Carotid artery stenosis (CAS) is a consequence of systemic atherosclerotic disease affecting the aging populations of the Western world. CAS is frequently associated with cognitive impairment. However, the mechanisms contributing to the development of vascular cognitive impairment (VCI) associated with CAS are multifaceted and not fully understood. In addition to embolization and decreased blood flow due to the atherosclerotic lesion in the carotid artery, microcirculatory dysfunction in the cerebral circulation also plays a critical role in CAS-related VCI. To better understand the microvascular contributions to cognitive decline associated with CAS and evaluate microvascular protective effects of therapeutic interventions, it is essential to examine the structural and functional changes of the microvessels in the central nervous system (CNS). However, there are some limitations of in vivo brain vascular imaging modalities. The retinal microvasculature provides a unique opportunity to study pathogenesis of cerebral small vessel disease and VCI, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. Similar microvascular pathologies may manifest in the brain and the retina, thus ocular examination can be used as a noninvasive screening tool to investigate pathological changes in the CNS associated with CAS. In this review, ocular signs of CAS and the retinal manifestations of CAS-associated microvascular dysfunction are discussed. The advantages and limitation of methods that are capable of imaging the ocular circulation  are discussed. The potential use of dynamic retinal vessel analysis (DVA), which allows for direct visualization of neurovascular coupling responses in the CNS, for understanding microvascular contributions to cognitive decline in CAS patients is also considered. Aging is a major risk factor for cardiovascular and cerebrovascular diseases, and advanced age is associated with increased prevalence and worsened prognosis of cardiovascular and cerebrovascular diseases. Carotid artery stenosis (CAS) is an important, potentially life-threatening consequence of systemic atherosclerotic disease in the aging population. A meta-analysis of four population-based studies  showed that prevalence of moderate (≥ 50% stenosis) asymptomatic CAS ranges from 0.2% in men aged < 50 years to 7.5% in men aged ≥ 80 years. The prePatients with carotid artery disease frequently exhibit cognitive impairment –11. The Additionally, an important element in our current understanding of the pathogenesis of VCI is the role played by endothelial cells in the regulation of cerebral blood flow . The cerUnderstanding microvascular manifestations of CAS is essential for preventing cognitive decline and reducing cerebrovascular mortality in this high-risk population. In this review, the effect of CAS and the pathological processes underlying CAS on the functional and structural integrity of the CNS microcirculation is considered. There are useful methods available to study the brain microcirculation and regulation of cerebral blood flow in humans, ranging from functional magnetic resonance imaging (fMRI)-based approaches to functional Near-Infrared Spectroscopy (fNIRS). Because many of these methods have important limitations , there is an urgent need for sensitive, non-invasive methods that can be used both in large-scale cross-sectional studies and in longitudinal studies to assess treatment efficiency.We present an argument for the view that the direct imaging of retinal microvessels can be used as a proxy measure to study pathological processes underlying cerebral small vessel disease and VCI. The retina is anatomically an extension of the brain  and is considered part of the CNS. The retinal and brain microcirculations share many anatomical and physiological features and the existing evidence strongly suggest that microcirculatory functional and structural alterations in the retina correlate closely with those in the brain. The potential use of novel imaging methods to assess the combined functional and structural impairment of the retinal microcirculation in CAS patients is discussed.It is important to distinguish the asymptomatic and symptomatic CAS cases as they are associated with differential risk of stroke. According to the Asymptomatic Carotid Surgery Trial, in asymptomatic cases with a degree of the stenosis between 60 and 99%, the annual stroke risk is 0.7–1.1%/year . Cases aABCA1 CD44, KLF2, PLIN2, ferritin, ACTB, CAIX, and ENO1 protein levels were significantly higher in ruptured plaques than in non-ruptured plaques. Bioinformatic analysis suggested that only ABCA1 has a preventive role in carotid plaque rupture and atherosclerosis progression during the inflammatory reaction [Atherosclerotic lesions in the carotid bifurcation can lead to cerebral embolization by rupture of the fibrous cap, which can expose intensely thrombogenic materials to blood elements . The molreaction . There areaction –52.  . Six feaThe comparison of the microarray studies’ target genes and proteins to imaging and histopathological features are the main goal in translational researches. Clinical scoring system will be based on these findings . FurtherIn current practice, the preferred method for diagnosis and evaluation of the severity of carotid artery stenosis is Duplex ultrasound. This fast, cheap and highly accurate method gives not only morphological information but also makes it possible to evaluate the extent of the stenosis by measuring the different flow velocities. Although Doppler ultrasound (DUS) can be a reliable examination method if performed by an experienced examiner, previous studies have shown that several human factors result in an increase in error and variability , 58. CT-Currently, conventional digital subtraction angiography (DSA) is not the first-line method for the assessment of carotid stenosis. It should not be performed in patients considered for revascularization, unless there are significant discrepancies on non-invasive imaging .According to the ESVS guideline , when CEAlthough the aforementioned imaging methods are effective in clinical practice and enable the evaluation of the degree of stenosis, the effect on the downstream microcirculation of the CNS cannot be assessed.In asymptomatic cases when the extent of the stenosis is less than 70%, pharmacological treatment is recommended (daily administration of thrombocyte aggregation inhibitors and statins) as well as lowering the modifiable risk factors . PharmacPatients with CAS frequently exhibit cognitive impairment –10. The Significant stenosis or occlusion of the carotid artery results in cerebral hypoperfusion if compensatory mechanisms are exhausted . CerebroEnergy demand in the brain varies both spatially and temporally with changes in neuronal activity, thus requiring prompt adjustments of regional cerebral blood flow  in a highly regulated fashion to maintain cellular homeostasis and function , 66, 67.Cerebral autoregulation is a critical homeostatic mechanism that maintains relatively stable cerebral blood flow despite changes in the cerebral perfusion pressure. A network model study of the cerebral autoregulation and collateral flow in circle of Willis found that collateral flow alone is unable to ensure adequate blood flow after major vessel occlusion . HoweverCollateral recruitment can partially compensate cerebral perfusion in patients with steno-occlusive disease of the carotid arteries . The priImportantly, functional hyperemia/neurovascular coupling and vascular autoregulation also occur in the retina. Studies using animal models have demonstrated that retinal neurovascular coupling shares many cellular mechanisms with neurovascular coupling in the brain, including a role for glia, neurons, pericytes, and endothelial cells , 89. In Cerebral MRI frequently reveals signs of cerebral small vessel disease in the form of white matter lesions and lacunar infarcts in CAS patients , 97, 98.The retinal microvasculature provides unique opportunities to study pathogenesis of cerebral small vessel disease, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. The direct visualization of retinal vessels using the methods detailed below provides a unique opportunity to study retinal microvascular health as a proxy for brain microvascular health in patients with CAS.The blood supply of the retina is provided by the retinal and choroidal vasculature. Both are derived from the ophthalmic artery, the first branch of the internal carotid artery. As a result, changes in blood flow parameters in the internal carotid artery may result in ophthalmic complications. Pathophysiological changes affecting the CNS and the cerebral microcirculation can also affect the retina and retinal microcirculation through shared cellular, molecular, thromboembolic and hemodynamic mechanisms. Further, the retina may also serve as an area of the CNS where pathological changes in tissue structure can be directly imaged for diagnostic purposes. The retina shares developmental origins with the brain as they derive from the same pluripotent neuroectodermal cells of the diencephalon. Thus, the retina can be viewed as an extension of the central nervous system . Just liSeveral established methods exist to image the ocular circulation ; however, these methods do not allow quantitative measurement of the blood supply. In the case of CAS, the existence of collateral blood supply means that imaging retinal anatomy may not detect altered blood supply of the retina. Doppler sonography of ocular arteries provides more information about the blood supply than simple angiography; however, it is limited to large ophthalmic arteries and is therefore less informative for study of the retinal microcirculation. Some newer methods are capable of providing better functional measurements. Optical coherence tomography (OCT) provides high resolution, cross-sectional morphological imaging of the retina and the choroid, while optical coherence tomography angiography (OCTA) is able to image the retinal vasculature by detecting the movement of red blood cells in consecutive scans. In addition, a novel method, dynamic retinal vessel analysis (DVA), allows investigation of the dynamic regulation of blood supply in the retina in response to neuronal activation by flickering light , 105.For several decades, fluorescein angiography (FA) has been the gold standard procedure for visualizing the retinal circulation. For this dye-based imaging technique, fluorescein dye is injected into a peripheral vein in the arm or hand. Thereafter the retina is illuminated with blue light. The dye emits a fluorescent green light which is recorded to image the retinal vasculature. FA enables the dynamic evaluation of contrast movement in real time. It provides information on the retinal vascular perfusion and the integrity of the inner blood-retinal barrier. Pictures can be obtained of the peripheral retina as well as the posterior pole of the eye. A notable disadvantage of FA is the inability of the method to provide quantitative information about the retinal blood supply.Doppler imaging has been used for a long time in imaging of orbital structures. Color Doppler imaging provides real-time information on the blood flow in a color-coded format. The method is suitable for examination of the ophthalmic artery, the central retinal artery and the posterior ciliary artery . HoweverOptical coherence tomography (OCT) is a rapid, non-invasive and non-contact imaging technique which allows in vivo visualization of retinal structures, the optic nerve head, and the retinal nerve fiber layer (RNFL) using low coherence interferometry . Since iA novel method for visualizing and analyzing the retinal and choroidal vasculature is optical coherence tomography angiography (OCTA) which is able to visualize the retinal and choroidal vasculature without the use of an intravenous dye. The imaging technique is based on motion contrast technology to detect the movement of the red blood cells within the vessels. It enables the accurate visualization of the microvasculature of the macular area and around the optic disc, and also provides quantitative information such as the vessel density (VD) in said areas and the size of the foveal avascular zone (FAZ). The examination is fast and easily repeatable and importantly, provides simultaneous structural and functional blood flow information. The method also has its limitations, the smallest capillaries where the velocity of blood cells is under the detectable threshold can’t be visualized and bleeding and leakage cannot be seen either. With the currently used OCT devices and software, only the central parts of the retina can be measured: a 3–8 mm square of the macular area or a 4.5–6 mm square of the peripapillary area. The most important limiting factors for OCTA are the ones affecting the image quality such as media opacities and various artifacts resulting from blinking or saccadic eye movements. Based on the signal quality acquired by the device, a signal quality score is automatically calculated for each scan. Previous studies highlighted the importance of the image quality as it affects the measurement error which is significantly larger in scans with lower quality scores –115. HowDynamic retinal vessel analysis (DVA) allows visualization and direct measurement of neurovascular coupling responses by assessing the change in the retinal arteriolar diameter in response to photoreceptor stimulation. Similar to functional hyperemia in the brain, neurovascular coupling responses in the retina play an important role in matching regional blood flow to the energetic demands of activated neurons through a process in involving astrocyte activation and endothelial release of the vasodilator NO , 68. PatThe eye receives its blood supply from the ipsilateral internal carotid artery through the ophthalmic artery. CAS can result in severe ophthalmic complications. A temporary decrease in blood flow can cause a painless unilateral transient vision loss termed amaurosis fugax. Amaurosis fugax is a type of TIA, caused by an embolus derived from the ipsilateral atherosclerotic carotid artery which transiently occludes the retinal arteries causing retinal hypoxia . In seveSeveral studies described functional and morphological changes of ophthalmological parameters in patients with CAS either compared to healthy individuals or between the two eyes of patients with unilateral stenosis. Early studies focused on perfusion and functional changes , 131. InKofoed et al. assessed ophthalmic artery systolic pressure by ocular pneumoplethysmography and performed fluorescein angiography in order to evaluate retinal perfusion and examined retinal function by multifocal electroretinography (mfERG) in patients with asymmetric significant carotid artery stenosis but no clinically manifest eye disease . In the Sayin et al. compared spectral domain optical coherence tomography (SD-OCT) parameters in patients with CAS to a healthy control group and found a significant decrease in macular choroidal thickness which showed no correlation with the degree of the stenosis. They also evaluated the thickness of the retinal nerve fiber layer (RNFL), the macula and the ganglion cell complex (GCC) but found no difference between the two study groups . AnotherStudies that have used Doppler sonography to compare blood flow parameters of patients with carotid artery stenosis to healthy individuals found a significant decrease in mean central retinal artery blood velocity and the average systolic velocity of the posterior ciliary artery . In a stThe effect of carotid endarterectomy on ocular manifestations of CAS has been widely studied in the recent years. Yan et al. observed an improvement in both subjective and objective visual function  in patients after surgical treatment . HoweverThese post-surgical benefits to retinal structure and function benefits may not be accompanied by improvements in retinal neurovascular coupling. For example, the decreased flicker stimulation-evoked retinal venous dilation in CAS patients discussed earlier was not improved after carotid endarterectomy . These rThe surgical benefits of endarterectomy on retinal flow density are similarly complicated. One group demonstrated that the reduced retinal flow density in CAS patients was improved post-surgery in the radial peripapillary capillary network of the optic nerve head but not in the superficial or deep layers of the macular area . AnotherTable CAS and CAS-related cognitive impairment are important health concerns in the aging societies of the Western world. Early detection of microvascular contributions to VCI and assessment of the efficiency of therapeutic approaches are key to improved patient outcomes. The retina and the brain have striking pathophysiological similarities, and as both the retina and the brain are downstream from the carotid artery, the retina may provide a window to enable non-invasive assessment of the severity of CAS complications in the CNS distal to the lesion. Likewise, due to the anatomical and physiological similarities between the brain and the retina, evaluating structural and vascular changes in the latter can bring us to a better understanding of the effect of CAS on the central nervous system, and in particular, the role of the microcirculation in CAS-associated cognitive decline. Numerous studies have reported alterations in the retinal structure and vasculature associated with CAS that mirror many changes that occur in the brain. Recent advancements in retinal imaging make fast and non-invasive visualization of the retinal structure and blood flow possible. Among powerful new methods, OCTA is an especially promising tool for detecting early changes related to CAS and assessing the effect of surgical treatment on the changes in the CNS microcirculation. For research purposes, using these ophthalmological methods provides a unique opportunity to image CAS related neurodegenerative processes longitudinally in vivo. Furthermore, the emerging ability to use DVA and OCTA imaging in animal models provides an opportunity to evaluate cellular and molecular mechanisms underlying microvascular complications of diseases such as CAS and correlate findings with similar outcomes in patients.


Genes on “Molecular Biomarkers in Solid Tumors” to provide a snapshot of newly available and/or bona fide biomarkers for the clinical management of patients with cancer. We aimed to offer a pathology-oriented angle on some of the hot subjects regarding biomarker-based oncology. Particular attention has been paid to the selection of articles focusing on tailored biomarkers assessment in terms of technology and analytical strategies. The present collection that we had the pleasure to edit consists of three original research articles and eight reviews covering different biomarkers in different types of cancer. Diagnostic strategies using a next-generation systematic approach have the potential to radically improve the outcome and subsequent quality of life of patients with cancer. Due to unprecedented technological developments, coupled with novel multidisciplinary approaches in translational research, a multitude of biomarkers at genomic, transcriptomic, proteomic, and immunologic levels have been discovered and validated . These bFour articles provide insights into the role of specific biomarkers in cancers using a histology-agnostic approach. Among these, original research by Gianluca Lopez and collaborators describes the prevalence and prognostic impact of somatic mutations in leucine-rich repeat kinase 2 (LRRK2), a major contributor to familial Parkinson’s disease, in different neoplastic settings . This woThen, we introduce a series of articles focusing on selected types of tumor. The Australian group of Allegra Freelander and colleagues summarizes the currently available data on prognostic, predictive, and pharmacodynamic molecular biomarkers in one of the most frequent types of tumor worldwide: the hormone receptor-positive breast cancer . AnotherOur understanding of the molecular landscape of solid tumors is expanding day by day. We believe that a biomarker-based approach at a single-patient level in the risk assessment and treatment selection would represent a quantum leap for the community of healthcare providers and patients.


Gestational diabetes mellitus (GDM) is a pregnancy complication in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. The diet and lifestyle of the mother during pregnancy as well as lactation have long-term effects on the child’s health and development. Detection of early risk markers of adult-age chronic diseases that begin during prenatal life and the application of complex nutritional interventions at the right time may reduce the risk of these diseases. Newborns adapt to the ectopic environment by developing intestinal immune homeostasis. Adequate initial colonization of bacteria is necessary for sufficient development of intestinal immunity. The environmental determinant of adequate colonization is breast milk. Although a developing newborn is capable of producing an immune response, the effector immune component requires bacterial stimulation. Breast milk stimulates the proliferation of a well-balanced and diverse microbiota, which initially influences the switch from an intrauterine TH2 predominant to a TH1/TH2 balanced response and the activation of T-regulatory cells by breast milk-stimulated specific organisms . Breastfeeding in newborns of mothers with diabetes mellitus regulates the adequate immune response of the newborn and prevents diseases of the neonatal and postnatal period. Gestational diabetes mellitus (GDM) is a pregnancy complication in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. It is the most common medical complication and metabolic disorder of pregnancy. Prevalence may vary from 1 to 14% among all pregnancies . There iIn women with GDM during pregnancy, there is a higher chance not only to develop type II diabetes mellitus during life, but also the risk for pancreatic cancer .Glucose metabolism in early pregnancy is characterized by hypoglycemia, hypoinsulinemia, ketogenesis, and fatty acid turnover. Between 24–28 weeks of gestation, the concentrations of placental and insulin-antagonistic factors increase, altering carbohydrate metabolism. This is interpreted as antagonism of the action of circulating insulin. Due to the reaction of the pancreas, insulin secretion increases. However, in some cases, the reserves of the pancreas can be reduced or depleted . Due to Insulin degradation on the maternal side of the placenta is unilateral, since insulin does not cross the placental barrier. The insulin resistance is of the post-receptor type and is hormonally conditioned. A decrease in the number of insulin receptors bound to peripheral target cells, along with a relative lack of circulating insulin, including post-receptor defects, leads to glucose intolerance and the development of gestational diabetes ,9.Changes in the mother’s glucose and insulin concentrations are followed by similar changes in the fetus. Maternal hyperglycemia leads to fetal hyperglycemia and hyperinsulinemia. The consequences of this excessive stimulation are reflected in the fetal pancreas in the form of islet hyperplasia with an increase in the number of beta cells and increased insulin values . The impThe priority of current studies is to discover mechanisms by which epigenetic modification prolongs the effects of environmental influences in early childhood and provides a long-lasting response to transient stimulus-modified gene expression and phenotype in adults .Thus, nutrition in the pre- and postnatal period positively influences health in adulthood . An adveThe human body harbors trillions of microbial cells and they are indispensable for human health. The gut microbiota resides on the intestinal mucosal surfaces and participates in epithelial homeostasis, energy harvest, and immune development . ColonizThe abundances of the Rothia families and Clostridium sensustricto, which may contain opportunistic pathogens that might cause enteric infections and childhood metabolic disorders, were significantly increased in the GDM neonates. Decreased richness of the enteric microbiota has been associated with elevated insulin resistance and proinflammatory markers . In addiBreast milk contains many complex proteins, lipids and carbohydrates, the concentrations of which are altered dramatically over a single feeding and/or lactation to reflect the infant’s needs. Breast milk contains a myriad of biologically active components .These molecules possess diverse roles, guiding the development of both the infant immune system and intestinal microbiota. It is believed that bacteria from the mother’s intestine may translocate to breast milk and dynamically transfer to the infant .Such an interplay between the mother and her infant is key to establishing a healthy infant intestinal microbiome. These intestinal bacteria protect against many respiratory and diarrheal illnesses, but are subject to environmental stresses such as antibiotic use. Orchestrating the development of the microbiota are human milk oligosaccharides (HMOs), the synthesis of which is partially determined by the maternal genotype .Human milk (HM) contains a large number of lipids that are essential for optimal growth and development. These lipids compose approximately 5% of the total milk profile and are packaged as milk fat globules. Milk fat globules are synthesized from triacylglycerol droplets within the endoplasmic reticulum of the mammary epithelium, and thus, the milk fat globule membrane (MFGM) is a tri-layer structure composed of many polar lipid species surrounding a nonpolar lipid core. The lipids of the MFGM make up approximately 2% of the HM lipidome and include phospholipids, such as phosphatidylinositol (PI), phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS), and sphingolipids, such as SM and sphingomyelin ceramides (Cer) .Breast milk fat is a major source of energy, providing over 40% of the total energy for infants during the first 6 months of life. Fat globules in breast milk consist of TAGs (98–99% of milk lipids) and small amounts of monoacylglycerols, diacylglycerols, and free fatty acids surrounded by milk fat membranes of different phospholipids . Some ofThe influence of breast milk on the initial intestinal microbiota also prevents the expression of immune-mediated diseases  later in life through a balanced initial immune response, underscoring the necessity of breastfeeding as the first source of nutrition .Premature birth causes an interruption of lung development and maturation and simultaneously exposes the neonate to profound alterations of these systems. Abrupt interruption of placental nutrition, lung exposure to a highly oxidant environment, disruption of the nascent microbiome by invasive procedures, hospital microbiota, broad-spectrum antibiotics and many other factors lead to acute and chronic lung disease. Maternal diabetes mellitus and excessive fetal carbohydrate exposure alter surfactant synthesis in term and near-term infants. Animals born from induced GDM mothers show impaired lung development and maturation, with decreased expression of surfactant proteins B and C and their regulatory factor FOXA2 associated with inducible nitric oxide synthase induction and the generation of reactive oxygen species, which is a possible mechanism explaining the respiratory failure in infants of diabetic mothers .In addition, antimicrobial factors such as lactoferrin, leukocytes, secretory IgA, complement factors, cytokines, lactoferrin and lysozyme play a fundamental immunomodulatory role. As recently discovered, human milk exosomes containing microRNA and other epigenetic factors interact with gene transcription and exert longstanding effects on gut homeostasis. Pasteurization, which is considered a standard for DBM out of concern for the transmission of infectious agents such as cytomegalovirus, human immunodeficiency virus and herpes simplex virus, inactivates many microcomponents and compromises its bactericidal and immunomodulatory properties .GDM could alter the serum metabolome and is associated with the neonatal meconium microbiota and metabolome, highlighting the importance of breastfeeding on early life metabolism .The diet and lifestyle of the mother during pregnancy as well as lactation have a long-term effect on the child’s health and development. Breastfeeding in newborns of mothers with diabetes mellitus prevents neonatal hypoglycemia, regulates the adequate immune response of the newborn and prevents diseases in the neonatal and postnatal period.


Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and safety, a small equipment footprint, as well as the ability to integrate in-line analysis and purification tools into telescoped sequences are often cited when comparing flow to analogous batch processes. In this short review, the latest developments regarding the exploitation of continuous flow protocols towards the synthesis of anticancer drugs are evaluated. Our efforts focus predominately on the period of 2016–2021 and highlight key case studies where either the final active pharmaceutical ingredient (API) or its building blocks were produced continuously. It is hoped that this manuscript will serve as a useful synopsis showcasing the impact of continuous flow chemistry towards the generation of important anticancer drugs. Drug shortages remain a significant public health issue in the 21st century. All types of drugs are affected by this problem such as anticancer medicines, antimicrobial drugs, analgesics, opioids, cardiovascular drugs, radiopharmaceuticals, and parenteral products. This global problem furthermore has severe economic implications and affects society as a whole . The shoRecently, both FDA (Food and Drug Administration) and EMA (European Medicines Agency) published updated reports analyzing this situation ,5. Drug To improve the manufacturing process, the chemical industry has started to embrace more advantageous emerging technologies, particularly continuous flow chemistry which allows for various improvements on the manufacturing process as documented previously ,11,12,13Compared to batch manufacturing, continuous manufacturing offers higher quality products and less batch-to-batch variability because of the high control over reaction conditions . For the same reason, flow technology enables chemists to easily perform reactions that would be very challenging in batch mode  due to eBecause of the many advantages  that canThe following 4) is a nitroso urea species widely used in anticancer therapies, especially to treat CNS tumors, throat and larynx tumors, lymphogranulomatosis, Hodgkin’s lymphoma, lung, and gastrointestinal tract tumors. This drug acts as a DNA-alkylating agent that produces chloroethyl carbenium ions and carbamylated intermediates in vivo . Th. Th66]. The chosen approach exploits the use of design of experiments (DoE) and high-throughput experimentation (HTE), coupled with DESI-MS as a quick characterization technique. Integrating these enabling techniques facilitated the optimization of the flow process in view of gaining a full understanding of potential side-products geared toward their subsequent minimization.The first stage involves a DoE for the amide coupling in flow mode. Based on batch and flow experiments, the most favorable conditions were identified to safely use the unstable and potentially explosive amidation reagent HATU. The information obtained from the DoE optimization process  led to t21 were sought using DoE/HTE experimentation coupled with DESI-MS for the instantaneous quantification of the desired reaction product . This micro-reactor approach (volume of 20 μL) enabled the generation of almost 100 mg of product in 12 h while consuming very small amounts of reactants during the optimization process. Larger flow reactors are available to provide gram quantities of the drug candidate 22 for further explorations.The two reactions were then successfully telescoped, leading to a fast synthesis of the target drug 28) is an inhibitor of checkpoint kinase 1 (CHK1), a protein involved in DNA replication and the repair of damaged DNA. Research into the efficacy of prexasertib for the treatment of acute myeloid leukemia, myelodysplastic syndrome, rhabdomyosarcoma, and medulloblastoma is ongoing. Due to the low oral bioavailability, the drug is administered via infusion . Af. Af84]. 42, In 2019, De M. Miranda et al. demonstrated a further improvement concerning the carbamoylation/deprotection step towards this anticancer target . StartinAs the case studies reported in the preceding section have demonstrated, flow chemistry has been exploited for the improved synthesis of several important anticancer drugs. In these cases, the majority of the synthetic route was conducted as a continuous flow process to benefit from reaction telescoping, allowing the isolation and offline purification of intermediates to be avoided. Academic laboratories, as well as pharmaceutical companies, have thereby explored flow processing to generate small samples of the API as proof-of-concept or to generate multiple kilograms such as in the case of prexasertib and merestinib. While in each case chemists are looking to overcome bottlenecks found in the initial synthesis, it is apparent that the development of more sustainable and safer routes are equally important targets. As the next section will demonstrate, the synthesis of specific building blocks needed in the production of anticancer drugs is another important area that has witnessed the exploitation of flow chemistry in recent years. Here, key drivers for using continuous approaches are improved safety, scalability, and process intensification. Unsurprisingly, the development of a single flow step is typically faster than the realization of a telescoped process, which is attractive for industrial chemists when faced with the decision between process development in batch versus flow mode. 45) is the core building block of osimertinib (46), sold under the brand name Tagrisso®. This anticancer drug is an orally active irreversible inhibitor of the epidermal growth factor receptor (EGRF), discovered and developed by AstraZeneca. It is used as a first-line treatment for patients with locally advanced or metastatic non-small cell lung carcinoma (NSCLC) with EGFR sensitizing mutations and as a treatment for patients with EGFR T790M-mutation-positive NSCLC that has progressed on or after EGFR-TKI therapy. The recommended dose in the U.S. is one 80 mg tablet taken once daily . . 58) tow58 through the rapid addition of KHDMS as the base. The resulting double salt 59 was then methylated by the addition of MeI. Because salts are involved in this reaction, it was critical to minimize the possibility of precipitation within a standard plug flow reactor. Therefore, CSTRs were connected in series, allowing the processing of 100 g of the substrate without clogging issues. This approach afforded the desired target after isolation in a high yield of 76% and in very high purity. The optimized procedure utilizes continuous-stirred tank reactors (CSTRs) to achieve deprotonation of the tertiary alcohol as well as the amide present in 58 without decomposition of the starting material. Precise control over reagent delivery and residence time furthermore mitigated issues of over-methylation and thus enhanced the quality of the entire process. Final recrystallization from aqueous acetic acid and ethanol provided the final API with >98% purity in 75% yield.The implementation of continuous processes enabled fast and complete deprotonation of substrate Flow chemistry has played a major part in developing effective syntheses of anticancer drugs. The advantages of miniaturization within flow reactors that lead to improved heat and mass transfer are commonly exploited to gain better process control and selectivity for a variety of transformations. This has been demonstrated for the telescoped flow synthesis of anticancer drugs by academic as well as industrial laboratories to either generate proof-of-concept case studies or for the preparation of multigram quantities of these anticancer drugs and their building blocks in a short time. Scale-up is thereby explored routinely by extending the processing time or applying scale-out principles . A recent trend is seen in the exploitation of flow technology for steps that are particularly challenging in the batch route. Pharmaceutical companies thereby opt to target individual steps for flow development, which may be of particular relevance towards the end of the synthesis where the material becomes more valuable, while the reactor containment will mitigate any concerns relating to the cytotoxicity of the final API at the same time. The relevance of natural products towards anticancer drugs has been highlighted in this review, and it is expected that flow technology will continue to facilitate their generation as exemplified in additional studies based on taxol , cannabi


This symposium co-sponsored by the Disasters and Older Adults and the Technology and Aging special interest groups of GSA aims to highlight the promise of, and barriers to, the use of telehealth to support continuity of care in the face of disasters and crises, such as the ongoing COVID-19 pandemic. M. Mattos will showcase a home-based medical care (HBPC) program to address chronically ill and homebound persons living with dementia and caregivers’ needs during the pandemic. T. Wyte-Lake will present the results of a national survey on how changes were made to the Department of Veterans Affairs (VA) HBPC programs in response to the pandemic. G. Demiris describes a large caregiver study in which problem solving therapy and positive appraisal theory interventions designed specifically to support family caregivers of hospice patients during the COVID-19 pandemic were implemented via telehealth. D. Lindeman will specifically discuss challenges and implementation strategies for telehealth solutions applied to low-income older adults living in affordable housing communities. Finally, H. Xu will present the results of an analysis examining the effectiveness of telehealth in reducing readmissions among heart failure patients during the COVID-19 pandemic. While the COVID-19 pandemic has especially impacted older adults and those who care for them, these talks highlight the potential of telehealth services and interventions to provide support and facilitate the continuity of care during times of crisis.


Research suggests that the effects of fear of falling on falls may differ by race/ethnicity. We investigated whether race/ethnicity  moderated the longitudinal effects of fear of falling on the incidence of falling and having a repeated fall among community-dwelling older adults. We used data from 2011-2018 of the National Health and Aging Trends Study (NHATS). These included a total of 19,516 person-intervals from 5,113 respondents. Self-reported any fall in the past year was the outcome variable with baseline fear of falling as the predictor and race/ethnicity as the moderator. Known risk factors for falls were included as covariates. Results showed that among respondents without the experience of falling at baseline, baseline fear of falling significantly increased the odds of a new-onset of fall at 1-year follow-up among Blacks, compared to Whites. Among respondents who already fell at baseline, baseline fear of falling significantly increased the odds of having a repeated fall later on among Hispanics, compared to Whites. Clear evidence of racial/ethnic differences was found in the relationship between fear of falling and falls among community-dwelling older adults in the U.S. Special attention should be paid to Black older adults with a fear of falling but have not fallen down recently and Hispanics with fear of falling and have fallen in the past year. Readily available educational programs should be actively advertised to older adults to reduce the fear of falling and culturally tailored educational programs should be developed for older adults from racial/ethnic minority backgrounds.


With the distinguished properties in electronics, thermal conductivity, optical transparence and mechanics, graphene has a powerful potential in nanosensors, nano-resonators, supercapacitors, batteries, etc. The resonant frequency of graphene is an important factor in its application and working environment. However, the random dispersed porosities in graphene evidently change the lattice structure and destroy the integrity and geometrical periodicity. This paper focuses on the effects of random porosities in resonant frequencies of graphene. Monte Carlo simulation is applied to propagate the porosities in the finite element model of pristine graphene. The statistical results and probability density distribution of porous graphene with atomic vacancy defects are computed based on the Monte Carlo finite element model. The results of porous graphene with atomic vacancy defects are compared and discussed with the results of graphene with bond vacancy defects. The enhancement effects of atomic vacancy defects are confirmed in porous graphene. The influences of atomic vacancy defects on displacement and rotation vector sums of porous graphene are more concentrated in local places. Graphene is a two-dimensional 2D) nanomaterial composed of a hexagonal honeycomb lattice . With thD nanomatThe challenges confronted for the study of random porosities in graphene are mainly concentrated around three aspects. First, the small size on the nanometer scale makes the precise measurement in physical experiments difficult and inconvenient, and the experimental equipment is supposed to satisfy more advanced and strict requirements ,26,27. SIn the investigation of porous graphene, the experimental, theoretical and numerical methods are the effective ways of knowledge exploration. Using an atomic force microscope, nano-indention is performed and detected in the center of a suspended monolayer graphene membrane . BesidesIn order to take random porosities into consideration, atomic vacancy defects are dispersed in graphene by MCS. The stochastic sampling process in MCS provides sufficient random numbers, which correspond to the serial numbers of atoms in graphene. The marked atoms in the MCS form atomic vacancy defects with three connected bonds. The results of porous graphene are compared with the previous work of random bond vacancy defects in graphene. The analysis of porous graphene in vibration is useful and helpful to understand the mechanical properties of graphene in the real service environment. The random distributed porosities are among the most important factors that contribute to uncertainties in graphene. It is necessary to have quantitative computation and effective propagation for porosities in the reliability and stability analysis of graphene.This article is structured as follows: In Given that the porosities are randomly dispersed in graphene, sufficient times of performing the Monte Carlo-based stochastic finite element method (MC-SFEM) are necessary to simulate the uncertainties in the location of porosities. In this study, the repetition time of MC-SFEM is settled as 1000 for porous graphene. The database of the stochastic finite element model for porous graphene is huge. The statistical results of resonant frequencies are computed from the original database of MC-SFEM. The mean, maximum, minimum and variance values of resonant frequencies of porous graphene with the corresponding percentage of atomic vacancy defects are listed in The mean values of resonant frequencies in porous graphene are computed from all the results in the sampling space. The maximum and minimum values of resonant frequencies in different vibration modes are tracked and captured in the result sets. The maximum and minimum values of resonant frequencies represent the extreme situations that can possibly appear in porous graphene. Besides the mean values of resonant frequencies in the statistical results, the maximum and minimum values also provide meaningful information as demonstrated in With the increase of the amount of atom vacancy defects in porous graphene, the mean values of resonant frequencies linearly decrease in the first- to fourth-order vibration modes. However, the minimum and maximum values of resonant frequencies are more complicated with fluctuations. More importantly, the enhancement effects by atomic vacancy defects are observed in In Resonant frequencies are the quotient of stiffness and mass matrices of porous graphene. The atomic vacancy defects in porous graphene cause the reduction of mass, which is the numerator in the computation of resonant frequencies. The atomic vacancy defects in porous graphene also play roles in the weakening effects in stiffness matrices, which are the denominators. When weakening effects in stiffness matrices are smaller than the reduction in mass matrices, the resonant frequencies are amplified. By contrast, when the decrease of stiffness matrices of graphene is more dominant than that of mass matrices, the resonant frequencies are cut down. Therefore, the enhancement effects happening in minor situations with the tiny percentage of atomic vacancy defects are reasonable.In addition, The probability density distribution of resonant frequencies in porous graphene is illustrated in Atomic vacancy defects are formed by the disappearance of atoms with three connected neighbor bonds, while bond vacancy defects are the absence of single bonds. In the honeycomb lattice of graphene, one atom is connected with three neighbor bonds, and one bond is the link between two atoms. In order to compare the atomic and bond vacancy defects in graphene, the statistical results of resonant frequencies for porous graphene with bond vacancy defects are listed in bPer equals Per, the mean values of resonant frequencies in porous graphene with bond vacancy defects are a little larger than those with atomic vacancy defects, except when bPer is 1.5%; then, the mean values of resonant frequencies in porous graphene with bond vacancy defects are smaller than those with atomic vacancy defects. With the increment of bond vacancy defects in porous graphene, the mean values of resonant frequencies also decrease. However, the regularity of atomic vacancy defects enables porous graphene with a more solid ability to resist the reduction in resonant frequencies, especially when the amount of vacancy defects is large, such as 1.5%. On the other hand, when bPer is equivalent to Per, the maximum values of resonant frequencies in porous graphene with atomic vacancy defects are larger than those with bond vacancy defects. The contrary phenomena are rare. Enhancement effects in porous graphene with bond vacancy defects are also observed, but are smaller than those with atomic vacancy defects. Therefore, porous graphene with atomic vacancy defects not only has a more solid robustness in the reduction of resonant frequencies, but also can result in stronger possible enhancement effects.In Per equals bPer, the amount of bond vacancy defects in porous graphene with atomic vacancy defects is larger than that with bond vacancy defects and is approximately 1.5 times that with bond vacancy defects. Even though the regularity in atomic vacancy defects causes robustness in resonant frequencies and provides more evident enhancement effects in porous graphene, bond vacancy defects lead to smaller variance and deviation.The variance values of resonant frequencies in porous graphene with two different vacancy defects are compared in The random distributed atomic vacancy defects cause the deviation of resonant frequencies in porous graphene. The vibration modes of one example in the MC-SFEM for porous graphene are depicted in Different from the influence of 5% bond vacancy defects in the literature , the geo2 hybrid orbitals. The carbon–carbon (C–C) covalent bonds are supposed to be the elastic beam elements in the characteristic lattice of graphene. The equivalent Young’s modulus and Poisson ratio are derived from the following equations.The carbon atoms in graphene are combined with covalent bonds in sp2 bonds, the Morse potential is expressed as:The analytical function representing bond energy is the Morse function :(1)Ur=DiThe energy of the bond angle is written as follows: Therefore, the equivalent parameters, the diameter The C–C bonds are simplified as the beam finite element model in pristine graphene. The beam finite element has a circular solid cross-sectional area. The length of each beam in the finite element model corresponds to the distance between the neighboring atoms in the honeycomb lattice of graphene. The original finite element model for graphene without vacancy defects was verified in our previous work, which reached a good agreement with the results computed by molecular dynamics, density function theory, etc. . CompareThe beam finite element used in this study is based on Timoshenko beam theory which includes first-order shear deformation effects. The element is a linear, quadratic and cubic two-node beam element in 3D. For each node, it has six degrees of freedom, which include translations in the x, y and z directions and rotations around the x-, y- and z-axes. The beam finite element is well-suited for linear, large rotation and/or large-strain nonlinear applications. Different from the truss element, the beam finite element has the capacities in axial and flexural computation.z and time t, E is the Young’s modulus, G is the shear modulus, A is the cross-section area. In this theory, Timoshenko shear coefficient The equation derived by Timoshenko that governs flexural vibrations of beams with a constant cross-section can be expressed as follows :(6)EIρA∂Besides A, B, C and In the normal mode, It is well known that solutions of the equation above behave differently according to Usually, coefficients For free vibration analysis for Timoshenko beam based on the principle of virtual work, the weak form of equation can be written as follows:L is the length of the beam and As defined above, MCS is a classical stochastic sampling method with a solid mathematical foundation . Each ataN), 6226 bonds (bN) and 18,678 elements. Therefore, the percentage of atomic vacancy defects in porous graphene can be defined as follows:The finite element model of pristine graphene consists of 4212 atoms (aD and bD are the amounts of atomic and bond vacancy defects, respectively. Similarly, the percentage of bond vacancy defects is computed as follows:In this paper, MCS is applied to propagate the porosities in the finite element model of pristine graphene as shown in Probability density distributions of resonant frequencies caused by random distributed atomic vacancy defects are not as regular as the Gaussian or Weibull distribution.Resonant frequencies can be amplified by the introduction of appropriate atomic vacancy defects in pristine graphene.Porous graphene has a stronger capacity to reduce fluctuations and deviations in low-order vibration modes than in high-order vibration modes.The porosities in graphene not only ensures a more solid robustness in the reduction of resonant frequencies, but also can result in stronger possible enhancement effects.The impacts of atomic vacancy defects are more concentrated in the local scope.In this paper, random atomic vacancy defects are taken into consideration in the vibration analysis of porous graphene. The MC-SFEM is applied to propagate stochastic porosities in pristine graphene and compute resonant frequencies. Statistical results and probability density distribution for porous graphene with atomic vacancy defects are computed and carried out. Based on this work, the following key points can be emphasized:


Transpterygoid approach is an expanded endonasal approach (EEA) that allows surgical access to the medial infratemporal fossa, to the skull base area of petrous bone and to the Meckel’s cave. During this approach, a sacrifice of sphenopalatine artery is often required, leading to the need of contralateral Hadad-Bassagasteguy flap (HBF) or alternative reconstructive techniques.We report a case of spontaneous CSF leak due to a meningo-encephalocele in the left lateral recess of sphenoid sinus, in which an ispilateral nasoseptal flap was harvest and sphenopalatine artery was preserved. We described the surgical technique adopted to preserve the ipsilateral nasoseptal vascular pedicle during transpterygoid approach and we performed a review of the pertinent literature. Wide exposure of the pterygoid base through transpterygoid approach could be obtained preserving the sphenopalatine artery, allowing skull base reconstruction with ipsilateral nasoseptal flap. Transpterygoid approach (TA) is an expanded endonasal approach (EEA) and a lateral extension of the endonasal corridor that, through the removal of pterygoid process base ,2, allowIt origins from the union of the greater superficial petrous nerve (GSPN) and the deep petrous nerve  in the pterygoid canal, entering the pterygopalatine fossa and joining the sphenopalatine ganglion . The vidian nerve runs in the pterygoid canal together with the homonymous artery just laterally to the petrous-paraclival junction of the internal carotid artery (ICA), running in the lateral area of the sphenoid sinus floor, and entering in the pterygopalatine fossa through the vidian foramen, which is situated in the antero-medial portion of pterygoid process base ,5. The sWe report a case of a patient with acute onset of meningitis, seizures and spontaneous cerebrospinal fluid (CSF) leak due to a left lateral sphenoidal recess meningo-encephalocele. Meningo-encephalocele and CSF fistula repair were performed through a left TA approach and ipsilateral HBF for skull base reconstruction while preserving ipsilateral sphenopalatine artery. We also performed a review of the literature for TA approach using an ipsilateral HBF as closure technique, and we found only five articles describing the preservation of the septal flap pedicle during an ipsilateral TA ,9,16–18.Surgical technique1. Preoperative managementAfter induction of general anesthesia and antibiotic prophylaxis with cefamezin 2 gr. , nasal c2. Patient positioning and tissue preparation for final reconstructionThe patient was placed supine with the head in neutral position and elevated to 10-30°. We used a 4K ultra-high definition endoscope  ,21. The 3. Approach step-by-stepa. Antrostomy and sphenoidotomy descriptionThe approach started with resection of left uncinate process, followed by identification of natural ostium of the maxillary sinus. The ipsilateral left middle turbinate was removed and the maxillary antrum opened, performing a middle turbinectomy and an antrostomy. A complete unilateral ethmoidectomy was then performed, resecting ethmoid bulla and extending to the posterior ethmoid. The posterior ethmoidal air cells were removed until sphenoid sinus was reached through a trans-ethmoidal route . The anterior sphenoidotomy was completed removing the sphenoid-ethmoidal septa, the anterior wall of the sphenoid sinus and the superior part of the vomer.b. Nasoseptal flap preparation and sphenopalatine foramenidentificationThe ipsilateral nasoseptal flap was prepared according to Hadad technique,6,22 desc. Sphenopalatine artery preservation In order to preserve the sphenopalatine artery, the orbital process and the medial part of maxillary sinus posterior wall removal started from the sphenopalatine foramen, achieving the exposition of pterygopalatine fossa contents. Bone removal proceeded laterally from the superior portion of the foramen toward the inferior orbital fissure and the foramen rotundum. The medial aspect of the pterygopalatine fossa and the greater palatine canal exposure  was achieved removing the superior portion of the palatine bone perpendicular plate. The pharyngeal branch of the internal maxillary artery was identified in the palatosphenoidal canal  through the removal of the sphenoid process of the palatine bone.d. Access to pterygopalatine fossa and lateral recess of sphenoid boneIn order to obtain the lateralization of the pterygopalatine fossa contents, the pharyngeal branch was coagulated and cut. Subsequently, the palatovaginal artery was identified and dissected, while bone removal of vidian nerve canal proceeded starting inferiorly and medially to the nerve identifying the junction between the petrous and paraclival portion of the ICA . After de. CSF leak identification and closureA CSF fistula and a small meningo-encephalocele were identified within left lateral recess of sphenoid sinus through previous fluorescein injection . The meningo-encephalocele was coagulated and resected; the bony edges of the defect were prepared, coagulated and repaired in a multilayer fashion with autologous fat and fascia lata. Therefore, ipsilateral nasoseptal flap was transposed into the lateral recess of sphenoid sinus in order to cover the defect . The inferior incision along the choana should cross the medial pterygoid plate below the sphenopalatine foramen, in order to obtain enough tissue to cover the defect. The ipsilateral nasoseptal flap was secured using fibrin glue and pieces of Merocel placed on the edges of the flap. Finally, a non-absorbable anterior nasal packing with has been performed in order to facilitate mucosal healing ad avoid the displacement of skull base reconstruction materials . f. Postoperative managementThe patient was admitted to the Neurosurgical ward after surgery. Lumbar drain was removed on postoperative day 3, while the anterior nasal packing was removed on postoperative day 4. During hospitalization, neurological examination and clinical evaluation to check postoperative CSF leak were performed daily. Patient was discharged on postoperative day 7 after an outpatient rhinoscopy. Further ORL outpatient rhinoscopies were performed at 30 and 90 days after surgery with evidence of good healing of nasal mucosa e no signs or symptoms of CSF leakage. The traditional endoscopic transsphenoidal approach is not adequate to expose diseases in the lateral recess of the sphenoid sinus or in the region of the sphenoid wing,16,23,24Kasemsiri et al.  classifiType A consist in a partial removal of pterygoid process and it is indicated for pterygopalatine fossa diseases; Type B is characterize by removal of the anterior portion of the base of the pterygoid process, allowing the access to the lateral recess of the sphenoid sinus; Type C includes the removal of the entire base of the pterygoid process with dissection of the vidian canal for the access to the petrous apex and the Meckel’s cave; Type D is associated to the removal of the pterygoid plates and dissection of the petrous ICA. It is used to treat infratemporal fossa lesions with control of the petrous ICA. Type D includes also Eustachian tube removal, in order to manage extensive lesions extended to the middle and posterior cranial fossa . Thus, TA allows the possibility to minimize the amount of bone resection preserving the sphenopalatine artery, based on the extension of the pathology treated . RemovinIn our experience, TA from type A to C leads to adequate access to the pterygopalatine fossa, lateral sphenoid recess, sphenoid wing and infratemporal region, allowing a successful skull base defect repair. The vidian nerve needs to be used as landmark for the ICA, and it can be sacrificed if necessary ,10,22,24They reported that vidian nerve preservation might limit the protection of the vascular pedicle when drilling the base of the pterygoid bone, suggesting vidian nerve scarification in order to achieve a simpler sphenopalatine artery preservation.Kaligkiotis et al.  reportedThe use of ipsilateral nasoseptal flap during TA is very useful when multiple skull base defects, especially bilateral CSF leaks, are detected. In our opinion, in presence of bilateral TAs or combination of TA and other endoscopic approaches, an attempt to preserve both sphenopalatine arteries and prepare a nasoseptal flap on both side for skull base reconstruction should be done. Furthermore, if ipsilateral nasoseptal flap is achieved during TA, the controlateral HBF can be preserved in cases of re-operation (e.g. tumor or CSF fistula recurrence).A Transpterygoid approach with ipsilateral HBF for skull base reconstruction while preserving ipsilateral sphenopalatine artery is a possible surgical option and it can be considered for skull base reconstruction. The present article and the previous literature showed that deep anatomical knowledge, surgical expertise and careful dissection of neurovascular structures are fundamental to achieve wide exposure of pterygoid base without compromising the blood supply of ipsilateral nasoseptal flap. Furthermore, this technique can be used for skull base reconstruction in case of bilateral TAs or TA combined with other endoscopic approaches  or for those cases with only one vascular pedicle available.


Metal additive manufacturing techniques are frequently applied to the manufacturing of injection molds with a conformal cooling channel (CCC) in order to shorten the cooling time in the injection molding process. Reducing the cooling time in the cooling stage is essential to reducing the energy consumption in mass production. However, the distinct disadvantages include higher manufacturing costs and longer processing time in the fabrication of injection mold with CCC. Rapid tooling technology (RTT) is a widely utilized technology to shorten mold development time in the mold industry. In principle, the cooling time of injection molded products is affected by both injection mold material and coolant medium. However, little work has been carried out to investigate the effects of different mold materials and coolant media on the cooling performance of epoxy-based injection molds quantitatively. In this study, the effects of four different coolant media on the cooling performance of ten sets of injection molds fabricated with different mixtures were investigated experimentally. It was found that cooling water with ultrafine bubble is the best cooling medium based on the cooling efficiency of the injection molded parts . Mold material has a greater influence on the cooling efficiency than the cooling medium, since cooling time range of different mold materials is 99 s while the cooling time range for different cooling media is 92 s. Based on the total production cost of injection mold and cooling efficiency, the epoxy resin filled with 41 vol.% aluminum powder is the optimal formula for making an injection mold since saving in the total production cost about 24% is obtained compared to injection mold made with commercially available materials. Wax injection molding is a frequently applied manufacturing technique for the production of investment casting wax patterns due to time efficiency. The cooling time of the wax patterns constitutes a large portion in cycle time. Nowadays, the conformal cooling channel (CCC) was incorporated in the wax injection mold to improve the cooling efficiency of the wax patterns in terms of uniform cooling during the cooling stage . Low-preThe wax injection mold with highly complex-shaped CCC capable of reduction cooling times can be fabricated by the metal powder AM, such as laser fusing, direct metal laser sintering, electron beam melting, selective laser melting, selective laser sintering, diffusion bonding, or direct metal deposition. However, operating consumables of the metal powder AM systems are costly. Thus, those approaches are not suitable for developing a new product since higher initial cost of the capital equipment and maintenance. To overcome this obstacle, RT technology was developed to meet this requirement since it is a cost-effective method that builds tools without the need for complex conventional machining operations. Typically, the RT technology is divided into two categories, namely direct tooling and indirect tooling. Indirect tooling is widely used to manufacture an injection mold for batch production of a new product in the research and development stage using commercial Al-filled epoxy resin. According to practical experience, both mechanical and physical properties of the wax injection mold fabricated by Al-filled epoxy resin are limited due to intrinsic material properties. Tomori et al.  proposedIn general, the cooling time of injection molded products is affected by both injection mold material and coolant medium. However, little work has been conducted to investigate the effects of different mold materials and coolant media on the cooling performance of epoxy-based injection molds. The goal of this study is to investigate the cooling performance of epoxy-based injection molds fabricated from different mold materials using different coolant media. In this study, ten sets of injection molds were fabricated using commercially available Al-filled epoxy resin and epoxy resin added with three different particle sizes of stainless steel, Al, and copper (Cu) powders. Four different kinds of cooling media, including cooling water, compressed gas, cooling water with ultrafine bubble, and cold stream are used to study the cooling performance using a low-pressure wax injection molding.Cooling media is a substance, which is widely applied to regulate or reduce temperature of injection mold during the injection molding process. An ideal cooling medium involves low cost, low viscosity, high specific heat capacity, non-toxic, and chemically inert of the cooling system in the injection mold. Air is a common form of a cooling media, which uses forced circulation to reduce temperature of injection mold during the injection molding process. Thus, four different kinds of cooling media  were applied to study the cooling efficiency of injection molds by low-pressure wax injection molding. Cold air comes from the vortex tube. To evaluate cooling performance of the injection molds, a simple and effective cooling time measurement system was designed and implemented. To ensure the molding materials can fill the cavity completely and smoothly, a direct gate was employed in this study. To investigate the upper limit of the volume percentage (vol.%) of the filler particles that can be added to the matrix material of epoxy resin, the vol.% of these three powders was varied from 15 to 65 vol.%. To investigate the precipitation of fillers in the injection mold, EDS was carried out in this study. ct) of the injection molded parts can be calculated by the following equation [α is the thermal diffusivity;wT is the mold cavity surface temperature;s is the part thickness;mT is the melt temperature;eT is the average ejection temperature.equation ,21,22:(1Q denotes the flow rate of the coolant;D denotes the diameter of the cooling channel;Generally, the cooling water flow rate is an important issue in the cooling performance of injection mold with CCC. The turbulent flow  having aThe viscosity of water and air is about 0.8 m Pa-s and 18 μ Pa-s, respectively. The viscosity of water is about 44.5 times that of air. Therefore, the gas is mixed into the water to form cooling water with ultrafine bubbles is efficient to improve cooling efficiency and shorten the cooling time of injection molded parts. To investigate cooling efficiency of cooling water with ultrafine bubbles at a temperature of 25 °C, four different coolant flow rates of cooling water with ultrafine bubbles are carried out. According to the results described above, the findings of this study are very practical and provide the greatest application potential in the precision mold industry, especially in the mold design stage. In this study, the internal surface of the CCC fabricated by additive manufacturing technology possesses high surface roughness compared with conventional cooling channel made by computer-numerical control machining . The serA low-cost recipe that can produce cooling efficiency better than that made of commercial materials was demonstrated. The epoxy resin with 41 vol.% Al powder seems to be the optimum recipe for making injection mold with high cooling efficiency.The cooling time of the injection molded parts is extremely sensitive to both injection mold material and the cooling medium. Cooling water with ultrafine bubbles is the best candidate of the cooling medium. Average cooling efficiency approximately 12.4% can be further increased compared with commonly used cooling water.Mold material has a significant effect on the cooling time of the injection molded part, which has a greater influence on the cooling efficiency than the cooling medium since cooling time range of different mold materials is 99 s while the cooling time range for different cooling media is only 92 s. In addition, The cooling medium can be replaced with cold air while the diameter of the cooling channel is less than 1.5 mm and the coolant medium is water.Generally, the cost-effectiveness depends on the cycle time of the injection molded products significantly in the mass production process of new products. The MAM method is frequently applied to speed up manufacturing for the production of injection mold with CCC. However, the major issue is expensive spending and longtime taking in the mold making process. The objective of this study is to study the cooling performance of epoxy-based injection molds fabricated by different mold materials using different coolant media. Based on the experimental results obtained from this work, the contributions and findings of this study can be summarized as follows:


Traumatic brain injury is a rapidly increasing source of morbidity and mortality across the world. As such, the evaluation and management of traumatic brain injuries ranging from mild to severe are under active investigation. Over the last two decades, quantitative pupillometry has been increasingly found to be useful in both the immediate evaluation and ongoing management of traumatic brain injured patients. Given these findings and the portability and ease of use of modern pupillometers, further adoption and deployment of quantitative pupillometers into the preclinical and hospital settings of both resource rich and medically austere environments. Traumatic brain injury (TBI) represents one of the world's most prevalent causes of morbidity and mortality. With recent estimates placing its worldwide annual incidence at 64–74 million cases per year, it far exceeds rates of other diseases such as tuberculosis (8.8 million/year) and stroke (16.9 million/year) .While TBI management in resource-wealthy areas is driven by imaging, intracranial monitoring, and neurological intensive care units (NICU), management of these injuries in both resource-poor areas and in the non/pre-hospital setting has significant limitations when compared to such an expensive paradigm. Mild TBI (mTBI), for example, is often diagnosed and followed through serial examinations, subjective complaints, and tools such as the standard assessment of concussion (SAC)  and miliQuantitative pupillometry (QP) is rapidly emerging as an effective, affordable, easy-to-use, and reliable tool to diagnose and follow patients with TBIs. The purpose of this Perspective is to advocate for the expanded use of QP in the evaluation and management of patients with TBIs. Deployment of these devices and the accurate use and interpretation of the data they provide offers the potential to improve clinical outcomes in TBI patients at both resource-rich settings such as well-developed intensive care units and resource limited areas such as the preclinical and military forward deployed settings.The pupillary light reflex consists of a complex relationship between photoreceptor activity levels and the pupillary radial and sphincter muscles which is mediated by both cranial nerves II and III. Visible light enters the eye through the iris and strikes the retina where it is converted to an electrical impulse by the rod and cone cells. This information is then refined by bipolar cells and transmitted through the layers of the retina until it leaves the retina as the axons of the ganglion cells which, together, form the optic nerve. The optic nerve proceeds posteriorly through the optic chiasm where the nasal retinal fibers decussate before the information continues posteriorly as the optic tracts. En route to the primary visual cortex, each optic tract gives off a pupillary fiber that travels to the pretectal nucleus of the midbrain. The pretectal nucleus then sends fibers which synapse bilaterally with a preganglionic parasympathetic nucleus called the Edinger-Westphal nucleus. The pretectal nerve then alters the baseline level of activity of the nucleus such that increasing levels of optic tract activity (representing increasing levels of light striking the retina) results in increased activity in the Edinger-Westphal nucleus .The output of the Edinger-Westphal nucleus is what ultimately controls the size of the pupil during the pupillary light reflex. These preganglionic parasympathetic fibers exit the midbrain and travel along bilateral cranial nerve III's to reach the ciliary ganglion. This bilateral output from each Edinger-Westphal nucleus is what is responsible for consensual pupillary constriction after a unilateral light stimulus is applied. After synapsing on the ganglion, postganglionic parasympathetic short ciliary nerve fibers then innervate the iris sphincter muscles and lead to pupillary constriction . Of noteQuantitative pupillometers are small, portable devices which utilize a combination of infrared and visible light to capture this variability in the pupillary light reflexes. At the outset of each measurement, the device measures the pupil at rest with infrared light which produces no pupillary response, and then measures the pupil throughout the entire pupillary light reflex to a flash of visible light. These devices measure pupil baseline size, constriction latency, constriction velocity, constriction percentage, minimum size, and dilation velocity . These vIn addition to data collection, modern pupillometers have also been designed to store the data, produce graphical representations over a period of time, and transmit the data to the electronic medical record making tracking a patient's pupillary responses and NPi's over time easy and useful. Furthermore, the devices themselves are portable and easy-to-use making them well-adapted for distribution to both neurological intensive care units and the forwardly deployed locations of military healthcare and global first responders where these injuries occur.Of the predicted 64–74 million TBIs per year, it is estimated that ~81%, or 52–60 million, are mTBIs , 12. In increase in constriction velocity . Comparatively, QP of the same athletes immediately following a game without a mTBI demonstrated only a statistically significant velocity . Taken tThese alterations in the pupillary light reflex have also been demonstrated in the subacute mTBI period. High school athletes recruited from high school concussion programs within 1 month of injury demonstrated a larger pupillary maximum and minimum diameter and a greater percent constriction when compared to controls . Within While each of these studies demonstrate a different group of changes following a mTBI, the presence of these alterations clearly allows for mTBI detection and monitoring through recovery. Further research will be needed to ensure not only that there is an accurate standard from which to compare, but also to better delineate which aspects of the pupillary light reflex and which timepoints during recovery from a mTBI should be evaluated. Nevertheless, the present data suggests that mTBI detection and monitoring would benefit from increased utilization of QP.While significantly less ubiquitous than mTBI, mod/sTBI represents no less of a medical challenge. With a median hospitalization cost of $55,267 per case and an estimated 5.5 million cases of mod/sTBI annually, ensuring optimal outcomes for invested resources represents a high value decision point , 20. WitThe classical neurological trauma examination includes two parts: the GCS score and the pupillary examination. While a patient's GCS score can be replicated with reasonable consistency, multiple reports have demonstrated that the same cannot be said for manual evaluation of the neurologically injured patient's pupillary reactivity. For example, a recent study demonstrated a 22% error rate amongst nurses in detecting anisocoria when compared to QP . AnotherSuch speed and accuracy becomes increasingly important when discussing surgical decision making for the mod/sTBI patient, especially for those worse off. While the GCS's ease of use contributes to its wide use in trauma evaluations, limitations regarding its ability to prognosticate, and therefore drive treatment decisions, have been raised , 24. An QP has also demonstrated utility in the management of mod/sTBI patients within the critical care unit. The management of the mod/sTBI patient is often dictated by frequent neurological evaluations and intermittent head CTs in response to neurological changes. QP has been demonstrated to detect episodes of increased intracranial pressure, specifically uncal herniation, prior to the onset of clinical symptoms , 27. WhiTBI represents a rapidly increasing pathology on a global scale. As both mTBIs and mod/sTBIs continue to increase in prevalence and we understand more regarding the implications of these injuries, identification and management in both the immediate and post-injury setting will become more important. Over the last two decades numerous studies have demonstrated the potential for QP to assist in the detection and management of TBI across its spectrum of severity and the longitude of its course. This utility coupled with the ease of QP and the durability of today's pupillometers make QP a resource that is easy to expand across countries of varying income levels and practice areas of varying levels of austerity.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.JB, MS, and BD developed the idea for and organized the manuscript. JB, MS, MM, GM, BC, and BD wrote, revised, and critically evaluated the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Tobacco smoking in pregnancy is a worldwide public health problem. A majority of pregnant smokers need assistance to stop smoking. Most scientific societies recommend nicotine replacement therapy (NRT) during pregnancy but this recommendation remains controversial because of the known fetal toxicity of nicotine. The objective of this systematic review was to provide an overview of human studies about child health outcomes associated with NRT use during pregnancy. The electronic databases MEDLINE, the Cochrane Database, Web of Science, and ClinicalTrials.gov were searched from the inception of each database until 26 December 2020. A total of 103 articles were identified through database searching using combination of keywords. Out of 75 screened articles and after removal of duplicates, ten full-text articles were assessed for eligibility and five were included in the qualitative synthesis. NRT prescription seems to be associated with higher risk of infantile colic at 6 months as in case of smoking during pregnancy, and with risk of attention-deficit/hyperactivity disorder. No association between NRT during pregnancy and other infant health disorders or major congenital anomalies has been reported. Well-designed controlled clinical trials with sufficient follows-up are needed to provide more information on the use of NRT or other pharmacotherapies for smoking cessation during pregnancy on post-natal child health outcomes. Maternal smoking during pregnancy is an important and preventable major risk factor of adverse obstetrical and neonatal outcomes including placental abruption, miscarriage, stillbirth, preterm birth, and low birthweight . TobaccoCessation of smoking during pregnancy benefits maternal and child health . Many prNicotine is a neurotoxin and may affect development of fetal nerve tissues and brain development ,12. The Therefore, the general view is that NRT during pregnancy is safer than smoking . SeveralDespite several systematic reviews and recommendations on the benefit-risk ratio of NRT during pregnancy, current knowledge is insufficient about health outcomes in children whose mother used NRT for smoking cessation in pregnancy. Therefore, the objective of this study was to provide a systematic review of published studies about child health outcomes associated with NRT administered during pregnancy.This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The eleNo restrictions on language, and publication status were applied. Abstracts were included if there was sufficient information to assess the study’s quality. Original studies that explored NRT during pregnancy and dealing with outcomes in childhood were eligible for inclusion. The exclusion criteria were: non-human research, review/meta-analysis/summary, opinion/letter/response, case reports, recommendations, articles with no data on the child health, and articles reporting only data on birth and neonates (before 28 days). The primary outcome of this analysis were data on postnatal health outcomes after 28 days.Two reviewers (JB and AN) conducted data extraction independently and then discussed to reach a consensus. The very first selection of the papers was made on the basis of papers title and abstract, and eligible ones were selected for full text review. All variables of interest concerning the studies and publications were extracted using a form. The extracted data were authors’ names, the year of publication, the type of study, the sample size, the period of inclusion, the country of the study, and the article main outcomes.A total of 103 articles were identified through database searching using combination of keywords. Out of 75 screened articles and after duplicates removed, ten full-text articles were assessed for eligibility and five included in qualitative synthesis .The studies included in the present review were conducted in Denmark (two studies) and in the United Kingdom (three studies). These papers reported different outcomes. One study investigated infantile colic , two stuThe five articles included in qualitative synthesis are summarized in n = 194, 93.7%), and a minority used two different types , inhalator and gum being the most popular combination. In most cases, NRT users preferred short-release products, and almost half of NRT users continued active smoking (combined smoking and slow-release NRT in most cases).In 2012, Milidou et al. published a study with the aim to examine whether the association between smoking and infantile colic is due to nicotine . This wan = 529) . Thn = 529) ,30. The In 2019, another secondary analysis of the SNAP trial was designed to investigate whether the absence of infants’ developmental impairments at 2 years was associated with maternal smoking status measured at different point in the trial . After aIn 2014, Zhu et al. published a study about 84,803 children who participated in the Danish National Birth Cohort and followed up to 8 to 14 years old . The infIn 2015, Dhalwani et al. reported on a pregnancy cohort from the Health Improvement Network (THIN), a database of prospectively collected data from 570 general practices across the United Kingdom . The preThis review provides an overview of human child health outcomes after NRT during pregnancy. It shows an association between exposition to NRT during pregnancy and infantile colic among the 6 months old in comparison with no exposition (no smoking). An association is also reported between exposition to NRT during pregnancy and attention-deficit/hyperactivity disorder in children after 5 years old in comparison with nonsmoking (in mothers and fathers). NRT exposure does not seem to be associated with infant behavioral impairment ; in comparison with placebo even a somewhat better outcome has been reported ,26,30. AThe results about infantile colic need to be confirmed because of the limitations of the related study . Hence, The data about major congenital anomalies seem reassuring about the safety of NRT during pregnancy, with moderate level of evidence but with a large sample size . HoweverThe association between NRT exposure during pregnancy and ADHD need also to be confirmed because of the limitations of the study of Zhu et al. . As in MSudden infant death syndrome (SIDS) is strongly and exposure dependently associated with maternal tobacco smoking during pregnancy ,32,33. TThe SNAP RCT provided the highest level of evidence about infant outcomes at the age of 2 years old ,26. The The most relevant comparison group to study the risk of NRT during pregnancy on child health is questionable. NRT are often prescribed if the pregnant smokers fail to quit without pharmacological help. The main clinical question is whether prenatal exposition to NRT  is associated with better child health outcomes than prenatal smoking exposure (nicotine plus other toxins of tobacco) and secondarily whether NRT during pregnancy increases the risk of postnatal child outcomes compared to those children whose mother did not smoke during pregnancy.Nicotine easily crosses the placental barrier, and in humans it can be detected in the fetal circulation at levels exceeding its maternal concentrations by 15%; amniotic fluid concentrations of nicotine are 88% higher than maternal plasma nicotine concentrations ,35. ThisIn 2013, the protocol of an Australian population-based cohort study using linked administrative data has been reported, the Maternal Use of Medications and Safety (MUMS) Smoking Study . This stIt is necessary for the future studies to also include a control group of women with no exposure to nicotine. This would make it possible to assess the potential role of pure nicotine on the health of the offspring. These future studies should be cohorts with precise control groups, with repeated assessment of child health, and with adjustment of confounding factors such as smoking, use of NRT in postnatal period, breastfeeding, second-hand smoke exposure, toxic substances consumption, or maternal psychiatric disorders. Furthermore, all future therapeutic trial dealing with pharmacotherapy smoking cessation should include children long-term follow-up, and use smoking biological markers exposure to be more objective. The combination of NRT, which could be associated with higher odds of smoking cessation  should aThe emergence of new nicotine containing products such as electronic cigarettes and other nicotine delivery systems represent new challenges. These products are often marketed as a safer option than smoking. Data about their efficacy and harm in pregnancy are lacking as do data about health outcome in children whose mothers used them during their pregnancy ,18.To the best of our knowledge, this is a first systematic review about fetal NRT exposure during pregnancy and postnatal health outcomes. The main limitation of this review is inherent to the paucity of existing data and the very few numbers of studies. The level of evidence of half of the studies is, at best moderate.Prenatal exposure to NRT does not seem to be associated with infant neurodevelopmental impairment but the only available evaluation with ASQ was done at one point, at two years of age. Repeated, prospective ASQ assessments are needed to identify the neurodevelopmental pattern. Moreover, the parents involved in the RCT SNAP trial may have under- or overestimated the capabilities of their child. It seems that potential social and cultural differences between parents are not factors deemed to alter the validity of their neurologic assessment of their child . HoweverConducting studies on the postnatal effect of prenatal NRT exposure remains methodically difficult because of the various galenic forms of NRT and the low rate of smoking cessation. One also may question the relevance of an intention-to-treat analysis in studies with low rates of adherence to NRT.This review provides an overview of child health outcomes after exposition to NRT during pregnancy. Low to moderate evidence suggests that NRT use may be associated with higher risk of infantile colic at 6 months similar to that associated with prenatal maternal smoking during pregnancy. NRT during pregnancy may be associated with risk of attention-deficit/hyperactivity disorder as maternal smoking. No association between NRT during pregnancy and infant neurodevelopmental impairment or major congenital anomalies has been shown. The small number of included studies and the large number of cofounding factors do not allow to bring any final conclusions. Well-designed controlled clinical trials are needed to provide more information on the postnatal outcomes regarding the use of NRT and other pharmacotherapies for smoking cessation during pregnancy.


The COVID-19 pandemic brought serious illness and death into close proximity for a large number of people, whether through personal experience, infection in family members or friends, or unremitting media coverage on the effects of the virus and widespread mortality. Because of a collective vulnerability to illness and the heightened possibility of death, more people began to contemplate what kinds of medical care they would want if they ever became seriously ill. In other words, more people began the process of advance care planning (ACP). This symposium explores how the COVID-19 pandemic shifted interest in and execution of ACP across a range of groups. The first presentation reviews survey data from a large, community-based sample of older adults about their ACP conversations before and after the start of the pandemic. Shifting to the experience of clinicians, the second presentation summarizes a survey with multidisciplinary healthcare professionals about ACP conversations in their personal lives during the pandemic and how their observations of patients influenced their own plans. The third presentation describes the reactions of undergraduate students to an ACP class exercise, including COVID-19 as a motivating factor for pursuing ACP. The final presentation concludes with a review of two clinical cases that illustrate how COVID-19 has upended traditional ACP and highlighted the need for new policies and processes, with a particular focus on ethics and equity. Together, these presentations offer diverse insights into how ACP may shift in a post-pandemic world.


This study evaluated the role of the built environment on residents’ wayfinding behaviours at Louis Brier Home in Vancouver, British Columbia, Canada. The goal of this study was to explore baseline mobility challenges for the residents traveling between their bedrooms and social spaces. In response to this, low-cost environmental interventions were proposed and implemented to support safe and independent wayfinding for the residents. The project consisted of three phases. First phase involved a mixed methods approach using behavior mapping and spatial observations of the residents interacting with their physical environment, combined with one focus group with the staff members. In the second phase, researchers presented actionable environmental interventions for the care home administration to consider and implement. The final phase involved post-implementation behaviour mapping, spatial observations and a focus group session. The implemented environmental interventions influenced in improved resident wayfinding and orientation in the long-term care home.


The apical papilla is a stem cell rich tissue located at the base of the developing dental root and is responsible for the progressive elongation and maturation of the root. The multipotent stem cells of the apical papilla (SCAP) are extensively studied in cell culture since they demonstrate a high capacity for osteogenic, adipogenic, and chondrogenic differentiation and are thus an attractive stem cell source for stem cell-based therapies. Currently, only few studies are dedicated to determining the role of the apical papilla in dental root development. In this review, we will focus on the architecture of the apical papilla and describe the specific SCAP signaling pathways involved in root maturation. Furthermore, we will explore the heterogeneity of the SCAP phenotype within the tissue and determine their micro-environmental interaction. Understanding the mechanism of postnatal dental root growth could further aid in developing novel strategies in dental root regeneration. Dental tooth development can be subdivided into different steps and starts with the formation of the crown during the bud, cap and bell stages. Once the crown has taken shape, the dental root starts to grow under coordination of the Hertwig’s epithelial root sheath (HERS) . This doFrom a macroscopic point of view, the apical papilla is located apical to the epithelial diaphragm and is partitioned from the dental pulp by a cell-rich zone . Within Recent studies have procured more information on the signaling pathways specifically involved in tooth root development. An important prerequisite for the start of dental root growth after crown formation is the de-activation of fibroblast growth factor-10 signaling in the dental papilla . At the Once root growth is initiated, apical odontoblasts emerge at the base of the developing roots displaying the expression of the aforementioned transcription factors i.e., Nfic, Osx, β-catenin and alkaline phosphatase . The difA vast amount of differentiation protocols have been successfully optimized in primary cell cultures of SCAP to demonstrate the high capacity of SCAP for osteogenic and adipogenic differentiation. SCAP are easily isolated from the apical papilla by tissue explant culture or by enzymatic digestion as demonstrated previously for dental pulp stem cells . However+ stem cell pool can be made based on STRO-1 expression  maintains STRO-1 expression up to 10 passages, increases their proliferation, and preserves the undifferentiated state of the isolated stem cells  proteins . MoreoveSince progression of dental root growth is associated with a reduction in apical papilla size and eventually disappears after final root maturation , one canStudies involved in comprehending the molecular mechanism of root formation has already provided novel insights in dental disorders. The pathology of short root anomaly is recognized by the development of abnormal short roots with a blunt appearance  and is aRD conceived and wrote the manuscript. TV, PG, and IL reviewed the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.