Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report ...the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.
Organisations such as the National Institute for Health and Care Excellence require the synthesis of evidence from existing studies to inform their decisions—for example, about the best available ...treatments with respect to multiple efficacy and safety outcomes. However, relevant studies may not provide direct evidence about all the treatments or outcomes of interest. Multivariate and network meta-analysis methods provide a framework to address this, using correlated or indirect evidence from such studies alongside any direct evidence. In this article, the authors describe the key concepts and assumptions of these methods, outline how correlated and indirect evidence arises, and illustrate the contribution of such evidence in real clinical examples involving multiple outcomes and multiple treatments
Purpose To evaluate the performance of an artificial intelligence (AI) tool using a deep learning algorithm for detecting hemorrhage, mass effect, or hydrocephalus (HMH) at non-contrast ...material-enhanced head computed tomographic (CT) examinations and to determine algorithm performance for detection of suspected acute infarct (SAI). Materials and Methods This HIPAA-compliant retrospective study was completed after institutional review board approval. A training and validation dataset of noncontrast-enhanced head CT examinations that comprised 100 examinations of HMH, 22 of SAI, and 124 of noncritical findings was obtained resulting in 2583 representative images. Examinations were processed by using a convolutional neural network (deep learning) using two different window and level configurations (brain window and stroke window). AI algorithm performance was tested on a separate dataset containing 50 examinations with HMH findings, 15 with SAI findings, and 35 with noncritical findings. Results Final algorithm performance for HMH showed 90% (45 of 50) sensitivity (95% confidence interval CI: 78%, 97%) and 85% (68 of 80) specificity (95% CI: 76%, 92%), with area under the receiver operating characteristic curve (AUC) of 0.91 with the brain window. For SAI, the best performance was achieved with the stroke window showing 62% (13 of 21) sensitivity (95% CI: 38%, 82%) and 96% (27 of 28) specificity (95% CI: 82%, 100%), with AUC of 0.81. Conclusion AI using deep learning demonstrates promise for detecting critical findings at noncontrast-enhanced head CT. A dedicated algorithm was required to detect SAI. Detection of SAI showed lower sensitivity in comparison to detection of HMH, but showed reasonable performance. Findings support further investigation of the algorithm in a controlled and prospective clinical setting to determine whether it can independently screen noncontrast-enhanced head CT examinations and notify the interpreting radiologist of critical findings.
RSNA, 2017 Online supplemental material is available for this article.
During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. ...Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.
•VWF heparin-binding domain binds to GFs.•VWF heparin-binding domain enhances angiogenesis in wound healing in collaboration with GFs.
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Brain Metastases (BM) complicate 20-40% of cancer cases. BM lesions can present as punctate (1 mm) foci, requiring high-precision Magnetic Resonance Imaging (MRI) in order to prevent inadequate or ...delayed BM treatment. However, BM lesion detection remains challenging partly due to their structural similarities to normal structures (e.g., vasculature). We propose a BM-detection framework using a single-sequence gadolinium-enhanced T1-weighted 3D MRI dataset. The framework focuses on the detection of smaller (<15 mm) BM lesions and consists of: (1) candidate-selection stage, using Laplacian of Gaussian approach for highlighting parts of an MRI volume holding higher BM occurrence probabilities, and (2) detection stage that iteratively processes cropped region-of-interest volumes centered by candidates using a custom-built 3D convolutional neural network ("CropNet"). Data is augmented extensively during training via a pipeline consisting of random ga mma correction and elastic deformation stages; the framework thereby maintains its invariance for a plausible range of BM shape and intensity representations. This approach is tested using five-fold cross-validation on 217 datasets from 158 patients, with training and testing groups randomized per patient to eliminate learning bias. The BM database included lesions with a mean diameter of ∼5.4 mm and a mean volume of ∼160 mm 3 . For 90% BM-detection sensitivity, the framework produced on average 9.12 false-positive BM detections per patient (standard deviation of 3.49); for 85% sensitivity, the average number of false-positives declined to 5.85. Comparative analysis showed that the framework produces comparable BM-detection accuracy with the state-of-art approaches validated for significantly larger lesions.
Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic ...features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.
Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers ...plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.
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•Insulin, but not glucose, is a major regulator of circulating BCAAs•Hypothalamic insulin lowers plasma BCAAs and induces hepatic BCAA catabolism•Acute overfeeding impairs the ability of brain insulin to lower circulating BCAAs•High-fat feeding in primates or obese/diabetic humans decreases hepatic BCKDH
Circulating branched-chain amino acid (BCAA) levels are elevated in obesity and diabetes. Shin et al. describe a brain insulin pathway that decreases BCAA levels by enhancing its degradation in the liver. High-fat-fed rodents and nonhuman primates, as well as diabetics, have reduced amounts of the enzyme responsible for degradation.
AbstractObjectiveTo determine changes in household purchases of drinks and confectionery one year after implementation of the UK soft drinks industry levy (SDIL).DesignControlled interrupted time ...series analysis.ParticipantsMembers of a panel of households reporting their purchasing on a weekly basis to a market research company (average weekly number of participants n=22 183), March 2014 to March 2019.InterventionA two tiered tax levied on manufacturers of soft drinks, announced in March 2016 and implemented in April 2018. Drinks with ≥8 g sugar/100 mL (high tier) are taxed at £0.24/L and drinks with ≥5 to <8 g sugar/100 mL (low tier) are taxed at £0.18/L. Drinks with <5 g sugar/100 mL (no levy) are not taxed.Main outcome measuresAbsolute and relative differences in the volume of, and amount of sugar in, soft drinks categories, all soft drinks combined, alcohol, and confectionery purchased per household per week one year after implementation of the SDIL compared with trends before the announcement of the SDIL.ResultsIn March 2019, compared with the counterfactual estimated from pre-announcement trends, purchased volume of drinks in the high levy tier decreased by 155 mL (95% confidence interval 240.5 to 69.5 mL) per household per week, equivalent to 44.3% (95% confidence interval 59.9% to 28.7%), and sugar purchased in these drinks decreased by 18.0 g (95% confidence interval 32.3 to 3.6 g), or 45.9% (68.8% to 22.9%). Purchases of low tier drinks decreased by 177.3 mL (225.3 to 129.3 mL) per household per week, or 85.9% (95.1% to 76.7%), with a 12.5 g (15.4 to 9.5 g) reduction in sugar in these drinks, equivalent to 86.2% (94.2% to 78.1%). Despite no overall change in volume of no levy drinks purchased, there was an increase in sugar purchased of 15.3 g (12.6 to 17.9 g) per household per week, equivalent to 166.4% (94.2% to 238.5%). When all soft drinks were combined, the volume of drinks purchased did not change, but sugar decreased by 29.5 g (55.8 to 3.1 g), or 9.8% (17.9% to 1.8%). Purchases of confectionery and alcoholic drinks did not change.ConclusionsCompared with trends before the SDIL was announced, one year after implementation, the volume of soft drinks purchased did not change. The amount of sugar in those drinks was 30 g, or 10%, lower per household per week—equivalent to one 250 mL serving of a low tier drink per person per week. The SDIL might benefit public health without harming industry.Trial registrationISRCTN18042742.
Covers a fascinating period of Theodore Roosevelt's life, his first six years in Washington.
Roosevelt the Reformer sheds light on an important chapter in the biography of the flamboyant 26th ...president of the United States. From 1889 to 1895--before he was a Rough Rider in the Spanish-American War and before he oversaw the building of the Panama Canal and won the 1906 Nobel Peace Prize--'Teddy' Roosevelt served as one of three civil service commissioners. This was a significant period of his life because he matured politically and learned how to navigate through Washington politics. He sparred with powerful cabinet officers and congressmen and survived their attempts to destroy him. He cultivated important friendships and allegiances, flourished intellectually, and strengthened his progressive views of social justice, racial theory, and foreign relations. It was a period altogether significant to the honing of administrative talent and intellectual acuity of the future president.
Richard White Jr. situates young Roosevelt within the exciting events of the Gilded Age, the Victorian era, and the gay nineties. He describes Roosevelt's relationships with family, friends, colleagues, and adversaries. Many of these people, such as Henry Cabot Lodge, Cecil Spring-Rice, Alfred Mahan, Henry Adams, and John Hay would significantly influence Roosevelt when he later occupied the White House. White explores TR's accomplishments in civil service reform, the effect of the commission experience on his presidency a decade later, and his administrative legacy.
In addition to Harvard University's immense collection of Roosevelt correspondence, White drew from original sources such as the Civil Service Commission files in the National Archives, the Library of Congress, the National Park Service Roosevelt Historical Site at Sagamore Hill, and the records of the National Civil Service Reform League.
Richard D. White Jr. is Marjory B. Ourso Excellence in Teaching Professor of Public Administration at Louisiana State University. Retired in 1994 at the rank of captain following a career in the U.S. Coast Guard, he has published articles in numerous scholarly journals, including Public Administration Review and Policy Studies Review.
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