation System (DRIVES). Baseline differences between African Americans and Caucasians were tested using t-tests and general linear models. Amyloid imaging and cerebrospinal fluid Alzheimer disease (AD) biomarkers were compared across groups. Linear mixed models examined change in daily driving behavior over time. Survival analyses tested time to a marginal or fail rating on the road test. RESULTS: There were no differences between African Americans (n=34) and Caucasians (n=143) in age, sex, education or vascular risk factors. Baseline self-reported driving behavior and road test performance were largely similar for both races. Longitudinal analyses using the DRIVES data aggregated monthly showed that African Americans had a greater reduction in number of trips made per month, miles driven per month and trips with aggressive behavior compared to Caucasians. These effects remained after controlling for AD biomarkers, age, education, and sex. CONCLUSIONS: In this sample of cognitively normal older adults, African Americans had a greater reduction of daily driving behavior compared to Caucasians. Observed racial differences may reflect differences in environmental/social factors, changes in cognition, and/or physical functioning.

This research discusses the key events that led to the establishment of the current regulations pertaining to the functioning of audit committees in six major capital markets of the world, namely, the U.S., U.K. Australia, India, South Africa, and Argentina, and also presents the findings based on a comparison of these regulations. Specifically, the authors review the changes that happened either proactively or sometimes as a reaction to certain events in each of these securities markets, leading to the current audit committee regulations. Also, the relevant local laws and requirements of the regulatory bodies along with the listing rules of the stock exchanges in the above six nations are examined to study how the requirements are both similar as well as different across the six continents. Given the increase in the number of multinational corporations selling shares in different capital markets where such entities have to conform to the regulations of each such market, a study of the audit committee regulations is expected to give some insight into how much rigor the different capital markets of the world have with respect to their expectations of the composition of the audit committee, what the committee’s role should be, how it should conduct its business, and to whom it should report. The study shows that each of these six nations has had its share of corporate scandals and/or abuses of power by senior business executives that first caused losses for investors, and eventually led to the current regulations. In some of these markets, audit committee regulations advanced from being recommendatory and “principles-based” to being mandatory mainly because of the pressure from external stakeholders. The newer regulations in each securities market generally, though not always, represented improvement over the previous versions. The study also shows that today the audit committees of companies listed on the different stock exchanges being examined in this study are subject to similar or sometimes identical requirements in some respects. At the same time, there are other requirements where the authors see minor as well as noticeable differences. All in all, NYSE emerges as the stock exchange with the most rigorous expectations from the audit committee on various matters and especially with respect to the monitoring of the independent auditor. While the audit committee regulations in the developed world of the U.S., U.K., and Australia have set good examples of governance practices before the rest of the world, the securities markets in the emerging economies of India, South Africa, and Argentina are not far behind. There are areas where the regulations in India and South Africa actually demand more from their audit committees compared to those in the developed markets.

BAG (Bcl-2 athanogene) family proteins are conserved in a wide range of eukaryotes, and they have been proposed to play a crucial role in plant programmed cell death (PCD). During the past decade, with the help of advanced bioinformatics tools, seven homologs of BAG genes have been identified in the Arabidopsis genome; these genes are involved in pathogen attack and abiotic stress conditions. In this study, gene expression of Arabidopsis BAG family members under environmental stresses was analyzed using the Botany Array Resource (BAR) expression browser tool and the in silico data were partially confirmed by qRT-PCR analysis for the selected stress- and hormone-treated conditions related to environmental stresses. Particularly, the induction of AtBAG6 gene in response to heat shock was confirmed by using GUS reporter lines. The loss of the AtBAG6 gene resulted into impairment in basal thermotolerance of plant and showed enhanced cell death in response to heat stress. To elucidate the regulatory mechanisms of BAG genes, we analyzed ∼1-kbp promoter regions for the presence of stress-responsive elements. Our transcription profiling finally revealed that the Arabidopsis BAG genes differentially respond to environmental stresses under the control of specifically organized upstream regulatory elements. Electronic supplementary material The online version of this article (doi:10.1007/s00709-016-0961-3) contains supplementary material, which is available to authorized users.

The previously published version of this Article contained errors in Figure 5. In panel c, the second and fourth blot images were incorrectly labeled ‘α-Myc’ and should have been labelled ‘α-HA’. These errors have been corrected in both the PDF and HTML versions of the Article.

cis-Dioxomolybdenum(VI) complex of 4,6-O-ethylidene-β-d-glucopyranosylamine derived ligand has been used as an efficient catalyst in the selective synthesis of a series of bis(indolyl)methanes (BIMs) by condensing indole derivatives with carbonyl compounds. The adopted synthetic procedure is green in nature as solvent free reactions have been carried out using naturally occurring d-glucose derived ligands. Total 15 BIMs have been synthesised including four new ones, which have been characterized by mp, FTIR, NMR and mass spectroscopy. The catalyst has afforded good to excellent yield of BIMs in short reaction time and the former has been recycled five times without any significant loss in it’s catalytic efficiency.

In Arabidopsis thaliana, CONSTANS (CO) plays an essential role in the regulation of photoperiodic flowering under long-day conditions. CO protein is stable only in the afternoon of long days, when it induces the expression of FLOWERING LOCUS T (FT), which promotes flowering. The blue-light photoreceptor FLAVIN-BINDING, KELCH REPEAT, F-BOX1 (FKF1) interacts with CO and stabilizes it by an unknown mechanism. Here, we provide genetic and biochemical evidence that FKF1 inhibits CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1)-dependent CO degradation. Light-activated FKF1 has no apparent effect on COP1 stability but can interact with and negatively regulate COP1. We show that FKF1 can inhibit COP1 homo-dimerization. Mutation of the coiled-coil domain in COP1, which prevents dimer formation, impairs COP1 function in coordinating flowering time. Based on these results, we propose a model whereby the light- and day length-dependent interaction between FKF1 and COP1 controls CO stability to regulate flowering time., CONSTANS promotes flowering under long-day conditions in Arabidopsis but is rapidly degraded in short-day conditions. Here the authors show that the blue-light photoreceptor FKF1 can interact with the E3 ligase COP1 in a light-dependent manner and prevent degradation of CO in long-day conditions.

This study takes a look at the rise in the total auditor compensation that has taken place over the past several years after the passage of Sarbanes-Oxley Act (SOX). Prior research, with the exception of a few studies, has mostly focused on the possible harmful effects of non-audit service fees on the auditor's independence. The results of those studies have been mixed, with more studies concluding that non-audit service fees threaten auditor independence. In response to such findings, the government has passed legislation (SOX) banning companies from purchasing certain non-audit services from their audit firms with a view to reducing the economic ties between a client and its auditor. However, the published data from a sample of companies show that while the amounts of non-audit fees received by audit firms have declined over the last several years, the overall auditor compensation has increased during the same period, even significantly in several cases. In most cases, the rise in the total auditor compensation has been caused by a significant rise in the audit fees paid by a company to its audit firm. The current study examines this rise in the total compensation paid by a sample of companies that are the audit clients of the Big Four CPA firms and finds that SOX has not really succeeded in reducing the economic bonding between a company and its auditor. Moreover, as total auditor compensation indicates a flow of money from clients to auditors, regardless of the service for which the money is being paid, the authors suggest that studies involving the issue of auditor compensation and its potential impact on auditor independence should focus primarily on the total auditor compensation and not just a segment of it such as non-audit service fees.

Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-beta protein (Abeta) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Abeta from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Abeta dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Abeta N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Abeta dimers, suggesting that plaque cores are largely inactive but sequester Abeta dimers that are synaptotoxic. We conclude that soluble Abeta oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.